Patent Description:
Magnetic apparatuses can be used for imaging. For example, a magnetic imaging apparatus such as a magnetic resonance imaging (MRI) apparatus uses magnetic fields to image or visualize internal structures of samples such as a physiological or biological sample. An MRI apparatus can use labels in the sample to help imaging.

<NPL> describes techniques comprising the use of magnetic fields for producing a change in the magnetic entropy of biogenic nanoparticles, which in turn may generate heat to gate temperature-sensitive ion channels.

Sruthi Polali, "Novel Mechanisms for Magnetogenetic Neuromodulation", (<NUM>) describes a mechanism based on the magnetocaloric effect to use paramagnetic ferritin to gate thermally sensitive TRPV4 channel.

The scope of the present invention is defined by the scope of the appended claims. Any embodiments which do not fall within the scope of the claims are examples which are helpful for understanding the invention, but do not form a part of the invention.

Referring to <FIG>, an apparatus <NUM> is shown that uses a magnetic apparatus <NUM> to perform one or more functions or operations on a sample <NUM>. The sample <NUM> is a three-dimensional body. The sample <NUM> can be a biological or physiological organism or tissue and can be alive. The magnetic apparatus <NUM> includes a magnet <NUM> that defines a sample volume <NUM> that is large enough to accommodate the sample <NUM>. The magnet <NUM> is configured to create a magnetic field having a magnitude B in the sample <NUM>. The apparatus <NUM> includes an energy supply <NUM> connected to the magnet <NUM> and a control system <NUM> connected to one or more components (such as the energy supply <NUM> and the magnet <NUM>) of the magnetic apparatus <NUM>.

The magnetic apparatus <NUM> includes a magnetically manipulatable structure <NUM> embedded within the body of the sample <NUM>. The magnetically manipulatable structure <NUM> is controlled by at least the magnet <NUM> to affect the function of and operation of the sample <NUM>. The magnetically manipulatable structure <NUM> includes one or more magnetically manipulatable materials, which can be magnetocaloric materials. The magnetocaloric material is a material that exhibits a transition between a first magnetic state and a second magnetic state in response to a change in a property associated with the sample <NUM> while the magnetic field having the magnitude B is maintained in the sample <NUM>. This transition can be used to affect the function of or operation of the sample <NUM>. Additionally, the magnetocaloric material experiences a temperature change in response to a changing magnetic field and this temperature change can be used to affect the function of or operation of the sample <NUM>. The magnetically manipulatable material <NUM> has magnetic properties that can be changed and this change can occur around the temperature of a living organism and also in the presence of large DC magnetic fields of MRI scanners.

While the magnetically manipulatable structure <NUM> is shown as a monolithic structure in the sample <NUM> in <FIG>, it is possible for the magnetically manipulatable structure <NUM> to be a diffuse or disconnected structure <NUM> within the sample <NUM>. For example, the structure <NUM> can include some materials in one region of the sample <NUM> and other materials in another distinct and separate region of the sample <NUM>.

Magnetocaloric materials can have a sharp and tunable transition of magnetization with respect to changes in an environment in which the magnetocaloric material is placed. For example, if the magnetocaloric material is within a sample (such as the sample <NUM>), then the magnetocaloric material has a sharp and tunable transition of magnetization with respect to changes in one or more properties of the sample when the sample is held at a particular magnetic field. A sample property that can be changed is the temperature or the magnetic field of the sample <NUM>. If the sample <NUM> is a biological sample, then it is held at a magnetic field that is suitable for the biological sample, and also held at temperatures that are suitable, for example, a typical physiological (body) temperatures and fields of several Teslas (for example, <NUM> to <NUM> Teslas). Thus, magnetocaloric materials can be made to be sharply visible or invisible (switchable) in typical magnetic resonance imaging (MRI) machines in response to small changes in properties (for example, temperature or magnetic field) associated with the sample. This makes magnetocaloric materials suitable as sensors and/or labels in the sample. Moreover, the location and properties of these magnetization transitions can be widely tunable in magnetocaloric materials by various materials science techniques of alloying, doping, annealing, for example, thus making the MRI sensor and label design possibilities wide ranging.

Magnetocaloric materials have magnetic properties that provide a close match to the requirements for the design of high contrast ratio switchable and tunable MRI labels. More specifically, careful examination of the magnetocaloric materials' magnetic properties reveals that some of them have extremely sharp first-order magnetic phase transitions at typical physiological temperatures and in the presence of the large Tesla-scale magnetic fields typical of MRI settings. Furthermore, these sharp first-order magnetic phase transitions can have a positive or negative slope of magnetization vs. temperature, making them even stronger candidates as versatile materials for high differential contrast switchable MRI labels. Finally, magnetocaloric materials can be engineered and their magnetic properties fine-tuned through materials science techniques such as doping, alloying, thermal treatments and the like to optimize their response under physiological and MRI-appropriate conditions. As discussed below, the basic magneto-physical and MRI measurements on samples of iron-rhodium (FeRh) are described in order to develop the case for and demonstrate the use of such materials for high differential contrast ratio MRI labels.

For example, the magnetocaloric material is a material selected from the group consisting of iron-rhodium (FeRh), alloys of iron-rhodium, alloys of manganese arsenide, Heusler alloys, alloys of manganese-iron, alloys of lanthanum, iron, and silicon, and gadolinium.

Accordingly, as discussed herein, magnetocaloric materials can be used as tunable and switchable labels and sensors for MRI applications. These magnetocaloric materials have sharp magnetic phase transitions at typical physiological temperatures and in the presence of the large DC magnetic field values associated with MRI machines. This means that they have a sharp change in magnetization for a small change in temperature or magnetic field in the experimental settings typical of MRI machines, which makes them uniquely suitable as MRI contrast agents and sensors. A change of magnetization of the magnetocaloric material can be detected in MRI by observing the effect this change in magnetization has on water or biological tissue surrounding the material. Furthermore, the magnetic properties of magnetocaloric materials can be tuned by appropriate materials science technique of alloying, doping, and temperature treatments, for example.

Magnetocaloric materials can be used as sensors of temperature or magnetic field in typical MRI settings of physiological temperature and large bias magnetic fields of <NUM>-<NUM> Tesla. Magnetocaloric materials can be used as switchable MRI labels in typical MRI settings of physiological temperature and large bias magnetic fields of <NUM>-<NUM> Tesla.

Magnetocaloric materials can be switched on or off in typical MRI settings of physiological temperature and large bias magnetic fields of <NUM>-<NUM> Tesla by either a change in magnetic field or a change in temperature or a combination of both. Magnetocaloric materials can have positive or negative slope of magnetization vs. temperature, which means that the labels can be made to be positive labels (can turn on with rise in temperature) or negative labels (can turn off with rise in temperature). This also means that multiple labels can mixed so that some turn on and some off with rise and temperature, and vice versa.

Magnetocaloric materials can be engineered and therefore tuned to have transitions at different magnetic fields and temperatures. This means that these materials can be used as labels so that they are visible or invisible at different magnetic fields of MRI machines.

Referring to <FIG>, in some implementations, the magnetically manipulatable structure <NUM> is a magnetically manipulatable structure <NUM> embedded within a sample <NUM> that is to be imaged within an imaging apparatus <NUM>. The imaging apparatus <NUM> includes a magnetic apparatus <NUM> that defines a sample volume <NUM> that is large enough to accommodate the sample <NUM> to be imaged. The magnetically manipulatable structure <NUM> includes and one or more magnetically manipulatable materials <NUM>. The magnetic apparatus <NUM> includes a magnet <NUM> that is configured to create a magnetic field having a magnitude B in the sample <NUM>. Each magnetically manipulatable material <NUM> is a material that exhibits a transition between a first magnetic state and a second magnetic state in response to a change in a property associated with the sample while the magnetic field having the magnitude B is maintained in the sample. Thus, each magnetically manipulatable material <NUM> can be a magnetocaloric material.

The apparatus <NUM> includes an energy supply <NUM> connected to the magnet <NUM>. The magnet <NUM> can be formed from electrically conductive wire coils through which current from the energy supply <NUM> is passed. The energy supply <NUM> can provide a direct current (DC) to the wire coils, which means that the energy supply <NUM> provides a constant voltage or current to the wire coils of the magnet <NUM>. Thus, the energy supply <NUM> can, for example, include an alternating current (AC) generator equipped with a device to produce the direct current, a device that converts AC to DC, or batteries to provide DC. In some implementations, the magnet <NUM> can be a superconducting magnet.

In some implementations, the magnetic field magnitude B is greater than <NUM> Tesla. In other implementations, the magnetic field magnitude B is in a range of <NUM>-<NUM> Tesla. The magnitude B of the magnetic field is limited by the design of the magnet <NUM>. Thus, for example, if the magnet <NUM> is a superconducting magnet, then the magnitude B can be as large as <NUM> Tesla. The large value of the magnitude B allows for higher-quality imaging, and the superconductivity enable the imaging apparatus to work more efficiently.

