Tag Archives: Peter Wick

Nanotechnology research protocols for Environment, Health and Safety Studies in US and a nanomedicine characterization laboratory in the European Union

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I have two items relating to nanotechnology and the development of protocols. The first item concerns the launch of a new web portal by the US National Institute of Standards and Technology.

US National Institute of Standards and Technology (NIST)

From a July 1, 2015 news item on Azonano,

As engineered nanomaterials increasingly find their way into commercial products, researchers who study the potential environmental or health impacts of those materials face a growing challenge to accurately measure and characterize them. These challenges affect measurements of basic chemical and physical properties as well as toxicology assessments.

To help nano-EHS (Environment, Health and Safety)researchers navigate the often complex measurement issues, the National Institute of Standards and Technology (NIST) has launched a new website devoted to NIST-developed (or co-developed) and validated laboratory protocols for nano-EHS studies.

A July 1, 2015 NIST news release on EurekAlert, which originated the news item, offers more details about the information available through the web portal,

In common lab parlance, a “protocol” is a specific step-by-step procedure used to carry out a measurement or related activity, including all the chemicals and equipment required. Any peer-reviewed journal article reporting an experimental result has a “methods” section where the authors document their measurement protocol, but those descriptions are necessarily brief and condensed, and may lack validation of any sort. By comparison, on NIST’s new Protocols for Nano-EHS website the protocols are extraordinarily detailed. For ease of citation, they’re published individually–each with its own unique digital object identifier (DOI).

The protocols detail not only what you should do, but why and what could go wrong. The specificity is important, according to program director Debra Kaiser, because of the inherent difficulty of making reliable measurements of such small materials. “Often, if you do something seemingly trivial–use a different size pipette, for example–you get a different result. Our goal is to help people get data they can reproduce, data they can trust.”

A typical caution, for example, notes that if you’re using an instrument that measures the size of nanoparticles in a solution by how they scatter light, it’s important also to measure the transmission spectrum of the particles if they’re colored, because if they happen to absorb light strongly at the same frequency as your instrument, the result may be biased.

“These measurements are difficult because of the small size involved,” explains Kaiser. “Very few new instruments have been developed for this. People are adapting existing instruments and methods for the job, but often those instruments are being operated close to their limits and the methods were developed for chemicals or bulk materials and not for nanomaterials.”

“For example, NIST offers a reference material for measuring the size of gold nanoparticles in solution, and we report six different sizes depending on the instrument you use. We do it that way because different instruments sense different aspects of a nanoparticle’s dimensions. An electron microscope is telling you something different than a dynamic light scattering instrument, and the researcher needs to understand that.”

The nano-EHS protocols offered by the NIST site, Kaiser says, could form the basis for consensus-based, formal test methods such as those published by ASTM and ISO.

NIST’s nano-EHS protocol site currently lists 12 different protocols in three categories: sample preparation, physico-chemical measurements and toxicological measurements. More protocols will be added as they are validated and documented. Suggestions for additional protocols are welcome at nanoprotocols@nist.gov.

The next item concerns European nanomedicine.

CEA-LETI and Europe’s first nanomedicine characterization laboratory

A July 1, 2015 news item on Nanotechnology Now describes the partnership which has led to launch of the new laboratory,

CEA-Leti today announced the launch of the European Nano-Characterisation Laboratory (EU-NCL) funded by the European Union’s Horizon 2020 research and innovation programm[1]e. Its main objective is to reach a level of international excellence in nanomedicine characterisation for medical indications like cancer, diabetes, inflammatory diseases or infections, and make it accessible to all organisations developing candidate nanomedicines prior to their submission to regulatory agencies to get the approval for clinical trials and, later, marketing authorization.

“As reported in the ETPN White Paper[2], there is a lack of infrastructure to support nanotechnology-based innovation in healthcare,” said Patrick Boisseau, head of business development in nanomedicine at CEA-Leti and chairman of the European Technology Platform Nanomedicine (ETPN). “Nanocharacterisation is the first bottleneck encountered by companies developing nanotherapeutics. The EU-NCL project is of most importance for the nanomedicine community, as it will contribute to the competiveness of nanomedicine products and tools and facilitate regulation in Europe.”

EU-NCL is partnered with the sole international reference facility, the Nanotechnology Characterization Lab of the National Cancer Institute in the U.S. (US-NCL)[3], to get faster international harmonization of analytical protocols.

