V.F.C. and A.F. contributed equally to this work. The authors thank the FCT—Fundacao para a Ciencia e Tecnologia—for financial support under framework of the Strategic Funding UID/FIS/04650/2013, project PTDC/ EEI-SII/5582/2014 and project UID/EEA/04436/2013 by FEDER funds through the COMPETE 2020—Programa Operacional Competitividade e Internacionalizacao (POCI). Funds provided by FCT in the framework of EuroNanoMed 2016 call, Project LungChek ENMed/0049/2016 are also gratefully acknowledged. V.F.C., A.F., C.R., and P.M. also thank the FCT for the grants SFRH/BPD/98109/2013, SFRH/BPD/104204/2014, SFRH/ BPD/90870/2012 and SFRH/BPD/96227/2013, respectively. Finally, the authors acknowledge funding by the Spanish Ministry of Economy and Competitiveness (MINECO) through the project MAT2016-76039C4-3-R (AEI/FEDER, UE) and from the Basque Government Industry Department under the ELKARTEK program.

Advances in Magnetic Nanoparticles for Biomedical Applications.

Recent advances in high-sensitivity detection methods for paper-based lateral-flow assay.

Magnetoresistive (MR) sensors have been identified as promising candidates for the development of high-performance magnetometers due to their high sensitivity, low cost, low power consumption, and small size. The rapid advance of MR sensor technology has opened up a variety of MR sensor applications. These applications are in different areas that require MR sensors with different properties. Future MR sensor development in each of these areas requires an overview and a strategic guide. An MR sensor roadmap (non-recording applications) was therefore developed and made public by the Technical Committee of the IEEE Magnetics Society with the aim to provide an research and development (R&D) guide for MR sensors intended to be used by industry, government, and academia. The roadmap was developed over a three-year period and coordinated by an international effort of 22 taskforce members from ten countries and 17 organizations, including universities, research institutes, and sensor companies. In this paper, the current status of MR sensors for non-recording applications was identified by analyzing the patent and publication statistics. As a result, timescales for MR sensor development were established and critical milestones for sensor parameters were extracted in order to gain insight into potential MR sensor applications (non-recording). Five application areas were identified, and five MR sensor roadmaps were established. These include biomedical applications, flexible electronics, position sensing and human–computer interactions, non-destructive evaluation and monitoring, and navigation and transportation. Each roadmap was analyzed using a logistic growth model, and new opportunities were predicted based on the extrapolated curve, forecast milestones, and professional judgment of the taskforce members. This paper provides a framework for MR sensor technology (non-recording applications) to be used for public and private R&D planning, in order to provide guidance into likely MR sensor applications, products, and services expected in the next 15 years and beyond.

/pdf/magnetoresistive-sensor-development-roadmap-non-recording-nb32j30mph.pdf

Magnetoresistive Sensor Development Roadmap (Non-Recording Applications)

The development of magnetic field sensors for biomedical applications primarily focuses on equivalent magnetic noise reduction or overall design improvement in order to make them smaller and cheaper while keeping the required values of a limit of detection. One of the cutting-edge topics today is the use of magnetic field sensors for applications such as magnetocardiography, magnetotomography, magnetomyography, magnetoneurography, or their application in point-of-care devices. This introductory review focuses on modern magnetic field sensors suitable for biomedicine applications from a physical point of view and provides an overview of recent studies in this field. Types of magnetic field sensors include direct current superconducting quantum interference devices, search coil, fluxgate, magnetoelectric, giant magneto-impedance, anisotropic/giant/tunneling magnetoresistance, optically pumped, cavity optomechanical, Hall effect, magnetoelastic, spin wave interferometry, and those based on the behavior of nitrogen-vacancy centers in the atomic lattice of diamond.

Ultrasensitive Magnetic Field Sensors for Biomedical Applications.

https://iopscience.iop.org/article/10.1088/1361-6463/aa66ec/pdf

Challenges and trends in magnetic sensor integration with microfluidics for biomedical applications