In some implementations, the first magnetic state of the magnetically manipulatable material <NUM> is an antiferromagnetic state or a paramagnetic state, which means that the magnetically manipulatable material <NUM> is so weakly magnetic that it is considered to be non-magnetic. In an antiferromagnetic state, adjacent moments that behave as tiny magnets spontaneously align themselves into opposite, or antiparallel, arrangements throughout the magnetically manipulatable material <NUM> so that the material <NUM> exhibits almost no gross external magnetism. In antiferromagnetic materials, the magnetism from magnetic moments oriented in one direction is canceled out by the set of magnetic moments that are aligned in the reverse direction. In a paramagnetic state, some of the atoms or ions in the magnetically manipulatable material <NUM> have a net magnetic moment due to unpaired electrons in partially filled orbitals; however, the individual magnetic moments do not interact magnetically, and the magnetization is zero when a field is removed. In the presence of a field, there is now a partial alignment of the atomic magnetic moments in the direction of the field, resulting in a net positive magnetization and positive susceptibility.

In some implementations, the second magnetic state of the magnetically manipulatable material <NUM> is a ferromagnetic state or a ferrimagnetic state, which means that the material is considered to be magnetic. In a ferromagnetic state, the spins in the material <NUM> exhibit parallel alignment of moments resulting in large net magnetization even in the absence of a magnetic field. In a ferrimagnetic state, the opposing moments of the spins in the material <NUM> are unequal and a spontaneous magnetization remains in the absence of a magnetic field.

If the sample <NUM> is a living physiological or biological tissue, then the magnetically manipulatable material <NUM> exhibits the transition while the temperature in the sample is at a physiological temperature, for example, between <NUM> and <NUM> Kelvin (K).

The property associated with the sample <NUM> that is altered can be a temperature. The transition occurs in response to a change in temperature that is less than a fraction of the temperature of the sample <NUM>. For example, the change in temperature can be a factor of ten times smaller than the temperature of the sample <NUM>. Thus, if the temperature of the sample <NUM> is about <NUM>-<NUM>, then the temperature change can be about <NUM>-<NUM>.

The property associated with the sample <NUM> that is altered can be a magnetic field of the sample. In this case, the transition occurs in response to a change in a magnitude of a magnetic field (ΔB), where the change in magnitude ΔB that is substantially smaller than the magnitude B of the magnetic field. The change in magnitude is substantially smaller than the magnitude B if it is a fraction of the magnitude B, an order of magnitude smaller than the magnitude B, or at least an order of magnitude smaller than the magnitude B.

The imaging apparatus <NUM> also includes a sample property scanning system <NUM> configured to change the property of the sample <NUM> while the magnetic field having magnitude B is maintained in the sample <NUM>. The sample property scanning system <NUM> therefore acts to cause the transition in the magnetically manipulatable material <NUM>.

In some implementations, the sample property scanning system <NUM> includes a temperature scanning system for changing, as the property, a temperature of the sample <NUM>. The temperature scanning system includes an apparatus thermally connected to the sample <NUM>. The thermally connected apparatus includes an induction heater that operates at either a medium frequency or a radio frequency range and includes a controller, and a heat inductor. The heat inductor can be a heating coil.

In other implementations, the sample property scanning system <NUM> includes a magnetic scanning system for changing, as the property, a magnetic field of the sample <NUM>. The magnetic scanning system includes a magnetic source that is configured to change the magnetic field of the sample <NUM>.

In some implementations, the magnetic apparatus <NUM> is a magnetic resonance imaging (MRI) apparatus. In this case, imaging apparatus <NUM> can include, in addition to the magnet <NUM> shown in <FIG>, one or more gradient magnets <NUM> configured to produce a variable magnetic field that ranges in strength an amount that is much less than (for example, one hundredth of) the magnitude B. This variable magnetic field can permit different parts of the sample <NUM> to be scanned. The imaging apparatus <NUM> can also include an electromagnetic source <NUM> configured to produce a varying electromagnetic field having a range of magnetic field magnitude that is much less than (for example, one hundredth of) the magnitude B. The varying electromagnetic field can be a radiofrequency field and can be produced by a set of coils that transmit the radiofrequency waves into specific regions of the sample <NUM>.

If the magnetically manipulatable material <NUM> is not inherently found in the sample <NUM>, then it can be added to the sample <NUM>. For example, the imaging apparatus <NUM> can include a delivery (or injection) apparatus <NUM> configured to transport the magnetically manipulatable material <NUM> from a source <NUM> of the material into the sample <NUM>. The magnetically manipulatable material <NUM> can be in the form of a plurality of spatially-separated particles. The particles are dispersed throughout at least one region of interest within the sample. If the sample <NUM> is a living organism, then the size of the particles can be on the order of the size of cells within the sample <NUM>. For example, the size of the particles is on the order of micrometers, for example, <NUM>-<NUM> micrometers (µm). In some implementations, each particle has a microscopic size (which means it is only viewable with the use of a microscope).

The particles of the magnetically manipulatable material <NUM> can be prepared prior to delivery into the sample <NUM> to be in a suitable state for operation or use in the sample <NUM>.

If the sample <NUM> is a living organism, the sample <NUM> is held at a physiological temperature to maintain the organism in a living state.

The imaging apparatus <NUM> includes a detector <NUM> that detects a signal produced as a result of the interaction between the magnetic field and the sample <NUM>. The imaging apparatus <NUM> can also include some sort of output device <NUM> such as a display. Additionally, the imaging apparatus includes a control system <NUM> connected to the magnetic apparatus <NUM>. The control system <NUM> is also connected to the other components of the imaging apparatus <NUM> such as the property scanning system <NUM>, the electromagnetic source <NUM>, the gradient magnets <NUM>, the injection apparatus <NUM>, the detector <NUM>, the display <NUM>, and the energy supply <NUM>. The control system <NUM> is configured to: receive data output from the detector <NUM>, the output relating to the detected signal; analyze the received data; and estimate the sample property based on the analysis. The control system <NUM> is also configured to create an image of the sample <NUM> at the display <NUM> based on the analysis.

The detector <NUM> detects the signal produced as a result of the interaction between the magnetic field and the sample <NUM> by detecting a signal produced by tissue within the sample <NUM> that is in proximity to the magnetically manipulatable material <NUM>. The signal produced by tissue within the sample <NUM> that is in proximity to the magnetically manipulatable material <NUM> includes electromagnetic radiation generated from protons within the sample <NUM> in proximity to the magnetically manipulatable material <NUM>.

The magnetically manipulatable material <NUM> remains magnetically unsaturated while the magnetic field having the magnitude B exists in the sample <NUM>. This means that the magnetically manipulatable material <NUM> is capable of exhibiting a transition between the first magnetic state and the second magnetic state even while the magnetic field having the magnitude B exists in the sample <NUM>.

In some implementations, the magnetically manipulatable structure <NUM> includes one or more different magnetically manipulatable materials <NUM> or magnetocaloric materials. In these implementations, each different magnetically manipulatable material <NUM> in the structure can have a transition that occurs in response to a distinct change in the property of the sample <NUM>. For example, a first magnetically manipulatable material <NUM> has a transition from the first magnetic state to the second magnetic state that occurs in response to an increase in the sample property; and a second magnetically manipulatable material <NUM> has a transition from the first magnetic state to the second magnetic state that occurs in response to a decrease in the sample property. As another example, a first magnetically manipulatable material <NUM> has a transition from the first magnetic state to the second magnetic state that occurs in response to an increase in the sample property; and a second magnetically manipulatable material <NUM> has a transition from the second magnetic state to the first magnetic state that occurs in response to an increase in the sample property. As a still further example, a first magnetically manipulatable material <NUM> has a transition between the first magnetic state and the second magnetic state that occurs in response to a change in a first sample property; and a second magnetically manipulatable material <NUM> has a transition between the first magnetic state and the second magnetic state that occurs in response to a change in a second sample property that is distinct from the first sample property.

In other implementations, the transition from the first magnetic state to the second magnetic state occurs in a first range of values of the property as the property is increased; the transition from the second magnetic state to the first magnetic state occurs in a second range of values of the property as the property is decreased; and the first range of values is distinct from the second range of values.

<FIG> shows a magnetic state M (or magnetic moment) of the magnetically manipulatable material <NUM> versus the sample property, where the sample property is the temperature T of the sample <NUM>. In the implementation shown in <FIG>, the magnetically manipulatable material <NUM> transitions from a first magnetic state <NUM> to a second magnetic state <NUM> at a transition temperature T(tr). In this implementation, the first magnetic state <NUM> is magnetic, for example, ferromagnetic or ferrimagnetic, and the second magnetic state <NUM> is non-magnetic, for example, an antiferromagnetic or a paramagnetic. Moreover, this transition occurs while the magnetic field having the magnitude B is maintained in the sample <NUM>, where the magnitude B is a value between <NUM>-<NUM> T. The transition temperature T(tr) can be between <NUM> and <NUM> or around <NUM>.

