Systems and methods for medical contrast imaging

Abstract

Systems and methods for medical contrast imaging are disclosed. Systems and methods of the present disclosure address the challenges of continental medical imaging by, for example, using contrast agents that facilitate use of low-risk wavelengths of imaging radiation, and / or by using imaging methods that facilitate imaging with resolution and / or image quality that are adequate for diagnosis, treatment, and / or any other suitable purpose(s). Examples of suitable wavelengths for the imaging radiation may include certain microwave and / or radio-frequency wavelengths that pose little to no health hazards.

Description

[0001] #3538269 086041-800003

[0002] I SYSTEMS AND METHODS FOR MEDICAL CONTRAST IMAGING

[0003] CROSS REFERENCE TO RELATED APPLICATION

[0004] This application claims the right of priority to U. S. Provisional Patent Application number 63 / 722,761 tiled on November 20, 2024, the entirety of which is hereby incorporated herein by reference in its entirety.

[0005] BACKGROUND

[0006] Medical imaging, including medical contrast imaging, of a patient may assist in the diagnosis of and even treatment of a patient. There are challenges in conventional medical contrast imaging. One challenge is that substances that might otherwise be suitable for use as contrast agents pose an unacceptable risk to patient safety, e.g., because they are toxic, carcinogenic, radioactive, or because they are unlikely to safely exit or be absorbed by the patient’s body in an acceptable timeframe. Another challenge is that the wavelengths of radiation that are known to work well with conventional contrast agents may typically only be applied to a patient’s body for a limited time interval without posing a risk to health. For example. X-rays used for medical imaging have enough energy to potentially damage human DNA, which is associated with an increased risk of developing cancer, and therefore a patient’s exposure to X-rays must be kept within an acceptable limit.

[0007] Therefore, there remains & need for improved medical imaging, including medical contrast imaging. #3538269 086041 -000003

[0008]

[0009] Tn certain aspects, systems and methods for medial contrast imaging are disclosed. In some aspects, methods include emitting electromagnetic radiation from an emission source, wherein said electromagnetic radiation comprises radiation in the range of between 0.5 GHz to 0.9 GHz; I GHz and 10 GHz, 1.6 GHz to 2.4 GHz, 2 GHz to 9 GHz, 3 GHz to 8 GHz, 4 GHz to 7 GHz, 5 GHz to 6 GHz, 900 MHz to 20 GHz. or 700 MHz to 20 GHz; helper bands may also be employed.

[0010] In other aspects methods include the act of administering to the patient a reflective contrast agent or absorptive contrast agent. Tn some aspects, a reflective contrast agent may comprise aluminum. In other aspects, an absorptive contrast agent may comprise iron oxide nanoparticles, nickel nanoparticles, cobalt nanoparticles, gadolinium compounds, titanium dioxide, barium titanate, lead zirconate titanate, zirconium dioxide, manganese chloride, bismuth-based compounds, tungsten oxides, or calcium carbonate.

[0011] Additional embodiments of the invention, as well as features and advantages thereof, will be apparent from the descriptions herein. #3538269 086041 -000003

[0012] 3

[0013] BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Fig, 1 is a schematic diagram of an illustrative system for contrast imaging in accordance with aspects of the present teachings.

[0015] Fig. 2 is a schematic diagram of an illustrative contrast agent carrier in accordance with aspects of the present teachings.

[0016] Fig. 3 is a schematic diagram of another illustrative system for contrast imaging in accordance with aspec ts of the present teachings.

[0017] Fig. 4 is a schematic diagram of another illustrative contrast agent carrier in accordance with aspects of the present teachings.

[0018] Fig. 5 is a schematic diagram of an illustrative nested carrier in accordance with aspects of the present teachings.

[0019] Fig. 6 is a flow chart depicting steps of an illustrative method for contrast imaging in accordance with aspects of the present teachings. #3538269 086041-000003

[0020] DETAILED DESCRIPTION

[0021] For the purposes of promoting an understanding of the principles of the invention, reference will now be made to certain embodiments, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such alterations and farther modifications, and such further applications of the principles of the invention as described herein being contemplated as would normally occur to one skilled in the art io which the invention relates. Additionally, in the detailed description below, numerous alternatives are given for various features. It will be understood that each such disclosed alternative, or combinations of such alternatives, may be combined with the more generalized features discussed in the Summary above, or set forth in the embodiments described below to provide additional disclosed embodiments herein.

[0022] Various aspects, examples, and embodiments of systems and methods for contrast imaging are described below and illustrated in the associated drawings. Unless otherwise specified, systems or methods in accordance with aspects of the present teachings, and / or various components of such systems and methods, may contain at least one of the structures, components, functionalities, and / or variations described, illustrated, and / or incorporated herein. Furthermore, unless specifically excluded, the process steps, structures, components, functionalities, and / or variations described, illustrated, and / or incorporated herein in connection with the present teachings may be included in other similar devices and methods, including being interchangeable between disclosed embodiments.

[0023] The following description of various embodiments is merely illustrative in nature and is in no way intended to limit the disclosure, its application, or uses. Additionally, the advantages provided by the examples and embodiments described below are illustrative in nature and not all examples and embodiments provide the same advantages or the same degree of advantages.

[0024] The following definitions apply herein, unless otherwise indicated.

[0025] “Comprising,” “including,” and “having” (and conjugations thereof) are used interchangeably to mean including but not necessarily limited to, and are open-ended terms not intended to exclude additional, unrecited elements or method steps.

[0026] Terms such as “first”, “second”, and “third” are used to distinguish or identify various members of a group, or the like, and are not intended to show serial or numerical limitation.

[0027] “AKA” means “also known as,” and may be used to indicate an alternative or corresponding term for a given element or elements. #3530269 086041-000003

[0028] 5

[0029] " Providing.” in the context of a method, may include receiving, obtaining, purchasing, manufacturing, generating, processing, preprocessing, and / or the like, such that the object or material provided is in a state and configuration for other steps to be carried out.

[0030] “Processing logic” describes any suitable device(s) or hardware configured to process data by performing one or more logical and / or arithmetic operations (e.g., executing coded instructions). For example, processing logic may include one or more processors (e.g., central processing units (CPUs) and / or graphics processing units (GPUs)), microprocessors, clusters of processing cores, FPGAs (field-programmable gate arrays), artificial intelligence (Al) accelerators, digital signal processors (DSPs), and / or any other suitable combination of logic hardware.

[0031] A “controller” or “electronic controller” includes processing logic programmed with instructions to cany out a controlling function with respect to a control element. For example, an electronic controller may be configured to receive an input signal, compare the input signal to a selected control value or setpoint value, and determine an output signa! to a control element (e.g., a motor or actuator) io provide corrective action based on the comparison. In another embodiments, an electronic controller may be configured to interface between a host device (e.g., a desktop computer, a mainframe, etc.) and a peripheral device (e.g., a memory device, an input'output device, etc.) to control and or monitor input and output signals to and from the peripheral device.

[0032] In this disclosure, one or more publications, patents, and / or patent applications may be incorporated by reference. However, such material is only incorporated to the extent that no conflict exists between the incorporated material and the statements and drawings set forth herein. In the event of any such conflict, including any conflict in terminology, the present disclosure is controlling.

[0033] A contrast agent (AKA a contrast medium) may be used to enhance medical imaging of a patient. For example, it is conventional to enhance X-ray-based imaging techniques by administering a radiocontrast agent to a region of interest of the patient’s body. The radiocontrast agent absorbs X-rays that would otherwise pass through the region of interest. The resulting X-ray image thus exhibits high contrast between the portions of the region of interest where the radiocontrast agent is present and the portions where it is absent. The high contrast tends to enhance visibility of the image, making it easier to distinguish internal structures of the patient and obtain information of interest (e.g., diagnostic information). #3538269 086041-800003

[0034] 6

[0035] However, there are challenges in conventional medical contrast imaging. One challenge is that some substances that might otherwise be suitable for use as contrast agents pose an unacceptable risk to patient safety, e.g., because they are toxic, carcinogenic, radioactive, or because they are unlikely to safely exit or be absorbed by the patient’s body in an acceptable timeframe. Another challenge is that the wavelengths of radiation that are known to work well with conventional contrast agents may typically only be applied to a patient’s body for a limited time interval without posing a risk to health. For example, X-rays used for medical imaging have enough energy to potentially damage human DNA, which is associated with an increased risk of developing cancer, and therefore a patient’s exposure to X-rays must be kept wit h in an acceptable limit.

[0036] Systems and methods of the present disclosure address these challenges by using contrast agents that facilitate use of low-risk wavelengths of imaging radiation, and / or by using imaging methods that facilitate imaging with resolution and / or image quality that are adequate for diagnosis, treatment, and / or any other suitable purpose(s). Examples of suitable wavelengths for the imaging radiation may include certain microwave and / or radio- frequency wavelengths that pose little to no health hazards.

[0037] The present teachings include embodiments of imaging systems and methods in which the contrast agent is configured to reflect and / or scatter the imaging radiation, and embodiments of imaging systems and methods in which the contrast agent is configured to absorb the imaging radiation. In some embodiments, the methods and apparatus of the current disclosure may be used in a hospital, an ambulance, a helicopter, a plane, or other vehicle that assists with medical treatment and / or diagnosis. Overview's of these embodiments and examples are provided below.

[0038] Reflective Contrast Agent

[0039] In some embodiments, a contrast agent in accordance with aspects of the present teachings comprises very small particles of a substance(s) configured to scatter and / or reflect low-risk wavelengths of radiation and to pose little or no risk to the imaging subject (e.g., a human or animal patient). Such contrast particles may be referred to herein as ‘■reflective contrast particles” or a “reflective contrast agent.” When an ensemble of reflective contrast particles is disposed at a particular part of the subject’s body (e.g., a particular organ and / or set of blood vessels), the imaging radiation scatters differentially from that particular part of the body compared to other parts of the body. The scattered radiation may be detected, and #3530269 086041-000003

[0040] based on the detected scattered radiation, information may be determined about the location of the contrast particles within the subject being imaged.

[0041] Based on this information, a visualization of an interior portion of the subject may be generated.

[0042] Accordingly, in at least some embodiments that include a reflective contrast agent, information about the subject is determined by emitting radiation toward the subject, detecting reflected radiation, and determining information about the position and / or spatial extent of contrast particles within the subject based on the time elapsed between emission and detection of the radi ation and an estimate of the travel speed of the radiation. Additionally, or alternatively, information about the speed and / or direction in which the contrast particles are moving within the subject (e.g., through the subject’s blood stream) may be determined based on changes in the position of the contrast particles over time and / or on Doppler shift(s) in the imaging radiation.

[0043] An example of a suitable substance the reflective contrast agent may comprise is aluminum, which poses at most a very low risk to human safety (e.g., in terms of toxicity, carcinogenicity, radioactivity, and the like). It is known, in the context of military radar countermeasures, to use aluminum particles called chaff to reflect a radio-frequency radar signal back toward the originating radar system, such that the system fails by detecting the chaff rather than a target of interest. However, microwave and radio-frequency radiation have conventionally been considered unsuitable for medical imaging because, according to conventional wisdom, they cannot achieve adequate resolution for medical imaging purposes.

[0044] Absorptive. Contrast Agent

[0045] In some embodiments in accordance with aspects of the present teachings, the contrast agent is configured to absorb low-risk wavelengths of radiation and to pose little or no risk to the imaging subject. Such contrast particles may be referred to herein as “absorptive contrast particles’' or an “absorptive contrast agent.” When an ensemble of absorpti ve contrast particles is disposed at a particular part of the subject’s body (e.g., a particular organ and / or set of blood vessels), the imaging radiation is absorbed differentially at that particular pail of the body compared to other parts of the body.

[0046] Radiation that passes through the body may be detected, and based on the detected radiation, information may be determined about the location of the contrast particles within the subject being imaged. Based on this information, a visualization of an interior portion of the subject may be generated. #3538269 086041-000003

[0047] 8

[0048] Accordingly, in at least some embodiments that include an absorptive contrast agent, information about the subject is determined by emitting radiation toward the subject from a first side of the subject, detecting transmitted radiation at a second, opposing side of the subject, and determining information about the position andfor spatial extent of contrast particles within the subject based on the transmitted radiation (including, e,g„ the reduction in transmitted radiation associated with absorption by the absorptive contrast particles). In some embodiments, information about the speed and / or direction in which the contrast particles are moving within the subject (e.g., through the subject’s blood stream) may be determined based on changes in the position of the contrast particles over time.

[0049] The following sections of this disclosure describe illustrative aspects of imaging systems and methods involving imaging radiation of low-risk wavelengths, such as microwave and / or radio wavelengths, and suitable reflective contrast agent(s) and / or absorptive contrast agent(s). The embodiments in these sections are intended for illustration and should not be interpreted as limiting the scope of the present disclosure and may include one or more distinct embodiments or examples, and / or contextual or related information, function, and / or structure.

[0050] In this disclosure, unless otherwise specified, no distinction is made between the terms “scatter” and “reflect.” The terms “radiation” and “light” are also used interchangeably with each other unless otherwise specified. Additionally, the subject being imaged may be referred to as a patient, but rise of the word “patient” is not intended to limit any particular example in this disclosure to a medical setting unless so specified.

[0051] Although the examples and embodiments described herein generally refer to a human or animal imaging subject, in some embodiments the imaging subject is an inanimate object.

[0052] Illustrative Imaging System for Reflection-Based Measurement

[0053] With reference to Fig. I, this section describes an illustrative system 100 configured for reflection-based imaging in accordance with aspects of the present teachings. System 100 includes at least one emitter 104 configured to emit electromagnetic radiation having desired wavelengths or frequencies. In this embodiment, the desired wavelengths comprise a range of primarily microwave and / or radio wavelengths, such that the spectrum of emitted electromagnetic radiation has adequate energy for imaging in microwave and / or radio wavelengths with the contrast media described herein, and has little or no energy in the wavelength ranges that may pose a health hazard to a patient being imaged, such as X-ray #3530269 086041-000003

[0054] 9

[0055] wavelengths. The exact intensity that is necessary or desirable at each wavelength may vary from embodiment to embodiment, based on the contrast media used, the body part being imaged, the properties desired for the image, and / or any other suitable factors, Examples of suitable wavelength ranges may include 0.5 GHz to 0.9 GHz; 1 GHz and 10 GHz, 1.6 GHz to 2.4 GHz, 2 GHz to 9 GHz, 3 GHz to 8 GHz, 4 GHz to 7 GHz, 5 GHz to 6 GHz, 900 MHz to 20 GHz. or 700 MHz to 20 GHz, and / or any other suitable wavelength ranges.