“We are excited to be part of this cooperative arrangement between Europe and the U.S.,” said Scott E. McNeil, director of U.S. NCL. “We hope this collaboration will help standardize regulatory requirements for clinical evaluation and marketing of nanomedicines internationally. This venture holds great promise for using nanotechnologies to overcome cancer and other major diseases around the world.”

A July 2, 2015 EMPA (Swiss Federal Laboratories for Materials Science and Technology) news release on EurekAlert provides more detail about the laboratory and the partnerships,

The «European Nanomedicine Characterization Laboratory» (EU-NCL), which was launched on 1 June 2015, has a clear-cut goal: to help bring more nanomedicine candidates into the clinic and on the market, for the benefit of patients and the European pharmaceutical industry. To achieve this, EU-NCL is partnered with the sole international reference facility, the «Nanotechnology Characterization Laboratory» (US-NCL) of the US-National Cancer Institute, to get faster international harmonization of analytical protocols. EU-NCL is also closely connected to national medicine agencies and the European Medicines Agency to continuously adapt its analytical services to requests of regulators. EU-NCL is designed, organized and operated according to the highest EU regulatory and quality standards. «We are excited to be part of this cooperative project between Europe and the U.S.,» says Scott E. McNeil, director of US-NCL. «We hope this collaboration will help standardize regulatory requirements for clinical evaluation and marketing of nanomedicines internationally. This venture holds great promise for using nanotechnologies to overcome cancer and other major diseases around the world.»

Nine partners from eight countries

EU-NCL, which is funded by the EU for a four-year period with nearly 5 million Euros, brings together nine partners from eight countries: CEA-Tech in Leti and Liten, France, the coordinator of the project; the Joint Research Centre of the European Commission in Ispra, Italy; European Research Services GmbH in Münster Germany; Leidos Biomedical Research, Inc. in Frederick, USA; Trinity College in Dublin, Ireland; SINTEF in Oslo, Norway; the University of Liverpool in the UK; Empa, the Swiss Federal Laboratories for Materials Science and Technology in St. Gallen, Switzerland; Westfälische Wilhelms-Universität (WWU) and Gesellschaft für Bioanalytik, both in Münster, Germany. Together, the partnering institutions will provide a trans-disciplinary testing infrastructure covering a comprehensive set of preclinical characterization assays (physical, chemical, in vitro and in vivo biological testing), which will allow researchers to fully comprehend the biodistribution, metabolism, pharmacokinetics, safety profiles and immunological effects of their medicinal nano-products. The project will also foster the use and deployment of standard operating procedures (SOPs), benchmark materials and quality management for the preclinical characterization of medicinal nano-products. Yet another objective is to promote intersectoral and interdisciplinary communication among key drivers of innovation, especially between developers and regulatory agencies.

The goal: to bring safe and efficient nano-therapeutics faster to the patient

Within EU-NCL, six analytical facilities will offer transnational access to their existing analytical services for public and private developers, and will also develop new or improved analytical assays to keep EU-NCL at the cutting edge of nanomedicine characterization. A complementary set of networking activities will enable EU-NCL to deliver to European academic or industrial scientists the high-quality analytical services they require for accelerating the industrial development of their candidate nanomedicines. The Empa team of Peter Wick at the «Particles-Biology Interactions» lab will be in charge of the quality management of all analytical methods, a key task to guarantee the best possible reproducibility and comparability of the data between the various analytical labs within the consortium. «EU-NCL supports our research activities in developing innovative and safe nanomaterials for healthcare within an international network, which will actively shape future standards in nanomedicine and strengthen Empa as an enabler to facilitate the transfer of novel nanomedicines from bench to bedside», says Wick.

You can find more information about the laboratory on the Horizon 2020 (a European Union science funding programme) project page for the EU-NCL laboratory. For anyone curious about CEA-Leti, it’s a double-layered organization. CEA is France’s Commission on Atomic Energy and Alternative Energy (Commissariat à l’énergie atomique et aux énergies alternatives); you can go here to their French language site (there is an English language clickable option on the page). Leti is one of the CEA’s institutes and is known as either Leti or CEA-Leti. I have no idea what Leti stands for. Here’s the Leti website (this is the English language version).

The shorter, the better for cellulose nanofibres

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Cellulose nanomaterials can be derived from any number of plants. In Canada, we tend to think of our trees first but there are other sources such as cotton, bananas, hemp, carrots, and more.

