MNP-enhanced microwave medical imaging by means of pseudo-noise sensing

Magnetic nanoparticles have been investigated for microwave imaging over the last decade. The use of functionalized magnetic nanoparticles, which are able to accumulate selectively within tumorous tissue, can increase the diagnostic reliability. This paper deals with the detecting and imaging of magnetic nanoparticles by means of ultra-wideband microwave sensing via pseudo-noise technology. The investigations were based on phantom measurements. In the first experiment, we analyzed the detectability of magnetic nanoparticles depending on the magnetic field intensity of the polarizing magnetic field, as well as the viscosity of the target and the surrounding medium in which the particles were embedded, respectively. The results show a nonlinear behavior of the magnetic nanoparticle response depending on the magnetic field intensity for magnetic nanoparticles diluted in distilled water and for magnetic nanoparticles embedded in a solid medium. Furthermore, the maximum amplitude of the magnetic nanoparticles responses varies for the different surrounding materials of the magnetic nanoparticles. In the second experiment, we investigated the influence of the target position on the three-dimensional imaging of the magnetic nanoparticles in a realistic measurement setup for breast cancer imaging. The results show that the magnetic nanoparticles can be detected successfully. However, the intensity of the particles in the image depends on its position due to the path-dependent attenuation, the inhomogeneous microwave illumination of the breast, and the inhomogeneity of the magnetic field. Regarding the last point, we present an approach to compensate for the inhomogeneity of the magnetic field by computing a position-dependent correction factor based on the measured magnetic field intensity and the magnetic susceptibility of the magnetic particles. Moreover, the results indicate an influence of the polarizing magnetic field on the measured ultra-wideband signals even without magnetic nanoparticles. Such a disturbing influence of the polarizing magnetic field on the measurements should be reduced for a robust magnetic nanoparticles detection. Therefore, we analyzed the two-state (ON/OFF) and the sinusoidal modulation of the external magnetic field concerning the detectability of the magnetic nanoparticles with respect to these spurious effects, as well as their practical application

Remotely Activated Nanoparticles for Anticancer Therapy

The present review highlights the importance of remotely activated nanoparticles for anticancer purposes.For each physical input, we present its possible active synergy with several nanomaterials.We report examples and the mechanism of action when clarified.Clinical trials involving remotely triggered nanoparticles are discussed. Cancer has nowadays become one of the leading causes of death worldwide. Conventional anticancer approaches are associated with different limitations. Therefore, innovative methodologies are being investigated, and several researchers propose the use of remotely activated nanoparticles to trigger cancer cell death. The idea is to conjugate two different components, i.e., an external physical input and nanoparticles. Both are given in a harmless dose that once combined together act synergistically to therapeutically treat the cell or tissue of interest, thus also limiting the negative outcomes for the surrounding tissues. Tuning both the properties of the nanomaterial and the involved triggering stimulus, it is possible furthermore to achieve not only a therapeutic effect, but also a powerful platform for imaging at the same time, obtaining a nano-theranostic application. In the present review, we highlight the role of nanoparticles as therapeutic or theranostic tools, thus excluding the cases where a molecular drug is activated. We thus present many examples where the highly cytotoxic power only derives from the active interaction between different physical inputs and nanoparticles. We perform a special focus on mechanical waves responding nanoparticles, in which remotely activated nanoparticles directly become therapeutic agents without the need of the administration of chemotherapeutics or sonosensitizing drugs. [Figure not available: see fulltext.

Nanomaterials responding to microwaves: an emerging field for imaging and therapy

In recent years, new microwave-based imaging, sensing and hyperthermia applications have emerged in the field of diagnostics and therapy. For diagnosis, this technology involves the application of low power microwaves, utilising contrast between the relative permittivity of tissues to identify pathologies. This contrast can be further enhanced through the implementation of nanomaterials. For therapy, this technology can be applied in tissues either through hyperthermia, which can help anti-cancer drug tumour penetration or as ablation to destroy malignant tissues. Nanomaterials can absorb electromagnetic radiation and can enhance the microwave hyperthermic effect. In this review we aim to introduce this area of renewed interest and provide insights into current developments in its technologies and companion nanoparticles, as well as presenting an overview of applications for diagnosis and therapy