<FIG> shows a magnetic state M (or magnetic moment) of the magnetically manipulatable material <NUM> versus the sample property, where the sample property is the temperature T of the sample <NUM>. In the implementation shown in <FIG>, the magnetically manipulatable material <NUM> transitions from a first magnetic state <NUM> to a second magnetic state <NUM> at a transition temperature T(tr). In this implementation, the first magnetic state <NUM> is non-magnetic, for example, antiferromagnetic or paramagnetic, and the second magnetic state <NUM> is magnetic, for example, ferromagnetic or ferrimagnetic. Moreover, this transition occurs while the magnetic field having the magnitude B is maintained in the sample <NUM>, where the magnitude B is a value between <NUM>-<NUM> T. The transition temperature T(tr) can be between <NUM> and <NUM> or around <NUM>.

<FIG> shows a magnetic state M (or magnetic moment) of the magnetically manipulatable material <NUM> versus the sample property, where the sample property is the magnetic field (represented by the magnitude B) within the sample <NUM>. In the implementation shown in <FIG>, the magnetically manipulatable material <NUM> transitions from a first magnetic state <NUM> to a second magnetic state <NUM> at a first transition magnetic field magnitude B1(tr), and from the second magnetic state <NUM> to a third magnetic state <NUM> at a second transition magnetic field magnitude B2 (tr). In this implementation, the first magnetic state <NUM> is non-magnetic, for example, antiferromagnetic or paramagnetic; the second magnetic state <NUM> is also non-magnetic, and the third magnetic state <NUM> is magnetic. Moreover, these transitions occur while the temperature within the sample <NUM> is maintained at a temperature T, which can have a value between <NUM> and <NUM> or around <NUM>. The magnitude B1(tr) can be any value between <NUM>-<NUM> T, for example <NUM> T, and the magnitude B2(tr) can be any other value between <NUM>-<NUM> T, for example, <NUM> T.

<FIG> shows a magnetic state M (or magnetic moment) of the magnetically manipulatable material <NUM> versus the sample property, where the sample property is the magnetic field (represented by the magnitude B) within the sample <NUM>, while maintaining the sample <NUM> at a constant temperature T. The transition from the first magnetic state <NUM> to the second magnetic state <NUM> occurs at a magnitude B1(tr) while the magnitude B is increased. On the other hand, the transition from the second magnetic state <NUM> to the first magnetic state <NUM> occurs at a different magnitude B2(tr) while the magnitude is decreased. The magnitude B2(tr) is less than the magnitude B1(tr). This is because of the hysteresis effect (in which the physical effect, that is, the magnetic state M, on the sample <NUM> is retarded or changed depending how the sample property is changed).

<FIG> shows a magnetic state M (or magnetic moment) of the magnetically manipulatable material <NUM> versus the sample property, where the sample property is the temperature (represented by T) within the sample <NUM>, while maintaining the sample <NUM> at a constant magnetic field magnitude B. The transition from the first magnetic state <NUM> to the second magnetic state <NUM> occurs at a temperature T1(tr) while the temperature T is increased. On the other hand, the transition from the second magnetic state <NUM> to the first magnetic state <NUM> occurs at a different temperature T2(tr) (which is less than the temperature T1(tr)) while the temperature T is decreased because of the hysteresis effect.

Furthermore, it is possible that the magnetically manipulatable material <NUM> only exhibits a transition in response to a change in two sample properties.

As mentioned above, and referring to <FIG>, the magnetically manipulatable structure <NUM> can include a plurality of different magnetically manipulatable materials <NUM> (that is, two or more magnetically manipulatable materials) within the sample <NUM>. In this example, there are two magnetically manipulatable materials 236a and 236b contained or embedded within the sample <NUM>. <FIG> shows an example of a graph of a magnetic state M (or magnetic moment) of the two magnetically manipulatable materials 236a, 236b within the sample <NUM> versus the sample property, where the sample property is the magnetic field (represented by the magnitude B) within the sample, while maintaining the sample <NUM> at a constant temperature T. In this implementation, the two magnetically manipulatable materials 236a, 236b have different transition points in response to a change in the magnetic field magnitude B.

The behavior of the first magnetically manipulatable material 236a is shown in the red graph <NUM> and the behavior of the second magnetically manipulatable material 236b is shown in the green graph <NUM>. The first magnetically manipulatable material 236a transitions from its first magnetic state <NUM> to its second magnetic state <NUM> at a magnetic field magnitude B1(tr) as the magnetic field magnitude B is being increased while the first magnetically manipulatable material 236a transitions from its second magnetic state <NUM> to its first magnetic state <NUM> at a magnetic field magnitude B2(tr) as the magnetic field magnitude B is being decreased. The second magnetically manipulatable material 236b transitions from its first magnetic state <NUM> to its second magnetic state <NUM> at a magnetic field magnitude B3(tr) as the magnetic field magnitude B is being increased while the second magnetically manipulatable material 236b transitions from its second magnetic state <NUM> to its first magnetic state <NUM> at a magnetic field magnitude B4(tr) as the magnetic field magnitude B is being decreased. These transitions points B1(tr), B2(tr), B3(tr), and B4(tr) are distinct from each other. For example, if the magnetic field magnitude B generally remains between <NUM>-<NUM> T and the temperature at which the sample <NUM> is held is about <NUM>, then the transition point B1(tr) can be <NUM> T, the transition point B2(tr) can be <NUM> T, the transition point B3(tr) can be <NUM> T, and the transition point B4(tr) can be <NUM> T. In this example, both of the magnetically manipulatable materials 236a, 236b are non-magnetic below <NUM> T, both of the magnetically manipulatable materials 236a, 236b are magnetic above <NUM> T, and the first magnetically manipulatable material 236a is magnetic while the second manipulatable material 236b is non-magnetic at <NUM> T.

In some implementations, the magnetically manipulatable material <NUM> transitions from a magnetic to a non-magnetic state with a rise in the sample property. For example, as shown in <FIG>, a first magnetically manipulatable material transitions from a magnetic state <NUM> to a non-magnetic state <NUM> at the transition temperature T1(tr) as the sample property of temperature T is increased while the first magnetically manipulatable material transitions from the non-magnetic state <NUM> to the magnetic state <NUM> at the transition temperature T2(tr) as the sample property of temperature T is decreased. In this example, the magnetic field magnitude B is held constant. As an example, the material Iron - Lanthanum - Silicon (Fe-La-Si) behaves in this manner.

In other implementations, the magnetically manipulatable material <NUM> transitions from a non-magnetic to a magnetic state with a rise in the sample property. For example, as shown in <FIG>, a second magnetically manipulatable material transitions from a non-magnetic state <NUM> to a magnetic state <NUM> at the transition temperature T3(tr) as the sample property of temperature T is increased while the second magnetically manipulatable material transitions from the magnetic state <NUM> to the non-magnetic state <NUM> at the transition temperature T4(tr) as the sample property of temperature T is decreased. In this example, the magnetic field magnitude B is held constant. For example, the material FeRh behaves in this manner.

If both the first and the second magnetically manipulatable materials of <FIG> are within the sample <NUM>, such as shown in <FIG>, then an exemplary combined transition graph is shown in <FIG> in which the transition temperature T3(tr) is equal to the transition temperature T1(tr) and the transition temperature T4(tr) is equal to the transition temperature T2(tr). In this implementation, the first and second magnetically manipulatable materials 236a, 236b can be switched on an off (that is, transitioned from the magnetic state to the non-magnetic state) in opposite manners. For example, the second magnetically manipulatable material 236b is magnetic and the first magnetically manipulatable material 236a is non-magnetic above the transition temperature T3(tr) (and T1(tr)) while the first magnetically manipulatable material 236a is magnetic and the second magnetically manipulatable material 236b is non-magnetic below the transition temperature T4(tr) (and T4(tr)). In this example, the temperature can be adjusted in a range of <NUM> to <NUM>.

While only two magnetically manipulatable materials 236a and 236b are discussed above, it is possible for the magnetically manipulatable structure <NUM> to include more than two different types of these materials.

Referring to <FIG>, in other implementations, the magnetically manipulatable structure <NUM> is a magnetically manipulatable structure <NUM> embedded within a sample <NUM> of an apparatus <NUM>. The apparatus <NUM> is designed to use magnetocaloric materials as physical actuators of biological constructs in genetically-modified cells while in a DC magnetic field. For simplicity, components shown in <FIG> are merely in block diagram form and are not to scale. A change to a property of the magnetocaloric material causes a change in the status of the biological construct because the magnetocaloric material is physically coupled with the biological construct. A physical coupling means that there is a coupling that is based on an exchange of matter or energy. For example, the physical coupling could be a thermal coupling. As another example, the physical coupling could be an electromagnetic coupling. The property of the magnetocaloric material that can be changed can be its magnetic state. The property of the magnetocaloric material that can be changed can be its temperature.

