Hand-held electron spin resonance scanner for subcutaneous oximetry using OxyChip.

PURPOSE: Electron spin resonance (ESR) is used to measure oxygen partial pressure (pO2) in biological media with many clinical applications. Traditional clinical ESR involves large magnets that encompass the subject of measurement. However, certain applications might benefit from a scanner operating within local static magnetic fields. Our group recently developed such a compact scanner for transcutaneous (surface) pO2 measurements of skin tissue. Here we extend this capability to subsurface (subcutaneous) pO2 measurements and verify it using an artificial tissue emulating (ATE) phantom. METHODS: We introduce a new scanner, tailored for subcutaneous measurements up to 2 mm beneath the skin's surface. This scanner captures pulsed ESR signals from embedded approximate 1-mm oxygen-sensing solid paramagnetic implant, OxyChip. The scanner features a static magnetic field source, producing a uniform region outside its surface, and a compact microwave resonator, for exciting and receiving ESR signals. RESULTS: ESR readings derived from an OxyChip, positioned approximately 1.5 mm from the scanner's surface, embedded in ATE phantom, exhibited a linear relation of 1/T2 versus pO2 for pO2 levels at 0, 7.6, 30, and 160 mmHg, with relative reading accuracy of about 10%. CONCLUSION: The compact ESR scanner can report pO2 data in ATE phantom from an external position relative to the scanner. Implementing this scanner in preclinical and clinical applications for subcutaneous pO2 measurements is a feasible next phase for this development. This innovative design also has the potential to operate in conjunction with artificial skin graft for wound healing, combining therapeutic and pO2 diagnostic features.

Pulsed Electron-Nuclear Double Resonance in the Fourier Regime.

Nuclear magnetic resonance (NMR) spectroscopy provides atomic-level molecular structural information. However, in molecules containing unpaired electron spins, NMR signals are difficult to measure directly. In such cases, data is obtained using the electron-nuclear double resonance (ENDOR) method, where nuclei are detected through their interaction with nearby unpaired electron spins. Unfortunately, electron spins spread the ENDOR signals, which challenges current acquisition techniques, often resulting in low spectral resolution that provides limited structural details. Here, we show that by using miniature microwave resonators to detect a small number of electron spins, integrated with miniature NMR coils, one can excite and detect a wide bandwidth of ENDOR data in a single pulse. This facilitates the measurement of ENDOR spectra with narrow lines spread over a large frequency range at much better spectral resolution than conventional approaches, which helps reveal details of the paramagnetic molecules' chemical structure that were not accessible before.

Diamond-based microwave quantum amplifier.

Amplification of weak microwave signals with minimal added noise is of importance to science and technology. Artificial quantum systems, based on superconducting circuits, can now amplify and detect even single microwave photons. However, this requires operating at millikelvin temperatures. Natural quantum systems can also be used for low-noise microwave amplification using stimulated emission effects; however, they generate a higher noise, especially when operating above ~1 K. Here, we demonstrate the use of electron spins in diamond as a quantum microwave amplifier operating with quantum-limited internal noise, even above liquid nitrogen temperatures. We report on the amplifier's design, gain, bandwidth, saturation power, and noise. This capability can lead the way to previously unavailable quantum science, engineering, and physics applications.

Superconducting micro-resonators for electron spin resonance - the good, the bad, and the future.

The field of electron spin resonance (ESR) is in constant need of improving its capabilities. Among other things, this means having better resonators to reach improved spin sensitivity and enable larger microwave-power-to-microwave-magnetic-field conversion factors. Surface micro-resonators, made of small metallic patches on a dielectric substrate, provide very good absolute spin sensitivity and high conversion factors due to their very small mode volume. However, such resonators suffer from relatively low spin concentration sensitivity and a low-quality factor, a fact that offsets some of their significant potential advantages. The use of superconducting patches to replace the metallic layer seems a reasonable and straightforward solution to the quality factor issue, at least for measurements carried out at cryogenic temperatures. Nevertheless, superconducting materials, especially those that can operate at moderate cryogenic temperatures, are not easily incorporated into setups requiring high magnetic fields due to the electric current vortices generated in the latter's surface. This makes the transition from normal conducting materials to superconductors highly nontrivial. Here we present the design, fabrication, and testing results of surface micro-resonators made of yttrium barium copper oxide (YBCO), a superconducting material that operates also at high magnetic fields and makes it possible to pursue ESR at moderate cryogenic temperatures (up to ∼ 80 K). We show that with a unique experimental setup, these resonators can be made to operate well even at high fields of ∼ 1.2 T. Furthermore, we analyze the effect of current vortices on the ESR signal and the spins' coherence times. Finally, we provide a head-to-head comparison of YBCO vs copper resonators of the same dimensions, which clearly shows their pros and cons and directs us to future potential developments and improvements in this field.