Differential ultra-wideband microwave imaging for medical applications

Elektromagnetische Ultrabreitband-Sensorik und -Bildgebung bieten vielversprechende Perspektiven für verschiedene biomedizinische Anwendungen, da diese Wellen biologisches Gewebe durchdringen können. Dabei stellt der Einsatz von leistungsarmen und nichtionisierenden Mikrowellen eine gesundheitlich unbedenkliche Untersuchungsmethode dar. Eine der Herausforderungen im Bereich der ultrabreitbandigen Mikrowellensensorik ist dabei die Extraktion der diagnostisch relevanten Informationen aus den Messdaten, da aufgrund der komplexen Wellenausbreitung im Gewebe meist rechenaufwändige Methoden notwendig sind. Dieses Problem wird wesentlich vereinfacht, wenn sich die Streueigenschaften des zu untersuchenden Objektes zeitlich ändern. Diese zeitliche Varianz der Streueigenschaften kann mit Hilfe einer Differenzmessung über ein bestimmtes Zeitintervall ausgenutzt werden. Im Rahmen dieser Arbeit wird der differentielle Ansatz mittels Ultrabreitband-Sensorik für zwei medizinische Anwendungsszenarien betrachtet. Die dabei genutzten Messsysteme basieren auf dem M-Sequenzverfahren, welches an der Technischen Universität Ilmenau entwickelt wurde. Die erste Anwendung bezieht sich auf das nicht-invasive Temperaturmonitoring mittels Ultrabreitband-Technologie während einer Hyperthermiebehandlung. Hyperthermie ist eine Wärmetherapie zur Unterstützung onkologischer Behandlungen (z. B. Chemo- oder Strahlentherapie). Während einer solchen Behandlung wird das Tumorgewebe um 4 °C bis 8 °C erhöht. Dabei ist es wichtig, dass die Temperatur die obere Grenze von 45 °C nicht überschreitet. In diesem Zusammenhang bietet das differentielle Ultrabreitband-Monitoring eine vielversprechende Technik zur kontinuierlichen und nicht-invasiven Messung der Temperatur im Körperinneren. Der Ansatz basiert auf den temperaturabhängigen dielektrischen Eigenschaften von biologischem Gewebe. Dabei werden elektromagnetische Wellen mit einer geringen Leistung in das Untersuchungsmedium eingebracht, die sich gemäß den dielektrischen Eigenschaften von Gewebe ausbreiten. Wird eine Zielregion (bspw. Tumor) erwärmt, so ändern sich dessen dielektrische Eigenschaften, was zu einem sich ändernden Streuverhalten der elektromagnetischen Welle führt. Diese Änderungen können mittels Ultrabreitband-Sensorik erfasst werden. Für die Evaluierung der gemessenen Änderungen im Radarsignal ist es notwendig, die temperaturabhängigen dielektrischen Eigenschaften von Gewebe im Mikrowellenfrequenzbereich zu kennen. Aufgrund der wenigen in der Literatur vorhandenen temperaturabhängigen dielektrischen Eigenschaften von Gewebe über einen breiten Mikrowellenfrequenzbereich werden in dieser Arbeit die dielektrischen Eigenschaften für Leber, Muskel, Fett und Blut im Temperaturbereich zwischen 30 °C und 50 °C von 500 MHz bis 7 GHz erfasst. Hierzu wird zunächst ein Messaufbau für die temperaturabhängige dielektrische Spektroskopie von Gewebe, Gewebeersatz und Flüssigkeiten vorgestellt und die wesentlichen Einflussfaktoren auf die Messungen analysiert. Die Messdaten werden mit Hilfe eines temperaturabhängigen Cole-Cole Models modelliert, um die dielektrischen Eigenschaften für beliebige Werte im untersuchten Temperatur- und Frequenzbereich berechnen zu können. In einem weiteren Experiment wird die nicht-invasive Erfassung von Temperaturänderungen mittels Ultrabreitband-Technologie in einem experimentellen Messaufbau nachgewiesen. Die Ergebnisse zeigen, dass eine Temperaturänderung von 1 °C zu Differenzsignalen führt, welche mit der genutzten Ultrabreitband-Sensorik (M-Sequenz) detektierbar sind. Die zweite Anwendung befasst sich mit der kontrastbasierten Mikrowellen-Brustkrebsbildgebung. Aufgrund des physiologisch gegebenen geringen dielektrischen Kontrastes zwischen Drüsen- und Tumorgewebe kann durch den Einsatz von Kontrastmitteln, im Speziellen magnetischen Nanopartikeln, die Zuverlässigkeit einer Diagnose verbessert werden. Der Ansatz beruht darauf, dass funktionalisierte magnetische Nanopartikel in der Lage sind, sich selektiv im Tumorgewebe zu akkumulieren, nachdem diese intravenös verabreicht wurden. Unter der Bedingung, dass sich eine ausreichende Menge der Nanopartikel im Tumor angesammelt hat, können diese durch ein äußeres polarisierendes Magnetfeld moduliert werden. Aufgrund der Modulation ändert sich das Streuverhalten der magnetischen Nanopartikel, was wiederum zu einem sich ändernden Rückstreuverhalten führt. Diese Änderungen können mittels leistungsarmen elektromagnetischen Wellen detektiert werden. In dieser Arbeit wird die Detektierbarkeit und Bildgebung von magnetischen Nanopartikeln mittels Ultrabreitband-Sensorik im Mikrowellenfrequenzbereich