In anticipation that cellulose nanofibres will become increasingly important constituents of various products and having noticed a resemblance to carbon nanotubes, scientists in Switzerland have investigated the possible toxicity issues according to a May 7, 2015 news item on Nanowerk,

Plant-based cellulose nanofibres do not pose a short-term health risk, especially short fibres, shows a study conducted in the context of National Research Programme “Opportunities and Risks of Nanomaterials” (NRP 64). But lung cells are less efficient in eliminating longer fibres.

Similar to carbon nanotubes that are used in cycling helmets and tennis rackets, cellulose nanofibres are extremely light while being extremely tear-resistant. But their production is significantly cheaper because they can be manufactured from plant waste of cotton or banana plants. “It is only a matter of time before they prevail on the market,” says Christoph Weder of the Adolphe Merkle Institute at the University of Fribourg [Switzerland].

A May 7, 2015 Swiss National Science Foundation (SNSF) press release, which originated the news item, provides more detail,

In the context of the National Research Programme “Opportunities and Risks of Nanomaterials” (NRP 64), he collaborated with the team of Barbara Rothen-Rutishauser to examine whether these plant-based nanofibres are harmful to the lungs when inhaled. The investigation does not rely on animal testing; instead the group of Rothen-Rutishauser developped a complex 3D lung cell system to simulate the surface of the lungs by using various human cell cultures in the test tube.

The shorter, the better

Their results (*) show that cellulose nanofibres are not harmful: the analysed lung cells showed no signs of acute stress or inflammation. But there were clear differences between short and long fibres: the lung cell system efficiently eliminated short fibres while longer fibres stayed on the cell surface.

“The testing only lasted two days because we cannot grow the cell cultures for longer,” explains Barbara Rothen-Rutishauser. For this reason, she adds, they cannot say if the longer fibre may have a negative impact on the lungs in the long term. Tests involving carbon nanotubes have shown that lung cells lose their equilibrium when they are faced with long tubes because they try to incorporate them into the cell to no avail. “This frustrated phagocytosis can trigger an inflammatory reaction,” says Rothen-Rutishauser. To avoid potential harm, she recommends that companies developing products with nanofibres use fibres that are short and pliable instead of long and rigid.

National Research Programme “Opportunities and Risks of Nanomaterials” (NRP 64)

The National Research Programme “Opportunities and Risks of Nanomaterials” (NRP 64) hopes to be able to bridge the gaps in our current knowledge on nanomaterials. Opportunities and risks for human health and the environment in relation to the manufacture, use and disposal of synthetic nanomaterials need to be better understood. The projects started their research work in December 2010.

I have a link to and a citation for the paper (Note: They use the term cellulose nanocrystals in the paper’s title),

Fate of Cellulose Nanocrystal Aerosols Deposited on the Lung Cell Surface In Vitro by Carola Endes, Silvana Mueller, Calum Kinnear, Dimitri Vanhecke, E. Johan Foster, Alke Petri-Fink, Christoph Weder, Martin J. D. Clift, and Barbara Rothen-Rutishauser. Biomacromolecules, 2015, 16 (4), pp 1267–1275 DOI: 10.1021/acs.biomac.5b00055 Publication Date (Web): March 19, 2015

Copyright © 2015 American Chemical Society

While tracking down the 2015 paper, I found this from 2011,

Investigating the Interaction of Cellulose Nanofibers Derived from Cotton with a Sophisticated 3D Human Lung Cell Coculture by Martin J. D. Clift, E. Johan Foster, Dimitri Vanhecke, Daniel Studer, Peter Wick, Peter Gehr, Barbara Rothen-Rutishauser, and Christoph Weder. Biomacromolecules, 2011, 12 (10), pp 3666–3673 DOI: 10.1021/bm200865j Publication Date (Web): August 16, 2011

Copyright © 2011 American Chemical Society

Both papers are behind a paywall.

Nanosafety research: a quality control issue

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Toxicologist Dr. Harald Krug has published a review of several thousand studies on nanomaterials safety exposing problematic research methodologies and conclusions. From an Oct. 29, 2014 news item on Nanowerk (Note: A link has been removed),

Empa [Swiss Federal Laboratories for Materials Science and Technology] toxicologist Harald Krug has lambasted his colleagues in the journal Angewandte Chemie (“Nanosafety Research—Are We on the Right Track?”). He evaluated several thousand studies on the risks associated with nanoparticles and discovered no end of shortcomings: poorly prepared experiments and results that don’t carry any clout. Instead of merely leveling criticism, however, Empa is also developing new standards for such experiments within an international network.