Compact electron spin resonance skin oximeter: Properties and initial clinical results.

PURPOSE: Skin oxygen level is of significance for the diagnosis and treatment of many clinical problems, such as chronic wounds and diabetic foot ulcers. Furthermore, skin oxygen levels can be correlated to arterial oxygen partial pressure, thereby revealing potentially dangerous conditions such as hyperoxia (too much oxygen), which may occur in ventilated neonates. Traditionally, skin oxygen levels are measured using electrochemical methods and, more recently, also by fluorescence lifetime techniques. These approaches suffer from several drawbacks, rendering them suboptimal. The purpose of this work is to develop an electron spin resonance (ESR) -based method for monitoring oxygen partial pressure (pO2 ) in skin tissue. METHODS: A compact sensor for pulsed ESR is designed and constructed. Our ESR-based method makes use of a unique exogenous paramagnetic spin probe that is placed on the skin in a special partially sealed sticker, and subsequently measuring its signal with the compact pulsed ESR sensor that includes a miniature magnet and a small S-band (~2.3 GHz) microwave resonator. The inverse of the spin-spin relaxation time (1/T2 ) measured by ESR is shown to be linearly correlated with pO2 levels. RESULTS: The sensor and its matching sticker were tested both in vitro and in vivo (with human subjects). Measured skin pO2 levels reached equilibrium after ~2-3 h and were found to be comparable to those measured by continuous-wave (CW) ESR using a large electromagnet. CONCLUSIONS: A compact pulsed ESR sensor with a matching paramagnetic sticker can be used for pO2 monitoring of the skin tissue, similar to large bulky CW ESR systems.

Proton polarization enhancement of up to 150 with dynamic nuclear polarization of plasma-treated glucose powder.

Dynamic nuclear polarization (DNP) for the enhancement of the NMR signals of specific metabolites has recently found applications in the context of magnetic resonance imaging (MRI). Currently, DNP signal enhancement is implemented in clinical systems through the use of exogenous stable organic free radicals, known as polarization agents (PAs), mixed in a solution with the metabolite of interest. These PAs are medically undesirable and thus must be filtered out prior to patient injection - a task that involves considerable technical complexity and consumes valuable time during which the polarization decays. Here, we aim to demonstrate DNP enhancements large enough for clinical relevance using a process free of exogenous PAs. This is achieved by processing (soft grinding) the metabolite in its solid form and subsequently exposing it to plasma in a dilute atmosphere to produce chemically-unstable free radicals (herein referred to as electrical-discharge-induced radicals - EDIRs) within the powder. These samples are then subjected to the normal DNP procedure of microwave irradiation while placed under a high static magnetic field, and their NMR signal is measured to quantify the enhancement of the protons' signal in the solid. Proton signal enhancements (measured as the ratio of the NMR signal with microwave irradiation to the NMR signal without microwave irradiation) of up to 150 are demonstrated in glucose. Upon fast dissolution, the free radicals are annihilated, leaving the sample in its original chemical composition (which is safe for clinical use) without any need for filtration and cumbersome quality control procedures. We thus conclude that EDIRs are found to be highly efficient in providing DNP enhancement levels that are on par with those achieved with the exogenous PAs, while being safe for clinical use. This opens up the possibility of applying our method to clinical scenarios with minimal risks and lower costs per procedure.