In some implementations, and as described herein, the property of the magnetocaloric material that is changed is the temperature, and the temperature of the magnetocaloric material is changed by a change in magnitude B of the magnetic field applied to the sample <NUM>. In these implementations, the physical coupling between the magnetocaloric material and the biological construct is a thermal coupling and the biological construct is a thermally-sensitive biological construct.

The apparatus <NUM> includes a magnetic apparatus <NUM> that defines an actuation volume <NUM> that is large enough to accommodate the sample <NUM>. The magnetic apparatus <NUM> includes a magnet <NUM> that is configured to create a magnetic field having a magnitude B in the sample <NUM> when supplied with a DC current from a DC energy supply <NUM>.

The apparatus <NUM> includes at least one thermally-sensitive biological construct <NUM> within the sample <NUM>. The magnetically manipulatable structure <NUM> is a magnetocaloric actuator <NUM> thermally coupled with the thermally-sensitive biological construct <NUM>. While one construct <NUM> and one actuator <NUM> is shown, it is possible to have a plurality of constructs <NUM> or a plurality of actuators <NUM> associated with each construct. Thermal coupling between two elements means that the heat is freely conducted between those two elements. Thus, heat is able to be thermally conducted between the biological construct <NUM> and the actuator <NUM>. Thermal coupling between two elements can mean that the two elements are near enough to each other so that heat does not dissipate substantially into the sample <NUM> before being conducted between the two elements. Thermal coupling between two elements can mean that the two elements have relative sizes that are complementary so that heat transfer between the two elements is enabled.

A change in the magnitude B of the magnetic field supplied with the DC current from the supply <NUM> to the magnet <NUM> causes the temperature of the magnetocaloric actuator <NUM> to change, and this change causes a change in a status of the thermally-sensitive biological construct <NUM>.

The apparatus <NUM> therefore operates under the application of a DC magnetic field, or a magnetic field that is very close to DC. That is, the magnetic field changes relatively slowly at the location of the actuator <NUM>.

The apparatus <NUM> also includes a control system <NUM> connected to the DC energy supply <NUM> to control the operation of the DC energy supply <NUM>.

The magnetocaloric actuator <NUM> can include one or more magnetically manipulatable materials 936i. The magnetically manipulatable material 936i exhibits a transition between a first magnetic state and a second magnetic state in response to the change in the magnitude B of the magnetic field produced by the magnet <NUM>. For example, the magnetically manipulatable material 936i of the actuator <NUM> exhibits the transition while the temperature in the sample <NUM> is between <NUM> and <NUM>. The magnetically manipulatable material 936i of the actuator <NUM> can include a material selected from the group consisting of iron-rhodium (FeRh), alloys of iron-rhodium, alloys of manganese arsenide, Heusler alloys, alloys of manganese-iron, alloys of lanthanum, iron, and silicon, and gadolinium.

Each magnetically manipulatable material 936i is a spatially-separated particle having a size that is large enough to retain heat long enough to cause the change in status in the thermally-sensitive biological construct <NUM>. For example, a cell in a living organism can be between <NUM>-<NUM> in diameter. If the biological construct <NUM> is on the order of a nanometer (nm), then the magnetocaloric actuator <NUM> can have a size on the order of about <NUM>-<NUM>.

The sample <NUM> can be a region of a live human body. In this implementation, the magnetically manipulatable material 936i of the actuator <NUM> exhibits the transition while the temperature in the live human body region is at a human body temperature. In some implementations, the sample <NUM> is a living organism and the sample <NUM> is held at a physiological temperature to maintain the organism in a living state.

The transition between the first magnetic state and the second magnetic state of the magnetically manipulatable material 936i can occur in response to a change in a magnitude of a magnetic field that is substantially smaller than the overall magnitude B of the magnetic field produced by the magnet <NUM>.

The temperature change caused to the magnetocaloric actuator <NUM> occurs without causing a change in status of materials within the sample <NUM> other than the at least one thermally-sensitive biological construct <NUM>. In this way, the apparatus <NUM> is able to finely heat and cool in local areas of the sample <NUM> without causing large-scale heating or cooling to other areas of the sample <NUM>.

In some implementations, the magnet <NUM> includes electrically conductive wire coils through which current from the DC energy supply <NUM> is passed. Thus, the DC energy supply <NUM> provides the DC current supplied to the wire coils. In some implementations, the magnet <NUM> is a superconducting magnet. And, the magnetic apparatus <NUM> can be a magnetic resonance imaging apparatus.

Moreover, the magnetic field magnitude B is greater than <NUM> Tesla or in a range of <NUM>-<NUM> Tesla. The magnitude B of the magnetic field can be in a range that does not cause any detrimental changes to the sample <NUM>. That is, the sample <NUM> does not deteriorate or degrade due to the magnitude B of the magnetic field that is created.

The temperature change dT that occurs in the magnetocaloric actuator <NUM> is governed by the following equation. <MAT> where T is the temperature of the magnetocaloric actuator <NUM>, CB is the heat capacity of the magnetocaloric actuator <NUM>, ∂M/∂T is the slope of the magnetization M of the magnetocaloric actuator <NUM> versus the temperature T at the specific magnetic field B, and dB is the change in magnetic field applied to the magnetocaloric actuator <NUM> by the magnet <NUM>. The temperature T of the actuator <NUM> changes as the magnetic field magnitude B changes. Moreover, the slope ∂M/∂T is an inherent property of the magnetocaloric actuator <NUM>. As an example, the magnetocaloric actuator temperature change dT is at least <NUM> for a change in magnitude of the magnetic field dB between <NUM>-<NUM> T.

In another example, if the magnetic field B supplied by the magnet <NUM> changes from <NUM> T to <NUM> T, then the value of dB is <NUM> T. As another example, if the magnetic field B supplied by the magnet <NUM> changes from <NUM> T to <NUM> T, then the value of dB is <NUM> T. The magnetically manipulatable materials 936i that are selected for the magneto-caloric actuator <NUM> are selected to provide a temperature change dT for as small a change in magnetic field B. Thus, the value of ∂M/∂T for the magnetically manipulatable materials 936i is as large as possible or at a maximum at typical physiological (biological) temperatures T (for example, around <NUM>). In particular, materials 936i that have suitable values of ∂M/∂T include gadolinium and FeRh. Other materials can have a large value of ∂M/∂T at temperatures T that are not typical physiological or biological temperatures, and those other materials would not be suitable for use in a physiological or biological sample <NUM>.

If the magnetic apparatus <NUM> is an MRI machine, then the apparatus <NUM> can include one or more of the other components for operating the MRI machine. For example, the apparatus <NUM> can also include one or more of the property scanning system <NUM> (which is used to scan or change the magnetic field of the sample <NUM> in this implementation), the electromagnetic source <NUM>, the gradient magnets <NUM>, the detector <NUM>, and the display <NUM>.

<FIG> are block diagrams of an implementation in which the at least one thermally-sensitive biological construct <NUM> within the sample <NUM> is an ion channel <NUM> positioned along a cellular structure <NUM> (for example, a cell membrane) of the sample <NUM>. The at least one magnetocaloric actuator <NUM> is a magnetocaloric actuator <NUM> that includes a plurality of magnetically manipulatable materials 936i near the ion channel <NUM>. The ion channel <NUM> has a status that is either closed (<FIG>) or open (<FIG>). For example, when closed, the ion channel <NUM> blocks other elements (such as molecules, ions, or atoms) nearby and within the sample <NUM> from passing through the cellular structure <NUM>. When open, the ion channel <NUM> permits these other nearby elements (such as molecules, ions, or atoms) to freely pass through the cellular structure <NUM> as long as the opening is large enough to accommodate the size of the element.

Temperature sensitive ion channels <NUM> can be integrated into the cell membrane (the cellular structure <NUM>) using a suitable technique such as cloning or genetic engineering. For example, the ion channel <NUM> can be genetically engineered into the cellular structure <NUM>. This means that the ion channel <NUM> may not be present in the wild-type or non-engineered cellular structure <NUM> of the sample <NUM>. The cellular structure <NUM> can be genetically altered through the exogenous delivery of a portion of deoxyribonucleic acid (DNA) comprising a gene that expresses the ion channel <NUM> in the sample <NUM>. For example, transgenic expression of a temperature-activated ion channel in a cell comprising the sample <NUM> leads to the insertion of the ion channel <NUM> into the cell membrane, identified as the cellular structure <NUM>.

In some implementations, the ion channel <NUM> is a transient receptor potential cation channel subfamily V member (such as TRPV1 or TRPV4). The TRPV channel changes its state from closed to open by warming up by about <NUM>-<NUM>. Thus, the change in magnitude B of the magnetic field supplied to the sample <NUM> should be large enough to increase the temperature of the magnetocaloric actuator <NUM> by enough of an amount such that the temperature of the TRPV increases by about <NUM>.

