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Magnetic nanoparticles have an important role as heat generators in magnetic fluid hyperthermia, a type of next-generation cancer treatment. Despite various trials to improve the heat generation capability of magnetic nanoparticles, iron oxide nanoparticles are the only approved heat generators for clinical applications, which require a large injection dose due to their low hyperthermia efficiency. In this study, iron oxide nanoclusters (NCs) with a highly enhanced hyperthermia effect and adjustable size were synthesized through a facile and simple solvothermal method. Among the samples, the NCs with a size of 25 nm showed the highest hyperthermia efficiency. Differently sized NCs exhibit inconsistent interparticle crystalline alignments, which affect their magnetic properties (e.g., coercivity and saturation magnetization). As a result, the optimal NCs exhibited a significantly enhanced heat generation efficiency compared with that of isolated iron oxide nanoparticles (ca. 7 nm), and their hyperthermia effect on skin cancer cells was confirmed.

Nanoparticles with multifunctionality and high colloidal stability are essential for biomedical applications. However, their use is often hindered by the formation of thick coating shells and/or nanoparticle agglomeration. Herein, we report a single nanoparticle coating strategy to form 1 nm polymeric shells with a variety of chemical functional groups and surface charges. Under exposure to alternating magnetic field, nanosecond thermal energy pulses trigger a polymerization in the region only a few nanometers from the magnetic nanoparticle (MNP) surface. Modular coatings containing functional groups, according to the respective choice of monomers, are possible. In addition, the surface charge can be tuned from negative through neutral to positive. We adopted a coating method for use in biomedical targeting studies where obtaining compact nanoparticles with the desired surface charge is critical. A single MNP with a zwitterionic charge can provide excellent colloidal stability and cell-specific targeting.

Contrast agents for magnetic resonance imaging (MRI) improve anatomical visualizations. However, owing to poor image resolution in whole-body MRI, resolving fine structures is challenging. Here, we report that a nanoparticle with a polysaccharide supramolecular core and a shell of amorphous-like hydrous ferric oxide generating strong T1 MRI contrast (with a relaxivity coefficient ratio of ~1.2) facilitates the imaging, at resolutions of the order of a few hundred micrometres, of cerebral, coronary and peripheral microvessels in rodents and of lower-extremity vessels in rabbits. The nanoparticle can be synthesized at room temperature in aqueous solution and in the absence of surfactants, has blood circulation and renal clearance profiles that prevent opsonization, and leads to better imaging performance than Dotarem (gadoterate meglumine), a clinically approved gadolinium-based MRI contrast agent. The nanoparticle's biocompatibility and imaging performance may prove advantageous in a broad range of preclinical and clinical applications of MRI.

The ideal combination of high optical transparency and high electrical conductivity, especially at very low frequencies of less than the gigahertz (GHz) order, such as the radiofrequencies at which electronic devices operate (tens of kHz to hundreds of GHz), is fundamental incompatibility, which creates a barrier to the realization of enhanced user interfaces and ‘device-to-device integration.’ Herein, we present a design strategy for preparing a megahertz (MHz)-transparent conductor, based on a plasma frequency controlled by the electrical conductivity, with the ultimate goal of device-to-device integration through electromagnetic wave transmittance. This approach is verified experimentally using a conducting polymer, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS), the microstructure of which is manipulated by employing a solution process. The use of a transparent conducting polymer as an electrode enables the fabrication of a fully functional touch-controlled display device and magnetic resonance imaging (MRI)-compatible biomedical monitoring device, which would open up a new paradigm for transparent conductors., The emergence of applications requiring device-to-device interactivity has to the need to develop conducting electrodes with high optical transparency at low radiofrequencies. Here, the authors demonstrate conductive polymer electrodes with high transparency in the MHz-order frequency range.

Magnetic nanoparticle (MNP)-mediated heating systems have emerged as an effective strategy for the fine control of biological systems from hyperthermia to cell signaling in a spatiotemporally controlled fashion. To achieve satisfactory performance, advanced design concepts have been developed to tailor the magnetism that directly affects the heating properties of nanoparticles. In this review, we focus on recent advances in magnetism-engineered nanoparticles. Fundamental principles of magnetic heating mechanisms and related key magnetic parameters are discussed first to provide instructive guidelines for the design of MNPs with enhanced heating efficiency. Then, we highlight recent progress in MNPs for optimized heat generation with unique design approaches to control magnetism. Finally, we discuss highly effective biomedical application studies such as dual-mode magnetic hyperthermia, magnetothermally triggered drug delivery, and the magnetothermal control of cellular activities.

