Surface dielectric resonator for in vivo EPR measurements.

This research report describes a novel surface dielectric resonator (SDR) with a flexible connector for in vivo electron paramagnetic resonance (EPR) spectroscopy. Contrary to the conventional cavity or surface loop-gap resonators, the newly developed SDR is constructed from a ceramic dielectric material, and it is tuned to operate at the L-band frequency band (1.15 GHz) in continuous-wave mode. The SDR is designed to be critically coupled and capable of working with both very lossy samples, such as biological tissues, and non-lossy materials. The SDR was characterized using electromagnetic field simulations, assessed for sensitivity with a B1 field-perturbation method, and validated with tissue phantoms using EPR measurements. The results showed remarkably higher sensitivity in lossy tissue phantoms than the previously reported multisegment surface-loop resonators. The new SDR can provide potential new insights for advancements in the application of in vivo EPR spectroscopy for biological measurements, including clinical oximetry.

First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip.

OBJECTIVE: The overall objective of this clinical study was to validate an implantable oxygen sensor, called the 'OxyChip', as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing. METHODS: Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry. RESULTS: Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4-128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6-73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5-144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation. CONCLUSIONS: Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes.

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.

Developments in Biodosimetry Methods for Triage With a Focus on X-band Electron Paramagnetic Resonance In Vivo Fingernail Dosimetry.

Instrumentation and application methodologies for rapidly and accurately estimating individual ionizing radiation dose are needed for on-site triage in a radiological/nuclear event. One such methodology is an in vivo X-band, electron paramagnetic resonance, physically based dosimetry method to directly measure the radiation-induced signal in fingernails. The primary components under development are key instrument features, such as resonators with unique geometries that allow for large sampling volumes but limit radiation-induced signal measurements to the nail plate, and methodological approaches for addressing interfering signals in the nail and for calibrating dose from radiation-induced signal measurements. One resonator development highlighted here is a surface resonator array designed to reduce signal detection losses due to the soft tissues underlying the nail plate. Several surface resonator array geometries, along with ergonomic features to stabilize fingernail placement, have been tested in tissue-equivalent nail models and in vivo nail measurements of healthy volunteers using simulated radiation-induced signals in their fingernails. These studies demonstrated radiation-induced signal detection sensitivities and quantitation limits approaching the clinically relevant range of ≤ 10 Gy. Studies of the capabilities of the current instrument suggest that a reduction in the variability in radiation-induced signal measurements can be obtained with refinements to the surface resonator array and ergonomic features of the human interface to the instrument. Additional studies are required before the quantitative limits of the assay can be determined for triage decisions in a field application of dosimetry. These include expanded in vivo nail studies and associated ex vivo nail studies to provide informed approaches to accommodate for a potential interfering native signal in the nails when calculating the radiation-induced signal from the nail plate spectral measurements and to provide a method for calibrating dose estimates from the radiation-induced signal measurements based on quantifying experiments in patients undergoing total-body irradiation or total-skin electron therapy.

Development of the Implantable Resonator System for Clinical EPR Oximetry.

Hypoxic tumors are more resistant to radiotherapy and chemotherapy, which decreases the efficacy of these common forms of treatment. We have been developing implantable paramagnetic particulates to measure oxygen in vivo using electron paramagnetic resonance. Once implanted, oxygen can be measured repeatedly and non-invasively in superficial tissues (<3 cm deep), using an electron paramagnetic resonance spectrometer and an external surface-loop resonator. To significantly extend the clinical applications of electron paramagnetic resonance oximetry, we developed an implantable resonator system to obtain measurements at deeper sites. This system has been used to successfully obtain oxygen measurements in animal studies for several years. We report here on recent developments needed to meet the regulatory requirements to make this technology available for clinical use. radio frequency heating is discussed and magnetic resonance compatibility testing of the device has been carried out by a Good Laboratory Practice-certified laboratory. The geometry of the implantable resonator has been modified to meet our focused goal of verifying safety and efficacy for the proposed use of intracranial measurements and also for future use in tissue sites other than the brain. We have encapsulated the device within a smooth cylindrical-shaped silicone elastomer to prevent tissues from adhering to the device and to limit perturbation of tissue during implantation and removal. We have modified the configuration for simultaneously measuring oxygen at multiple sites by developing a linear array of oxygen sensing probes, which each provide independent measurements. If positive results are obtained in additional studies which evaluate biocompatibility and chemical characterization, we believe the implantable resonator will be at a suitable stage for initial testing in human subjects.

Advances in in vivo EPR Tooth BIOdosimetry: Meeting the targets for initial triage following a large-scale radiation event.