As another example, the ion channel <NUM> is a transient receptor potential cation channel subfamily M member (such as TRPM8). By contrast, the TRPM channel changes its state from closed to open by cooling down by about <NUM>-<NUM>. Thus, the change in magnitude B of the magnetic field supplied to the sample <NUM> should be large enough to decrease the temperature of the magnetocaloric actuator <NUM> by enough of an amount so that the temperature of the TRPM decreases by about <NUM>.

Referring also to <FIG>, in some implementations, an increase in the magnitude B of the magnetic field supplied with the DC energy supply <NUM> causes an increase in the temperature of the magnetocaloric actuator <NUM> and an increase in the temperature of the thermally-sensitive biological construct <NUM>. And, a decrease in the magnitude B of the magnetic field supplied with the DC energy supply <NUM> causes a decrease in the temperature of the magnetocaloric actuator <NUM> and a decrease in the temperature of the thermally-sensitive biological construct <NUM>. For example, a magnetocaloric actuator <NUM> in which its magnetically manipulatable material 936i includes gadolinium exhibits this property. For example, the temperature of gadolinium (as the magnetically manipulatable material 936i) increases by about <NUM>-<NUM> for every <NUM> T increase in the magnitude B of the magnetic field at a physiological or biological temperature.

In other implementations, an increase in the magnitude B of the magnetic field supplied with the DC energy supply <NUM> causes a decrease in the temperature of the magnetocaloric actuator <NUM> and a decrease in the temperature of the thermally-sensitive biological construct <NUM>. Moreover, a decrease in the magnitude B of the magnetic field supplied with the DC energy supply <NUM> causes an increase in the temperature of the magnetocaloric actuator <NUM> and an increase in the temperature of the thermally-sensitive biological construct <NUM>. A magnetocaloric actuator <NUM> in which its magnetically manipulatable material 936i includes an alloy of iron-rhodium (FeRh) exhibits this property. For example, the temperature of FeRh (as the magnetically manipulatable material 936i) decreases by about <NUM> for every <NUM> T increase in the magnitude B of the magnetic field at a physiological or biological temperature.

Thus, in this way, the apparatus <NUM> can be used to either heat or cool the actuator <NUM>, and because of this flexibility, there are more options for how to affect the thermally-sensitive biological construct <NUM>.

<FIG> is a block diagram of a sample <NUM> that includes a plurality of thermally-sensitive biological constructs 1130A, 1130B,. <NUM> (where K is an integer greater than <NUM>). In some implementations, these biological constructs 1130A, 1130B,. <NUM> can be associated with the same structure within the sample <NUM>. In other implementations, one or more of these biological constructs 1130A, 1130B,. <NUM> are associated with a structure that is different from the structures associated with the other biological constructs. Moreover, a magnetocaloric actuator <NUM> can be associated with each of these biological constructs. For example, a magnetocaloric actuator 1135i is thermally coupled with a first thermally-sensitive biological construct 1130A, a magnetocaloric actuator 1135j is thermally coupled with a second thermally-sensitive biological construct 1130B,. and a magnetocaloric actuator <NUM> is thermally coupled with a last thermally-sensitive biological constructs <NUM>. Each magnetocaloric actuator 1135i, 1135j,. <NUM> is distinct from each of the other magnetocaloric actuators.

<FIG> is a block diagram of a single magnetocaloric actuator <NUM> having different magnetically manipulatable materials 1236i, 1236j, <NUM> that are mixed together (but do not interact with each other). The labels i, j, and k denote three different types of materials. While only three are shown there can be any number of different materials in the magnetocaloric actuator <NUM>. For example, the material 1236i can heat up as the magnetic field is decreased while the material 1236j can cool down as the magnetic field is decreased.

Referring again to <FIG>, the apparatus <NUM> works with a change in magnetic field that is caused by a DC current from the DC energy supply <NUM>, and thus a thermal magnetic treatment in a biological or medical sample <NUM> is enabled without the use of AC or RF (radio frequency) fields, which can cause more damage to the sample <NUM>. In Tesla-scale magnetic fields (such as those used in modern magnetic resonance imaging or NMR spectrometers), temperature differences obtained by the magnetocaloric actuator <NUM> can be on the order of <NUM> or more. Furthermore, in the implementations of <FIG>, in which the thermally-sensitive biological construct <NUM> is an ion channel <NUM> positioned along a cellular structure <NUM> of the sample <NUM>, these ion channels <NUM> can be inserted into biological cells such as neurons, that are sensitive to heat and cold. Temperature differences on the order of <NUM>-<NUM> are large enough to open or close such ion channels <NUM>. Therefore, magnetically manipulatable materials 936i can be on the order of a micron in size (for example <NUM> in diameter), and placed next to such cells, which can be activated by exposing them to magnetic fields that change due to changes supplied by a DC energy supply <NUM>. In this way, the ion channel <NUM> can be remotely activated, which means that an invasive procedure that disrupts the sample <NUM> is not needed in order to activate the ion channel <NUM>.

Referring to <FIG>, a test apparatus <NUM> is shown for demonstrating the feasibility of using magnetocaloric materials as thermal actuators of temperature-sensitive biological constructs in genetically-modified cells while in a DC magnetic field. <FIG> shows a schematic representation of the test apparatus <NUM> in which the at least one thermally-sensitive biological construct <NUM> within the sample <NUM> is an ion channel (such as discussed above) <NUM> positioned in a cellular structure <NUM> of a neuron <NUM> within a biological sample <NUM>. The behavior of the neurons <NUM> in the sample <NUM> is tested with conductors <NUM>, through which current flows to a current measurement device <NUM>, and the current value is an indicator of whether the neurons fire in response to some stimulus.

In this test, some of the neurons 1318B are configured with ion channels <NUM> while some of the neurons 1318A lack any ion channels <NUM>. Moreover, some of the neurons 1318A that lack ion channels are thermally coupled with at least one magnetocaloric actuator <NUM> while the others of the neurons 1318A that lack ion channels are not thermally coupled with a magnetocaloric actuator <NUM>. Similarly, some of the neurons 1318B with the ion channels <NUM> are thermally coupled with at least one magnetocaloric actuator <NUM> while the others of the neurons 1318B with the ion channels <NUM> are not thermally coupled with a magnetocaloric actuator <NUM>. The test apparatus <NUM> includes at least one conductor <NUM> associated with each neuron <NUM>. Thus, the conductor <NUM> registers a change in current when the neuron <NUM> fires. Moreover, the test apparatus <NUM> can be configured so that a neuron 1318B only fires when it is activated by the opening or closing of its ion channel <NUM>. In this way, the effect of the ion channel <NUM> changing its state (between open and close) can be measured or detected with the current signal measured from the conductor <NUM>.

To test, the sample <NUM> is placed in an actuation volume (such as volume <NUM>) and a magnetic field having a magnitude B is applied by the magnet (such as magnet <NUM>). The magnitude B of the magnetic field is changed (for example, by changing the DC current from the DC energy supply <NUM>). The change of the magnitude B of the magnetic field causes the temperature of the magnetocaloric actuator <NUM> to change, and this temperature change causes a change in status of the ion channel <NUM> that is thermally coupled to a magnetocaloric actuator <NUM>, and this change in status of the ion channel <NUM> causes the neuron 1318B to which it is associated or in proximity of to fire (or change its current output). Thus, it is expected that the change in magnitude B of the magnetic field leads to only a change in current output of the neurons 1318B that are associated with ion channels <NUM> that are in thermal coupling with an actuator <NUM>, while the neurons 1318B having ion channels <NUM> that are not in thermal coupling with an actuator <NUM> and the neurons 1318A should not produce any change in current output.

Switchable and tunable labels with high contrast ratio are developed for MRI using magnetocaloric materials that have sharp first order magnetic phase transitions at physiological temperatures and typical MRI magnetic fields. Selection of appropriate magnetic materials for tunable labels in typical MRI settings of Tesla-scale DC magnetic fields and physiological temperatures of around <NUM> is hampered by the basic physical properties of most classical magnetic materials such as iron, iron oxides, and the like. Most magnetic materials have Curie temperatures in the hundreds of degrees Celsius, and therefore have a very flat saturation magnetization with respect to temperature at the physiological body temperatures of around <NUM> (<NUM>). Moreover, standard MRI settings place these labels in large DC magnetic fields typically between <NUM>-<NUM> Tesla where all of these materials are magnetically saturated and therefore have constant contrast in the MRI. Therefore, magnetic materials are identified, designed, or engineered that have switchable and tunable properties with high differential contrast ratios in the MRI settings where the DC magnetic fields are very large (on the scale of Teslas) and in-vivo physiological temperatures are around <NUM>.

A magnetocaloric material such as iron-rhodium (FeRh) can be prepared by melt mixing, high-temperature annealing, and ice-water quenching. Temperature and magnetic field dependent magnetization measurements of wire-cut FeRh samples can be performed on a vibrating sample magnetometer. Temperature-dependent MRI of FeRh samples can be performed on <NUM>. 7T scanner.