An Oct. 29, 2014 Empa press release (also on EurekAlert), which originated the news item, describes the new enthusiasm for research into nanomaterials and safety,

Researching the safety of nanoparticles is all the rage. Thousands of scientists worldwide are conducting research on the topic, examining the question of whether titanium dioxide nanoparticles from sun creams can get through the skin and into the body, whether carbon nanotubes from electronic products are as hazardous for the lungs as asbestos used to be or whether nanoparticles in food can get into the blood via the intestinal flora, for instance. Public interest is great, research funds are flowing – and the number of scientific projects is skyrocketing: between 1980 and 2010, a total of 5,000 projects were published, followed by another 5,000 in just the last three years. However, the amount of new knowledge has only increased marginally. After all, according to Krug the majority of the projects are poorly executed and all but useless for risk assessments.

The press release goes on to describe various pathways into the body and problems with research methodologies,

How do nanoparticles get into the body?

Artificial nanoparticles measuring between one and 100 nanometers in size can theoretically enter the body in three ways: through the skin, via the lungs and via the digestive tract. Almost every study concludes that healthy, undamaged skin is an effective protective barrier against nanoparticles. When it comes to the route through the stomach and gut, however, the research community is at odds. But upon closer inspection the value of many alarmist reports is dubious – such as when nanoparticles made of soluble substances like zinc oxide or silver are being studied. Although the particles disintegrate and the ions drifting into the body are cytotoxic, this effect has nothing to do with the topic of nanoparticles but is merely linked to the toxicity of the (dissolved) substance and the ingested dose.

Laboratory animals die in vain – drastic overdoses and other errors

Krug also discovered that some researchers maltreat their laboratory animals with absurdly high amounts of nanoparticles. Chinese scientists, for instance, fed mice five grams of titanium oxide per kilogram of body weight, without detecting any effects. By way of comparison: half the amount of kitchen salt would already have killed the animals. A sloppy job is also being made of things in the study of lung exposure to nanoparticles: inhalation experiments are expensive and complex because a defined number of particles has to be swirled around in the air. Although it is easier to place the particles directly in the animal’s windpipe (“instillation”), some researchers overdo it to such an extent that the animals suffocate on the sheer mass of nanoparticles.

While others might well make do without animal testing and conduct in vitro experiments on cells, here, too, cell cultures are covered by layers of nanoparticles that are 500 nanometers thick, causing them to die from a lack of nutrients and oxygen alone – not from a real nano-effect. And even the most meticulous experiment is worthless if the particles used have not been characterized rigorously beforehand. Some researchers simply skip this preparatory work and use the particles “straight out of the box”. Such experiments are irreproducible, warns Krug.

As noted in the news item, the scientists at Empa have devised a solution to some to of the problems (from the press release),

The solution: inter-laboratory tests with standard materials
Empa is thus collaborating with research groups like EPFL’s Powder Technology Laboratory, with industrial partners and with Switzerland’s Federal Office of Public Health (FOPH) to find a solution to the problem: on 9 October the “NanoScreen” programme, one of the “CCMX Materials Challenges”, got underway, which is expected to yield a set of pre-validated methods for lab experiments over the next few years. It involves using test materials that have a closely defined particle size distribution, possess well-documented biological and chemical properties and can be altered in certain parameters – such as surface charge. “Thanks to these methods and test substances, international labs will be able to compare, verify and, if need be, improve their experiments,” explains Peter Wick, Head of Empa’s laboratory for Materials-Biology Interactions.

Instead of the all-too-familiar “fumbling around in the dark”, this would provide an opportunity for internationally coordinated research strategies to not only clarify the potential risks of new nanoparticles in retrospect but even be able to predict them. The Swiss scientists therefore coordinate their research activities with the National Institute of Standards and Technology (NIST) in the US, the European Commission’s Joint Research Center (JRC) and the Korean Institute of Standards and Science (KRISS).

Bravo! and thank you Dr. Krug and Empa for confirming something I’ve suspected due to hints from more informed commentators. Unfortunately my ignorance. about research protocols has not permitted me to undertake a better analysis of the research. ,

Here’s a link to and a citation for the paper,

Nanosafety Research—Are We on the Right Track? by Prof. Dr. Harald F. Krug. Angewandte Chemie International Edition DOI: 10.1002/anie.201403367 Article first published online: 10 OCT 2014

This is an open access paper.