Transcutaneous oxygen measurement in humans using a paramagnetic skin adhesive film.

PURPOSE: Transcutaneous oxygen tension (TcpO2 ) provides information about blood perfusion in the tissue immediately below the skin. These data are valuable in assessing wound healing problems, diagnosing peripheral vascular/arterial insufficiency, and predicting disease progression or the response to therapy. Currently, TcpO2 is primarily measured using electrochemical skin sensors, which consume oxygen and are prone to calibration errors. The goal of the present study was to develop a reliable method for TcpO2 measurement in human subjects. METHODS: We have developed a novel TcpO2 oximetry method based on electron paramagnetic resonance (EPR) principles with an oxygen-sensing skin adhesive film, named the superficial perfusion oxygen tension (SPOT) chip. The SPOT chip is a 3-mm diameter, 60-µm thick circular film composed of a stable paramagnetic oxygen sensor. The chip is covered with an oxygen-barrier material on one side and secured on the skin by a medical adhesive transfer tape to ensure that only the oxygen that diffuses through the skin surface is measured. The method quantifies TcpO2 through the linewidth of the EPR spectrum. RESULTS: Repeated measurements using a cohort of 10 healthy human subjects showed that the TcpO2 measurements were robust, reliable, and reproducible. The TcpO2 values ranged from 7.8 ± 0.8 to 22.0 ± 1.0 mmHg in the volar forearm skin (N = 29) and 8.1 ± 0.3 to 23.4 ± 1.3 mmHg in the foot (N = 86). CONCLUSIONS: The results demonstrated that the SPOT chip can measure TcpO2 reliably and repeatedly under ambient conditions. The SPOT chip method could potentially be used to monitor TcpO2 in the clinic.

Electron-Spin-Resonance Dipstick.

Electron spin resonance (ESR) is a powerful analytical technique used for the detection, quantification, and characterization of paramagnetic species ranging from stable organic free radicals and defects in crystals to gaseous oxygen. Traditionally, ESR requires the use of complex instrumentation, including a large magnet and a microwave resonator in which the sample is placed. Here, we present an alternative to the existing approach by inverting the typical measurement topology, namely placing the ESR magnet and resonator inside the sample rather than the other way around. This new development relies on a novel self-contained ESR sensor with a diameter of just 2 mm and length of 3.6 mm, which includes both a small permanent magnet assembly and a tiny (∼1 mm in size) resonator for spin excitation and detection at a frequency of ∼2.6 GHz. The spin sensitivity of the sensor has been measured to be ∼1011 spins/√Hz, and its concentration sensitivity is ∼0.1 mM, using reference samples with a measured volume of just ∼10 nL. Our new approach can be applied for monitoring the partial pressure of oxygen in vitro and in vivo through its paramagnetic interaction with another stable radical, as well as for simple online quantitative inspection of free radicals generated in reaction vessels and electrochemical cells via chemical processes.

Advanced surface resonators for electron spin resonance of single microcrystals.

Electron spin resonance (ESR) spectroscopy of paramagnetic species in single crystals is a powerful tool for characterizing the latter's magnetic interaction parameters in detail. Conventional ESR systems are optimized for millimeter-size samples and make use of cavities and resonators that accommodate tubes and capillaries in the range 1-5 mm. Unfortunately, in the case of many interesting materials such as enzymes and inorganic catalytic materials (e.g., zeolites), single crystals can only be obtained in micron-scale sizes (1-200 µm). To boost ESR sensitivity and to enable experiments on microcrystals, the ESR resonator needs to be adapted to the size and shape of these specific samples. Here, we present a unique family of miniature surface resonators, known as "ParPar" resonators, whose mode volume and shape are optimized for such micron-scale single crystals. This approach significantly improves upon the samples' filling factor and thus enables the measurement of much smaller crystals than was previously possible. We present here the design of such resonators with a typical mode dimension of 20-50 µm, as well as details about their fabrication and testing methods. The devices' resonant mode(s) are characterized by ESR microimaging and compared to the theoretical calculations. Moreover, experimental ESR spectra of single microcrystals with typical sizes of ∼25-50 µm are presented. The measured spin sensitivity for the 50-µm resonator at cryogenic temperatures of 50 K is found to be ∼1.8 × 106 spins/G √Hz for a Cu-doped single crystal sample that is representative of many biological samples of relevance.