[0056] Emitter 104 may comprise any suitable device(s) for generating electromagnetic radiation at the desired wavelengths, and causing or allowing the generated electromagnetic radiation to be directed to a subject 108 (e.g., a body or body portion of a human or animal being imaged, or any other suitable imaging subject). For example, emitter 104 may comprise one or more transmitters configured io generate a suitable signal (e.g., a radio-frequency and / or microwave signal) coupled to one or more antennae configured to radiate the signal. In some embodiments, the one or more antennae comprise an array of antennae, such as a phased array.

[0057] In some embodiments, system 100 includes a plurality of’ emitters 104. The emitters of the plurality of emitters may have similar structures or different structures from one another, and may be configured to emit light of similar or different wavelengths. In some embodimen ts, all of the emitters or subset(s) of the emitters share common components, such as common circuitry, a common power source, and / or any other suitable components or subsystems.

[0058] Including more than one emitter 104 in system 100 is feasible because the wavelengths of light used by system 100 pose no known health risks to patients, and therefore increasing the amount of light incident on the patient by increasing the number of emitters does not noticeably increase the patient's risk. In contrast, many known medical imaging systems use higher energy radiation such as X-ray radiation, which poses enough risk to the patient that multiple emitters are conventionally considered unacceptably risky. Additionally, unlike conventional higher-energy radiation, microwave and radio-frequency radiation may optionally be directed onto a patient in a continuous stream rather than in pulses.

[0059] As stated above, emitter 104 is configured to emit radiation onto subject 108. Subject 108 contains a plurali ty of con trast particles 112 configured to reflect at least a subset of the wavelengths of light emitted by emitter 104, such that particles 112 tend to alter a propagation direction of the emitted light (e.g., by reflecting the light back toward the #3538269 086041 -000003

[0060] 10

[0061] emitter). Particles 112 may be administered to the subject in any suitable maimer, illustrative embodiments of which are described elsewhere herein.

[0062] System 100 further includes at least one receiver 116 (AKA a detector). Receiver 116 may include any suitable devicefs) configured to detect radiation emitted by emitter 104, inchiding at least the wavelengths that particles 112 are configured to reflect. For example, receiver 116 may comprise one or more antennae configured to receive the reflected signal, coupled to suitable electronics configured to process the received signal such that the desired data may be obtained based on the signal.

[0063] Receiver 116 is positioned such that it detects radiation that is emitted by emitter 104 and reflected by particles 112 that are within subject 108. Any suitable arrangement of the emitter and receiver may be used. In some embodiments, receiver 116 is disposed adjacent emitter 104 such that the receiver is positioned to detect radiation reflected by contrast particles 1 12 generally back in the direction from which it was emitted. In some embodiments, receiver 116 and emitter 104 are disposed in a common housing. In some embodiments, receiver 116 and emitter 104 share a common antenna that both emits radiation and receives radiation reflected back by particles 1 12. Fig, 1 depicts an embodiment in. which emitter 104 and receiver 116 comprise a same device (e.g., the same antenna or same antenna array).

[0064] In some embodiments, system 100 includes a plurality of receivers 116, In some embodiments, each receiver of the plurality of receivers shares a common antenna with a respective emitter, such that the system includes a plurality of integrated emltter / receiver devices. Including a plurality of receivers may facilitate imaging subject 108 from two or more angles and / or imaging two or more portions of subject 108 (e.g., simultaneously and / or in rapid succession). Additionally, or alternatively, including a plurality of receivers may enable depth perception, such as creation of a three-dimensional image or video of the subject.

[0065] System 100 further comprises a data processing system 120 (AKA a computer, computing system, and / or computer system). Data processing system 120 is configured to receive data from receiver) s) 116 and to determine information about the imaging subject based on the received data. Determining information about the imaging subject ay comprise determining information about the location(s) of contrast particles 112 within the imaging subject. Based on the part(s) of the imaging subject’s body where contrast particles are #3530269 086041-000003

[0066] expected to be, the information about the spatial position(s) of the contrast particles may be used to determine information about the imaging subject's body.

[0067] For example, in a coronary angiography process, contrast particles may be administered to the patient’s major coronary artery (e.g., by inserting a catheter into a more accessible artery' and through the arterial system into the major coronary' artery, and injecting the contrast particles through the catheter). The contrast particles flow with the blood through the coronary arteries. Radiation emitted by emitter 104 and detected by receiver 116 may be used to determine information about the location and / or spatial extent of the contrast particles. Based on this determined information, information about the arteries (such as the size of arterial openings) may be determined.

[0068] In some embodiments, the information about the imaging subject is used to generate a visualization of the imaging subject (or a portion thereof), such as an image, series of 10 images, and / or video. Optionally, system 100 further comprises a display 120 on which the visualization may be displayed. Display 120 may be coupled to data processing system 120, or data may be transferred from the data processing system to the display in another suitable way (e.g., via easily removable storage media such as compact disks or thumb drives).

[0069] In some embodiments, data processing system 120 and / or display 124 are local (e.g., located in the same room, building, or portion of a building as the receiver). In other embodiments, the data processing system or the display or both are remote from the receiver.

[0070] For example, data processing system 120 may be a remote server located in a different geographic location from the imaging subject, receiver, and emitter. As another embodiment, 20 display 124 may be a remote display; for example, the visualization information obtained by the imaging system may be transmitted to a display at a different geographic location.

[0071] This may facilitate telehealth, remote training, and / or other suitable uses of the imaging system.

[0072] Illustrative Carrier

[0073] With reference to Fig, 2, this section describes an illustrative carrier 150 in accordance with aspects of the present teachings. Carrier 150 is configured to deliver contrast particles to a region of interest of an imaging subject, such as a portion of a body of a human or animal patient. In some embodiments, carrier 150 may be referred to as a nanocarrier because in such embodiments it has a size (e.g., a diameter) in the range of 30 approximately 1 nanometer – 1000 nanometers. #3530269 086041-000003

[0074] Fig. 2 schematically depicts carrier 150 and is not intended to be limiting with regard to size, shape, or dimension. In general, carrier 150 may comprise any suitable object configured to transport a plurality of contrast particles 154, to carry the contrast particles for a suitable length of time, and to release the contrast particles after the suitable time has elapsed. Freeing the contrast particles from the carrier allows the contrast particles to travel into regions of interest of the subject to facilitate imaging.

[0075] In the depicted embodiment, carrier 150 comprises an outer layer 158 configured to contain particles 154; in other embodiments, however, a carrier may be configured to transport particles in another suitable manner, such as by carrying particles that are bound to an outer surface of the carrier.

[0076] Returning to the depicted embodiment, carrier 150 may be configured such that particles 154 may be released from outer layer 158 by any suitable process(es). Examples of suitable processes may include, without limitation, degradation of outer layer 158; diffusion of particles 154 across outer layer 158; solvent-controlled release mechanism(s) such as osmosis-controlled release and / or swelling-controlled release; and destruction of outer layer 158 by a suitable stimulus (e g... light, pH, temperature, ionic strength, acoustic waves, electric and or magnetic fields, etc.). A carrier may be selected for a given use case based on its release mechanism (among other factors, in some cases). For example, a particular type of release mechanism may be well suited to deliver particles 154 to a particular part of the human body.

[0077] In general, particles 154 may have any suitable size for being delivered to the region of interest of the imaging subject, facilitating contrast imaging in accordance with aspects of the present teachings, and exiting (or ceasing to be within) the imaging subject with an acceptably low risk of harm to the imaging subject. Carrier 150 may have any suitable size for delivering particles 154 to the region of interest and exiting (or ceasing to be within) the imaging subject with an acceptably low risk of harm to the imaging subject. In some embodiments, carrier 150 is 6 nm or less in size (e.g., in diameter); this size permits the carrier to be renally excreted by a human imaging subject’s kidney, because objects larger than 6 nm generally cannot fit through the glomerular filtration apparatus.

[0078] In other embodiments, however, carrier 150 is larger than 6 nm (e.g., 10 nm or larger, 20 nm or larger, 50 nm or larger, 100 nm or larger, and / or any other suitable size). In embodiments in which carrier 150 is larger than 6 nm, it may be excreted in feces, be destroyed by the imaging subject’s immune system, naturally degrade within the imaging #3530269 086041-000003

[0079] 13

[0080] subject, and / or otherwise suitably cease being present within the subject in a suitable timeframe.

[0081] A single carrier 150 is depicted schematically in Fig. 2. However, some methods of imaging in accordance with aspects of the present teachings include administering a plurality of carriers to the imaging subject. In some embodiments, the plurality of carriers administered to the imaging subject includes carriers of different sizes, carriers configured to release contrast particles in different ways, carriers configured to travel through the imaging subject in different ways, and / or carriers configured to be excreted or otherwise to cease to be present in different ways.

[0082] Carrier(s) 150 may be administered to an imaging subject in any suitable manner. For example, the carrier(s) may be injected into an appropriate area of the imaging subject, swallowed by a human or animal imaging subject, inhaled by a human or animal imaging subject, and / or administered in any other suitable way(s). In some embodiments, carriers are administered by two or more methods,

[0083] Illustrative embodiments of suitable carriers may include, without limitation, one or more of the following: liposomes (which may comprise spherical vesicles with one or more lipid bilayers and may be biocompatible, biodegradable, and / or capable of carrying both hydrophilic and hydrophobic drugs); micelles (which may comprise spherical structures formed by the self-assembly of amphiphilic molecules and may be well-suited to carrying hydrophobic particles); polymeric nanoparticles (which may comprise solid particles made from biodegradable polymers, such as nanospheres comprising solid matrix systems throughout which the contrast particles are dispersed, or core-shell systems in which the contrast particles are enclosed in a polymeric shell); dendrimers (which may comprise highly branched, tree-like structures with a central core, and may have a high capacity for loading contrast particles, and / or be able to carry multiple types of contrast particles, and / or to carry other particles along with contrast particles); nanogels (which may comprise hydrogel particles at the nanoscale and may be capable of absorbing large amounts of water and releasing their contrast particles in response to stimuli like pH, temperature, and / or other suitable stimuli); solid lipid nanoparticles (SLNs) (which may comprise solid nanoparticles made from lipids that are solid at room temperature and may in which carrier 150 is larger than 6 nm, it may be excreted in feces, be destroyed by the imaging subject’s immune system, naturally degrade within the imaging subject, and / or otherwise suitably cease being present within the subject in a suitable timeframe. #3530269 086041-000003

[0084] 1

[0085] A single carrier 150 is depicted schematically in Fig. 2. However, some methods of imaging in accordance with aspects of the present teachings include administering a plurali ty of carriers to the imaging subject. In some embodiments, the plurality of carriers administered to the imaging subject includes carriers of different sizes, carriers configured to release contrast particles in different ways, carriers configured to travel through the imaging subject in different ways, and / or carriers configured to be excreted or otherwise to cease to be present in different ways.

[0086] Carrier(s) 150 may be administered to an imaging subject in any suitable manner. For example, the carrier(s) may be injected into an appropriate area of the imaging subject, swallowed by a human or animal imaging subject, inhaled by a human or animal imaging subject, and / or administered in any other suitable way(s). In some embodiments, carriers are administered by two or more methods.

[0087] Illustrative embodiments of suitable carriers may include, without limitation, one or more of the following; liposomes (which may comprise spherical vesicles with one or more lipid bilayers and may be biocompatible, biodegradable, and / or capable of carrying both hydrophilic and hydrophobic drugs); micelles (which may comprise spherical structures formed by the self-assembly of amphiphilic molecules and may be well-suited to carrying hydrophobic particles); polymeric nanoparticles (which may comprise solid particles made from biodegradable polymers, such as nanospheres comprising solid matrix systems throughout which the contrast particles are dispersed, or core-shell systems in which the contrast particles are enclosed in a polymeric shell); dendrimers (which may comprise highly branched, tree-like structures with a central core, and may have a high capacity for loading contrast particles, and / or be able to carry multiple types of contrast particles, and / or to carry other particles along w'ith contrast particles); nanogels (which may comprise hydrogel particles at the nanoscale and may be capable of absorbing large amounts of water and releasing their contrast particles in response to stimuli like pH, temperature, and-'or other suitable stimuli); solid lipid nanoparticles (SLNs) (which may comprise solid nanoparticles made from lipids that are solid at room temperature and may metals (e.g., copper, silver, gold, steel, brass, etc.); dielectric materials (e.g., glass, ceramics, quartz, sapphire); high dielectric materials (e.g., polytetrafluoroethylene (FTFE), polycarbonate, polystyrene); graphene; graphite; gold nanoparticles; silver nanoparticles; copper nanoparticles; carbon nanotubes; fullerenes; polyaniline; polypyrrole; poly(3,4-ethylenedioxythiophene); gallium; gallium alloys; eutectic gallium-indium; aluminum oxide; engineered metamaterials; #3530269 086041-000003

[0088] 15

[0089] cadmium selenide; lead sulfide: lead selenide; silver-gallium alloys; copper-indium-gallium-selenide.

[0090] In general, the reflective substance(s) may be disposed in and / or on particles 154 in any suitable manner. In some embodiments, particles 154 are at least partially coated in the reflective substance, with the interior portions of the particles not necessarily comprising that same substance. In some embodiments, the reflective substance(s) are distributed throughout a given particle (e.g., in some cases, uniformly throughout the particle), such that the reflective substance is disposed in interior portions of the particle.