HER2 is a prognostic and predictive biomarker in breast cancer, normally assessed in tumour biopsy and used to guide treatment choices. Circulating tumour cells (CTCs) escape the primary tumour and enter the bloodstream, exhibiting great metastatic potential and representing a real-time snapshot of the tumour burden. Liquid biopsy offers the unique opportunity for low invasive sampling in cancer patients and holds the potential to provide valuable information for the clinical management of cancer patients. This study assesses the performance of the RUBYchip™, a microfluidic system for CTC capture based on cell size and deformability, and compares it with the only FDA-approved technology for CTC enumeration, CellSearch®. After optimising device performance, 30 whole blood samples from metastatic breast cancer patients were processed with both technologies. The expression of HER2 was assessed in isolated CTCs and compared to tissue biopsy. Results show that the RUBYchipTM was able to isolate CTCs with higher efficiency than CellSearch®, up to 10 times more, averaging all samples. An accurate evaluation of different CTC subpopulations, including HER2+ CTCs, was provided. Liquid biopsy through the use of the RUBYchipTM in the clinic can overcome the limitations of histological testing and evaluate HER2 status in patients in real-time, helping to tailor treatment during disease evolution.

HER2 Expression in Circulating Tumour Cells Isolated from Metastatic Breast Cancer Patients Using a Size-Based Microfluidic Device

In the pursuit of point-of-care systems that present high sensitivity and fast turnaround time, lateral flow is considered a remarkable promising class of in vitro diagnostics, and popularized by the pregnancy tests. A variety of lateral flow tests have emerged able to provide cardiac panels in emergency conditions, infectious disease screening, drug abuse, among others. However, most commercial tests only provide qualitative results, limiting their applicability for quantification thresholds of most biomarkers. In this paper, we propose a novel detection architecture for quantification of biomolecules labeled with magnetic nanoparticles employing two spin valve sensors. The main goal of this paper is to demonstrate that this architecture can detect and monitor MNPs flowing in a LFT strip for detection and quantification of different solutions varying in MNP concentration. In addition, we present preliminary analytical results that support our strategy for achieving biomolecular quantification using the proposed solution.

Dynamical Detection of Magnetic Nanoparticles in Paper Microfluidics With Spin Valve Sensors for Point-of-Care Applications

Spintronic microfluidic chips allied with the magnetic labeling of cells is a newer version of flow cytometry. Here, the commonly used fluorescent tags are replaced by magnetic beads that are excited by a magnetic field and detected by a magnetoresistive (MR) sensor. In addition to the important role played by the sensors, in such systems the magnetic beads can determine the sensitivity, and accuracy of the assay depending on their magnetic moment as well as the specificity defined by their surface functionalization. In this paper, the tailoring of magnetic beads to be used as magnetic labels for magnetic flow cytometrer is reported. Polymeric beads loaded with different contents of magnetite nanoparticles ranging from 14 to 44 wt% and diameters between 120 and 190 nm were prepared and tested in the spintronic microfluidic chip. The objective was to attain a compromise between beads' magnetic content and signal generated in the MR sensor. The optimal magnetic content was found to be around 30 wt% of magnetite. Further functionalization of the magnetic beads with protein A for antibody conjugation allowed their use in immunomagnetic cell labeling. The final objective is to use these magnetic beads as labels for the detection and counting of circulating tumor cells directly from patient whole blood samples.

Customized design of magnetic beads for dynamic magnetoresistive cytometry

We report the design and characterization of a lateral and vertical hydrodynamic focusing feature for whole cell detection on a miniaturized flow cytometer. The developed system, based on magnetic sensing, incorporates spin valve sensors on the bottom of the microfluidic channels that detect cells labeled with magnetic beads. An adaptable 3D hydrodynamic focusing system was developed that pushes labeled cells towards the bottom of the microchannel, closer to the sensors, allowing increased signal amplitude for cells labeled with magnetic beads and enhanced discrimination of labeled cells. Fluorescence microscopy indicates that the lateral and vertical hydrodynamic focusing effect was adequately implemented, consistent with simulation predictions. The sensitivity of the system to detect labeled cells was improved by at least two-fold. By estimating the coverage of magnetic beads on cells, the signal from labeled cells could be predicted using a mathematical model, which also demonstrated the sensitivity of the signal to the height of the cells relative to the sensor. The system is versatile allowing interchangeable flow rates for cells with different diameters.

Alexandre Chicharo

Papers

Challenges and trends in magnetic sensor integration with microfluidics for biomedical applications

HER2 Expression in Circulating Tumour Cells Isolated from Metastatic Breast Cancer Patients Using a Size-Based Microfluidic Device

Dynamical Detection of Magnetic Nanoparticles in Paper Microfluidics With Spin Valve Sensors for Point-of-Care Applications

Customized design of magnetic beads for dynamic magnetoresistive cytometry

Enhanced magnetic microcytometer with 3D flow focusing for cell enumeration