Developing innovative tools that facilitate the understanding of sophisticated biological systems has been one of the Holy Grails in the physical and biological sciences. In this Commentary, we discuss recent advances, opportunities, and challenges in the use of nanomaterials as a precision tool for biology and medicine.

Recent suggestions of nanoscale heat confinement on the surface of synthetic and biogenic magnetic nanoparticles during heating by radio frequency-alternating magnetic fields have generated intense interest because of the potential utility of this phenomenon for noninvasive control of biomolecular and cellular function. However, such confinement would represent a significant departure from the classical heat transfer theory. Here, we report an experimental investigation of nanoscale heat confinement on the surface of several types of iron oxide nanoparticles commonly used in biological research, using an all-optical method devoid of the potential artifacts present in previous studies. By simultaneously measuring the fluorescence of distinct thermochromic dyes attached to the particle surface or dissolved in the surrounding fluid during radio frequency magnetic stimulation, we found no measurable difference between the nanoparticle surface temperature and that of the surrounding fluid for three distinct nanoparticle types. Furthermore, the metalloprotein ferritin produced no temperature increase on the protein surface nor in the surrounding fluid. Experiments mimicking the designs of previous studies revealed potential sources of the artifacts. These findings inform the use of magnetic nanoparticle hyperthermia in engineered cellular and molecular systems.

Contrast agents for magnetic resonance imaging (MRI) improve anatomical visualizations. However, owing to poor image resolution in whole-body MRI, resolving fine structures is challenging. Here, we report that a nanoparticle with a polysaccharide supramolecular core and a shell of amorphous-like hydrous ferric oxide generating strong T

A flexible magnetic wire inserted in a blood vessel improves the capture of magnetically labelled circulating tumour cells.

Multidrug resistance (MDR) is a leading cause of failure in current chemotherapy treatment and constitutes a formidable challenge in therapeutics. Here, we demonstrate that a nanoscale magnetic tandem apoptosis trigger (m-TAT), which consists of a magnetic nanoparticle and chemodrug (e.g., doxorubicin), can completely remove MDR cancer cells in both in vitro and in vivo systems. m-TAT simultaneously activates extrinsic and intrinsic apoptosis signals in a synergistic fashion and downregulates the drug efflux pump (e.g., P-glycoprotein) which is one of the main causes of MDR. The tandem apoptosis strategy uses low level of chemodrug (in the nanomolar (nM) range) to eliminate MDR cancer cells. We further demonstrate that apoptosis of MDR cancer cells can be achieved in a spatially selective manner with single-cell level precision. Our study indicates that nanoscale tandem activation of convergent signaling pathways is a new platform concept to overcome MDR with high efficacy and specificity.

Sensors that detect specific molecules of interest in a living organism can be useful tools for studying biological functions and diseases. Here, we provide a protocol for the construction of nanosensors that can noninvasively detect biologically important targets with magnetic resonance imaging (MRI). The key operating principle of these sensors is magnetic resonance tuning (MRET), a distance-dependent phenomenon occurring between a superparamagnetic quencher and a paramagnetic enhancer. The change in distance between the two magnetic components modulates the longitudinal (T1) relaxivity of the enhancer. In this MRET sensor, distance variation is achieved by interactive linkers that undergo binding, cleavage, or folding/unfolding upon their interaction with target molecules. By the modular incorporation of suitable linkers, the MRET sensor can be applied to a wide range of targets. We showcase three examples of MRET sensors for enzymes, nucleic acid sequences, and pH. This protocol comprises three stages: (i) chemical synthesis and surface modification of the quencher, (ii) conjugation with interactive linkers and enhancers, and (iii) MRI sensing of biological targets. The entire procedure takes up to 3 d. This protocol describes the synthesis of magnetic resonance tuning (MRET) sensors. The sensors consist of two magnetic components separated by a linker and can be modularly designed for targets such as enzymes, nucleic acid sequences, and pH values.