[0091] In some embodiments, the entire particle comprises the reflective substance and is substantially free of any other substance. For example, the entire particle may be made up of the reflective substance (e.g., the particle may be entirely aluminum, in embodiments where the reflective substance is aluminum). In general, any suitable purity of the reflective substance may be used. In some embodiments, the purity is at least 90%, at least 95%, at least 98%, at least 99%, at least 99.9%, or any other suitable purity.

[0092] As described above, in general, particles 154 may have any suitable size and shape for being delivered to the region of interest of the imaging subject, facilitating contrast imaging in accordance with aspects of the present teachings, and exiting (or ceasing to be within) the imaging subject with an acceptably low risk of harm to the imaging subject. Particles 154 may be configured to exit and / or otherwise cease to be within the imaging subject in any suitable manner(s), including those described above with reference to carrier 150.

[0093] In some embodiments, the size of particles 154 is selected based at least in part on the imaging subject. For example, if the imaging subject is a human or animal, the size of particles 154 may be selected based at least in part on the bodily organ(s) or system(s) the particles will need to be located at in order to facilitate imaging. In some embodiments, particles 154 have a size in the range of 1 nm – 600 nm (inclusive).

[0094] Suitable shape(s) for particles 154 may include, without limitation, spherical, roughly spherical, polyhedral, irregular, elongate, or sheet-like. The particles being used in a given situation need not all have the same shape or size, but may have the same shape and / or size.

[0095] Illustrative Imaging, 5

[0096]

[0097] )781601 for Abswtfo^

[0098] With reference to Fig. 3, this section describes an illustrative system 170 configured for imaging using an absorptive contrast agent in accordance with aspects of the present teachings. Imaging using an absorptive contrast agent may be referred to as absorption-based, #3530269 086041-000003

[0099] 16

[0100] because the contrast agent absorbs radiation, or as transmission-based, because the radiation being measured is radiation that is transmitted through the imaging subject.

[0101] In many respects, system 170 is similar to system 100, and so an abbreviated description of certain components is provided here. System 170 includes at least one emitter 174. Like emitter 104 of system 100, emitter 174 may comprise any suitable device(s) configured to emit electromagnetic radiation having desired wavelengths or frequencies. Suitable example wavelengths are described above with reference to emitter 104.

[0102] Emitter 174 is configured to direct radiation toward an imaging subject 178 (similar to im aging subject 108 described above). Subject 178 contains a plurality of contrast particles 182 configured to absorb at least a subset of the wavelengths of light emitted by emitter 174.

[0103] System 170 further includes at least one receiver 186 (AKA a detector). Receiver 186 may include any suitable device(s) configured to detect radiation emitted by emitter 174, including at least the wavelengths that particles 182 are configured to absorb.

[0104] Emitter 174 and receiver 186 are positioned relative to subject 178 such that at least some of the light emitted by emitter 174 impinges on the subject, and light that passes through the subject is detected by receiver 186. For example, emitter 174 and receiver 186 may be disposed on opposing sides of the imaging subject’s body, or opposing sides of a portion of the imaging subject's body.

[0105] In some embodiments, system 170 includes a plurality of emitters 174 and / or a plurality of receivers 186, which may enable depth perception (e.g., 3-D imaging), imaging the subject from two or more different angles, and / or imaging two or more portions of the subject.

[0106] System 170 further comprises a data processing system 190, which may be similar to data processing system 120 described above. Optionally, system 170 comprises a display 194, which may be similar to display 124 described above.

[0107] Illustrative Carrier and Absorptive Contrast Particles

[0108] With reference to Fig, 4, this section describes an illustrative carrier 200 and an illustrative absorptive contrast particle 204 in accordance with aspects of the present teachings.

[0109] Carrier 200 is similar to carrier 150 in many respects, and so an abbreviated description is provided here. Carrier 200 is configured to deliver contrast particles 204 to a region of interest of an imaging subject, such as a portion of a body of a human or animal #3530269 086041-000003

[0110] patient. In the depicted embodiment, carrier 200 comprises an outer layer 208 configured to contain particles 204, though as described above with reference to carrier 150, in other embodiments a carrier may be configured to transport particles in another suitable manner.

[0111] In this embodiment, contrast particles 204 are absorptive contrast particles. Particles 204 are examples of particles 182 described above with reference to system 170.

[0112] Absorptive contrast particles 204 may comprise any suitable substances) that are configured to absorb radiation of the wavelength(s) being used sufficiently to facilitate imaging, and configured to pose an acceptably low' risk of harm to the imaging subject.

[0113] Examples of suitable absorptive substances may include, without limitation, the following: iron oxide nanoparticles, nickel nanoparticles, cobalt nanoparticles, gadolinium compounds, titanium dioxide, barium titanate, lead zirconate titanate, zirconium dioxide, manganese chloride, bismuth-based compounds, tungsten oxides, calcium carbonate solutions. As described above with reference to reflective contrast particle 154, any suitable purity of the absorptive substances) may be used.

[0114] As described above with reference to reflective contrast particle 154, the absorptive substancefs) of particle 204 may comprise any suitable portion of particle 204.

[0115] For example, the absorptive substance(s) may comprise one or more coatings, may be distributed throughout at least a portion of the particle, may comprise the entirety of the particle, and / or may be part of the particle in any other suitable way.

[0116] Absorptive contrast particles 204 may have any suitable size and shape, as described above with reference to reflective contrast particles 154.

[0117] Illustrative Nested Carrier

[0118] With reference to Fig. 5, this section describes an illustrative nested carrier 250 in accordance with aspects of the present teachings. Nested carrier 250 comprises an outer carrier 254 configured to carry a plurality of inner carriers 258, which are each configured to cany a plurality of contrast particles 262. Inner carriers 258 may be examples of carrier 150 or 200 described above. Contrast particles 262 may be examples of reflective contrast particles 154 or absorptive contrast particles 204; in some embodiments, contrast particles 262 comprise some particles that are reflective and some particles that are absorptive.

[0119] Outer carrier 254 may comprise any suitable substance(s) and structure(s) configured to carry and release the plurality of inner carriers 258 in any suitable manner. #3530269 086041-000003

[0120] 18

[0121] For example, outer carrier 254 may comprise a capsule configured to contain inner carriers 258. In some embodiments, outer carrier 254 comprises one or more of the example structures or substances described above with reference to carrier 150. Put another way, outer carrier 254 may be similar to carrier 150 or 200 and big enough to contain one or more other carriers (e.g., carriers smaller than outer carrier 254).

[0122] Outer carrier 254 is further configured to release inner carriers 258 at a suitable time. In some embodiments, imaging takes place after inner carriers 258 have been released from outer carrier 254 and contrast particles 262 have been released from inner carriers 258. Accordingly, in such embodiments, outer carrier 254 is configured to carry inner carriers 258 for a sufficiently long time to accomplish this, and inner carriers 258 are configured to carry contrast particles 262 for a sufficiently long time to accomplish this.

[0123] In some embodiments, imaging takes place while inner carriers 258 are still within outer carrier 254 and contrast particles 262 are still within inner carriers 258. In such embodiments, outer carrier 254 is configured to carry inner carriers 258 for a sufficiently long time to facilitate imaging.

[0124] Although the embodiment depicted in Fig. 5 includes a single outer carrier containing a plurality of inner carriers, in other embodiments, a nested carrier includes a first outer carrier containing a plurality of second outer carriers, and the second outer carriers each contain inner carriers that contain contrast particles. In some embodiments, yet more layers of nesting are used. Furthermore, in some embodiments the carriers described herein as inner carriers are not contained within the outer carrier, but are configured to be transported by the outer carrier in another way. For example, the inner carrier may be attached to a surface (e.g., an outer surface) of the outer carrier.

[0125] An illustrative method of using nested carriers to detect tumors is described next. With known technology, tumor detection is typically performed using PET scans, which require the use of radioactive material and thus pose some level of risk to the patient. Using contrast imaging in accordance with aspects of the present teachings, however, tumors may be detected using a nonradioactive contrast agent. This significantly reduces the risk to the patient and thus al lo ws the tumor detection process to be performed more frequently than is feasible using PET scans. For example, tumor detection according to this embodiment may be used for cancer screening even in healthy populations, because there is no need to wait until cancer symptoms develop to justify the risk of the scan. #3538269 086041 -000003

[0126] 19

[0127] In this method, the outer carrier has a size of 100-300 nm. This allows the nested carriers to accumulate within and / or near tumors due to the enhanced permeability and retention (EPR) effect typically exhibited by at least some types of tumors. Optionally, the outer carrier has PEG (polyethylene glycol) affixed to it. which helps prolong the amount of time the outer carrier spends near and / or within a tumor. Put another way, the PEG increases the half-life of the outer earner being near or wi thin the tumor.

[0128] The inner carrier has a size of approximately 5 nm and contains a plurality of contrast particles comprising aluminum.

[0129] Continuing this method, a plurality of nested carriers are administered to the patient and the outer carriers (still containing the inner carriers, which still contain the contrast particles) tend to accumulate in or near tumors due to the EPR effect. Imaging radiation of microwave and / or radio frequencies is shone onto the region of the patient where the tumor is located. Contrast image(s) and / or video are acquired of the tumor. In some embodiments, the image(s) and / or video are 3D.

[0130] The outer carriers are configured to remain near the tumors for a sufficiently long time for imaging to take place, and then to degrade such that the inner carriers are released. The inner carriers are sufficiently small to be renally excreted by the imaging subject. In this embodiment, the contrast particles are not released from the inner carriers while the inner carriers are within the imaging subject’s body. Instead, the outer carriers are configured to accumulate near the features of interest (i.e., the tumors to be imaged) and thus to hold the contrast particles there. Accordingly, there is no need to release the contrast particles so that the particles may travel within the patient.

[0131] Illustrative Aspects

[0132] This section describes illustrative aspects of an contrast medical imaging process in accordance with aspects of the present teachings. In this embodiment, the contrast particles are intended to be delivered to a portion of a human patient's body that is approximately 15- 20 cm below the surface of the body (i.e., at a depth of 15-20 cm). The contrast particles in this embodiment are reflective contrast particles comprising aluminum; however, suitable aspects of this embodiment may be applied to absorption-based systems and methods. As an example, the fi'equency range of 1-10 GHz described below may be suitable for at least some absorption-based systems and methods. Helper bands may also be employed in some embodiments of the present disclosure. #3530269 086041-000003

[0133] 20

[0134] In general, in this embodiment, the frequency range is selected to achieve adequate penetration while also enabling adequate imaging resolution. In human tissue, lower frequencies penetrate more deeply (put another way, experience less attenuation) but enable lower resolution, while higher frequencies enable higher resolution but experience greater attenuation. Imaging radiation in the frequency range of approximately 1 to 10 GHz is used in this embodiment, which may be described as broadband. Radiation of frequency 1 GHz has an attenuation coefficient a of 0.3 decibels per centimeter (dB / cm) in the body, which means that radiation of I GHz that penetrates 20 cm into the body attenuates by 6 dB. Radiation of frequency 5 GHz has an attenuation coefficient of 1.5 dB / cm, corresponding to attenuation of 30 dB at a depth of 20 cm, and radiation of frequency 10 GHz has an attenuation coefficient of 3.0 dB / cm, corresponding to attenuation of 60 dB at a depth of 20 cm. Accordingly, the lower portion of the 1-10 GHz frequency range (approximately 1-5 GHz) has sufficient penetration depth in the human body to scan through at least 20 cm of tissue. Resolution-enhancing techniques may be used to improve imaging resolution, which may help to make imaging with the lower portion of the frequency range practical even in cases where the relatively low resolution associated w th the lower portion of the frequency range might otherwise make imaging impractical. The higher portion of the frequency range (approximately 5-10 GHz) tends to have a higher resolution than the lower portion, but tends to experience greater attenuation. Techniques configured to mitigate the effects of attenuation may be used, which may help to make imaging with the higher portion of the frequency range practical even in cases where the relatively high attenuation associated with the higher portion of the frequency range might otherwise make imaging impractical. Illustrative embodiment resolution-enhancing techniques and attenuation-mitigating techniques are described elsewhere herein.

[0135] In this embodiment using imaging radiation in the frequency range of approximately 1 to 10 GHz, contrast particles comprising aluminum may be used. Ensembles of aluminum particles have high reflectivity, which enables strong backscatter even at the higher end of the 1-10 GHz band (e.g., even at 5-10 GHz).

[0136] Backscatter analysis may be used in the disclosed methods and apparatus disclosed herein.

[0137] Consider factors affecting the resolution of data obtained using this embodiment system. The range resolution of imaging radiation of a particular bandwidth refers to the smallest distance between two targets that may be resolved using that bandwidth. #3530269 086041-000003

[0138] Quantitatively, the range resolution R is calculated as R ~ c / 28, where B is the bandwidth of the imaging radiation and c is the speed of light in vacuum, which is typically a good approximation of the speed of light in the patient’s tissue. A more precise estimate of the speed of light in the patient’s tissue may be used to calculate the range resolution if desired. As the expression for range resolution shows, the range resolution is inversely proportional to the bandwidth of the imaging radiation. For example, if a resolution of 0.04175 mm is desired, then a bandwidth of approximately 3.6 THz would be required.

[0139] Although it is contemplated herein that imaging radiation of Terahertz bandwidth could be used, achieving such a high bandwidth is technologically demanding.

[0140] Accordingly, one or more resolution-enhancing processes may be used to enhance resolution beyond the limit associated with the physical bandwidth of the imaging radiation. Illustrative embodiments of suitable resolution-enhancing processes may include, without limitation, synthetic aperture radar (SAR): artificial intelligence (Al) such as machine learning algorithms configured to improve image clarity, reduce noise, and / or extract features: adaptive beamforming; phased arrays (including ultra-wideband phased arrays): interferometric techniques; and / or any other suitable techniques. Backscatter analysis may be used in embodiments of the disclosed methods and apparatus. Select embodiments of resolution-enhancing processes are described elsewhere herein.

[0141] Additionally, or alternatively, bandwidth-efficient waveforms and or compressed sensing technique(s) may be used to simulate higher resolution imaging (e.g., to obtain the benefits of higher resolution imaging without necessarily increasing the physical resolution of a given imaging method).