Recent trends in high spin sensitivity magnetic resonance.

Magnetic resonance is a very powerful methodology that has been employed successfully in many applications for about 70years now, resulting in a wealth of scientific, technological, and diagnostic data. Despite its many advantages, one major drawback of magnetic resonance is its relatively poor sensitivity and, as a consequence, its bad spatial resolution when examining heterogeneous samples. Contemporary science and technology often make use of very small amounts of material and examine heterogeneity on a very small length scale, both of which are well beyond the current capabilities of conventional magnetic resonance. It is therefore very important to significantly improve both the sensitivity and the spatial resolution of magnetic resonance techniques. The quest for higher sensitivity led in recent years to the development of many alternative detection techniques that seem to rival and challenge the conventional "old-fashioned" induction-detection approach. The aim of this manuscript is to briefly review recent advances in the field, and to provide a quantitative as well as qualitative comparison between various detection methods with an eye to future potential advances and developments. We first offer a common definition of sensitivity in magnetic resonance to enable proper quantitative comparisons between various detection methods. Following that, up-to-date information about the sensitivity capabilities of the leading recently-developed detection approaches in magnetic resonance is provided, accompanied by a critical comparison between them and induction detection. Our conclusion from this comparison is that induction detection is still indispensable, and as such, it is very important to look for ways to significantly improve it. To do so, we provide expressions for the sensitivity of induction-detection, derived from both classical and quantum mechanics, that identify its main limiting factors. Examples from current literature, as well as a description of new ideas, show how these limiting factors can be mitigated to significantly improve the sensitivity of induction detection. Finally, we outline some directions for the possible applications of high-sensitivity induction detection in the field of electron spin resonance.

Surface loop-gap resonators for electron spin resonance at W-band.

Electron spin resonance (ESR) is a spectroscopic method used to detect paramagnetic materials, reveal their structure, and also image their position in a sample. ESR makes use of a large static magnetic field to split the energy levels of the electron magnetic moment of the paramagnetic species. A strong microwave magnetic field is applied to excite the spins, and subsequently the ESR system detects their faint microwave signal response. The sensitivity of an ESR system is greatly influenced by the magnitude of the static field and the properties of the microwave resonator used to detect the spin signal. In general terms, the higher the static field (microwave frequency) and the smaller the resonator, the more sensitive the system will be. Previous work aimed at high-sensitivity ESR was focused on the development and testing of very small resonators operating at moderate magnetic fields in the range of ∼0.1-1.2 T (maximum frequency of ∼35 GHz). Here, we describe the design, construction, and testing of recently developed miniature surface loop-gap resonators used in ESR and operating at a much higher frequency of ∼95 GHz (W-band, corresponding to a field of ∼3.4 T). Such resonators can greatly enhance the sensitivity of ESR and also improve the resulting spectral resolution due to the higher static field employed. A detailed description of the resonator's design and coupling mechanism, as well as the supporting probe head, is provided. We also discuss the production method of the resonators and probe head and, in the end, provide preliminary experimental results that show the setup's high spin sensitivity and compare it to theoretical predictions.

Dynamic nuclear polarization in solid samples by electrical-discharge-induced radicals.

Dynamic nuclear polarization (DNP) is a method for enhancing nuclear magnetic resonance (NMR) signals that has many potential applications in chemistry and medicine. Traditionally, DNP signal enhancement is achieved through the use of exogenous radicals mixed in a solution with the molecules of interest. Here we show that proton DNP signal enhancements can be obtained for solid samples without the use of solvent and exogenous radicals. Radicals are generated primarily on the surface of a solid sample using electrical discharges. These radicals are found suitable for DNP. They are stable under moderate vacuum conditions, yet readily annihilate upon compound dissolution or air exposure. This feature makes them attractive for use in medical applications, where the current variety of radicals used for DNP faces regulatory problems. In addition, this solvent-free method may be found useful for analytical NMR of solid samples which cannot tolerate solvents, such as certain pharmaceutical products.

