TECHNICAL FIELD

The invention relates to the field of magnetic resonance imaging and, more specifically, to methods of measuring temperatures utilizing a magnetic resonance imaging contrast agent.

BACKGROUND OF DISCLOSURE

Temperature is a fundamental parameter reflecting the biological status of the body and individual tissues. Clinical studies indicate that localized temperature measurements could be a useful method for the detection of a variety of health problems, including certain tumors and inflammations. Precise determination of tissue temperature is also important in various thermal medical intervention procedures. In hyperthermia therapy for selective tumor treatment, temperature of tumor affected tissue is raised to 40°C-43°C and followed by other cancer treatment modalities. Thermal ablation therapies such as laser, radio-frequency (RF), microwave, and high intensity focused ultrasound therapies utilize much higher temperature exposure (48°C-100°C) for tissue necrosis through thermal coagulation. The exact value of applied temperature depends on the type of disease, heating modality, target size and position, and tissue heat conducting and absorption. Additionally, temperature reporting is critical for monitoring the temperature of tissue around medical metallic implants during standard magnetic resonance imaging that is caused by fast switching magnetic gradients and radio- frequency pulses.

Conventional thermometry is usually invasive, allows only single point temperature measurements, and may interfere with the therapeutic and imaging instrument. The ability to do in vivo monitoring of temperature in three dimensions is thus important for both diagnosing and treatment of patients. These limitations could be addressed using a minimally invasive Magnetic Resonance (MR) thermometry that produces high thermal, spatial, and temporal resolution temperature maps superimposed on anatomical images within the targeted tissue.

Thermometry based on the numbers of MR temperature sensitive tissue parameters, such as shift of proton resonance frequency (PRF), diffusion coefficient, Ti and T2 nuclear relaxation times, magnetization transfer and proton density, has been developed. For its high accuracy, (0.2°C in phantoms), linearity and wide temperature range, PRF is the current gold standard for temperature measurements in aqueous tissues. However, as these methods rely on comparison to a baseline image, they are sensitive to motion and thermally induced susceptibility artifacts during scanning which prevents highly accurate in vivo MRI thermometry.

In addition to the use of intrinsic temperature sensitive MR parameters, MR thermometry with various temperature-sensitive contrast agents have been attempted. These include paramagnetic thermo-sensitive liposomes containing encapsulated gadolinium or manganese compounds, paramagnetic lanthanide complexes, and spin transition molecular materials. The phospholipid membranes of liposomes possess gel- liquid phase transition at distinctive temperature T _m above which it becomes permeable toward the water. This allows water exchange between liposome interior and bulk water, and release of entrapped paramagnetic agents increasing Ri relaxivity. This unique combination of proportionality below T _m and the off-on feature at T _m allows for both relative and absolute temperature determination using thermo-sensitive liposomes.

Another temperature-sensitive mechanism for MR contrast exists which is based on the Curie temperature (T _c ) at which a ferromagnetic material loses its spontaneous net magnetization. The idea was initially tested by measuring the correlation between the temperature and magnetic susceptibility artifact area caused by a piece of solid

gadolinium wire suspended in water. This experiment proved the concept of using materials with a temperature dependent magnetization to measure temperature.

However, it is not practical for clinical applications due to the sensor's size and the fact that its operational temperature could not be optimized for human use.

Thus, there is a need for a non-invasive method of temperature measurement within a human or other tissue which utilizes temperature changes of the net magnetic moment of magnetic particles.

SU MMARY OF INVENTION

Consistent with the above-mentioned needs, the present invention provides a novel temperature-sensitive MRI contrast agent by using net magnetic moment engineering in magnetic nanoparticles. These particles create a local dipole magnetic field that will modulate the homogeneity of the main static magnetic field of the MRI scanner and consequently broaden the NMR line. This results in a shortening of the effective nuclear spin-spin relaxation time (T2*) of the tissue near the magnetic particle, which can be measured directly with image guided localized NMR spectroscopy as linewidth broadening.

One aspect of this disclosure a method of measuring the temperature within a tissue including providing a contrast agent comprising magnetic particles that have substantial thermal changes of magnetization, injecting the contrast agent into a tissue, subjecting the tissue to magnetic resonance imaging (MRI), measuring a linewidth broadening by image guided localized NMR spectroscopy, and associating the linewidth broadening with a temperature of the tissue.