[0142] Aside from resolution, another factor affecting the usefulness of data obtained using this embodiment is signal-to-noise ratio. The free space path loss FSPL for a signal having a frequency f measured in MHz propagating through free space over a transmitter-to-receiver distance d measured in kilometers (km) is FSPL =20log₁₀(f) + 20log₁₀(d)+32.44. For a signal of frequency 1 GHz, the free space path loss over a distance of 1 meter is 32.44 dB, and a signal of frequency 10 GHz, the free space path loss over a distance of 1 meter is 52.44 dB. The free space path loss is a theoretical prediction of the loss the signal would experience due to propagating through free space, and is generally different from the loss the signal would experience propagating through a medium, such as a human patient. However, the free space path loss calculation above illustrates that the signal loss associated with traveling from the transmitter to the receiver may be large even without accounting for a propagation medium, #3530269 086041-000003

[0143] obstacles, or other real-world factors. Signal loss may be mitigated using suitable technique(s), which may include high-gain antennae, adaptive beamforming, signal amplification, pulse compression (e.g., to facilitate correlating received signals with transmitted pulses), error correction algorithms, signal averaging over a plurality of signal acquisitions, and / or any other suitable techniques.

[0144] It is contemplated that a suitable combination of enhancement techniques in this embodiment may enhance resolution well beyond the target of 0.04175 mm. For example, in some cases, synthetic aperture technique(s) may enhance resolution by a factor of 200, Al technique(s) may enhance resolution by factor of 2, adaptive

[0145] beamforming may enhance resolution by a factor of 1.5, and interferometric techniques may enhance resolution by a factor of 1.5, for a total enhancement factor of 900. In principle, a total enhancement factor of 900 may achieve resolution of 2 microns or better.

[0146] The foregoing techniques and enhancement factors are illustrative embodiments only, and in some cases smaller or greater enhancement factors are achieved and / or different enhancement techniques or different combinations of techniques are used.

[0147] An illustrative, non-limiting embodiment of an antenna system suitable for use in this embodiment comprises a phased array antenna configured to operate across a frequency range including at least 1 - 10 GHz. The dimensions of this embodiment array may be 50 cm by 50 cm, because a 50 cm x 50 cm array is well suited to accommodate ultra-wideband frequency ranges. However, any suitable dimensions may be used. The phased array antenna is configured to be a high-gain phased array antenna so as to mitigate free space path loss. The phased array antenna is configured to be moved across a synthetic aperture length of at least two meters to facilitate synthetic aperture imaging. The moving may comprise mechanically moving the array, electronically steering the array, a combination of both mechanical movement and electronic steering, and / or any other suitable method(s). With a synthetic aperture length of 2 meters and a movement speed of 0.1 meters / second, it takes 20 seconds for the phased array to move across the aperture. In some embodiments, acquiring a contrast image includes moving the antenna three times across the aperture length (put another way, taking three passes across the aperture length), in which case the total imaging time is 60 seconds. Notably, a 60-second exposure to radiation in the 1-10 GHz range generally poses little to no risk to human or animal imaging subjects.

[0148] Turning now to power considerations, the power transmitted by the imaging radiation in this embodiment is generally selected to facilitate sufficient signal -to-noise ratio while #3530269 086041-000003

[0149] 23

[0150] keeping incident power at acceptably low levels for the imaging patient Safety guidelines for imaging radiation may be characterized in terms of the specific absorption rate, which is a measure of the rate at which energy of the imaging radiation is absorbed by the imaging subject’s body. According to some guidelines, an acceptably safe limit for specific absorption rate is 1.6 Watts / kilogram (W / kg). It is roughly estimated that in at least some situations in accordance with this embodiment, given a power density of imaging radiation of 0.01 Watts per square meter, a tissue density of 1000 kilogram per cubic meter, and a tissue electrical conductivity of 1.0 Siemen per meter, the specific absorption rate will be approximately 0.0038 W / kg, which is well below the 1.6 W / kg guideline. The duty cycle of the transmitted power may be controlled so as to prevent overheating of the imaging subject. Preventing overheating of the imaging subject facilitates a continuous imaging process, e.g., for a particular time interval, continuously exposing the imaging subject to imaging radiation having the selected duty cycle. In various embodiments, the time interval may be a minute, several minutes, tens of minutes, an hour, or longer. If the duty cycle were not controlled to prevent overheating, then in at least some embodiments, preventing overheating of the imaging subject would require pausing the imaging process during the time interval for a sufficient time to allow the imaging subject to cool down, which may be disadvantageous in certain cases where continuous imaging is desirable.

[0151] Illustrative Image Enhancement Processes

[0152] This section describes, without limitation, illustrative processes for enhancing resolution and or otherwise increasing the amount or quality of information obtained using systems or methods in accordance with aspects of the present teachings. These processes may be combined with each other and / or with other suitable processes in any suitable combination. The processes in this section may be described in the context of reflection¬ based imaging; however, suitable aspects of these embodied processes may be applied to absorption-based imaging.

[0153] Synthetic Aperture Radar

[0154] Synthetic aperture radar (SAR) may increase resolution by moving the radar antenna in a manner that simulates a larger antenna aperture. This may enhance spatial resolution without requiring an antenna that is physically large in size. #3530269 086041-000003

[0155] 24

[0156] AI-Enhanced. Imaging

[0157] Machine learning algorithm(s) and. or other suitable Al processes may be used to improve resolution and / or otherwise improving imaging capability of a given imaging system so as to enhance effective resolution and target detection capabilities.

[0158] For example, machine learning algorithms may be trained and used to distinguish signals of interest from tissue reflections. Such algorithms may be trained on typical echo patterns from human or animal tissue, as appropriate. The trained algorithms may then be able to identify signals that are reflected by the contrast particles rather than by tissue.

[0159] In some embodiments, super resolution algorithms (Al or otherwise) are used to enhance resolution.

[0160] Adaptive Beamforming

[0161] Adaptive beamforming comprising steering, shaping, and / or focusing the beam of transmitted imaging radiation in a desired manner. For example, adaptive beamforming may be used to dynamically adjust the imaging radiation beam pattern to focus on specific directions and reduce interference. This may improve signal-to-noise ratio (SNR) and target detection accuracy.

[0162] In some embodiments, adaptive beamforming is used to scan the imaging radiation beam across a depth range of 15-20 cm in the imaging subject. For example, a phased array antenna may be used to dynamically steer imaging radiation through different angles and depths in that range. In this way, the imaging radiation may be directed at and / or focused on the contrast particles even when it is not known precisely where in that depth range the particles are presently positioned. Dynamically adjusting the focal point of the beam facilitates systematic scanning of the desired depth range with little or no loss in resolution.

[0163] As an example, with imaging radiation of 5 GHz generated by an antenna having a 50 cm by 50 cm aperture, the beamwidth is approximately 6.87“. This beamwidth is generally suitable for being directed to specific areas within the desired depth range of the imaging subject.

[0164] Time-Gating

[0165] Time-gating may be used in embodiments in which the contrast particles are expected to be located within a particular depth range in the imaging subject, but their exact position within that range is unknown. Because the exact depth of the particles is unknown, it is #3530269 086041-000003

[0166] unknown how long it would take for imaging radiation to be transmitted, reflect from the particles, and be received. However, this round-trip time may be estimated for various points along the depth range, such as the extremes of the depth range. This yields a particular window of time in which signals of interest are expected. Signals received within this time window may be used to compute imaging information. Using time-gating in this manner allows the system to scan the entire depth range in which contrast particles may be located without missing any reflected signals.

[0167] As an illustration, consider again an embodiment in which the particles are expected to be at a depth of 15-20 cm within the imaging subject. The round-trip time for imaging radiation to travel to a depth of 15 cm and back is 1.33 ns, and the round-trip time for imaging radiation to travel to a depth of 20 cm and back is 1.78 ns, assuming a travel speed in the imaging subject of 2.25 x 108m / s. In this case, time-gating may be used to focus on receiving imaging signals that are received within 1.33 ns to 1.78 ns of the time the original imaging radiation was transmitted. The specific numbers used in this embodiment are intended as illustrative, nonlimiting examples.

[0168] Time-gating methods may be complicated by the presence of heterogeneous tissues in the imaging subject, because wave propagation speed and scattering properties tend to vary between tissue types. The variation in tissue properties may cause unexpected time delays or overlapping signals, complicating the ability to isolate reflections from the depth range(s) where contrast particles are expected to be.

[0169] In some embodiments, adaptive time-gating is used to help address this problem. In an adaptive time-gating method, the time window is adjusted dynamically based on the depth and tissue type. Adjusting the time window to account for variations in wave propagation speed facilitates more accurate isolation of signals reflected from the target depths. In some embodiments of adaptive time-gating, the time window is adjusted in real time. For example, the window may be adjusted in real time based on the measured signal. The measured signal may be monitored as the beam is swept through a range of depths, and based on the measured signal, it may be determined that the signal is encountering tissue of a particular type or encountering changes in tissue composition.

[0170] Based on this determination, the time window may be adjusted to compensate for the change in wave propagation speed associated with the encountered tissue or change in tissue.

[0171] Adaptive time-gating may include range-adaptive gating, which includes directing the signal to a small range of depths (such as 15-20 cm) while gradually adjusting the time #3530269 086041-000003

[0172] window as more data is obtained about tissue characteristics in that range. This may allow the imaging system to home in on the exact depth of the contrast particles even in the presence of complex tissue echoes.

[0173] Additionally, or alternatively, adaptive time-gating may include multi-range gating. In multi-range gating, a plurality of time windows are used to facilitate analysis of a corresponding plurality of depth ranges. This facilitates simultaneous monitoring of several depth ranges, which may help avoid inadvertently missing a signal due, e.g., to contrast particles being located at an unexpected depth.

[0174] Data about the dielectric properties of different tissue layers, and / or about wave propagation speed and / or travel time of the imaging radiation in different tissue layers, may be obtained in any suitable manner. In some embodiments, an initial scan of one or more tissue layers of the imaging subject is performed, and the data obtained in the initial scan is used to estimate the time window(s) associated with the depth range(s) of interest. The data from the initial scan may optionally be updated based on data obtained during imaging (e.g., in real time).

[0175] In some embodiments, machine learning algorithms are used to improve the accuracy of time-gating by learning the echo patterns associated with different tissue types and applying corrections at suitable times and / or in real time.

[0176] In some embodiments, adaptive time-gating includes using phase interferometry to measure small phase differences between signals returned from different tissue layers. Based on these phase differences, the depth of different layers may be determined, and these depths may be used to adjust the time window of the time-gating method. In some embodiments, the depth of the layer(s) containing the contrast particles is determined using phase interferometry. In some embodiments, multi-pass interferometry is used, with the phase information obtained from each pass being combined to obtain more precise data about the depth of tissue layers and / or of the contrast particles.

[0177] Pulse Compression

[0178] Pulse compression may be used to improve range resolution. Pulse compression increases signal-to-noise ratio by spreading the radar signal over a wide bandwidth and compressing the signal upon reception. This technique helps distinguish the signal of interest from background noise and multipath reflections. In some embodiments, chirped pulses are used to distinguish return signals from different depths within the imaging subject. #3530269 086041-000003

[0179] Separating such signals is particularly beneficial when the contrast particles are located relatively deep in the imaging subject’s tissue.

[0180] Averaging and / or Integrating Signals

[0181] Averaging and / or integrating a plurality of received pulses may improve signal-to-noise ratio by reducing the impact of random noise. As random noise varies from pulse to pulse, averaging and / or integrating the signals over many pulses causes the noise to cancel out, but the generally non-random signal reflected from the contrast particles is reinforced.

[0182] In some embodiments, a plurality of received pulses are integrated in a phase-coherent manner (referred to as phase-coherent integration). Phase-coherent integration tends to be particularly useful for detecting weak signals buried in noise or multipath reflections.

[0183] Phased Array

[0184] A phased array of antenna comprises an array of individual antennae that are controlled to generate beams having a particular phase relationship to one another, such that the beams of the antennae are superposed with one another to form a collective beam(s). The direction of the collective beam may be controlled by controlling the phase relationship between the individual antennae. This allows for rapid beam steering and focusing. In some embodiments, an ultra-wideband (UWB) phased array is used, which combines ultra- wideband radiation’s broad frequency range (which may, e.g., help balance the demands of penetration and resolution) with the phased array’s directional control.

[0185] Interferometric Teclmiques

[0186] Interferometric techniques may be used to extract phase information from multiple imaging radiation signals. This may enhance depth perception and spatial resolution. For example, interferometry may be used to determine phase differences in returning signals.

[0187] Because the contrast particles generally produce phase shifts in the return signal that are distinct from the phase shifts produced by echoes from biological tissue, phase differences determined via interferometric techniques may be used to identify the depth of the contrast particles (e.g., their depth within the expected range). #3530269 086041-000003

[0188]

[0189] Computational

[0190] The computational load to perform certain processes described herein, such as realtime beamforming, synthetic aperture radar, and Al-based signal processing may be high, and may be particularly high when seeking to achieve sub-millimeter resolution. Suitable techniques for handling the computational load may include high-performance computing (HPC), distributed processing architecture(s), and / or any other suitable processes.

[0191] In some embodiments, graphics processing units (GPUs) are used for parallel processing. This may allow the imaging system to perform real-time processing, including beamforming and synthetic aperture techniques, much faster than traditional CPU-based systems, GPUs are generally well-suited for handling the large datasets and complex algorithms required for high-resolution radio-frequency imaging. One or more GPUs configured for parallel processing may allow the system to process imaging data in real time, allowing for immediate image generation and analysis without significant delays.

[0192] In some embodiments, the imaging system may offload some of the signal processing tasks to a cloud-based distributed computing network. This allows computationally expensive tasks, such as AI-based super-resolution algorithms, to be performed in the cloud, reducing the processing burden on the local hardware. Selectively using cloud-based computing may allow the system io scale up its computational power based on the amount of computational power needed at any given moment, which helps ensure that even very computationally demanding tasks may be completed with little or no delay.