The magnetocaloric material FeRh can be demonstrated to act as a high contrast ratio switchable MRI contrast agent due to its sharp first order magnetic phase transition in DC magnetic field of MRI and at the physiologically relevant temperature. A wide range of magnetocaloric materials are available that can be tuned by materials science techniques to optimize their response under MRI-appropriate conditions and be controllably switched in-situ with temperature, magnetic field, or a combination of both.

Examples of the apparatus, materials, and tests performed on these magnetically manipulatable materials <NUM> or 936i using the apparatus are described next.

Moreover, the development of novel contrast mechanisms and labeling agents for MRI facilitates further the advancements in non-invasive cell imaging, tracking, and readout of physiological conditions in-vivo. More specifically, the extremely sharp first-order magnetic phase transitions these magnetocaloric materials have at typical physiological temperatures and in the presence of the large DC magnetic field values associated with MRI machines provide an ideal match to the requirements for the design of novel MRI labels. Furthermore, a wide range of magnetocaloric materials are available that can be engineered and fine-tuned to optimize their response under MRI-appropriate conditions.

One magnetocaloric material that can be used is iron-rhodium, which is discussed next. The iron-rhodium is prepared by mixing the components (Fe and Rh) in an arc melting furnace. Next, the mixed components are subjected to a high-temperature annealing in an Argon gas quartz tube furnace at <NUM>,<NUM> for two weeks, and subsequently rapidly quenched in ice-water. This procedure typically results in the ordered (body-centered-cubic CsCl-type crystal structure) binary alloy FeRh with the bulk saturation magnetization of MS=<NUM>×<NUM><NUM> A/m in the ferromagnetic state. The prepared FeRh can be cut into mm-scale sample disks and buffed to a shiny metallic surface with an optical fiber polishing paper in order to remove any oxide from the samples. Temperature and field dependent magnetic measurements of the samples can be performed in a <NUM>-Tesla Vibrating Sample Magnetometer (for example, procured from VSM, Quantum Design, Inc. In order to demonstrate the basic proof-of-concept feasibility of a magnetocaloric material as a tunable and switchable high differential contrast agent at physiological temperatures and typical MRI settings, a <NUM> Tesla MRI scanner (produced by Bruker Biospin, Inc. ) can be used. The available MRI polarizing magnetic field of such a scanner is closest to the value where the sharp first order magnetic phase transition happens near the physiological temperature of <NUM> (<NUM>°K).

Two sets of iron-rhodium granules are prepared for testing. The first set is Fe <NUM>% - Rh <NUM>% atomic composition, of <NUM>% nominal purity and is discussed with reference to <FIG> and <FIG> and the second set is Fe <NUM>% - Rh <NUM>% atomic composition, of <NUM>% nominal purity) and is discussed with reference to <FIG> and <FIG>. The granules of FeRh can be obtained from American Elements Corporation (Model FE-RH-<NUM> for <NUM>% purity or Model FE-RH-<NUM> for <NUM>% purity).

In <FIG>, the magnetocaloric material (<NUM> or 936i) used in the magnetically manipulatable structure is FeRh. <FIG> show the measurements of the magnetic moment of the FeRh structure as a function of temperature at different constant magnetic fields. Measurements are taken with the 9T vibrating sample magnetometer. Both FeRh structures exhibited a sharp first order magnetic transition from an antiferromagnetic to a ferromagnetic state over a very narrow range of physiologically relevant temperatures, as discussed next.

<FIG> shows the measurement of the magnetic moment of a <NUM>% purity FeRh structure as a function of temperature in different bias DC magnetic fields, for example, 1T (1401A), 3T (1403A), and 5T (1405A). The FeRh structure exhibits a sharp magnetic phase transition from an antiferromagnetic to a ferromagnetic state over a very narrow range of physiologically relevant temperatures. More specifically, the FeRh structure has a sharp transition around body temperature (<NUM> = <NUM>) in a constant magnetic field (the DC bias field) of around <NUM> Tesla.

<FIG> shows the measurement of the magnetic moment of a <NUM>% purity FeRh structure as a function of temperature in different bias DC magnetic fields, for example, 1T (1401B), 3T (1403B), 5T (1405B), and 7T (1407B). The FeRh structure exhibits a sharp transition from an antiferromagnetic to a ferromagnetic state over a very narrow range of physiologically relevant temperatures. More specifically, the FeRh structure has a sharp magnetic phase transition around body temperature (<NUM> = <NUM>) in the DC bias field of around <NUM> Tesla.

These results are in line with the previously reported measurements of FeRh and demonstrate several features. The most important one is that the magnetization of FeRh changes through the transition by a factor of about <NUM> in absolute value, and it does so over a very narrow temperature range around the physiological body temperature and in the presence of a large Tesla-scale magnetic field. The second feature is that the temperature dependence and magnetic properties of FeRh (and magneto-caloric materials in general) are highly dependent on the purity of the FeRh. Conversely, this demonstrates the attractive feature of FeRh (and other magneto-caloric materials) that, through careful materials science preparation and process control of impurities and crystal structure, one can tune and engineer FeRh to have a sharp magnetic phase transition at the desired temperature and bias magnetic field (nominally at the physiological body temperature and magnetic field of the MRI machine used). Furthermore, such temperature dependence of magnetization demonstrates that, once the proper magneto-caloric material is prepared for a specific magnetic field of the MRI used, the magnetization of that magneto-caloric label can in principle be switched in-situ by modest temperature changes on the order of a few degrees Celsius.

<FIG> show the measurements of the magnetic moment of the FeRh structure as a function of varying magnetic field at constant temperature (at a room temperature of <NUM>=<NUM> or at a physiological body temperature of <NUM> = <NUM>, respectively). Measurements are taken with the 9T vibrating sample magnetometer.

Referring to <FIG>, the magnetization of the FeRh structure is tuned with the magnetic field. In this measurement, the magnetic moment of a <NUM>% purity FeRh structure is measured as a function of the magnetic field at various constant temperatures, for example, <NUM> (<NUM>10A) and <NUM> (1500A). As evident, the sharp transition is present at large DC magnetic field values and around physiologically relevant temperatures.

Referring to <FIG>, the magnetization of the FeRh structure is tuned with the magnetic field. In this measurement, the magnetic moment of a <NUM>% purity FeRh structure is measured as a function of the magnetic field at various constant temperatures, for example, <NUM> (1530B), <NUM> (1520B), <NUM> (1510B), and <NUM> (1500B). Again, the sharp transition is present at large DC magnetic field values and around physiologically relevant temperatures.

Specifically, the <NUM>% purity FeRh structure (<FIG>) has a sharp magnetic phase transition around the room and body temperatures at the magnetic field values between <NUM>-<NUM> Tesla, while the <NUM>% purity FeRh structure (<FIG>) has a sharp magnetic phase transition around the room and body temperatures at the magnetic field values between <NUM>-<NUM> Tesla. These results demonstrate another feature that, once the proper magnetocaloric material is fabricated as a switchable MRI label for the specific magnetic field of the MRI used, the magnetization of that magnetocaloric label can be switched in-situ with additionally added or subtracted magnetic field or by temporarily removing the sample from the MRI bore.

Measurements described in <FIG>, <FIG> guide experimental choices for demonstrating the basic proof-of-concept feasibility of a magnetocaloric FeRh material as a switchable high differential contrast MRI agent. Of the two FeRh structures that were prepared, <NUM>% purity FeRh structure displayed a sharper first order magnetic transition at a higher bias DC magnetic field (of around <NUM> Tesla) at the physiological temperature of <NUM>.

Referring to <FIG>, for the MRI demonstration, a testing apparatus <NUM> is used. In the testing apparatus <NUM>, the disk of FeRh <NUM> is embedded in agarose <NUM> next to an MRI-compatible optical fiber-based thermometer <NUM> (which can be procured from FISO Technologies, Inc. The disk <NUM> and the agarose <NUM> are held within a container <NUM>, which is sealed with a cap <NUM>. The container <NUM> is wrapped in tubing <NUM> connected to a temperature-controlled water circulating bath in order to sweep and control the temperature of the disk <NUM> and its environment around physiologically relevant temperature range (<NUM>-<NUM>).

The testing apparatus <NUM> of <FIG> can be used to create representative gradient-echo images of the effect of the mm-scale disk of FeRh <NUM> on the surrounding agarose <NUM> as the temperature is swept from the antiferromagnetic phase below the transition temperature to the ferromagnetic phase above the transition temperature of the FeRh structure <NUM> and then cooled. In order to produce a gradient-echo image, the testing apparatus <NUM> is inserted into a magnet (such as the magnet <NUM>, which in this test case is an MRI magnet). RF pulses and gradient pulses are applied to the entire FeRh structure <NUM>. The resonant signal from the surrounding agarose <NUM> is detected by inductive detection coils of the magnetic apparatus <NUM> (which is an MRI machine) in which the apparatus <NUM> is placed. The resonant signal is affected by how magnetic the FeRh structure <NUM> is in the middle of agarose <NUM>.