A related aspect of this disclosure is a method of measuring the temperature within a tissue, including providing a contrast agent comprising magnetic particles that have substantial thermal changes of magnetization, injecting the contrast agent into a tissue, subjecting the tissue to magnetic resonance imaging (MRI), measuring a ratio of MRI image intensity between an MRI image of the tissue and an MRI image of tissue comprising the contrast agent, and

associating the MRI image intensity ratio with a temperature of the tissue.

In these methods, the contrast agent may include gadolinium (Gd) particles. The contrast agent may further include one or more dopant(s). The dopant(s) may be one or more of copper (Cu) and cobalt (Co).

In these methods, the tissue may be a tumor tissue. The tissue may contain a medical implant, including and metal-containing medical implants. The tissue may be an inflamed tissue.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 shows the temperature dependence of magnetization in Gd powder for selected magnetic fields in a superconducting quantum interference device;

Fig. 2 shows the temperature changes of relative NMR line broadening in a mixture of 1 % agar gel with suspended Gd powder with an applied magnetic field of 364 mT;

Fig. 3 shows an example of gradient-echo MRI images of phantoms at different temperatures;

Fig. 4 shows the thermal changes of ratios of images intensity of pure agar to agar with Gd particles for various Gd concentrations; Fig. 5 shows an example MRI image of pure agar gel and agar gel with Gd particles at 10°C and 45°C;

Fig. 6 shows the temperature dependence of the magnetic moment in Gd powder for selected magnetic fields;

Fig. 7 shows the temperature changes of local magnetic field inhomogeneity in a mixture of 1 % agar gel and Gd powder; and

Figs. 8A and 8B both show MRI gradient echo images of pure agar gel (top) and agar gel with Gd particles (bottom, left and right) at 10°C (Fig. 8A) and 45°C (Fig. 8B).

DESCRIPTION OF EMBODIMENTS

The present disclosure is drawn to a non-invasive method of temperature measurement within tissue that may utilize temperature changes of the net magnetic moment of magnetic particles. The magnetic particles embedded in or near the tissue create a local dipole magnetic field that modulate the homogeneity of the main static magnetic field of the MRI scanner and broaden the NMR line. Consequently, the effective nuclear spin-spin relaxation time (J 2*) of the tissue near the magnetic particles will be shortened. This effect may then be measured directly with image guided localized NMR spectroscopy as linewidth broadening. The linewidth broadening can be visible as a darker area on MRI images acquired with the gradient echo method, which is very sensitive for local field inhomogeneity. Different line widths, or shades of gray, may be calibrated to obtain a map of temperature or to report the achievement of a certain temperature threshold in a specific tissue during interventional procedures.

Various methods may be utilized to adjust the transition temperature of the magnetic particles that form a contrast agent used in these methods of temperature measurement. For example, smaller magnetic particles may be used. The magnetic particle size may be varied between 1 μηη and 100μηη. Generally, using smaller magnetic particles moves the transition temperature down. While the use of smaller particles is not a useful method for Gd, the change in T _c based on particle size may be useful for other materials. Additionally, different alloy compositions may be utilized. For example, Permalloy Ni ₈ oFe ₂ o has a T _c of 576°C. With Cu doping (48.5%), however, the T _c may be reduced to 43°C. Further, dopants may be added which have a higher exchange coupling. For example, Co-Gd exchange is 4-fold stronger than Gd-Gd exchange. The Co-Gd coupling stabilizes the Gd against thermal fluctuations. But, Co couples antiparallel to Gd, reducing the net moment.

The disclosure now being generally described will be more readily understood by reference to the following examples, which are included merely for the purposes of illustration of certain aspects of the embodiments of the present disclosure. The examples are not intended to limit the disclosure, as one of skill in the art would recognize from the above teachings and the following examples that other techniques and methods can satisfy the claims and can be employed without departing from the scope of the claimed disclosure.