[0193] In some embodiments, edge computing (e.g., performing computations on hardware that is physically near to the imaging system) is used to reduce latency when reduced latency is particularly desirable. Performing computations locally, or at least in close physical proximity to the imaging system, may reduce the time required to process and transmit data, This may be particularly helpful for operations intended to be performed in real time or near real time, such as beamforming and synthetic aperture techniques.

[0194] Illustrative Methods for Mitigating the Effect of Echoes from Tissue Layers

[0195] Imaging radiation that reflects from tissue layers of the imaging subject (e.g., skin, fat, muscle, and / or other tissue(s) may create interference with the imaging signal that reflects from the contrast particles. The heterogeneity of human and animal tissues and their complex dielectric properties may cause a variety of scattering, absorption, and reflection of electromagnetic waves. This may make it difficult to accurately detect the contrast particles #3530269 086041-000003

[0196] 29

[0197] through the layers of tissue, because different tissue types may behave differently with respect to electromagnetic waves. This section describes methods for reducing the impact of radiation reflected from tissue layers (referred to as '‘echoes”) on the ability to measure the signal of interest. However, these embodiments are nonlimiting; the methods may be used for other purposes, and other methods may be used to address the effect of tissue echoes.

[0198] The embodied processes in this section may be described in the context of reflection¬ based imaging, and some are primarily helpful in the context of reflection-based imaging; however, suitable aspects of the processes described in this section may be applied to absorption-based imaging.

[0199] Calibration Data

[0200] In some embodiments, a reference scan (also called a calibration scan) is performed using known tissue types, or simulated using previously obtained data and / or models of tissue types. The data obtained from the calibration scan may be used to adjust data obtained from an actual imaging subject to account for properties of tissue in the imaging volume, such as specific scattering and attenuation properties of that tissue. Calibration data may be obtained by measuring reflected signals from skin, fat, muscle, and / or other relevant tissue types across the full wavelength range of imaging radiation. This measured data may be used to determine how each tissue type affects imaging radiation (e.g., by scattering, absorption, and / or other effects) in a wavelength-dependent manner.

[0201] When an actual imaging subject is imaged, the effect of each tissue type may be subtracted and / or otherwise suppressed from the return signal. New calibration data need not be obtained for each imaging subject, though in some embodiments it is. In some embodiments, calibration data is obtained once for a given imaging system, or is obtained initially and checked or updated intermittently later. In some embodiments, calibration data is obtained from an external source, such as a central database, and is not newly measured or confirmed for individual imaging systems.

[0202] Time-Gating and Depth Scanning

[0203] Time-gating and depth scanning may be used to limit the analysis to time intervals) that correspond to the depth within the imaging subject where the contrast particles are expected to be. Signals outside the time interval(s) of interest may be rejected. This may #3538269 086041 -000003

[0204] 30

[0205] result in rejecting a large fraction of tissue echoes, because reflected signals outside the time interval(s) of interest largely correspond to tissue echoes.

[0206] Artificial Intelligence

[0207] Machine learning models may be trained to identify tissue echoes based on typical tissue reflection patterns. This allows the models to be used to identify echoes so that the echoes may be suppressed and non-echo signals (which are likely to be signals of interest reflected by the contrast particles) may be amplified. In some embodiments, the same or different machine learning models may be trained to identify signals that are reflected by the contrast particles, rather than simply identifying tissue echoes and assuming that other signals are likely to have been reflected by the contrast particles. In some embodiments, machine learning models may be trained and used to identify and classify echo patterns from different tissue types, so that unwanted echoes may be identified and suppressed (in some cases, using a suppression method that is based on identified tissue type),

[0208] In some embodiments, Al or super-resolution techniques, such as compressed sensing and Fourier transform methods, are used to improve the effective resolution of the imaging system. This may allow the signal of interest to be detected even in the presence of unwanted signals from tissue and other noise. For example, compressed sensing reconstructs high- resolution images from sparse data, facilitating detection of fine details such as contrast particles even when the associated signal is weak. Compressed sensing may also separate the signal of interest from tissue echoes by identifying the most significant return signals.

[0209] Pulse Compression

[0210] Pulse compression (including chirping) and / or interferometry may be used to help distinguish received signals that were reflected at different depths in the imaging subject, particularly when the signals from different depths overlap due to having been reflected multiple times in multiple directions within the imaging subject.

[0211] Polarization

[0212] Polarization diversity may be used to address the problems associated with tissue heterogeneity. Different tissue types reflect electromagnetic waves differently depending on the polarization of the waves. For example, fat and muscle may scatter waves having a first polarization more strongly, and bone may scatter waves having a second polarization more #3530269 086041-000003

[0213] 3!

[0214] strongly. By using more than one polarization in the imaging signal (e.g., both horizontal and vertical polarization), more information about the tissue structure within the imaging subject may he obtained. This information may be used to separate the signal reflected from the contrast particles from signal reflected by tissue,

[0215] Nonlinear Effects

[0216] Nonlinear effects may be used to separate tissue echoes from the signal of interest. Biological tissues and artificial objects such as the contrast particles generally exhibit different nonlinear behaviors when subjected to electromagnetic radiation.

[0217] Accordingly, analyzing the nonlinear component of the received signal may help to distinguish the signal of interest from tissue echoes or other unwanted background, A high- power signal generation system such as a nonlinear microwave imaging (NMI) system may be used to generate the imaging radiation; using a high-power signal may allow the nonlinear effects to be strong enough to be observed.

[0218] . Adaptive Beamforming

[0219] Beamforming may be used to direct the imaging signal primarily toward depth range within the imaging subject where contrast particles are expected to be. This helps avoid the creation of tissue echoes from other layers. For example, using phased array antennas, the system may steer the imaging signal beam dynamically across multiple angles and depths. This allows the signal to be directed primarily to specific tissue layers of interest while rejecting off-axis signals, which reduces unwanted reflections from nearby structures such as tissue.

[0220] At the imaging radiation wavelengths enabled by the contrast particles described herein, the beamwidth of the imaging radiation may be relatively small. For example, at 5 GHz, the beam of a phased array may be narrowed to approximately 6.87°. This narrow beamwidth helps reduce multipath scattering within the imaging subject and focuses energy on the depth where the contrast particles are expected to be.

[0221] Additionally, or alternatively, an imaging signal may scan the region of interest in the imaging subject from multiple angles. For example, two or more phased arrays may generate imaging signals from different angles relative to the region of interest, or a single phased array may be scanned across different angles. Multi-angle scanning may be used to obtain more detailed information about the tissue structure of the imaging subject, which may be #3538269 086041-800003

[0222] 32

[0223] used to more accurately remove unwanted signals. Because the imaging radiation wavelengths enabled by the contrast particles described herein pose little or no health risk, scanning the imaging subject from multiple angles also does not pose a significant health risk.

[0224] Additionally, or alternatively, depth-adaptive beamforming may be used to dynamically adapt the focal point of the imaging beam to the expected depth range of the contrast particles. This allows the imaging process to prioritize signals from the expected depth range rather than signals from shallower depths. This reduces the effect of echoes from overlying tissues.

[0225] Synthetic Aperture

[0226] Synthetic aperture techniques may be used to further enhance resolution of the obtained imaging data. In some embodiments, phase-coherent synthetic aperture measurements are used; obtaining phase- sensitive measurements may allow for correcting phase shifts and phase-dependent scattering associated with heterogeneous tissue within the imaging subject.

[0227] Spectral Differentiation

[0228] Different types of tissue have different dielectric properties, which are typically significantly different from those of the contrast particles. These differences may be used to help distinguish reflections from contrast particles from unwanted reflections from tissue.

[0229] In some embodiments, imaging radiation of several different frequencies may be used. For example, if the desired range of imaging radiation is 1-10 GHz, several different frequencies from within that range may be used to image the imaging subject. Biological tissues, such as fat, muscle, and bone, typically reflect these different frequencies differently, whereas at least some contrast particles reflect them in substantially the same way (that is, substantially independently of frequency). The frequency-dependent response of the tissue and the largely frequency-independent response of the contrast particles within this frequency range may be used to help distinguish the signal of interest from tissue echoes.

[0230] In some embodiments, the radar cross-section (RCS) of the contrast particles across the spectrum of imaging radiation is used to identify the signal of interest. The radar cross¬ section of the contrast particles generally differs significantly from that of biological tissues like muscle and bone, allowing signal reflected by the contrast particles to be identified. For example, the received imaging signal may be compared to a known radar cross-section of the #3530269 086041-000003

[0231] contrast particles and to known radar cross-section(s) of tissue(s), so that the contribution of contrast particle and tissue to the measured signal may be identified.

[0232] The known radar cross-sections may be obtained in any suitable way (e.g., measured, looked up in a database, modeled, etc.).

[0233] Matched Filtering

[0234] Matched filtering may be used to identify the signal reflected by the contrast particles, rather than by tissue. In a matched filtering technique, the received signal is correlated with a reference signal (also called a template), which corresponds to the expected signal associated with reflection by the contrast particles. Filtering in this manner maximizes the response to signals that match the template while suppressing signals that don’t match, helping to isolate the signal of interest from other reflections.

[0235] Deconvolution

[0236] Deconvolution may be used to reverse the effects of signal distortion, which may be caused by tissue scattering and attenuation. By deconvolving the received signal, the signal reflected from the contrast particles may be recovered. In some embodiments, deconvolution is applied in both the time and frequency domains, which may remove distortions caused by multiple tissue layers and recover the signal of interest.

[0237] Illustrative Methods for Mitigating the Effect of Thermal Noise

[0238] This section describes, without limitation, illustrative methods that may be used to account for the effects of thermal noise associated with the imaging subject’s body. The methods described herein may additionally or alternatively be used for other purposes, and other methods may be used for the purpose of addressing the effects of thermal noise. The processes in this section may be described in the context of reflection-based imaging; however, suitable aspects of these processes may be applied to absorption-based imaging.

[0239] Filtering

[0240] Using narrowband filters on the receiver allows specific frequency bands that are less affected by thermal noise to be isolated and analyzed. For instance, human tissues emit thermal radiation in the microwave range, so filtering microwave frequencies out (e.g., via an #3530269 086041-000003

[0241] 34

[0242] appropriately selected bandpass filter) may reduce the impact of these emissions on received signal. In the time domain, smoothing filters may reduce noise spikes.

[0243] Adaptive Noise Cancellation

[0244] Thermal noise may be measured and estimated before the imaging is performed. By performing an initial scan without transmitting imaging radiation, the baseline thermal noise emitted by the imaging subject may be determined. This baseline noise may be filtered out from the imaging data. In some embodiments, thermal noise is monitored during the imaging scan., and adaptive noise cancellation techniques are used to adjust the noise filter (e.g., in real time) based on the thermal noise detected during imaging.

[0245] Cooling the Receiver(s)

[0246] in some embodiments, noise is reduced by cooling the receiving electronics of the imaging system, which reduces the receiver’s own thermal noise. For example, the receiver(s) or portions thereof may be cryogenically cooled.

[0247] Low Noise Amplifiers (LNAs)

[0248] Including Low Noise Amplifiers (LNAs) in the receiver chain may significantly reduce thermal noise. LNAs are configured to amplify weak signals without introducing significant additional noise, thereby improving the signal-to-noise ratio of the system. Placing the LNA near to the receiver allows the system to amplify the signal of interest without significantly amplifying thermal noise.

[0249] Machine Learning

[0250] Machine learning algorithms may be trained on baseline noise patterns (such as thermal noise from the body) and used to automatically detect and subtract these patterns from the imaging data.

[0251] Illustrative Methods for Mitigating the Effect of Body Movement

[0252] This section describes, without limitation, illustrative methods that may be used to account for the effects of movement of the imaging subject’s body. The methods described herein may additionally or alternatively be used for other purposes, and other methods may be used for the purpose of addressing the effects of body movement. The embodied processes #3538269 086041 -000003

[0253] 35

[0254] in this section may be described in the context of reflection-based imaging; however, suitable aspects of these processes may be appli ed to absorption-based imaging.

[0255] Motion Detection

[0256] In some embodiments, motion tracking is used to estimate body movement so that the movement may be accounted for in the imaging data. In some embodiments, phase shifts in the received signal are measured and used to detect small movements of internal tissues, such as those caused by the imaging subject’s breathing or heartbeat. These phase shifts may be used to estimate the extent of the motion. In preferred embodiments, cine-rate centroid precision is used.

[0257] In some embodiments, radar or radar-like methods are used to estimate body movement. For example, a Doppler radar system may be used to detect and measure movements such as breathing or the heartbeat. By measuring the Doppler shift caused by these movements, the radar system may track the motion in real time. The Doppler radar system may have components in common with the imaging system, or may be completely separate from the imaging system, in some embodiments, optical motion capture systems may be used to track external body movements.

[0258] Phase-corrected Synthetic Aperture Processing

[0259] In embodiments in which synthetic aperture techniques are used to image the subject, movement of the imaging subject may cause phase errors that degrade image quality. Phase-corrected synthetic aperture radar processing may be used to estimate and compensate for errors caused by the movement. In some cases, phase shifts due to movement are detected and compensated for in real time.

[0260] Subpixel Motion Estimation

[0261] Subpixel motion estimation techniques may detect and correct for movements that are smaller than the imaging system’s resolution grid, which in some embodiments is extremely fine (e.g., submillimeter). Subpixel motion estimation techniques use high-precision motion models to estimate tiny displacements in tissue of the imaging subject and apply corrections to the received data accordingly. #3530269 086041-000003

[0262] 36

[0263] Gating and / or Synchronization

[0264] In some embodiments, the imaging scan is synchronized with a physiological signal, such as breathing or the heartbeat. By gating imaging pulses to specific points in the respiratory or cardiac cycle, the impact of motion artifacts may be reduced. For example, based on signals from an electrocardiogram (ECG) and / or respiratory monitor, the imaging radiation may be timed to coincide with a time when the body is least likely to be moving, such as between heartbeats and / or at the end of exhalation.

