Nondestructive in-line sub-picomolar detection of magnetic nanoparticles in flowing complex fluids

www.nature.com/scientificreports OPEN Received: 3 October 2017 Accepted: 16 January 2018 Published: xx xx xxxx Nondestructive in-line subpicomolar detection of magnetic nanoparticles in flowing complex fluids Lykourgos Bougas1, Lukas D. Langenegger2, Carlos A. Mora 2, Martin Zeltner2, Wendelin J. Stark2, Arne Wickenbrock1, John W. Blanchard3 & Dmitry Budker1,3,4,5 Over the last decades, the use of magnetic nanoparticles in research and commercial applications has increased dramatically. However, direct detection of trace quantities remains a challenge in terms of equipment cost, operating conditions and data acquisition times, especially in flowing conditions within complex media. Here we present the in-line, non-destructive detection of magnetic nanoparticles using high performance atomic magnetometers at ambient conditions in flowing media. We achieve sub-picomolar sensitivities measuring ~30 nm ferromagnetic iron and cobalt nanoparticles that are suitable for biomedical and industrial applications, under flowing conditions in water and whole blood. Additionally, we demonstrate real-time surveillance of the magnetic separation of nanoparticles from water and whole blood. Overall our system has the merit of in-line direct measurement of trace quantities of ferromagnetic nanoparticles with so far unreached sensitivities and could be applied in the biomedical field (diagnostics and therapeutics) but also in the industrial sector. Functionalized magnetic nanoparticles have emerged as unique objects for a variety of applications, ranging from usage in life sciences1 to data storage2 and industrial wastewater treatment3. Especially, an increasing number of applications in biomedicine, such as in diagnostics, imaging, drug delivery and other therapeutic approaches, use magnetic nanoparticles due to their intrinsic properties4. In any of those applications the magnetic properties of the nanoparticles are either used for their detection and subsequent readout of information (e.g. diagnostic devices), or for physical manipulation of the particles, mostly in separation processes. Health and environmental risks associated with the release of and exposure to engineered nanoparticles are unclear and hamper many applications especially in the medical field. Those risks could be either addressed by the utilization of inherently safe nanoparticles or by the prevention of exposure to the nanoparticles. While the assessment of the safety of nanomaterials advanced over the last years and standards are being established, residual risks remain, as biological interactions are complex and effects could occur years after exposure. Therefore, a promising alternative is to prevent any exposure by implementing means of sensitive detection combined with shutdown mechanisms that seal contaminated parts. One concept, which would particularly benefit from the implementation of such a measurement as part of the safety mechanism, is magnetic particle-based blood purification (MPBP). MPBP has been proposed as a new therapeutic approach to remove disease causing factors such as toxins, proteins, or whole pathogens directly from a patient’s blood in an extracorporeal circuit (see ref.5 and references therein). Magnetic nanoparticles functionalized with capturing moieties (e.g. antibodies) are applied in an extracorporeal circuit where they bind to their targets and are separated by a magnetic field before the blood is recirculated to the patient. Several setups utilizing this concept have been proposed and tested in vitro6–10, as well as in animal trials11,12. 1 Johannes Gutenberg-Universität Mainz, 55128, Mainz, Germany. 2Functional Materials Laboratory, Department of Chemistry and Applied Biosciences, ETH Zurich, CH-8093, Zurich, Switzerland. 3Helmholtz-Institut Mainz, 55128, Mainz, Germany. 4Department of Physics, University of California, Berkeley, CA, 94720-7300, USA. 5Nuclear Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA. Lykourgos Bougas and Lukas D. Langenegger contributed equally to this work. Correspondence and requests for materials should be addressed to L.B. (email: ) Scientific REPOrtS | (2018) 8:3491 | DOI:10.1038/s41598-018-21802-2 1 www.nature.com/scientificreports/ Translation from a lab concept to clinical applications in humans demands thorough assessment of possible risks for the patients. Although some ferromagnetic particles have proven to be bio-compatible13–17, the best way to minimize acute and long term exposure risks is to fully remove the particles from blood before it is recirculated to the patient18. Detection of small amounts of nanoparticles in flowing blood coupled to a shutdown mechanism that stops the procedure in case of a failure could, therefore, drastically reduce overall risks associated with MPBP10. Up to date, particle detection methods applied in the context of MPBP have been inadequately sensitive [≥1 ppm (w/w)]10, but most importantly indirect and destructive11,12,18, and thus, impractical for implementation in a therapeutic setting. In general, detection of trace quantities of nanomaterials is very challenging due to low sensitivities and serious matrix effects. In addition, the often very expensive instrumentation, destructive nature of measurement, tedious sample preparation, and long processing times, prevent real-time analysis of small nanoparticle concentrations, which are highly desired. Metallic ferromagnetic nanoparticles are particularly beneficial for separation processes in complex media, as they exhibit higher saturation magnetizations and allow for fast and complete separation using high gradient magnetic separators. In addition, the detection of the magnetic moment of metallic ferromagnetic nanoparticles is promising and such a direct method could be applied in most media without matrix effects, avoiding sample preparation or destruction. This can be achieved using magnetometric methods, which are not based on optical data acquisition and, therefore, can operate in complex media, such as opaque whole blood. However, the magnetic moments of nanoparticles are extremely small, and thus, any employed measurement methods need to be correspondingly sensitive. There exist several magnetic particle detection technologies that have demonstrated competitive sensitivity relevant to the aforementioned applications: superconducting quantum interference devices (SQUIDs)19–21, giant magneto-resistive (GMR) sensors22–24, atomic magnetometers25,26, and diamond-based magnetometers27–29. The requirements in terms of size, price, operating conditions, usability, and need for sample preparation, restricts broad application of many of those technologies, especially to MPBP-related applications. Atomic-based magnetometers though, offer highest magnetic field sensitivity, allow for non-invasive and non-destructive sensing modalities, and can be operated at ambient conditions (no cryogens) requiring only magnetic shielding. (...truncated)