EXAMPLES

In one example, gadolinium particles are prepared by a mechanical method that results in the particles having an average grain size of 5 μηη. The temperature effect of the Gd particles on the ¹ H NMR line broadening and MRI image intensity was determined using Gd particles suspended in a 1% agar-Ringer's solution gel. This creates an isotonic solution similar to the bodily fluids of an animal and prevents particles from

sedimentation. For NMR and MRI measurements, a mixture containing 20 cc of 1% agar- Ringer's solution and 10 mg of Gd powder was prepared (100% concentration). The sample is diluted with 1 % agar-Ringer's solution to obtain additional mixtures of 50%, 25%, and 12.5% of the maximum concentration. The mixtures are kept in a liquid state at 90°C in a water bath and constantly stirred before transferring to 5 mm tubes for NMR studies (of 0.12 cc volume) and to Nalgene cryogenic plastic vials to make an MRI phantom. Mixtures were rapidly cooled in ice water to preserve an even distribution of Gd particles in the gel.

The magnetization of the Gd powder was measured in the range of 0°C to 60°C at different magnetic fields using a superconducting quantum interference device (SQUID) magnetometer to determine the temperature dependence of the magnetization and Curie point.

To obtain temperature dependence of the NMR line width, a low field (364 mT/15.5 MHz) pulsed spectrometer was used. The application of the low magnetic field allows for a minimized shift of Tc toward higher temperatures. During the NMR measurements, the samples were cooled and ¹ H NMR spectra were taken after the temperature was stabilized, from 5°C to 50°C, at 5°C increments. MRI temperature dependent images of phantom containing Gd particles in agar gel were taken using a preclinical scanner with 1.5 T, 30 cm bore magnet equipped with a temperature control system. A schematic diagram of the temperature setup is shown in Fig. 1. The phantom consists of three Nalgene plastic vials (10 mm inner diameter and 80 mm long) placed inside a polycarbonate cell. One vial contains pure agar-Ringer's solution (two concentrations in one vial). The continuous flow of proton-less

perfluorocarbon (fluorinert) coolant through the cell forced by a standard circulating bath stabilizes phantom temperature without contaminating ¹ H images with additional signals. For imaging, multi-slice imaging parameters: FOV=3x3 cm, slick thickness=3mm, matrix 64x64, TE=2.5 ms. A long repetition time of TR= 5.0 s was used to avoid signal loss due to relatively long Ti relaxation time. The phantom temperature was monitored by signal conditioner using a high-precision fiber optic sensor placed in the space near vials.

Fig. 2 shows the results of SQUI D measurements at selected magnetic fields. A low magnitude field of 0.5 mT was used to determine the transition from the

ferromagnetic to paramagnetic state of the gadolinium powder. It is estimated that the Curie temperature of the sample is approximately 19°C. Larger values of magnetic field were applied to match fields of N MR spectrometer (364 mT) used for measurement of NMR line broadening and commercially available clinical MRI scanners (1.5 T and 3.0 T). Fig. 2 demonstrates that an increase of magnetic field shifts the transition to the paramagnetic state toward higher temperatures and makes regular gadolinium particles a useful temperature sensitive contrast within our projected target range.

Fig. 3 shows the thermal dependence of the NMR linewidth broadening due to the presence of Gd particles. A Fourier transform of free induction signal from the water was used to determine the line width. The results of relative line broadening were obtained by subtracting the NMR linewidth at full width at half maximum (FWHM) in pur agar gel from the linewidth at FWHM in agar gel with suspended Gd particles.

Fig. 4 shows images of the sample with the maximum Gd concentration and the sample with pure agar. The top row is undoped agar gel and the bottom row shows the agar gel doped with the highest content of Gd particles (100%). The images of agar gel with Gd show a strong temperature-dependent increase in brightness.

Fig. 5 shows temperature dependent relative MR intensity (ratio of image intensity of pure agar gel to image intensity of gel with Gd particles) for different Gd concentrations. The image intensity was calculated across the entire axial slice using a Matlab platform program. This data demonstrates that several different concentrations of Gd allow for temperature-dependent measurements.

Analysis of SQUID and NMR data demonstrates a strong correlation between the magnetic moment and NMR line width broadening for 100% Gd concentration (p<0.001). Linear parts of line width broadening (temperature range from 5°C to 30 °C on Fig. 3) and ratios of MR images intensity (temperature range 10.8°C to 39.1 °C on Fig. 4 and Fig. 5) for 100% concentration of Gd were statistically analyzed using regression of means. Results demonstrate that both line width broadening and images intensity ratios are strongly correlated with temperature changes (R2=0.99). From the regression's 95% confidence bands, the accuracy of temperature determination in the phantom using NMR line width broadening is +/-1.0°C (at 16°C) and using Mr image intensity is +/-1.2°C (at 24°C).