[0265] Signal Processing

[0266] Signal processing may be used to deal with noise and artifacts associated with motion of the imaging subject. For example, machine learning algorithms may be trained and used to automatically detect and compensate for motion artifacts, e.g., by detecting patterns in the image data that correspond to motion and removing them.

[0267] In some embodiments, suitable signal processing techniques include using Kalman filter(s) to estimate the position and velocity of the imaging subject’s moving body (or portions thereof). Kalman filters may allow for body motion to be estimated and corrected for in real time. Additionally, or alternatively, Kalman filters may be used to predict future movement based on past movement. This may allow for artifacts of body movement to be removed from the imaging data as the imaging data is generated, based on body movement that was detected just beforehand.

[0268] In some embodiments, time-domain and / or frequency-domain filters are applied to remove unwanted noise and interference. In the time domain, smoothing filters may reduce noise spikes and motion artifacts. This may help to clean up the radar data and improve the clarity of the image. In the frequency domain, bandpass filters may isolate the frequencies corresponding to the contrast particle reflections and reject frequencies associated with noise or motion artifacts.

[0269] Illustrative Methods for Mitigating the Effect of Attenuation and / or Multipath Reflection This section describes, without limitation, illustrative methods that may be used to account for the effects of attenuation, which may be associated with the distance traveled by the imaging radiation signal and or with reflections from tissue, which effectively increase distance traveled by the radiation and may introduce phase shifts. #3530269 086041-000003

[0270] The methods described herein may additionally or alternatively be used for other purposes, and other methods may be used for the purpose of addressing the effects of attenuation. The processes in this section may be described in the context of reflection-based imaging; however, suitable aspects of these embodied processes may be applied to absorption-based imaging.

[0271] Power

[0272] In some embodiments, power scaling is used to adjust the power of the transmitted signal dynamically based on the depth of the tissue and the expected attenuation associated with that depth. For example, higher power may be used for deeper tissue scans, and lower power may be used for shallower scans to conserve power and avoid exceeding patient exposure guidelines.

[0273] In some embodiments, a pulsed imaging signal with high peak power but low average power is used to increase the signal’s ability to penetrate tissue without overheating or exceeding patient exposure guidelines.

[0274] Gain Control

[0275] Gain control may be used to adjust the receiver's gain dynamically based on the strength of the incoming signal. This allows for amplifying the potentially weak signals of interest while preventing overload that could otherwise be caused by strong tissue echoes. In some embodiments, gain control is adjusted automatically, in some cases in real time. Realtime automatic gain control methods automatically adjust the receiver gain in real time, compensating for attenuation as the imaging signal penetrates deeper into the tissue.

[0276] Multi-Angle Beamforming

[0277] Multi -angle beamforming, described elsewhere herein, may reduce the effect of multipath reflections.

[0278] Interference Cancellation Algorithms

[0279] Interference cancellation algorithms may help suppress unwanted reflections caused by multipath effects in certain embodiments. These algorithms predict the paths that multipath signals are likely to take and subtract the corresponding signal from the measured data. In some embodiments, adaptive filters are used to monitor and subtract multipath #3530269 086041 -000003

[0280] 38

[0281] signals in real time. This may help to reduce noise associated with reflections from tissue layers.

[0282] Phase-Coherent Processing

[0283] Multipath signals often cause phase shifts in the received data, which may blur the image. Phase-coherent processing techniques detect and correct these phase shifts, improving signal-to-noise ratio and image clarity.

[0284] In embodiments including synthetic aperture techniques, phase-corrected synthetic aperture techniques may be used. Maintaining phase coherence during synthetic aperture data acquisition allows phase errors introduced by multipath reflections to be compensated for.

[0285] Illustrative Methods for Mitigating the Effect of Electromagnetic Interference

[0286] This section describes, without limitation, illustrative methods that may be used to account for the effects of electromagnetic interference (e.g., from external sources such as cellular communications, Bluetooth® communications, wireless internet communications, radio- frequency equipment other than the imaging system, and / or other sources). The methods described herein may additionally or alternatively be used for other purposes, and other methods may be used for the purpose of addressing the effects of electromagnetic interference. The processes in this section may be described in the context of reflection-based imaging; however, suitable aspects of these processes may be applied to absorption-based imaging.

[0287] Frequency Selection

[0288] Notable common sources of electromagnetic interference include Wi-Fi (2.4 GHz, 5 GHz), Bluetooth® (2.4 GHz), and cellular signals (up to 6 GHz), as well as other medical devices operating in nearby frequencies. Accordingly, the 1-2 GHz and 7-10 GHz bands experience less interference in comparison to the 2-7 GHz band in most environments.

[0289] Accordingly, in some embodiments, imaging radiation that has significant strength in the 1-2 GHz and 7-10 GHz bands may be used. These bands may provide a good balance between penetration, resolution, and lack of interference. #3538269 086041 -000003

[0290] 39

[0291] Frequency-Hopping Spread Spectrum

[0292] Frequency-hopping spread spectrum (FHSS) may be used to reduce electromagnetic interference. In this technique, the imaging radiation signal rapidly hops between different frequency channels within the imaging radiation band (e.g., the 1-10 GHz band). Since the signal spends only a brief time on a given channel before hopping to another channel, it has a reduced likelihood of experiencing interference from external sources that may be occupying specific frequencies. Spreading the signal over a wide range of frequencies in this manner makes it less vulnerable to narrowband interference, such as Wi-Fi operating at 2.4 GHz, The impact of encountering interference on a given frequency is reduced because data may still be gathered from the other frequencies to which the signal has hopped.

[0293] Adaptive Frequency Selection

[0294] In some embodiments, the frequency band on which the imaging radiation may operate is scanned for external signals and the imaging radiation is adjusted dynamically to avoid heavily occupied frequencies and / or to move to quiet bands. This may be described as a type of cognitive radar technique in which the imaging signal dynamically adapts to the RF environment.

[0295] In some embodiments, the imaging system is configured to detect interference of the imaging radiation as it occurs and switch to a different frequency, where signal -to-noise ratio is expected to be higher. This real-time adaptability allows the system to operate effectively even in changing RF environments.

[0296] Shielding

[0297] In some embodiments, components of the imaging system (e.g,, processing electronics) are shielded from electromagnetic radiation. For example, components of the system may be disposed within a Faraday cage configured to block external electric fields, including RF signals. This protects the system from electromagnetic interference.

[0298] The system in its entirely cannot be enclosed in a Faraday cage, because this would prevent the system from transmitting the imaging signal and receiving the reflected signal. However, the receiver electronics and processors may be shielded. In some embodiments, power supplies, signal processors, amplifiers, and / or other suitable components of the imaging system are isolated from sources of electromagnetic interference. Power supply #3538269 086041 -000003

[0299] 40

[0300] filters and isolation transformers may be used to help reduce the amount of noise that may enter the imaging system via its power lines.

[0301] In some embodiments, some, most, or all cables and other electrical connectors of the imaging system are shielded to help prevent external RF signals from entering the system through them. Shielding the connectors helps to reduce the likelihood that interference will reach sensitive system components such as the receiver.

[0302] In some embodiments, electromagnetic compatibility (EMC) testing is performed on the imaging system itself (e.g., initially, at regular intervals, or on demand) to confirm that the system complies with standards and guidelines for resistance to electromagnetic interference and that it does not itself introduce excessive interference into the environment.

[0303] Antenna Design

[0304] In some embodiments, aspects of the design of the antenna are used to help avoid and / or mitigate electromagnetic radiation. For example, a highly directional antenna may be used to precisely direct the imaging beam toward the region of interest in the imaging subject; the high directionality reduces the likelihood of picking up off-axis energy from external sources.

[0305] In some embodiments, a phased array antenna is used and is electronically steered to focus on the region of interest, which helps reduce exposure to unwanted RF signals.. A narrow beamwidth may reduce the chance of external interference entering the system ’s field of vi ew.

[0306] In a preferred embodiment, transmitters and receivers are located on a c-arm which can be placed with a patien t between the two arms of the c-arm. In one embodiment, one arm of the c-arm comprises a transmi tter and one arm of the c-arm comprises a recei ver.

[0307] Signal Processing and Filtering Techniques

[0308] Signal processing and filtering may be used to reduce the effect of interference. In some embodiments, adaptive notch filters are used to remove from the measured data the signal associated with specific frequencies at which interference is expected or detected to occur (e.g., from Wi-Fi at 2.4 GHz). A notch filler may be used to identify and suppress narrowband interference while preserving the radar signal at other frequencies. In some embodiments, the received signal is monitored for the presence of narrowband interference. In response to detecting narrowband interference, (e.g., above a threshold level), a notch filter #3530269 086041-000003

[0309] 4!

[0310] is applied to remove the interfering frequency from the signal, leaving other frequencies generally unaffected.

[0311] In the frequency domain, bandpass filters may be used to isolate frequencies that contain the imaging signal and reject frequencies where interference is detected. In some embodiments, the bandpass filters are dynamic bandpass filters configured to adjust the pass band based on detected levels of interference.

[0312] In some embodiments, pulse compression and / or chirp modulation techniques are used to reduce interference. These techniques help distinguish the return signal from narrowband interference, which may take the form of localized noise in the frequency domain. Spreading the signal pulse over time and frequency helps reduce the impact of this localized noise.

[0313] hi some embodiments, time-domain techniques such as clutter suppression algorithms and / or signal averaging are used to help reduce interference. Clutter suppression algorithms may be used to identify unwanted signals (such as interference or extraneous “clutter” signals) in the time domain and subtract them from the measured data. Signal averaging may include averaging a plurality of received pulses. This reduces the impact of short-duration interference because random interference signals are averaged out and the non-random signal of interest is reinforced.

[0314] Real-Time Interference Detection and Mitigation

[0315] In some embodiments, the imaging system includes a monitoring system configured to scan the RF spectrum (or other relevant frequency band) for interference sources. The monitoring system may be configured to scan in real time, at regular intervals, on demand, and / or in any other suitable fashion. In response to detecting an interference source using the monitoring system, the imaging system is configured to automatically adjust aspects of the imaging radiation (e.g., frequency, power, and / or other properties) and / or aspects of its signal processing to combat interference.

[0316] In some embodiments, the monitoring system includes a spectrum analyzer configured to detect external signals that overlap with the imaging system's frequency band and provide feedback to the imaging system’s control system.

[0317] In some embodiments, automatic gain control is used to automatically adjust the imaging system’s receiver gain based on the strength of the incoming signal. In response to detecting strong sources of interference (e.g., using the monitoring system), automatic gain. #3530269 086041-000003

[0318] 42

[0319] control is used to reduce receiver gain to prevent overload and reduce the impact of the interference. This helps to prevent the received signal from being overwhelmed, by strong external signals.

[0320] Illustrative Absorption-Based Embodiment

[0321] This section describes illustrative aspects of an. absorption-based contrast medical imaging process in accordance with aspects of the present teachings.

[0322] In this embodiment, the contrast particles comprise iron oxide nanoparticles (Fe3O4. Iron oxide nanoparticles have good absorptive properties in the general frequency range of 700 MHz – 20 GHz. They typically exhibit a high dielectric loss tangent in the microwave frequency range. Additionally, iron oxide nanoparticles are currently relatively inexpensive to produce and are mass-produced for use in various industries, which tends to make them an economical choice of contrast agent, furthermore, iron oxide is well-studied and has been shown to be biocompatible, in that it has low toxicity and is generally safe for use in biological environments. Indeed, iron oxide nanoparticles are already in use as a therapeutic and diagnostic agent, including in theranostic applications. Iron oxide nanoparticles may be magnetically manipulated and used for applications like magnetic hyperthermia, adding flexibility to their use.

[0323] Considering the absorption cross-section of iron oxide nanoparticles, for this illustrative embodiment, it is assumed that each nanoparticle is 5 nanometers in diameter, which facilitates high absorption and surface area but low scattering, and that an ensemble of approximately 1018nanoparticles are disposed in a region of the imaging subject that is roughly equivalent in volume to a 5 mm sphere. It. is estimated that this embodiments corresponds to a strong absorption cross section at 5 GHz, making it suitable for absorption- based contrast imaging as described herein. The numbers provided in this paragraph are approximate figures intended to illustrate an approximate calculation, and are not intended to be limiting.

[0324] The absorption of electromagnetic radiation within the imaging subject inherently corresponds to an increase in temperature; however, it is estimated that the temperature increase is well within safe limits. Using the example numbers of this section, it is estimated that a one-hour exposure time corresponds to approximately a 0.37 °C temperature increase, which is well within safe limits. Selecting a suitable a duty cycle for the imaging radiation #3530269 086041-000003

[0325] 43

[0326] and / or selecting a shorter exposure time could reduce the temperature increase below even this small amount.

[0327] Any suitable processes for enhancing resolution and / or improving image quality may be used in this embodiment. For example, synthetic aperture (SAR) processes may be used to enhance resolution. Coherent integration may be used to increase signal-to-noise ratio. In some embodiments, super-resolution methods are used to effectively improve the resolution of the acquired data beyond the resolution achievable by the measurement device(s) themselves. Super-resolution methods may include compressed sensing, Fourier transform¬ based interpolation, and / or any other suitable methods. In some embodiments, super-resolution methods incorporate the use of AI

[0328] Adaptive beamforming and / or multi-angle SAR integration may be used to improve resolution. For example, the imaging radiation may be emitted by a phased array antenna that is electronically controlled to focus the radiation on the region of the imaging subject where the nanoparticles are located. This may reduce noise from off-target tissue and improve resolution by causing most or ail of the radiation to be directed to the location of interest. A narrow beamwidth, may be helpful. for this purpose. For example, as described with reference to other embodiments herein, a 50 cm x 50 cm antenna array emitting radiation of 5 GHz frequency would have a beamwidth of approximately 6.87,;‘.

[0329] As another example, multi-angle SAR imaging may be used to enhance resolution by combining data acquired from multiple angles, creating an interferometric synthetic aperture. This may facilitate determining relatively detailed 3D image information using the data acquired from different angles and / or using phase shifts.