in Hinblick auf die Brustkrebsdetektion betrachtet. Dabei werden zunächst verschiedene Einflussfaktoren, wie die Abhängigkeit der Masse der magnetischen Nanopartikel, die Magnetfeldstärke des äußeren Magnetfeldes sowie die Viskosität des Umgebungsmediums, in das die Nanopartikel eingebettet sind, auf die Detektierbarkeit der magnetischen Nanopartikel untersucht. Die Ergebnisse zeigen eine lineare Abhängigkeit zwischen dem gemessenen Radarsignal und der Masse der magnetischen Nanopartikel sowie einen nichtlinearen Zusammenhang zwischen der Antwort der magnetischen Nanopartikel und der Feldstärke des äußeren Magnetfeldes. Darüber hinaus konnten die magnetischen Nanopartikel für alle untersuchten Viskositäten erfolgreich detektiert werden. Basierend auf diesen Voruntersuchungen wird ein realistischer Messaufbau für die kontrastbasierte Brustkrebsbildgebung vorgestellt. Die Evaluierung des Messaufbaus erfolgt mittels Phantommessungen, wobei die verwendeten Phantommaterialien die dielektrischen Eigenschaften von biologischem Gewebe imitieren, um eine möglichst hohe Aussagekraft der Ergebnisse hinsichtlich eines praktischen Messszenarios zu erhalten. Dabei wird die Detektierbarkeit und Bildgebung der magnetischen Nanopartikel in Abhängigkeit der Tumortiefe analysiert. Die Ergebnisse zeigen, dass die magnetischen Nanopartikel erfolgreich detektiert werden können. Dabei hängt im dreidimensionalen Bild die Intensität des Messsignals, hervorgerufen durch die magnetischen Nanopartikel, von deren Position ab. Die Ursachen hierfür sind die pfadabhängige Dämpfung der elektromagnetischen Wellen, die inhomogene Ausleuchtung des Mediums mittels Mikrowellen, da eine gleichmäßige Anordnung der Antennen aufgrund der Magnetpole des Elektromagneten nicht möglich ist, sowie das inhomogene polarisierende Magnetfeld innerhalb des Untersuchungsmediums. In Bezug auf den letzten Aspekt wird das Magnetfeld im Untersuchungsbereich ausgemessen und ein Ansatz präsentiert, mit dem die Inhomogenität des Magnetfeldes kompensiert werden kann. Weiterhin wurden die Störeinflüsse des polarisierenden Magnetfeldes auf das Messsystem untersucht. In diesem Zusammenhang werden zwei verschiedene Modulationsarten (eine Modulation mit den zwei Zuständen AN/AUS und eine periodische Modulation) des äußeren polarisierenden Magnetfeldes analysiert. Es wird gezeigt, dass mit beiden Modulationen die magnetischen Nanopartikel bildgebend dargestellt werden können. Abschließend werden die Ergebnisse in Hinblick auf die Störeinflüsse sowie ein praktisches Anwendungsszenario diskutiert.Electromagnetic ultra-wideband sensing and imaging provide promising perspectives in various biomedical applications as these waves can penetrate biological tissue. The use of low-power and nonionizing electromagnetic waves in the microwave frequency range offers an examination method that is harmless to health. One of the challenges in the field of ultra-wideband microwave sensor technology is the extraction of diagnostically relevant information from the measurement data, since the complex wave propagation in tissue usually requires computationally intensive methods. This problem is simplified when the scattering properties of the object under observation change with time. Such a time variance of the scattering properties can be exploited by means of a differential measurement over a certain time interval. In this work, a differential approach using ultra-wideband sensing is considered for two medical applications. The measurement systems used in this work are based on the M-sequence technology developed at the Technische Universität Ilmenau. The first application relates to noninvasive temperature monitoring using ultra-wideband technology during hyperthermia treatment. Hyperthermia is a thermal therapy to support oncological treatments (e.g. chemotherapy or radiotherapy). During such a treatment, the tumor tissue is heated by 4 °C to 8 °C, whereby it is important that the temperature does not exceed the upper limit of 45 °C. In this context, differential ultra-wideband monitoring offers a promising technique for continuous and noninvasive temperature monitoring inside the body. The approach is based on the temperature-dependent dielectric properties of biological tissue. In this method, low power electromagnetic waves are emitted into the medium under investigation. These waves propagate according to the dielectric properties of tissue. If a target region (e.g. tumor) is heated, its dielectric properties will change, which leads to a changing scattering behavior of the electromagnetic wave. These changes can be detected in the measured reflection signals using ultra-wideband microwave technology. To evaluate the