These gradient-echo images are shown in <FIG>. These images are taken while maintaining the magnetic field magnitude at <NUM>. The FeRh structure <NUM> is <NUM>% purity FeRh disk having a volume of <NUM><NUM>. The images are taken through the center of the disk <NUM> at various temperatures as the disk <NUM> is heated and then cooled. In each of the images, a stable image feature <NUM> is visible. This feature <NUM> is produced by the thermometer <NUM> next to the FeRh disk <NUM>. The thermometer <NUM> is non-magnetic, and thus, it does not exhibit any appreciable change in the images as the magnetic field changes (due to the change in the temperature) from <FIG>. The feature <NUM> is difficult to see in <FIG> (but it is labeled to show its location) because the signal from the FeRh disk <NUM> overwhelms it. <FIG> shows a width of the MRI signal <NUM> (or image artifact) created by signal loss due to the magnetic field gradients from the FeRh disk <NUM> as a function of the set-up temperature.

Specifically, <FIG> show six representative gradient-echo images (out of <NUM>) of the effect of the FeRh mm-scale disk <NUM> on the surrounding agarose <NUM> as the temperature of the set-up is swept through physiologically relevant temperature range (<NUM>-<NUM>) at the constant MRI magnetic field of <NUM> Tesla. The image parameters are as follows: TRITE = <NUM>/<NUM>, FA = <NUM> degrees, nominal resolution = <NUM> × <NUM> × <NUM>, FOV = <NUM> × <NUM>. In chronological order, <FIG> shows the gradient-echo image taken at a temperature of <NUM>; <FIG> shows the gradient-echo image taken at a temperature of <NUM>; <FIG> shows the gradient-echo image taken at a temperature of <NUM>; <FIG> shows the gradient-echo image taken at a temperature of <NUM>; <FIG> shows the gradient-echo image taken at a temperature of <NUM>; and <FIG> shows the gradient-echo image taken at a temperature of <NUM>.

The demonstrated agarose image phase shift with concomitant magnetic field change emanating from the magnetocaloric FeRh disk <NUM> is seen in the increase of the MRI signal <NUM> around the sample in <FIG>. As the magnetization data of <FIG> dictates, the temperature increase drives the FeRh disk <NUM> to transition from the low-moment antiferromagnetic phase below the transition temperature to the high-moment ferromagnetic phase above the transition temperature and then back to the low-moment antiferromagnetic phase as the FeRh disk <NUM> is cooled. When the magnetically manipulatable material <NUM> goes to a magnetic state (for example, increasing temperature for FeRh) from a non-magnetic state, the surrounding substance (for example, agarose <NUM>), that is, the substance around the magnetically manipulatable material <NUM>, sees both the background magnetic field produced by the magnet <NUM> and the magnetic field produced from the now-magnetic material (in this example, the FeRh in the disk <NUM>). That extra field from the FeRh disk <NUM> is non-uniform and in essence alters the MRI signal <NUM> around the FeRh to some distance, it puts it out of detection range. This is why the gradient-echo image looks much larger and darker as the magnetic field increases. It is not that the FeRh disk <NUM> is any bigger, it is that the FeRh disk <NUM> changes its magnetic state, which in turn changes the MRI signal of the surrounding substance <NUM> and makes the image change to a larger darker spot.

Loss of signal in the MRI of <FIG> due to the changing magnetic state of the magnetocaloric material closely follows the magnetic properties that are shown in <FIG>. The size of the region with signal dropout due to the high magnetic field gradients approximately doubles in each dimension, a factor of <NUM> in volume. This effect is plotted in <FIG>, which shows the MRI signal loss region size (in a linear dimension) as a function of temperature. The image parameters are as follows: TRITE = <NUM>/<NUM>, FA = <NUM> degrees, nominal resolution = <NUM> × <NUM> × <NUM>, FOV = <NUM> × <NUM>.

The clearly demonstrated phase shift with concomitant magnetic field change is seen in the increase of the MRI signal void. There was a larger hysteresis and lower apparent moment increase in the MRI data than in the magnetometer data, which may be related to mechanical stress when cutting the material (the FeRh disk <NUM>) to a smaller size. This hysteresis effect could be viewed as a benefit, in that once a particle in the FeRh disk <NUM> is turned "on" then it will remain on until removed from the field.

In general, this result can be assumed to apply for the magnetocaloric materials in the structure <NUM> when it is placed in the magnet <NUM>. When the magnetocaloric material is in a non-magnetic state (for example, at a low temperature for FeRh or at a high temperature for La-Fe-Si), the water surrounding the structure <NUM> experiences just the MRI magnetic field supplied by the magnet <NUM> on the order of Tesla (depending on the scanner magnetic field). But when the magnetocaloric material goes to a magnetic state (for example, at a high temperature for FeRh or at a low temperature for La-Fe-Si), the water around the structure <NUM> experiences both the MRI scanner magnetic field (from the magnet <NUM>) and the magnetic field from the now magnetic magnetocaloric material in the structure <NUM>. That extra field from the magnetic magnetocaloric material is non-uniform and in essence alters the MRI water signal around the structure <NUM> to some distance, it puts it out of detection range.

Switching protocols for using FeRh as the magnetically manipulatable structure <NUM> are discussed next with reference to <FIG>. A switching protocol describes the transition of the magnetocaloric material in the structure <NUM> from the first magnetic state to the second magnetic state. <FIG> shows the MRI magnetic field at the value where the center of the first order magnetic phase transition of the magnetocaloric material is at the physiological temperature of <NUM>. Temporary heating and cooling switches the magnetocaloric material between the MRI visible (ON) and invisible (OFF) states. <FIG> shows the MRI magnetic field is at the value where the center temperature of the magnetocaloric material first order magnetic phase transition is higher than the physiological temperature of <NUM>. Temporary heating switches the magnetocaloric material to the MRI visible (ON) state while thermal relaxation to equilibrium temperature brings the magnetocaloric material back to the MRI invisible (OFF) state. <FIG> shows the multiplexing of two magnetocaloric materials that have phase transitions at two different magnetic field values at the physiological temperature. The two magnetocaloric materials are visible or invisible at different magnetic fields and can therefore be differentiated in images from different MRI scanners (in this example at 1T, 4T, and 7T).

As discussed above, FeRh is a suitable switchable and tunable magnetocaloric material in the typical MRI settings (Tesla-scale magnetic fields) and in-vivo physiological temperatures (around <NUM>) through a very sharp first order magnetic phase transition. FeRh is only one in a large repertoire of magnetocaloric materials that have similar switching characteristics under similar environmental conditions, where sharp first order magnetic phase transition with a positive M vs. T slope is observed at physiological temperatures and Tesla-scale magnetic fields. Furthermore, there are many magnetocaloric materials where the sharp first-order magnetic phase transitions can also have a negative M vs. T slope at physiological temperatures and Tesla-scale fields, or even a combination of sharp positive and negative slopes, making magnetocaloric compounds even stronger candidates as versatile materials for high differential contrast switchable MRI labels.

The switching protocols can be used for in-vivo MRI settings. The MRI contrast agent using FeRh can be reversibly switched by thermal cycling of the entire sample set-up over the physiologically relevant temperature range. Other potential engineering solutions to magnetocaloric MRI label switching include heating by MRI compatible focused ultrasound or high-frequency inductive heating, cooling by MRI compatible thermo-electric coolers, or magnetocaloric material switching by adding or subtracting to the main magnetic field of the MRI (in the simplest version this can be accomplished by temporarily removing the sample from the MRI bore).

When considering such MRI label switching solutions, magneto-thermal properties of the magnetocaloric material are also considered, especially the location of the first order magnetic phase transition of the magnetocaloric material. <FIG> schematically describe specific examples. In <FIG>, the MRI label has two stable magnetic states (indicated by the solid black dots) at <NUM> (<NUM>). This example is well represented by the <NUM>% purity FeRh magnetocaloric material at <NUM> Tesla, as shown in <FIG>. In the low magnetic moment state the magnetocaloric material is MRI invisible (Label OFF). The magnetocaloric material can be switched on by temporarily raising its temperature by few degrees C (approximately ΔT=<NUM> for our <NUM>% purity FeRh magnetocaloric material at <NUM> Tesla shown in <FIG>) through application of a heating pulse (by any of the above listed potential methods). Once the magnetocaloric material is thermally relaxed back to the equilibrium temperature of <NUM>, it remains in the high magnetic moment state and is MRI visible (Label ON). It can be switched off again by active cooling where the temperature of the magnetocaloric material is temporarily lowered. Once the magnetocaloric material relaxes back to the equilibrium temperature of <NUM>, it will be in the low magnetic moment state and again MRI invisible (Label OFF). This is also the procedure performed for obtaining the gradient-echo images as described in <FIG>.

