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.

Cell-free DNA (cfDNA) refers to short fragments of acellular nucleic acids detectable in almost all body fluids, including blood, and is involved in various physiological and pathological phenomena such as immunity, coagulation, aging, and cancer. In cancer patients, a fraction of hematogenous cfDNA originates from tumors, termed circulating tumor DNA (ctDNA), and may carry the same mutations and genetic alterations as those of a primary tumor. Thus, ctDNA potentially provides an opportunity for noninvasive assessment of cancer. Recent advances in ctDNA analysis methods will potentially lead to the development of a liquid biopsy tool for the diagnosis, prognosis, therapy response monitoring, and tracking the rise of new mutant sub-clones in cancer patients. Over the past few decades, cancer-specific mutations in ctDNA have been detected using a variety of untargeted methods such as digital karyotyping, personalized analysis of rearranged ends (PARE), whole-genome sequencing of ctDNA, and targeted approaches such as conventional and digital PCR-based methods and deep sequencing-based technologies. More recently, several chip-based electrochemical sensors have been developed for the analysis of ctDNA in patient samples. This paper aims to comprehensively review the diagnostic, prognostic, and predictive potential of ctDNA as a minimally invasive liquid biopsy for cancer patients. We also present an overview of current advances in the analytical sensitivity and accuracy of ctDNA analysis methods as well as biological and technical challenges, which need to be resolved for the integration of ctDNA analysis into routine clinical practice.

Circulating tumor DNA and liquid biopsy: opportunities, challenges, and recent advances in detection technologies

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.

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Magnetoresistive Sensor Development Roadmap (Non-Recording Applications)

Nucleic acid detection offers critical information in diagnosing pathogen infection and monitoring disease treatment. Point-of-care testing (POCT), with ideal characteristics such as rapidness, user-friendly, sensitivity, specificity, and robustness, has drawn wide attention, especially in resource-poor settings where lack the healthcare infrastructure. Accompanied by the development of microfluidic technologies and new amplification methods, POCT of nucleic acids greatly improves health monitoring and prevents outbreak of infectious diseases. This review summarizes recent advances in diagnostics of nucleic acids in POC formats, and discusses challenges associated with POCT of nucleic acids.

Point-of-care-testing of nucleic acids by microfluidics

Magnetic particles are widely used as signal labels in a variety of biological sensing applications, such as molecular detection and related strategies that rely on ligand-receptor binding. In this review, we explore the fundamental concepts involved in designing magnetic particles for biosensing applications and the techniques used to detect them. First, we briefly describe the magnetic properties that are important for bio-sensing applications and highlight the associated key parameters (such as the starting materials, size, functionalization methods, and bio-conjugation strategies). Subsequently, we focus on magnetic sensing applications that utilize several types of magnetic detection techniques: spintronic sensors, nuclear magnetic resonance (NMR) sensors, superconducting quantum interference devices (SQUIDs), sensors based on the atomic magnetometer (AM), and others. From the studies reported, we note that the size of the MPs is one of the most important factors in choosing a sensing technique.

Biosensing Using Magnetic Particle Detection Techniques

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

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

Cell-free DNA (cfDNA) is foreseen as a promising source for liquid biopsies in cancer diagnostics. Despite its promise, methods available for its evaluation lack in robustness or, in the case of next-generation sequencing (NGS), are extremely sensitive but overly complex for routine operation. In contrast to NGS, integrated lab-on-chip devices offer advantages particularly in terms of automation, cost and speed. These devices, however, have rarely demonstrated the detection of biologically relevant DNA fragments originating from blood. To this end, we present a strategy for the magnetic labeling and detection of cfDNA fragments, using an array of 30 magnetoresistive (MR) sensors integrated in a portable biochip platform. As a proof-of-concept, we selected the fragments ALU115 and ALU247, recently identified as promising cancer targets in cfDNA integrity assessment. This work reveals a rational optimization of the DNA probes design and density at the surface which allowed achieving specific target detection and increased inhibition of unspecific interactions, without the need for blocking agents. The developed strategy is adaptable for the detection of mutations, homologous or truncated sequences such as the case of ALU115 and ALU247, sequences that share great similarity. Upon optimization, the MR sensors detected a concentration of the ALU elements within the picomolar range, showing potential for cfDNA analysis in cancer diagnostics.

Implementing a strategy for on-chip detection of cell-free DNA fragments using GMR sensors: A translational application in cancer diagnostics using ALU elements

Correction for ‘One-step trapping of droplets and surface functionalization of sensors using gold-patterned structures for multiplexing in biochips’ by T. M. Dias et al., RSC Adv., 2017, 7, 43273–43282.

/pdf/one-step-trapping-of-droplets-and-surface-functionalization-y4t375zswn.pdf

One-step trapping of droplets and surface functionalization of sensors using gold-patterned structures for multiplexing in biochips

Small extracellular vesicles (sEVs), including exosomes, are enriched in multiomics information mirroring their parental cells. They have been investigated in health and disease and utilised in several applications from drug discovery to diagnostics. In disease diagnostics, sEVs can be sampled via a blood draw, enabling the convenient liquid biopsy of the tissue they originate from. However, few applications with sEVs have been translated into clinical practice. We developed a Nanoparticle EXOsome Sensing (NEXOS) technology, for the ultrasensitive and multi-dimensional detection of sEVs. NEXOS comprises two methods: a novel nanoelectronics method, E-NEXOS, and a high-throughput optical detection method, O-NEXOS. Both methods share the same steps for the immunocapture and antibody-labelling of sEVs and can be combined to derive differentiated detection parameters. As a proof of concept, we show the analytical detection and sensitivity of these methods in detecting pre-prepared cancer cell-derived CD9+CD81+ and CD9+HER2+ sEVs. Both sEV populations were diluted in PBS and spiked in processed plasma. We also provide a novel approach for the determination of target sEVs (TEVs), target epitopes in sEVs (TEPs), and epitopes per target sEV, as yet unseen from current and emerging technologies. Further, we demonstrate the higher sensitivity of O-NEXOS compared to the gold standard techniques, as well as demonstrating that E-NEXOS possesses commensurate sensitivity whilst only being powered by 36 nanogap-based sensors per nanochip. Finally, this manuscript lays the groundwork for a scalable electronics miniaturization of E-NEXOS nanochip with millions of nanogap-based sensors for the translation of NEXOS into standard clinical practice.

T. M. Dias

Papers

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

Implementing a strategy for on-chip detection of cell-free DNA fragments using GMR sensors: A translational application in cancer diagnostics using ALU elements

One-step trapping of droplets and surface functionalization of sensors using gold-patterned structures for multiplexing in biochips

An electro-optical bead-nanochip technology for the ultrasensitive and multi-dimensional detection of small extracellular vesicles and their markers