Objective To report the first large case series of extremely rare bilateral congenital cholesteatoma (CC). Study design A retrospective cohort study. Setting University hospital otology referral clinic. Patients Six hundred four children with surgically confirmed CC. Main outcome measures The bilateral CCs were compared with the unilateral CCs. Results The incidence of bilateral CC was 3.6% (22/615) per case or 1.8% (11/604) per child. Bilateral CC did not differ from unilateral CC regarding its demographics, and invasiveness by the proportion of advanced CC as 31.8% (7/22) versus 28.2% (167/594). But the invasiveness or location randomly differed between the ears, that advanced CC per child was higher as 45.4% (5/11). Bilateral exploration was attempted with a concern for hearing loss, which featured a combination of laser myringotomy to treat early CC and endaural laser-assisted single-stage inside-out cholesteatoma surgery to treat advanced CC. Bilateral exploration was difficult in three children with initially negative otoendoscopy. Among the seven advanced CC, proportion of anterior type was 71.4% (5/7), who all exhibited more than 20 dB HL, but two posterior type retained normal hearing. Therefore, bilateral advanced CCs of anterior origin showed poorest hearing outcome as bilateral more than 20 dB HL, which were in two children. Six second-look operations and one third-look operation were required to treat six residual CCs (30%) in four children (40%), including bilateral residual CC in two (20%); such reoperations were significantly more frequent than in unilateral CC. Conclusion The diagnosis of bilateral CC required high index of suspicion from TBCT, and early bilateral exploration.

Cell-based therapies are attractive for treating various degenerative disorders and cancer but delivering functional cells to the region of interest in vivo remains difficult. The problem is exacerbated in dense biological matrices such as solid tissues because these environments impose significant steric hindrances for cell movement. Here, we show that neural stem cells transfected with zinc-doped ferrite magnetic nanoparticles (ZnMNPs) can be pulled by an external magnet to migrate to the desired location in the brain. These magnetically labeled cells (Mag-Cells) can migrate because ZnMNPs generate sufficiently strong mechanical forces to overcome steric hindrances in the brain tissues. Once at the site of lesion, Mag-Cells show enhanced neuronal differentiation and greater secretion of neurotrophic factors than unlabeled control stem cells. Our study shows that ZnMNPs activate zinc-mediated Wnt signaling to facilitate neuronal differentiation. When implemented in a rodent brain stroke model, Mag-Cells led to significant recovery of locomotor performance in the impaired limbs of the animals. Our findings provide a simple magnetic method for controlling migration of stem cells with high therapeutic functions, offering a valuable tool for other cell-based therapies.

Magnetic nanoparticles have been extensively explored as a versatile platform for magnetic resonance imaging (MRI) contrast agents due to their strong contrast enhancement effects together with the platform capability for multiple imaging modalities. In this tutorial review, we focus on recent progress in the use of magnetic nanoparticles for MRI contrast agents and multi-mode imaging agents such as T1-T2 MRI, MRI-optical, and MRI-radioisotopes. This review also highlights emerging magnetic imaging techniques such as magnetic particle imaging (MPI), magneto-motive ultrasound imaging (MMUS), and magneto-photoacoustic imaging (MPA).

The magnetic exchange coupling interaction between hard and soft magnetic phases has been important for tailoring nanoscale magnetism, but spin interactions at the core–shell interface have not been well studied. Here, we systematically investigated a new interface phenomenon termed enhanced spin canting (ESC), which is operative when the shell thickness becomes ultrathin, a few atomic layers, and exhibits a large enhancement of magnetic coercivity (HC). We found that ESC arises not from the typical hard–soft exchange coupling but rather from the large magnetic surface anisotropy (KS) of the ultrathin interface. Due to this large increase in magnetism, ultrathin core–shell nanoparticles overreach the theoretical limit of magnetic energy product ((BH)max) and exhibit one of the largest values of specific loss power (SLP), which testifies to their potential capability as an effective mediator of magnetic energy conversion.

© 2017 The Royal Society of Chemistry. Magnetic nanoparticles (MNPs) are widely used in biomedical and clinical applications, including medical imaging, therapeutics, and biological sample processing. Rapid characterization of MNPs, notably their magnetic moments, should facilitate optimization of particle synthesis and accelerate assay development. Here, we report a compact and low-cost magnetometer for fast, on-site MNP characterization. Termed integrated microHall magnetometer (iHM), our device was fabricated using standard semiconductor processes: an array of Hall sensors, transistor switches, and amplifiers were integrated into a single chip, thus improving the detection sensitivity and facilitating chip operation. By applying the iHM, we demonstrate versatile magnetic assays. We measured the magnetic susceptibility and moments of MNPs using small sample amounts (∼10 pL), identified different MNP compositions in mixtures, and detected MNP-labeled single cells.

Nanoparticle clusters (NPCs) have attracted significant interest owing to their unique characteristics arising from their collective individual properties. Nonetheless, the construction of NPCs in a structurally well-defined and size-controllable manner remains a challenge. Here we demonstrate a strategy to construct size-controlled NPCs using the DNA-binding zinc finger (ZnF) protein. Biotinylated ZnF was conjugated to DNA templates with different lengths, followed by incubation with neutravidin-conjugated nanoparticles. The sequence specificity of ZnF and programmable DNA templates enabled a size-controlled construction of NPCs, resulting in a homogeneous size distribution. We demonstrated the utility of magnetic NPCs by showing a three-fold increase in the spin-spin relaxivity in MRI compared with Feridex. Furthermore, folate-conjugated magnetic NPCs exhibited a specific targeting ability for HeLa cells. The present approach can be applicable to other nanoparticles, finding wide applications in many areas such as disease diagnosis, imaging, and delivery of drugs and genes.