Electron spin resonance microscopic imaging of oxygen concentration in cancer spheroids.

Oxygen (O2) plays a central role in most living organisms. The concentration of O2 is important in physiology and pathology. Despite the importance of accurate knowledge of the O2 levels, there is very limited capability to measure with high spatial resolution its distribution in millimeter-scale live biological samples. Many of the current oximetric methods, such as oxygen microelectrodes and fluorescence lifetime imaging, are compromised by O2 consumption, sample destruction, invasiveness, and difficulty to calibrate. Here, we present a new method, based on the use of the pulsed electron spin resonance (ESR) microimaging technique to obtain a 3D mapping of oxygen concentration in millimeter-scale biological samples. ESR imaging requires the incorporation of a suitable stable and inert paramagnetic spin probe into the desirable object. In this work, we use microcrystals of a paramagnetic spin probe in a new crystallographic packing form (denoted tg-LiNc-BuO). These paramagnetic species interact with paramagnetic oxygen molecules, causing a spectral line broadening that is linearly proportional to the oxygen concentration. Typical ESR results include 4D spatial-spectral images that give an indication about the oxygen concentration in different regions of the sample. This new oximetry microimaging method addresses all the problems mentioned above. It is noninvasive, sensitive to physiological oxygen levels, and easy to calibrate. Furthermore, in principle, it can be used for repetitive measurements without causing cell damage. The tissue model used in this research is spheroids of Human Colorectal carcinoma cell line (HCT-116) with a typical diameter of ∼600µm. Most studies of the microenvironmental O2 conditions inside such viable spheroids carried out in the past used microelectrodes, which require an invasive puncturing of the spheroid and are also not applicable to 3D O2 imaging. High resolution 3D oxygen maps could make it possible to evaluate the relationship between morphological and physiological alterations in the spheroids, which would help understand the oxygen metabolism in solid tumors and its correlation with the susceptibility of tumors to various oncologic treatments.

Misery loves company? A meta-regression examining aggregate unemployment rates and the unemployment-mortality association.

PURPOSE: Individual-level unemployment has been consistently linked to poor health and higher mortality, but some scholars have suggested that the negative effect of job loss may be lower during times and in places where aggregate unemployment rates are high. We review three logics associated with this moderation hypothesis: health selection, social isolation, and unemployment stigma. We then test whether aggregate unemployment rates moderate the individual-level association between unemployment and all-cause mortality. METHODS: We use six meta-regression models (each using a different measure of the aggregate unemployment rate) based on 62 relative all-cause mortality risk estimates from 36 studies (from 15 nations). RESULTS: We find that the magnitude of the individual-level unemployment-mortality association is approximately the same during periods of high and low aggregate-level unemployment. Model coefficients (exponentiated) were 1.01 for the crude unemployment rate (P = .27), 0.94 for the change in unemployment rate from the previous year (P = .46), 1.01 for the deviation of the unemployment rate from the 5-year running average (P = .87), 1.01 for the deviation of the unemployment rate from the 10-year running average (P = .73), 1.01 for the deviation of the unemployment rate from the overall average (measured as a continuous variable; P = .61), and showed no variation across unemployment levels when the deviation of the unemployment rate from the overall average was measured categorically. Heterogeneity between studies was significant (P < .001), supporting the use of the random effects model. CONCLUSIONS: We found no strong evidence to suggest that unemployment experiences change when macroeconomic conditions change. Efforts to ameliorate the negative social and economic consequences of unemployment should continue to focus on the individual and should be maintained regardless of periodic changes in macroeconomic conditions.

A magnetic resonance probehead for evaluating the level of ionizing radiation absorbed in human teeth.