measured changes in the radar signal, it is necessary to know the temperature-dependent dielectric properties of tissue in the microwave frequency range. Due to the lack of knowledge of temperature-dependent dielectric properties of tissues over a wide microwave frequency range, the dielectric properties for liver, muscle, fat and blood in the temperature range between 30 °C and 50 °C from 500 MHz to 7 GHz are acquired in this work. For this purpose, a measurement setup for the temperature-dependent dielectric spectroscopy of tissue, tissue substitutes and fluids is presented. Furthermore, the main influences on measuring the temperature-dependent dielectric properties are analyzed. The measured data are modeled using a temperature-dependent Cole-Cole model in order to calculate the dielectric properties for arbitrary values in the investigated temperature and frequency range. In a further experiment, the noninvasive detection of temperature changes using ultra-wideband microwave technology is demonstrated in an experimental measurement setup. The results show that a temperature change of 1 °C results in differential signals that are detectable by means of ultra-wideband pseudo-noise sensing (M-sequence). The second application is dealing with contrast enhanced microwave breast cancer imaging. Due to the physiologically given low dielectric contrast between glandular and tumor tissue, the use of contrast agents, specifically magnetic nanoparticles, can improve the diagnostic reliability. The approach is based on the assumption that functionalized magnetic nanoparticles are able to selectively accumulate in tumor tissue after intravenous administration. Provided that a sufficient amount of nanoparticles has accumulated in the tumor, they can be modulated by an external polarizing magnetic field. Due to the modulation, the scattering behavior of the magnetic nanoparticles changes, which results a changing backscattering behavior. This change can be detected using low-power electromagnetic waves. In this work, the detectability and imaging of magnetic nanoparticles by means of ultra-wideband pseudo-noise sensing in the microwave frequency range is considered with respect to breast cancer detection. First, various influencing factors on the detectability of the magnetic nanoparticles are investigated, such as the mass of the magnetic nanoparticles, the magnetic field strength of the external polarizing magnetic field and the viscosity of the surrounding medium in which the nanoparticles are embedded. The results reveal a linear dependence between the measured radar signal and the mass of the magnetic nanoparticles as well as a nonlinear relationship between the response signal of the magnetic nanoparticles and the magnetic field intensity of the external magnetic field. Furthermore, the magnetic nanoparticles can be successfully detected in all investigated viscosities of the surrounding medium. Based on these preliminary investigations, a realistic measurement setup for contrast enhanced microwave breast cancer imaging is presented. The evaluation of the measurement setup is performed by phantom measurements, where the used phantom materials mimic the dielectric properties of biological tissue to obtain significance of the results with respect to a practical measurement scenario. In this context, the detectability and imaging of the magnetic nanoparticles are analyzed depending on the tumor position and penetration depth, respectively. The results show that the magnetic nanoparticles can be successfully detected. However, the magnetic poles of the electromagnet limit the space for the transmitting and receiving antennas, resulting in an inhomogeneous microwave illumination of the medium under test, which leads to a location-dependent magnetic nanoparticle response. Furthermore, the intensity of the response signal caused by the magnetic nanoparticles in the three-dimensional image depends on their position due to the path-dependent attenuation and the inhomogeneous magnetic field within the investigated medium. Regarding the last point, the external polarizing magnetic field is measured in the investigation area and an approach to compensate for the inhomogeneity of the magnetic field is presented. In addition, the disturbing influences of the polarizing magnetic field on the measurement setup are analyzed. In this context, two different modulation types (a two-state and a periodic modulation) of the external polarizing magnetic field are investigated. It is shown that both modulations can be used to image the magnetic nanoparticles. Finally, the results are discussed with respect to the spurious effects as well as a practical application scenario