[0330] Image contrast may be enhanced using different frequencies (or a range of frequencies) of Imaging radiation and / or using frequency hopping. This may allow for improved image contrast by taking advantage of the different depth penetration and tissue contrast characteristics of different frequencies of radiation. For example, imaging radiation in the band 1 -10 GHz may be used. The lower end of the band (e.g., roughly 1-5 GHz) has the benefit of deeper penetration, and the higher end of the band ( e.g., roughly 5-10 GHz) has the benefit of higher absorption by iron oxide nanoparticles and therefore higher contrast images, as well as the higher resolution associated with shorter wavelengths. Using the entire 1-10 GHz band for imaging incorporates all these benefi ts. #3530269 086041 -000003

[0331] 44

[0332] In some embodiments, imaging is performed using a plurality of imaging scans of different frequencies (e.g., first scanning at a higher frequency, and then scanning at a lower frequency). This may facilitate isol ating the absorption signal of the contrast agen t.

[0333] Adaptive filtering may optionally be used to further facilitate isolating the absorption signal.

[0334] In some embodiments, artificial intelligence is used to improve image quality. For example, machine learning algorithms may be trained to recognize absorption patterns associated with iron oxide nanoparticles and / or to distinguish those patterns from other signals, such as signals associated with the imaging subject’s tissue. Additionally, or alternatively, machine learning algorithms may be trained and used to apply pattern recognition to distinguish areas of high absorption (indicative of the contrast agent) from normal tissue, thereby improving the system’s ability to localize and resolve the contrast agent. This may allow for belter determination of the location of the contrast agent and thus for better data about the imaging subject.

[0335] In some embodiments, artificial intelligence is used for adaptive noise reduction, e.g., dynamically applying filters based on factors such as signal strength, tissue types, and / or any other suitable factors. Factors may be detected automatically by the artificial intelligence or another part of the system, input by a user, and / or otherwise suitably incorporated into the adaptive filter process. Intelligent filtering reduces background noise, allowing weaker or more subtle absorption signals to be detected.

[0336] In some embodiments, signal-to-noise ratio is enhanced by suitably selecting the duty cycle of the imaging radiation. For example, pulsing the imaging radiation at a 10% duty cycle may prevent thermal buildup in the imaging subject, while still allowing use of a strong signal during the “on” portion o f the duty cycle.

[0337] In some embodiments, the power of the imaging signal is selectively increased for a short interval to improve signal-to-noise ratio in the absorption signal. This may be particularly helpful for imaging deep inside the imaging subject, because when the contrast particles are located deep inside the imaging subject, the imaging radiation may experience significant attenuation before even reaching the contrast particles.

[0338] Illustrative Method for Imaging a Subject

[0339] This section describes steps of an illustrative method 300 for imaging a subject; see Fig. 6. Aspects of systems and methods described elsewhere herein may be utilized in the #3538269 086041-000003

[0340] 45

[0341] method steps described below. Where appropriate, reference may be made to components and systems that may be used in carrying out each step. These references are for illustration, and are not intended to limit the possible ways of carrying out any particular step of the method.

[0342] Fig. 6 is a flowchart illustrating steps performed in an illustrative method, and may not reci te the complete process or all steps of the method. Although various steps of method 300 are described below and depicted in Fig. 6, the steps need not necessarily all be performed, and in some cases may be performed simultaneously or in a different order than the order shown,

[0343] At step 304, method 300 optionally includes administering contrast agent (e.g., contrast particles) to an imaging subject. The imaging subject may be a human, animal, or inanimate object, in some embodiments, administering the contrast particles comprises administering a carrier (e.g., a nanocarrier) to the subject, with the carrier carrying the contrast particles. In some embodiments, the contrast particles are reflective contrast particles comprising one or more substances configured to reflect and / or scatter imaging radiation of the frequencies described below with reference to step 308, In some embodiments, a suitable reflective substance is aluminum. Alternatively, or additionally, the contrast particles may be absorptive contrast particles comprising one or more substances configured to absorb imaging ra d iation of the frequencies described be low wi th reference to step 308,

[0344] In some methods for imaging a subject, contrast particles have already been administered to the subject, and so step 304 need not be performed. At step 308, method 300 includes emitting imaging radiation to the subject. The imaging radiation may be emitted to the subject’s entire body and / or to one or more regions of interest of the subject, such as the chest, the abdomen, one or more extremities, and / or any other suitable region(s), The imaging radiation is generally within a radio and / or microwave frequency range that poses little or no risk to human health. In some embodiments, the imaging radiation is in the frequency range 1-10 GHz, which facilitates adequate penetration into the imaging subject as well as adequate resolution for imaging. In some embodiments, step 308 includes emitting imaging radiation to the imaging subject using a phased array antenna. At step 312, method 300 includes receiving an imaging signal. In embodiments in which the contrast particles are reflective contrast particles, the imaging signal comprises radiation that has reflected from the reflective contrast particles within the imaging subject. The received radiation may therefore be referred to as a return signal. Because the reflective contrast particles reflect the #3538269 086041 -000003

[0345] 46

[0346] imaging radiation more strongly than the imaging subject’s body, the presence and / or position of the reflective contrast particles within the imaging subject may be determined based on the received signal. For example, receiving a strong return signal from a given location in the body tends to indicate that reflective contrast particles are present at that location, and receiving a weak return signal or no return signal from a given location tends to indicate that there are few or no reflective contrast particles there. The strength of the return signal may indicate the amount or concentration of reflective contrast particles in a given location.

[0347] In embodiments in which the contrast particles are absorptive contrast particles, the imaging signal comprises radiation sensed on the far side of the imaging subject relative to the emitter. The imaging signal thus comprises sensed radiation that has passed through the imaging subject. The absorptive contrast particles absorb the imaging radiation more strongly than the imaging subject’s body, and therefore the presence and / or position of the absorptive contrast particles may be determined based on the received signal. For example, a weaker imaging signal from a given location in the imaging subject’s body tends to indicate that absorptive contrast particles are present at that location (i.e., because the absorptive contrast particles absorbed radiation that would otherwise have passed through the imaging subject’s body at that location). On the other hand, a stronger imaging signal from a given location in the body tends to indicate that few or no absorptive contrast particles are present there. The strength of the imaging signal may indicate the amount or concentration of absorptive contrast particles in a gi ven location.

[0348] In some embodiments in which the contrast particles are reflective, the radiation is received at step 312 by the same device that emitted it at step 308. For example, an antenna may be configured to both receive and emit radiation. However, in some embodiments in which the contrast particles are reflective, the radiation is received by a different antenna (or other device) than the device that emitted it.

[0349] In some embodiments, radiation is emitted by a plurality of emitters at step 308 and / or received by a plurality of receivers at step 312. This may allow the depth of the contrast particles in the imaging subject to be determined from a plurality of different angles, which may enable determination of three-dimensional information about the location of the particles in the imaging subject.

[0350] In some embodiments, radiation is emitted at step 308 and received at step 312 continuously or in rapid succession. This may allow information about the imaging subject to #3538269 086041 -000003

[0351] 47

[0352] be visualized in the form of a video. Alternatively, or additionally, it may allow for obtaining information about the imaging subject at different points in a biological process of the subject (e.g., at different parts of a cardiac or respiratory cycle).

[0353] In some embodiments that use reflective contrast particles, instead of (or in addition to) detecting radiation that is reflected from the reflective contrast particles, step 312 includes detecting radiation that passes through the imaging subject. The reflective contrast particles reflect the radiation and thus inhibit the radiation from passing through the imaging subject, so the amount of radiation passing through the imaging subject is lower in the regions where the reflective contrast particles are located, information about where the reflective contrast particles are located may therefore be determined based on the radiation that passes through the imaging subject.

[0354] At step 316, method 300 includes determining information about the imaging subject based on the received imaging signal. In some embodiments including reflective contrast particles, step 316 includes determining the locations in the imaging subject where reflective contrast particles are disposed based on the time at which the imaging radiation was emitted, the time at which the received signal was received, and an estimate of the travel speed of the radiation. Put another way, based on the time interval between emission and reception and the estimated speed of the radiation, the distance traveled by the radiation is estimated, and the location of the reflective contrast particles is estimated based on the distance. For example, in embodiments in which the radiation is emitted and received by the same device, such as the same antenna, the distance traveled by the radiation is twice the distance between the antenna and the reflective contrast particles.

[0355] In some embodiments, knowledge of the location or system of the imaging subject’s body to which the contrast particles (whether reflective or absorptive or some of each) were administered is used at step 316. For example, if it is known that the contrast particles were administered into the patient’s blood stream, then it may be determined that the location of the contrast particles determined at step 316 corresponds to the patient’s veins (or, in some cases, to internal bleeding or bruising within the patient). In some embodiments, the amount of time the particles have been in the patient’s body is also used (e.g., because the particles are administered to one part of the body hut will propagate to another part of the body, and the latter part will be imaged). #3538269 086041 -000003

[0356] 48

[0357] In some embodiments, step 316 includes creating a visualization of the imaging subject based on the determined information. For example, an image, series of images, or video of the imaging subject may be generated based on the determined information.

[0358] In this manner, method 300 allows a medical care provider or other party to look at a visualization of the imaging subject, which may aid in medical diagnosis or treatment. For example, the medical care provider may be able to see a feature of interest (e.g., a tumor, bleeding, abnormal cardiac function, etc.) in the image or video. Alternatively, or additionally, Al may be trained and used to recognize feature(s) of interest in the image or video, and / or in the information used to generate the image or video. In some embodiments, Al or other software is used to identify feature(s) of interest without displaying an image or video suitable for human viewing.

[0359] Optionally, method 300 may include one or more of the following: enhancing a generated image or video (e.g., enhancing resolution and / or otherwise increasing the amount or quality of information obtainable based on the received radiation); mitigating the effect of echoes from tissue layers; mitigating the effect of thermal noise; mitigating the effect of body movement; mitigating the effect of attenuation; mitigating the effect of multipath reflection; mi tigating the effect of electromagnetic interference.

[0360] In some embodiments of method 300, reflective contrast particles and absorptive contrast particles are both used. Accordingly, radiation that is reflected from the imaging subject and radiation that is transmitted through the imaging subject are both detected.

[0361] Suitable imaging radiation may be emitted from any suitable location(s) at any suitable time(s) io facilitate the reflective measurement and the transmissive measurement. For example, the reflective measurement and the transmissive measurement may be performed simultaneously, one after the other, alternatingly, in overlapping fashion, and / or in any other suitable manner. The reflected signal, the transmitted signal, or both signals may be used to determine information about the imaging subject. Including both reflective contrast particles and absorptive contrast particles may be appropriate in situations where different information may be obtained using reflection than using absorption, and / or it is unclear whether reflection or absorption will yield better information, and / or in any other suitable situations. #3530269 086041-000003

[0362] Illustrative Methods and Use Cases

[0363] This section describes illustrative methods and use cases involving contrast imaging in accordance with aspects of the present teachings. In some embodiments, contrast imaging in accordance with aspects of the present teachings is suitable for use in most or all situations in which conventional types of medical contrast imaging are used, including coronary angiography, V / Q scans, and so on. Examples of contrast imaging as described herein may generally be used in situations when, e.g., MRI with contrast, CT with contrast, and / or CT angiography would generally be used.

[0364] In some embodiments, blood pressure and / or related vital signs such as mean arterial pressure and venous pressures are determined using contrast imaging in accordance with aspects of the present teachings. For example, contrast particles may be administered into a patient's blood, the velocity of the contrast particles through the patient’s body may be determined based on contrast imaging, and the blood pressure may be determined based on the velocity.

[0365] In some embodiments, contrast imaging in accordance with aspects of the present teachings is used to image chamberts) of the imaging subject’s heart. This may allow for determining cardiac function (e.g., as part of a cardiac stress test).

[0366] In some embodiments, contrast particles are administered to the lungs (e.g., by being aerosolized) and contrast imaging as described herein is used to visualize the lungs. This may be used to determine ventilation and / or perfusion of the lungs (e.g., as a conventional V / Q scan may be used). Alternatively, or additionally, this may be used io image the lungs to detect masses and / or blockages, and / or to visualize the patient’s airways.

[0367] In some embodiments, a contrast imaging system in accordance with aspects of the present teachings is configured to provide real-time images and / or video to a head-mounted device (e.g., a surgical optic) configured to be worn by a surgeon or other suitable medical personnel. This may allow the wearer to view contrast images of vasculature and / or other suitable anatomical structure during surgery or other suitable procedures.

[0368] In some embodiments, a contrast imaging system in accordance with aspects of the present teachings is configured to be used for training. For example, contrast particles as described herein may be injected or otherwise administered into an individual, and contrast images and / or video may be acquired and displayed to allow observers to view anatomical structures of the individual (e.g., to view the individual’s heat! and / or watch the individual’s heart beat in real time).. A plurality of imaging radiation sources may be used to facilitate 3D #3530269 086041-000003

[0369] 50

[0370] imaging. The images and / or video acquired may be displayed on any suitable display device(s). In some embodiments, the images and / or video are displayed on head-mounted displays worn by the observers, which may be configured to display augmented reality and / or virtual reality displays based on the acquired images and / or video.

[0371] In embodiments in which the contrast imaging system is used for training, the observers may be medical trainees or students and the individual being imaged may be an instructor and / or volunteer imaging subject. Because contrast imaging in accordance with aspects of the present teachings may pose very little to no risk to the imaging subject, it is feasible to image an individual for training purposes rather than (or in addition to) for the purpose of facilitating medical treatment. A training kit comprising an imaging radiation emitter and receiver (either as separate devices or as one emitter / receiver device), contrast particles, and optionally a computing device and or software configured to determine imaging information based on the recei ved radiation is con templated.

[0372] hi some embodiments, a contrast imaging system comprises a receiver and emitter that are relatively small in size. For example, the receiver and emitter may be small enough for use at a person’s home, rather than being installed in a relatively large dedicated space at a medical facility, such as an MRI imaging facility. This may be feasible because at least some embodiments of contrast imaging system according to aspects of the present teachings have only low power requirements that may generally be met by a residential power system. In contrast, known imaging systems that use ionizing radiation generally require more power than a residential power system could provide.