Several important recent advances in the development and evolution of in vivo Tooth Biodosimetry using Electron Paramagnetic Resonance (EPR) allow its performance to meet or exceed the U.S. targeted requirements for accuracy and ease of operation and throughput in a large-scale radiation event. Ergonomically based changes to the magnet, coupled with the development of rotation of the magnet and advanced software to automate collection of data, have made it easier and faster to make a measurement. From start to finish, measurements require a total elapsed time of 5 min, with data acquisition taking place in less than 3 min. At the same time, the accuracy of the data for triage of large populations has improved, as indicated using the metrics of sensitivity, specificity and area under the ROC curve. Applying these standards to the intended population, EPR in vivo Tooth Biodosimetry has approximately the same diagnostic accuracy as the purported 'gold standard' (dicentric chromosome assay). Other improvements include miniaturisation of the spectrometer, leading to the creation of a significantly lighter and more compact prototype that is suitable for transporting for Point of Care (POC) operation and that can be operated off a single standard power outlet. Additional advancements in the resonator, including use of a disposable sensing loop attached to the incisor tooth, have resulted in a biodosimetry method where measurements can be made quickly with a simple 5-step workflow and by people needing only a few minutes of training (which can be built into the instrument as a training video). In sum, recent advancements allow this prototype to meet or exceed the US Federal Government's recommended targets for POC biodosimetry in large-scale events.

FLEXIBLE, WIRELESS, INDUCTIVELY COUPLED SURFACE COIL RESONATOR FOR EPR TOOTH DOSIMETRY.

Managing radiation injuries following a catastrophic event where large numbers of people may have been exposed to life-threatening doses of ionizing radiation relies on the availability of biodosimetry to assess whether individuals need to be triaged for care. Electron Paramagnetic Resonance (EPR) tooth dosimetry is a viable method to accurately estimate the amount of ionizing radiation to which an individual has been exposed. In the intended measurement conditions and scenario, it is essential that the measurement process be fast, straightforward and provides meaningful and accurate dose estimations for individuals in the expected measurement conditions. The sensing component of a conventional L-band EPR spectrometer used for tooth dosimetry typically consists of a surface coil resonator that is rigidly, physically attached to the coupler. This design can result in cumbersome operation, limitations in teeth geometries that may be measured and hinder the overall utility of the dosimeter. A novel surface coil resonator has been developed for the currently existing L-band (1.15 GHz) EPR tooth dosimeter for the intended use as a point of care device by minimally trained operators. This resonator development provides further utility to the dosimeter, and increases the usability of the dosimeter by non-expert operators in the intended use scenario.

Surface Dielectric Resonators for X-band EPR Spectroscopy.

A new resonator for X-band electron paramagnetic resonance (EPR) spectroscopy, which utilizes the unique resonance properties of dielectric substrates, has been developed using a single crystal of titanium dioxide. As a result of the dielectric properties of the crystal(s) chosen, this novel resonator provides the ability to make in vivo EPR spectroscopy surface measurements in the presence of lossy tissues at X-band frequencies (up to 10 GHz). A double-loop coupling device is used to transmit and receive microwave power to/from the resonator. This coupler has been developed and optimized for coupling to the resonator in the presence of lossy tissues to further enable in vivo measurements, such as in vivo EPR spectroscopy of human fingernails or teeth to measure the dose of ionizing radiation that a given individual has been exposed to. An advantage of this resonator for surface measurements is that the magnetic fields generated by the resonator are inherently shallow, which is desirable for in vivo nail dosimetry.

Dielectric-Backed Aperture Resonators for X-Band in vivo EPR Nail Dosimetry.

A new resonator for X-band in vivo EPR nail dosimetry, the dielectric-backed aperture resonator (DAR), is developed based on rectangular TE102 geometry. This novel geometry for surface spectroscopy improves at least a factor of 20 compared to a traditional non-backed aperture resonator. Such an increase in EPR sensitivity is achieved by using a non-resonant dielectric slab, placed on the aperture inside the cavity. The dielectric slab provides an increased magnetic field at the aperture and sample, while minimizing sensitive aperture resonance conditions. This work also introduces a DAR semi-spherical (SS)-TE011 geometry. The SS-TE011 geometry is attractive due to having twice the incident magnetic field at the aperture for a fixed input power. It has been shown that DAR provides sufficient sensitivity to make biologically relevant measurements both in vitro and in vivo Although in vivo tests have shown some effects of physiological motions that suggest the necessity of a more robust finger holder, equivalent dosimetry sensitivity of approximately 1.4 Gy has been demonstrated.