The second possibility is described in <FIG>. In this case the magnetocaloric material has only one stable magnetic state (indicated by the solid black dot) at <NUM> (<NUM>). This example is well represented by <NUM>% purity FeRh magnetocaloric material at <NUM> Tesla, as shown in <FIG>. In this low magnetic moment state the magnetocaloric material is MRI invisible (Label OFF). The magnetocaloric material can be temporarily switched on by raising its temperature through application of a larger heat pulse than was described in <FIG> since higher temperature change is required to take the magnetocaloric material through the first order magnetic phase transition (In the case of our <NUM> % purity FeRh at 3T as shown in <FIG>, it would take approximately ΔT=<NUM> to switch the magnetocaloric material). The magnetocaloric material remains MRI visible (Label ON) in the high magnetic moment state as long as the temperature of the magnetocaloric material is above the phase transition temperature. As the magnetocaloric material thermally relaxes back to the equilibrium temperature of <NUM>, it automatically goes back through the phase transition into a low magnetic moment state and becomes MRI invisible again (Label OFF). The advantage of this configuration is that active cooling is not required for switching the magnetocaloric material into the MRI invisible OFF state, while the disadvantage is that the higher temperature increase is required to temporarily switch the label into the MRI visible ON state.

Another feature of MRI switchable labels brought about by the variety of magneto-thermal properties of magnetocaloric materials is the possibility of multiplexed labels made MRI visible or invisible at different magnetic field or temperature values by appropriate materials science design. <FIG> describes the possibility of two switchable MRI labels that can be differentiated in images from MRI scanners operating at different magnetic field values. Label <NUM> has a first order magnetic phase transition at <NUM> Tesla and is well represented by the <NUM>% purity FeRh magnetocaloric material at <NUM> (<NUM>) shown in <FIG>. Label <NUM> has a first order magnetic phase transition at <NUM> Tesla and is well represented by the <NUM>% purity FeRh magnetocaloric material at <NUM> (<NUM>) shown in <FIG>. In a 1T MRI scanner, both of these labels would be in the low magnetic moment state below their respective first order magnetic phase transition temperatures and therefore invisible in the MRI (both labels OFF). In a 4T MRI scanner, Label <NUM> would be in the high magnetic moment state above its magnetic phase transition temperature and therefore MRI visible (Label <NUM> ON), while Label <NUM> would still be in the low magnetic moment state below its magnetic phase transition temperature and therefore still MRI invisible (Label <NUM> OFF). Finally, in a 7T MRI scanner, both of these labels would be in the high magnetic moment states above their respective magnetic phase transition temperatures and therefore MRI visible (both labels ON). Images from these MRI scanners with different operating DC magnetic fields would readily differentiate the two labels.

Referring to <FIG>, two different magnetically manipulatable materials are shown that function similarly to the examples shown in <FIG>, respectively. In <FIG>, the magnetically manipulatable material is Fe-La-Si, while in <FIG>, the magnetically manipulatable material is <NUM>% purity FeRh. <FIG> is a graph of the magnetic state of Fe-La-Si versus temperature T within the sample <NUM>, while maintaining the sample <NUM> at a constant magnetic field of <NUM> T. As shown in this graph, Fe-La-Si transitions from a magnetic to a non-magnetic state with a rise in the temperature T. <FIG> is a graph of the magnetic state of <NUM>% purity FeRh versus temperature T within the sample <NUM>, while maintaining the sample <NUM> at a constant magnetic field of <NUM> T. As shown in this graph, FeRh transitions from a non-magnetic to a magnetic state with a rise in the temperature T.

Referring to <FIG>, a procedure <NUM> is performed by the apparatus <NUM> for using the magnetic apparatus <NUM> and the magnetically manipulatable structure <NUM> to control, alter, or operate on the sample <NUM>. For example, the structure <NUM> can include the magnetically manipulatable materials <NUM>, the magnetic apparatus <NUM> can be an MRI machine, and the materials <NUM> can act as one or more tunable and switchable labels in the MRI machine <NUM>.

The procedure <NUM> includes receiving the sample <NUM> in the sample volume <NUM> defined by the magnetic apparatus <NUM> and the magnet <NUM> (<NUM>). The sample <NUM> can be placed inside the magnet <NUM> using any suitable technique that is used in MRI machines. The sample <NUM> can be a whole living organism, or it can be a portion or a region of a living organism. The magnetically manipulatable structure <NUM> and the material <NUM> are prepared within the sample <NUM> (<NUM>). For example, the structure <NUM> can be embedded within the sample <NUM> using the injection apparatus <NUM> and this can occur prior to or after the sample <NUM> is placed inside the magnet <NUM>.

The magnetic field having the magnitude B is created in the sample <NUM> (<NUM>). For example, the control system <NUM> can send a signal to the energy supply <NUM> to provide current to the electrically conductive wire coils of the magnet <NUM>. The magnitude B of the magnetic field is generally greater than <NUM> Tesla and can be in a range of <NUM>-<NUM> Tesla.

A property associated with the sample <NUM> is changed while generally maintaining the magnetic field magnitude B constant in the sample <NUM> (<NUM>). The property that is changed (<NUM>) can be the magnetic field or a temperature or both the magnetic field and the temperature of the sample <NUM>. If the property that is changed is the magnetic field, then the change in the magnetic field is substantially smaller than the magnitude B of the field that is held constant. The change in magnetic field is at least an order of magnitude smaller than the magnitude B. Similarly, if the overall temperature of the sample <NUM> is between about <NUM>-<NUM>, and the property to be changed (<NUM>) is the temperature, then the change in the temperature is substantially less than the overall temperature of the sample <NUM>. For example, the temperature change can be about <NUM>-<NUM>. The change in the property (<NUM>) can be affected by the sample property scanning system <NUM>, as discussed above.

Because the magnetically manipulatable structure <NUM> includes magnetically manipulatable materials <NUM>, the change in the property (<NUM>) causes the magnetically manipulatable materials <NUM> to transition from a first magnetic state to a second magnetic state, and this transition causes a change in the sample <NUM> near to the structure <NUM>. This change in the sample <NUM> is detected (<NUM>). This means that the structure <NUM> can be turned on and off by the procedure <NUM> and has the effect that it can be used as a high-contrast tunable and switchable label for MRI machines <NUM>. The structure <NUM> can therefore be used as an MRI contrast agent or a sensor because of these properties. Thus, the change in the magnetization of the magnetically manipulatable materials <NUM> of the structure <NUM> can be detected by the apparatus <NUM> by observing the effect the change has on the water or biological tissue surrounding the materials <NUM>.

Referring to <FIG>, a procedure <NUM> is performed by the apparatus <NUM> for actuating (for example, activating and de-activating) a biological construct (which can be the thermally-sensitive biological construct <NUM>) within a sample <NUM>. The sample <NUM> is received in the actuation volume <NUM> defined by the magnet <NUM> of the magnetic apparatus <NUM> (<NUM>). The magnetically manipulatable structure <NUM> is physically (for example, thermally) coupled with the biological construct within the sample <NUM> (<NUM>) such that the biological construct changes its status in response to a change in property of the magnetically manipulatable structure <NUM>. Thus, if the physical coupling is a thermal coupling and the biological construct is a thermally-sensitive biological construct <NUM>, then the thermally-sensitive biological construct <NUM> changes its status in response to a change in a temperature of the magnetically manipulatable structure <NUM>.

A characteristic within the sample <NUM> is changed (<NUM>) For example, the characteristic of the sample <NUM> that is changed (<NUM>) is the magnetic field within the sample, <NUM>. The magnetic field within the sample <NUM> can be changed by changing a DC current supplied to the magnet <NUM>. The change in the magnetic field is substantially smaller than the magnitude B of the field that is held constant. The change in magnetic field is at least an order of magnitude smaller than the magnitude B. The change in the characteristic within the sample <NUM> (<NUM>) can be affected by the sample property scanning system <NUM>, as discussed above.

Claim 1:
An apparatus (<NUM>) comprising:
a magnetic apparatus (<NUM>) that defines an actuation volume that is large enough to accommodate a sample, the magnetic apparatus (<NUM>) including a magnet (<NUM>) that is configured to create a magnetic field having a magnitude B in the sample when supplied with a DC current, the magnetic field magnitude B being greater than <NUM> Tesla or in a range of <NUM>-<NUM> Tesla;
at least one biological construct (<NUM>) within the sample, the biological construct (<NUM>) configured to change its status in response to a change in temperature of a magnetocaloric actuator; and
at least one magnetocaloric actuator (<NUM>) coupled with the biological construct (<NUM>), wherein each magnetocaloric actuator (<NUM>) is a particle having a size on the order of about <NUM>-<NUM>;
wherein each magnetocaloric actuator (<NUM>) is configured such that a change in magnitude B of the created magnetic field in the sample causes the temperature of the magnetocaloric actuator (<NUM>) to change, which causes a change in the status of the biological construct (<NUM>).