Thermal ablation of biological tissues in disease treatment: A review of computational models and future directions

Percutaneous thermal ablation has proved to be an effective modality for treating both benign and malignant tumors in various tissues. Among these modalities, radiofrequency ablation (RFA) is the most promising and widely adopted approach that has been extensively studied in the past decades. Microwave ablation (MWA) is a newly emerging modality that is gaining rapid momentum due to its capability of inducing rapid heating and attaining larger ablation volumes, and its lesser susceptibility to the heat sink effects as compared to RFA. Although the goal of both these therapies is to attain cell death in the target tissue by virtue of heating above 50 oC, their underlying mechanism of action and principles greatly differs. Computational modelling is a powerful tool for studying the effect of electromagnetic interactions within the biological tissues and predicting the treatment outcomes during thermal ablative therapies. Such a priori estimation can assist the clinical practitioners during treatment planning with the goal of attaining successful tumor destruction and preservation of the surrounding healthy tissue and critical structures. This review provides current state-of- the-art developments and associated challenges in the computational modelling of thermal ablative techniques, viz., RFA and MWA, as well as touch upon several promising avenues in the modelling of laser ablation, nanoparticles assisted magnetic hyperthermia and non- invasive RFA. The application of RFA in pain relief has been extensively reviewed from modelling point of view. Additionally, future directions have also been provided to improve these models for their successful translation and integration into the hospital work flow

Assessing Detection Limits in Magnetic Nanoparticle Enhanced Microwave Imaging

Magnetic nanoparticles-aided microwave imaging is an emerging modality for the diagnosis of early stage tumors. It exploits the possibility of modulating the response at microwaves of magnetic nanoparticles, employed as contrast agent selectively accumulated into the tumor. In this paper, we describe the results of an experimental study aimed at establishing the actual detection limits of the approach, namely the minimum amount of magnetic nanoparticles to be delivered for a reliable imaging. The assessment is carried out on breast phantoms made of ex-vivo minced pig tissues and using commercially available magnetic nanoparticles. The results show that it is possible to detect amounts of magnetic nanoparticles between 2 and 7 mg, dispersed in a volume of about one cubic centimeter, depending on the breast type. While such quantities are already consistent with those currently reachable via active selective targeting, an in-depth analysis of the results allows to identify strategies to further lower the detection limits up to four times, by refining the measurement set-up and setting the amplitude of the polarizing magnetic field modulating the nanoparticle response to a suitable value

Femtosecond laser generation of bimetallic oxide nanoparticles with potential X-ray absorbing and magnetic functionalities for medical imaging applications