[0373] In some embodiments, a contrast imaging system is battery-powered and portable. For example, a battery-powered portable system may be suitable for use by a traveling medical care provider, in emergency situations, and / or as a military field unit.

[0374] In some embodiments, a smartphone may be used as the emitter (or one of the emitters) of a contrast imaging system. Many known smartphones are capable of emitting radiation of suitable wavelengths.

[0375] In some embodiments, contrast particles are injected into a patient’s blood and contrast imaging as described herein is used to detect the presence or absence of blood in portions of the patient. For example, internal bleeding or internal bruising in a patient may be detected. This may be used to monitor trauma or post-operative patients for internal bleeding or bruising that might otherwise go undetected. As another example, a lack of perfusion to an anatomical region of the patient may be detected (e.g., to monitor a diabetic patient for a lack #3538269 086041-000003

[0376] 5!

[0377] of perfusion to extremities such as the toes). In some embodiments, one or more organs of a patient undergoing surgery are monitored for lack of perfusion. This represents an improvement over known methods in which fluorescent dye and visible spectrum light are used to monitor for lack of perfusion; these known methods suffer the drawback that they may only detect lack of perfusion at the surface level of the patient. Contrast imaging in accordance with aspects of the present teachings may visualize vasculature and thus detect lack of perfusion deeper in the patient (e.g., at all levels of the patient).

[0378] In embodiments in which contrast imaging is used to monitor for the presence or absence of blood, the contrast imaging data may be monitored by a human, monitored automatically, monitored both by human(s) and automatically, or monitored by a combination of human and automatic monitoring. In some embodiments, contrast particles are administered into the patient's blood continuously or at suitable intervals to facilitate continuous monitoring (using, e.g., a radio emission source) for hemorrhages and / or internal bleeding.

[0379] In some embodiments, contrast imaging in accordance with aspects of the present teachings is used to locate atypical vasculature or anatomy in a patient before surgery. In some embodiments, contrast imaging data (e.g., of many patients and / or of many images of the same patient) is used to train Al to recognize particular anatomy and or to recognize atypical anatomy.

[0380] in some embodiments, contrast imaging as described herein is used to visualize hypovolemia based on vasculature being less inflated when hypovolemic. In some embodiments, molecular biomarkers are attached to the carrier to visualize areas of inflammation in the body, for example, macrophage antigens may be attached to the surface of the carrier, and contrast imaging as described herein may be used to detect inflammation based on the biomarkers. As another example, antibodies may be attached to the surface of the carrier, with the antibodies being configured to bind antigens of a desired target, such as tumor antigens or cancer markers in the blood. Contrast imaging as described herein may be used to determine the presence and / or concentration of the biomarkers and to determine the presence and / or concentration of the target based on the determined presence and / or concentration of the biomarkers.

[0381] Other illustrative applications and / or use cases may include: octreotide scans; serotonin release assays; military field angiography either at base or in the field (e.g., using a battery-powered mobile unit); attaching contrast particles to suitable molecular target(s) for #3530269 086041-000003

[0382] 52

[0383] diagnosis and / or aid in finding diseases; hysterosalpingograms; angiography of pregnant women and / or infant(s) in utero; identify developing hematomas in newly born infants; myelograms (e.g.. visualizing cerebral spinal fluid into which contrast particles have been administered); triple source bronchoscopy (e.g., to visualize aspirated material, which is frequently used in pediatrics); detecting and / or observing cardiovascular anatomy abnormalities (e.g., in utero and / or later in life); gastric emptying studies; detecting signs of cancer by tagging glucose with contrast particles and using radio imaging to locate the glucose (e.g., as an annual cancer screening); as a replace and / or supplement io barium swallow imaging; imaging renal calculi; imaging gallstones; Doppler analysis may be added to the received signal to find areas of valve regurgitation, stenosis of blood vessels, and / or other features of interest; whole body imaging may be accomplished by following the ensemble of contrast particles as it progresses through organs or regions of the body, with AI optionally being used to identify anomalies in structure and / or function based on the acquired image data.

[0384] Illustrative Data Processing System

[0385] Aspects of imaging systems and methods in accordance with aspects of the present teachings may be embodied as a computer method, computer system, or computer program product. Accordingly, such aspects may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, micro-code, and the like), or an embodiment combining software and hardware aspects, all of which may generally be referred to herein as a “circuit,” “module,” or “system.” Furthermore, such aspects may take the form of a computer program product embodied in a computer-readable medium (or media) having computer-readable program code / instructions embodied thereon, Any combination of computer-readable media may be utilized. Computer-readable media may be a computer-readable signal medium and / or a computer-readable storage medium. A computer-readable storage medium may include an electronic, magnetic, optical, electromagnetic, infrared, and / or semiconductor system, apparatus, or device, or any suitable combination of these. More specific examples of a computer-readable storage medium may include the following: an electrical connection having one or more wires, a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or Flash memory), an optical fiber, a portable compact disc read-only memory' (CD-ROM), an optical storage device, a magnetic #3530269 086041-000003

[0386] 53

[0387] storage device, and / or any suitable combination of these and / or the like. In the context of this disclosure, a computer-readable storage medium may include any suitable non-transitory, tangible medium that may contain or store a program for use by or in connection with an instruction execution system, apparatus, or device. A computer-readable signal medium may include a propagated data signal with computer -readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electro-magnetic, optical, and / or any suitable combination thereof. A computer-readable signal medium may include any computer- readable medium that is not a computer-readable storage medium and that is capable of communicating, propagating, or transporting a program for use by or in connection with an instruction execution system, apparatus, or device.

[0388] Program code embodied on a computer-readable medium may be transmitted using any appropriate medium, including but not limited to wireless, wireline, optical fiber cable, RF, and / or the like, and / or any suitable combination of these. Computer program code for carrying out operations for aspects of contrast imaging may be written in one or any combination of programming languages, including an object-oriented programming language (such as Java, C++), conventional procedural programming languages (such as C), and functional programming languages (such as Haskell). Mobile apps may be developed using any suitable language, including those previously mentioned, as well as Objective-C, Swift, C#, HTML5, and the like. The program code may execute entirely on a user's computer, partly on the user’s computer, as a stand-alone software package, partly on the user's computer and partly on a remote computer, or entirely on the remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer through any type of network, including a local area network (LAN) or a wide area network (WAN), and / or the connection may be made to an external computer (for example, through the Internet using an Internet Service Provider ).

[0389] Aspects of contrast imaging systems may be described in this disclosure with reference to flowchart illustrations and / or block diagrams of methods, apparatuses, systems, and / or computer program products. Each block and / or combination of blocks in a flowchart and / or block diagram may be implemented by computer program instructions.

[0390] The computer program instructions may be programmed into or otherwise provided to processing logic (e.g., a processor of a general purpose computer, special purpose computer, field programmable gate array (FPGA), or other programmable data processing apparatus) to #3530269 086041-000003

[0391] 54

[0392] produce a machine, such that the (e.g., machine-readable) instructions, which execute via the processing logic, create means for implementing the functions / acts specified in the flowchart and / or block diagram block(s).

[0393] Additionally or alternatively, these computer program instructions may be stored in a computer-readable medium that may direct processing logic and or any other suitable device to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instructions which implement the function / act specified in the flowchart and / or block diagram block(s).

[0394] The computer program instructions may also be loaded onto processing logic and / or any other suitable device to cause a series of operational steps to be performed on the device to produce a computer-implemented process such that the executed instructions provide processes for implementing the functions / acts specified in the flowchart and / or block diagram block(s).

[0395] Any flowchart and / or block diagram in the drawings is intended to illustrate the architecture, functionality, and / or operation of possible implementations of systems, methods, and computer program products according to aspects of the contrast imaging systems and methods described in this disclosure and are not limiting. In this regard, each block may represent a module, segment, or portion of code, which comprises one or more executable instructions for implementing the specified logical function(s). In some implementations, the functions noted in the block may occur out of the order noted in the drawings. For example, two blocks shown in succession may, in fact, be executed substantially concurrently, or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. Each block and / or combination of blocks may be implemented by special purpose hardware-based systems (or combinations of special purpose hardware and computer instructions) that perform the specified functions or acts.

[0396] The uses of the terms ”a” and ”an" and ''the" and similar references in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly #3538269 086041-000003

[0397] 5

[0398] contradicted by context. The use of any and all examples, embodiments, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claitned element as essential to the practice of the invention.

[0399] While the invention has been illustrated and described in detail in the drawings and the foregoing description, the same is to be considered as illustrative and not restrictive in character, it being understood that only the preferred embodiment has been shown and described and that all changes and modifications that come within the spirit of the invention are desired to be protected. In addition, all references cited herein are indicati ve of the level of skill in the art and are hereby incorporated by reference in their entirety.

[0400] EMBODIMENTS

[0401] The following provides an enumerated listing of some of the embodiments disclosed herein. It will be understood that this listing is non-limiting, and that individual features or combinations of features (e.g. 2, 3 or 4 features) as described in the Detailed Description above may be incorporated with the below-listed Embodiments to provide additional disclosed embodiments herein.

[0402] 1. A method for imagining a patient or portion of a patient in need of treatment or diagnosis comprising the acts of:

[0403] positioning said patient:

[0404] emitting electromagnetic radiation from an emission source, wherein said electromagnetic radiation comprises radiation in the range of between 0.5 GHz to 0.9 GHz; I GHz and 10 GHz, 1.6 GHz to 2,4 GHz, 2 GHz to 9 GHz, 3 GHz to 8 GHz, 4 GHz to 7 GHz, 5 GHz to 6 GHz, 900 MHz to 20 GHz, 700 MHz to 20 GHz, or a combination thereof;

[0405] passing said electromagnetic radiation through the positioned patient or portion of said patient; and

[0406] receiving said electromagnetic radiation after it has passed through said patient or portion of said patient through a receiver. #3538269 086041-000003

[0407] 56

[0408] 2. The method of embodiment 2, further comprising the act of administering to the patient a reflective contrast agent or absorptive contrast agent.

[0409] 3. The method of embodiment 2, wherein said reflective contrast agent comprises aluminum.

[0410] 4. The method of embodiment 2, wherein said absorptive contrast agent comprises absorptive contrast particles.

[0411] 5. The method of embodiment 2, wherein said absorptive contrast agent comprises iron oxide nanoparticles, nickel nanoparticles, cobalt nanoparticles, gadolinium compounds, titanium dioxide, barium titanate, lead zirconate titanate, zirconium dioxide, manganese chloride, bismuth-based compounds, tungsten oxides, or calcium carbonate.

[0412] 6. The method of embodiment 2, wherein said reflective contrast agent or absorptive contrast agent comprises a coating.

[0413] 7. The method of embodiment 6, wherein said coating comprises and antibody.

[0414] 8. The method of embodiment 2 further comprising the act of determining information about the position or spatial extent of said reflective contrast agent or absorptive contrast agent within the subject based on the time elapsed between emission and detection of the radiation and an estimate of the travel speed of the radiation.

[0415] 9. The method of embodiment 2 further comprising the act of determining information about the speed or direction of which said reflective contrast agent or absorptive contrast agent within said subject are moving.

[0416] 10. The method of embodiment 9, wherein said speed or direction of which said reflective contrast agent or absorptive contrast agent within said subject are determined based on changes in the position of the contrast particles over time. #3538269 086041-000003

[0417] 11. The method of embodiment 1, wherein said emission source comprises a plurality of antennas.

[0418] 12. The method of embodiment 1, wherein said receiver comprises a plurality of antennas.

[0419] 13. The method of embodiment 1, wherein said method further comprises the act of processing the information received from said receiver.

[0420] 14. The method of embodiment 13, further comprising the act of generating an image from said information received from said receiver.

Claims

#3530269 086041-00000358CLAIMSWhat is claimed is:

1. A method for imagining a patient or portion of a patient in need of treatment or diagnosis comprising the acts of:positioning said patient;emitting electromagnetic radiation from an emission source, wherein said electromagnetic radiation comprises radiation in the range of between 0.5 GHz to 0.9 GHz; 1 GHz and 10 GHz, 1.6 GHz to 2.4 GHz, 2 GHz to 9 GHz, 3 GHz to 8 GHz, 4 GHz to 7 GHz, 5 GHz to 6 GHz, 900 MHz to 20 GHz, 700 MHz to 20 GHz, or a combination thereof;passing said electromagnetic radiation through the positioned patient or portion of said patient; andreceiving said electromagnetic radiation after it has passed through said patient or portion of said patient through a receiver.

2. The method of claim 1, further comprising the act of administering to the patient a reflective contrast agent or absorptive contrast agent.

3. The method of claim 2, wherein said reflective contrast agent comprises aluminum.

4. The method of claim 2, wherein said absorptive contrast agent comprises absorptive contrast particles.

5. The method of claim 2, wherein said absorptive contrast agent comprises iron oxide nanoparticles, nickel nanoparticles, cobalt nanoparticles, gadolinium compounds, titanium dioxide, barium titanate, lead zirconate titanate, zirconium dioxide, manganese chloride, bismuth-based compounds, tungsten oxides, or calcium carbonate.

6. The method of claim 2, wherein said reflective contrast agent or absorptive contrast agent comprises a coating.

7. The method of claim 6, wherein said coating comprises and antibody.#3538269 086041 -000003598. The method of claim 2 further comprising the act of determining information about the position or spatial extent of said reflective contrast agent or absorptive contrast agent within the subject based on the time elapsed between emission and detection of the radiation and an estimate of the travel speed of the radiation.

9. The method of claim 2 further comprising the act of determining information about the speed or direction of which said reflective contrast agent or absorptive contrast agent within said subject are moving.

10. The method of claim 9, wherein said speed or direction of which said reflective contrast agent or absorptive contrast agent within said subject are determined based on changes in the position of the contrast particles over time.

11. The method of claim 1, wherein said emission source comprises a plurality of antennas.

12. The method of claim 1, wherein said receiver comprises a plurality of antennas.

13. The method of claim 1, wherein said method further comprises the act of processing the information received from said receiver.

14. The method of claim 13, further comprising the act of generating an image from said information received from said receiver.

Images