One of the holy grails in biomedical imaging technology is to achieve accurate imaging of biological targets. The development of sophisticated instrumentation and the use of contrast agents have improved the accuracy of biomedical imaging. However, the issue of false imaging remains a problem. Here, we developed a dual-mode artifact filtering nanoparticle imaging agent (AFIA) that comprises a combination of paramagnetic and superparamagnetic nanomaterials. This AFIA has the ability to perform “AND logic gate” algorithm to eliminate false errors (artifacts) from the raw images to enhance accuracy of the MRI. We confirm the artifact filtering capability of AFIA in MRI phantoms and further demonstrate that artifact-free imaging of stem cell migration is possible in vivo.

This paper presents an automated DFM solution to generate Bit Line Pattern Dummy (BLPD) for memory devices. Dummy shapes are aligned with memory functional bits to ensure uniform and reliable memory device. This paper will present a smarter approach that uses an analysis based technique for adding the dummy shapes that have different types according to the space available. Experimental results based on layout of Mobile dynamic random access memory (DRAM).

Nanoscale distance-dependent phenomena, such as Forster resonance energy transfer, are important interactions for use in sensing and imaging, but their versatility for bioimaging can be limited by undesirable photon interactions with the surrounding biological matrix, especially in in vivo systems. Here, we report a new type of magnetism-based nanoscale distance-dependent phenomenon that can quantitatively and reversibly sense and image intra-/intermolecular interactions of biologically important targets. We introduce distance-dependent magnetic resonance tuning (MRET), which occurs between a paramagnetic 'enhancer' and a superparamagnetic 'quencher', where the T1 magnetic resonance imaging (MRI) signal is tuned ON or OFF depending on the separation distance between the quencher and the enhancer. With MRET, we demonstrate the principle of an MRI-based ruler for nanometre-scale distance measurement and the successful detection of both molecular interactions (for example, cleavage, binding, folding and unfolding) and biological targets in in vitro and in vivo systems. MRET can serve as a novel sensing principle to augment the exploration of a wide range of biological systems.

Temperature control is an important method of self-defense in biological systems. For example, one response mounted by humans in an effort to fight injury, including viral and bacterial infections, involves an increase in body temperature, thus producing the well-recognized symptoms of fever.[1] Today, the idea of using artificial temperature control for disease removal is being realized with the aid of various techniques, such as ultrasound, near-infrared light, and magnetic field by increasing localized temperature in a targeted region.[2] Magnetic nanoparticles have attracted considerable attention for hyperthermia applications owing to their ability to generate heat effectively when exposed to an alternating magnetic field without a penetration depth limit.[3] Hyperthermia, the artificially induced heat treatment of a disease, uses temperatures ranging between 42 °C and 47°C. Generally, a temperature below 45 °C induces apoptotic cell death.[4] As compared to necrosis, apoptosis is a more benign form of “programmed” cell death.[5] Nonliving cells produced as the result of apoptotic process are cleaned by phagocytosis without affecting neighboring normal cells. In contrast, necrosis, typically generated by harsh and high-temperature hyperthermia, is considered relatively harmful because it can be correlated with inflammatory disease and metastasis.[6] However, achieving effective apoptotic hyperthermia is often difficult, as cells typically acquire resistance to induced thermal stress.[7] Repeated exposures to high temperatures with high concentration of magnetic nanoparticles are usually necessary to achieve a useful level of therapeutic efficacy even though the conditions could favor necrotic cell death rather than apoptosis. Because cancer cells are susceptible to heat at about 43 °C, while most normal tissues remain undamaged,[8] hyperthermia using this temperature defines a recognized but unmet goal.

Stem-cell-based therapies have attracted considerable interest in regenerative medicine and oncological research. However, a major limitation of systemic delivery of stem cells is the low homing efficiency to the target site. Here, we report a serendipitous finding that various iron-based magnetic nanoparticles (MNPs) actively augment chemokine receptor CXCR4 expression of bone-marrow-derived mesenchymal stem cells (MSCs). On the basis of this observation, we designed an iron-based nanocluster that can effectively label MSCs, improve cell homing efficiency, and track the fate of the cells in vivo. Using this nanocluster, the labeled MSCs were accurately monitored by magnetic resonance imaging and improved the homing to both traumatic brain injury and glioblastoma models as compared to unlabeled MSCs. Our findings provide a simple and safe method for imaging and targeted delivery of stem cells and extend the potential applications of iron-based MNPs in regenerative medicine and oncology.