Bimetallic nanoparticles have gained vivid attention due to their unique and synergistic properties. They can be used in fields such as solar cells, optics, sensing, as well as medicine. The generation of bimetallic nanoparticles, containing oxide phases of both magnetic and X-ray attenuating metals for bioimaging applications has been challenging with traditional chemical synthesis methods. An alternative is the generation of nanoparticles from binary oxide ceramics by laser ablation in liquid. However, the applicability of this technique for production of hybrid nanoparticles consisting of magnetic and X-ray absorbing elements has not been demonstrated yet. In this work, novel ceramics composed of bimetallic oxide phases of iron-tantalum, iron-tungsten, and ironbismuth were produced by a reaction-sintering method. The bulk samples were characterized with scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffractometry. Nanoparticles were produced in aqueous and ethanol solutions by employing a femtosecond laser and characterized with transmission electron microscopy, selected area electron diffraction, and energy dispersive X-ray spectroscopy. The results demonstrated that the production of binary oxide bulk ceramics and their subsequent laser ablation in liquids leads to the successful generation of bimetallic oxide nanoparticles, without a core-shell morphology. In addition, it was found that the ablation threshold fluence of bulk samples as well as the crystallinity of the synthesized nanoparticles is governed by both the nature of the metallic oxide ceramics and the employed liquid. The results pave the way for a single step generation of well-defined bimetallic nanoparticles by laser ablation that could potentially exhibit X-ray and magnetic absorption properties suitable for multimodal imaging applications.This research has been partially funded by the Spanish Ministerio de Ciencia e Innovacion through the research project MAT2015-67354R (MINECO-FEDER). Funding through a Marie Sklodowska-Curie Individual Fellowships (MSCA-IF 2014, 656908-NIMBLIS-ESR) of the Horizon 2020 program, and the Project PI-0030-2017 of the Junta de Andalucia in the framework of the integrated territorial initiative 20142020 for research and innovation in biomedicine and health sciences in the province of Cadiz is also greatly appreciated. The authors acknowledge support for scanning electron microscopy by Dr. Stephan Puchegger and the faculty center for nanostructure research at the University of Vienna

Rare earth based nanostructured materials: Synthesis, functionalization, properties and bioimaging and biosensing applications

Rare earth based nanostructures constitute a type of functional materials widely used and studied in the recent literature. The purpose of this review is to provide a general and comprehensive overview of the current state of the art, with special focus on the commonly employed synthesis methods and functionalization strategies of rare earth based nanoparticles and on their different bioimaging and biosensing applications. The luminescent (including downconversion, upconversion and permanent luminescence) and magnetic properties of rare earth based nanoparticles, as well as their ability to absorb X-rays, will also be explained and connected with their luminescent, magnetic resonance and X-ray computed tomography bioimaging applications, respectively. This review is not only restricted to nanoparticles, and recent advances reported for in other nanostructures containing rare earths, such as metal organic frameworks and lanthanide complexes conjugated with biological structures, will also be commented on.European Union 267226Ministerio de Economía y Competitividad MAT2014-54852-

Hydroxyapatite Nanoparticles for Improved Cancer Theranostics

Beyond their well-known applications in bone tissue engineering, hydroxyapatite nanoparticles (HAp NPs) have also been showing great promise for improved cancer therapy. The chemical structure of HAp NPs offers excellent possibilities for loading and delivering a broad range of anticancer drugs in a sustained, prolonged, and targeted manner and thus eliciting lower complications than conventional chemotherapeutic strategies. The incorporation of specific therapeutic elements into the basic composition of HAp NPs is another approach, alone or synergistically with drug release, to provide advanced anticancer effects such as the capability to inhibit the growth and metastasis of cancer cells through activating specific cell signaling pathways. HAp NPs can be easily converted to smart anticancer agents by applying different surface modification treatments to facilitate the targeting and killing of cancer cells without significant adverse effects on normal healthy cells. The applications in cancer diagnosis for magnetic and nuclear in vivo imaging are also promising as the detection of solid tumor cells is now achievable by utilizing superparamagnetic HAp NPs. The ongoing research emphasizes the use of HAp NPs in fabricating three-dimensional scaffolds for the treatment of cancerous tissues or organs, promoting the regeneration of healthy tissue after cancer detection and removal. This review provides a summary of HAp NP applications in cancer theranostics, highlighting the current limitations and the challenges ahead for this field to open new avenues for research