These results demonstrate that the NMR linewidth of ¹ H is strongly affected by the presence of Gd particles in aqueous solutions. Gradient echo images of phantoms at 1.5 T with various concentrations of Gd particles show strong intensity increase when temperature is changed from about 10.8°C to 39.1°C (Figs. 4 and 5) allowing for temperature determining with an accuracy of +/-1.2°C at 24°C. This demonstrates that Gd is a promising element in designing an MRI temperature contrast agent and that magnetic particles with substantial thermal changes of magnetization are suitable for temperature measurements as temperature sensitive MRI contrast.

In another example, small Gd particles having an average size of 10 μηη were used. Among the different ferromagnetic metals, Gd is characterized by transition from ferromagnetic to paramagnetic state around 20°C that is very close to human body temperature. Gd also possesses a large magnetic moment, allowing it to create a local dipolar field, the magnitude of which will depend strongly on temperature.

The magnetic properties of Gd powder were measured in the range of 272K to 334K at different magnetic fields using SQUID. The temperature effect of the presence of Gd on ¹ H NMR line broadening was then determined using Gd particles suspended in 1 % agar-deionized water gel. To lower the effect of the magnetic field on the shift of the Curie point, a pulsed NMr spectrometer operating at a low magnetic field

(364mT/15.5MHz) was used. Finally, six different concentrations of Gd particles were used to be phantom tested using 1.5T MR imager at two temperatures, 10°C and 45°C. Fig. 6 shows the SQUID results at selected magnetic fields. A low magnitude field of 2.5 mT was used to determine the transition from the ferromagnetic to paramagnetic state of the Gd powder. The Curie temperature of the sample was estimated to be approximately 292K (19°C). Larger values of magnetic field were applied to match fields of NMR spectrometer (364mT) used for measurement of NMR line broadening and of commercially available clinical MRI scanners (1.5T and 3.0T). Fig. 1 demonstrates that an increase of magnetic field shifts the transition to paramagnetic state toward higher temperatures and makes regular Gd particles a useful temperature sensitive contrast within the target range.

Fig. 7 shows the thermal dependence of the magnetic field inhomogeneity due to the presence of Gd particles. A mixture containing 20 ml of 1% agar gel and 10 mg of GD powder was prepared and kept in a liquid state at 90°C in a water bath and constantly stirred. To make the NMR sample, a small amount (about 0.12ml) of hot, liquid mixture was transferred to a standard 5 mm NMR glass tube and rapidly cooled to preserve an even distribution of Gd particles in the gel. During NMR measurements, the sample was cooled down and ¹ H spectra were taken after the temperature was stabilized from 278K to 323K every 5K. The Fourier transform was used to determine the line broadening. The results were obtained by subtracting the NMR linewidth at FWHM in pure agar gel from linewidth at FWHM in agar gel with suspended Gd particles. Then line broadening (in Hz) was converted to a magnetic field inhomogeneity (in μΤ).

Gradient echo images of cylindrical phantoms made of different concentrations of Gd particles in 1 % Ringer's solution-agar gel were taken at 10°C and 45°C. Fig. 8 shows selected images of two different concentrations of Gd and a control sample of pure agar gel.

These results demonstrate that the NMR line width of ¹ H is strongly affected by the presence of Gd particles and changes due to the thermal changes of the particles' magnetic moment and can be used as a temperature sensitive parameter for temperature measurements. Regression analysis (Fig. 7) shows a linear dependence of line broadening in a range of 278K to 303K (R ² =0.98) with a strong slope of 1.5 μΤ/Κ or 64 Hz/K.

Temperature stimulated change in NMR line width in the phantom is correlated with MR image intensity changes (Fig. 8). As the magnetic moment of particles drops as temperature is increased, MR images get significantly brighter. The foregoing examples of the present disclosure have been presented for purposes of illustration and description. Furthermore, these examples are not intended to limit the disclosure to the form disclosed herein. Consequently, variations and modifications commensurate with the teachings of the description of the disclosure, and the skill or knowledge of the relevant art, are within the scope of the present disclosure. The specific embodiments described in the examples provided herein are intended to further explain the best mode known for practicing the disclosure and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with various modifications required by the particular applications or uses of the present disclosure. It is intended that the appended claims be construed to include alternative embodiments to the extent permitted by the prior art.