This study provides an easy and simple method to obtain inorganic nanoparticles that can penetrate the blood–brain barrier, the heavily guarded system in the brain, via cross-linked serum albumin surface coatings. Their intact BBB permeability was confirmed in both in vitro and in vivo tests.

Early detection and treatment of disease is the most important component of a favorable prognosis. Biomedical researchers have thus invested tremendous effort in improving imaging techniques and treatment methods. Over the past decade, concepts and tools derived from nanotechnology have been applied to overcome the problems of conventional techniques for advanced diagnosis and therapy. In particular, advances in nanoparticle technology have created new paradigms for theranostics, which is defined as the combination of therapeutic and diagnostic agents within a single platform. In this Account, we examine the potential advantages and opportunities afforded by magnetic nanoparticles as platform materials for theranostics. We begin with a brief overview of relevant magnetic parameters, such as saturation magnetization, coercivity, and magnetocrystalline anisotropy. Understanding the interplay of these parameters is critical for optimizing magnetic characteristics needed for effective imaging and therapeutics, which include magnetic resonance imaging (MRI) relaxivity, heat emission, and attractive forces. We then discuss approaches to constructing an MRI nanoparticle contrast agent with high sensitivity. We further introduce a new design concept for a fault-free contrast agent, which is a T1 and T2 dual mode hybrid. Important capabilities of magnetic nanoparticles are the external controllability of magnetic heat generation and magnetic attractive forces for the transportation and movement of biological objects. We show that these functions can be utilized not only for therapeutic hyperthermia of cancer but also for controlled release of cancer drugs through the application of an external magnetic field. Additionally, the use of magnetic nanoparticles to drive mechanical forces is demonstrated to be useful for molecular-level cell signaling and for controlling the ultimate fate of the cell. Finally, we show that targeted imaging and therapy are made possible by attaching a variety of imaging and therapeutic components. These added components include therapeutic genes (small interfering RNA, or siRNA), cancer-specific ligands, and optical reporting dyes. The wide range of accessible features of magnetic nanoparticles underscores their potential as the most promising platform material available for theranostics.

Achieving high accuracy in the imaging of biological targets is a challenging issue. For MRI, to enhance imaging accuracy, two different imaging modes with specific contrast agents are used; one is a T1 type for a “positive” MRI signal and the other is a T2 type for a “negative” signal. Conventional contrast agents respond only in a single imaging mode and frequently encounter ambiguities in the MR images. Here, we propose a “magnetically decoupled” core−shell design concept to develop a dual mode nanoparticle contrast agent (DMCA). This DMCA not only possesses superior MR contrast effects but also has the unique capability of displaying “AND” logic signals in both the T1 and T2 modes. The latter enables self-confirmation of images and leads to greater diagnostic accuracy. A variety of novel DMCAs are possible, and the use of DMCAs can potentially bring the accuracy of MR imaging of diseases to a higher level.

On page 4412, the Acknowledgment section should include “Research at Yonsei University was supported by National Creative Research Initiatives Program (2010-0018286) and Korea Healthcare Technology R&D Project, Ministry for Health & Welfare Affairs, Republic of Korea (HI08C2149)”. This change does not affect the reported results, discussions, or conclusion in this paper. The authors apologize for this oversight.

Previously, pulsed magneto-motive ultrasound (pMMUS) imaging has been introduced as a contrast-agent-assisted ultrasound-based imaging modality capable of visualizing biological events at the cellular and molecular level. In pMMUS imaging, a high intensity pulsed magnetic field is used to excite cells or tissue labeled with magnetic nanoparticles. Then, ultrasound (US) imaging is used to monitor the mechanical response of the tissue to an externally applied magnetic field (i.e., tissue displacement). Signal to noise ratio (SNR) in pMMUS imaging can be improved by using superparamagnetic nanoparticles with larger saturation magnetization. Metal-doped magnetic nanoparticles with enhanced tunable nanomagnetism are suitable candidates to improve the SNR and, therefore, sensitivity of pMMUS imaging, which is essential for in vivo pMMUS imaging. In this study, we demonstrate the capability of pMMUS imaging to identify the presence and distribution of zinc-doped iron oxide nanoparticles in live nude mice bearing A431 (human epithelial carcinoma) xenograft tumors.