A miniature electron spin resonance (ESR) probehead that includes a static field source and a microwave resonator for in vivo measurement of paramagnetic defects in tooth enamel was developed. These defects are known to be a good marker for quantifying the ionizing radiation dose absorbed in teeth. The probehead has a typical length of just 30 mm and total weight of 220 g. The patient "bites" into the probehead while the measurement procedure is being carried out. The probehead operates in pulsed mode at a frequency of ∼ 11.2 GHz and supplies a static magnetic field of ∼ 400 mT. A detailed design of the probehead is provided together with its specifications in terms of measurement volume and signal-to-noise ratio for a typical sample. A specially developed simulation program was used to predict the spatial distribution of the acquired signal under conditions of grossly inhomogeneous static and RF fields. Experimental results with irradiated incisor teeth validated the probehead's sensitivity, being able to detect signals in tooth irradiated by only 2 Gy. Subject to additional improvements and tests, this type of probehead can potentially have significant clinical applications ranging from mass triage following major nuclear events to routine occupational evaluation of ionizing radiation absorbed over long periods of time.

High resolution in-operando microimaging of solar cells with pulsed electrically-detected magnetic resonance.

The in-operando detection and high resolution spatial imaging of paramagnetic defects, impurities, and states becomes increasingly important for understanding loss mechanisms in solid-state electronic devices. Electron spin resonance (ESR), commonly employed for observing these species, cannot meet this challenge since it suffers from limited sensitivity and spatial resolution. An alternative and much more sensitive method, called electrically-detected magnetic resonance (EDMR), detects the species through their magnetic fingerprint, which can be traced in the device's electrical current. However, until now it could not obtain high resolution images in operating electronic devices. In this work, the first spatially-resolved electrically-detected magnetic resonance images (EDMRI) of paramagnetic states in an operating real-world electronic device are provided. The presented method is based on a novel microwave pulse sequence allowing for the coherent electrical detection of spin echoes in combination with powerful pulsed magnetic-field gradients. The applicability of the method is demonstrated on a device-grade 1-µm-thick amorphous silicon (a-Si:H) solar cell and an identical device that was degraded locally by an electron beam. The degraded areas with increased concentrations of paramagnetic defects lead to a local increase in recombination that is mapped by EDMRI with ∼20-µm-scale pixel resolution. The novel approach presented here can be widely used in the nondestructive in-operando three-dimensional characterization of solid-state electronic devices with a resolution potential of less than 100 nm.

Statistical reconstruction algorithms for continuous wave electron spin resonance imaging.

Electron spin resonance imaging (ESRI) is an important branch of ESR that deals with heterogeneous samples ranging from semiconductor materials to small live animals and even humans. ESRI can produce either spatial images (providing information about the spatially dependent radical concentration) or spectral-spatial images, where an extra dimension is added to describe the absorption spectrum of the sample (which can also be spatially dependent). The mapping of oxygen in biological samples, often referred to as oximetry, is a prime example of an ESRI application. ESRI suffers frequently from a low signal-to-noise ratio (SNR), which results in long acquisition times and poor image quality. A broader use of ESRI is hampered by this slow acquisition, which can also be an obstacle for many biological applications where conditions may change relatively quickly over time. The objective of this work is to develop an image reconstruction scheme for continuous wave (CW) ESRI that would make it possible to reduce the data acquisition time without degrading the reconstruction quality. This is achieved by adapting the so-called "statistical reconstruction" method, recently developed for other medical imaging modalities, to the specific case of CW ESRI. Our new algorithm accounts for unique ESRI aspects such as field modulation, spectral-spatial imaging, and possible limitation on the gradient magnitude (the so-called "limited angle" problem). The reconstruction method shows improved SNR and contrast recovery vs. commonly used back-projection-based methods, for a variety of simulated synthetic samples as well as in actual CW ESRI experiments.

Cryogenic electron spin resonance microimaging probe.

A new probe for acquiring ESR images with microscopic resolution and high spin sensitivity, at a temperature range of ~4.2-300 K, is presented. Details of the probe design, as well as its principle of operation, are provided. The probe incorporates a unique surface loop-gap microresonator. Experimental results demonstrate the system's capability to acquire two - as well as three-dimensional images with a flat test sample of phosphorus-doped silicon. The imaging results also allow verifying the resonator's resonance mode - they show its B(1) distribution, which also makes it possible to estimate the number of spins measured in the sample.