Patent Description:
Advances in computing technology have resulted in a concomitant advance in medical device technologies, including within the field of diagnostic and interventional medicine. Particularly, the past century has demonstrated significant advances in medical imaging devices. Such advances have been hallmarked by the advent of radiologic devices such as computed tomography, magnetic resonance imaging, ultrasound, and other imaging devices that allow for the non-invasive viewing and exploration of internal structures of the body. These devices are often utilized within interventional radiology and minimally invasive surgeries as well, providing image guidance for any of a plethora of medical devices operated by the physician.

The non-invasive nature of medical imaging devices provide certain advantages, but they also have their limitations. Magnetic resonance imaging, for example, requires a patient to hold completely still in a confined area while the overly large, loud, and expensive imaging machine obtains imaging data. Other medical imaging devices, such as those utilized for medical ultrasound, are less expensive but often cannot provide high-resolution images of deep tissue sites.

Further, medical imaging devices are limited by the kind of information reported. Ultrasound, for example, generally relies on sonically reflective surfaces to produce an image and provides little information outside of the image data that can be derived from sonically reflective surfaces within the body. In some instances, ultrasound can be used to detect and monitor blood flow and heart rate, but ultrasound lacks the resolving power to identify the presence or absence-let alone the concentration-of biomarkers within the body. The other medical imaging techniques and devices available similarly lack the ability to identify biomarkers within the body, and while the medical imaging devices developed over the past century have allowed physicians and clinicians to better document, treat, and understand pathologies, they have their limits.

<NPL>, discloses a wireless chemical-sensing scheme using ultrasonic imaging of a microbubble-functionalised hydrogel. By incorporating oxygen microbubbles into a hydrogel, its volume transition, which is responsive to the chemical microenvironment, can be wirelessly monitored by ultrasonic imaging;
measuring volume directly or measuring the reflected acoustic density from the surface of the hydrogel. <CIT> discloses a method for enhancing ultrasound visibility of hyperechoic materials in which a hydrogel plug is placed under stress during a curing stage, by application of an externally applied force, or during or after the dehydration process. The elastic limit of the plug is exceeded when the external force is applied so that the plug substantially retains its stress, size and shape when the external force is removed.

Accordingly, there are a number of disadvantages with medical imaging devices that can be addressed.

The invention is related to a system for identifying one or more changes in a biomarker sensitive hydrogel according to claim <NUM>.

Examples of the present disclosure solve one or more of the foregoing or other problems in the art with medical imaging devices. In particular, one or more examples can include a system for identifying one or more dimensional changes in a biomarker sensitive hydrogel positioned within an in vivo environment using ultrasound. The system includes a biomarker sensitive hydrogel positioned within an in vivo environment and configured to dimensionally change in response to interaction with one or more predefined biomarkers. The system additionally includes an ultrasound transducer for locating and identifying one or more characteristics of the biomarker sensitive hydrogel and a computer system in electrical communication with the ultrasound transducer. The computer system includes one or more processors and is configured to receive the one or more characteristics of the biomarker sensitive hydrogel from the ultrasound transducer and to determine, at the one or more processors, one or more dimensional changes of the biomarker sensitive hydrogel based on the received one or more characteristics of the biomarker sensitive hydrogel.

In some examples the computer system receives the one or more characteristics of the biomarker sensitive hydrogel from the ultrasound transducer at a first time and at a second time. Based on differences between the one or more characteristics of the biomarker sensitive hydrogel at the first time and at the second time, the computer system determines, at the one or more processors, the one or more dimensional changes of the biomarker sensitive hydrogel. The biomarker sensitive hydrogel can include one or more markers or contrast agents, and the differences between the one or more characteristics of the biomarker sensitive hydrogel at the first time and at the second time can be (i) a change in an average density of one or more markers or contrast agents or (ii) a distance between at least two markers or contrast agents of the one or more markers or contrast agents.

In some examples, a system for identifying one or more changes in a biomarker sensitive hydrogel positioned within an in vivo environment further comprises a control hydrogel positioned within the in vivo environment, the control hydrogel configured not to dimensionally change in response to interaction with one or more predefined biomarkers. The ultrasound transducer is further configured to locate the control hydrogel and identify one or more control characteristics of the control hydrogel. Accordingly, the computer system is further configured to receive the one or more control characteristics from the ultrasound transducer and determine, at the one or more processors, one or more dimensional changes of the biomarker sensitive hydrogel based on differences between the one or more characteristics of the biomarker sensitive hydrogel and the one or more control characteristics of the control hydrogel. The biomarker sensitive hydrogel and the control hydrogel can each comprise one or more markers or contrast agents. The one or more markers or contrast agents can comprise one or more of: a metal, a plurality of microspheres, a plurality of microbubbles, a plurality of microwires, a plurality of nanowires, or a plurality of sonically reflective nanoparticles. The one or more markers or contrast agents can additionally be positioned to render a plurality of barber pole stripes along or within the biomarker sensitive hydrogel and the control hydrogel or be positioned to render one or more foci along or within the biomarker sensitive hydrogel and the control hydrogel.

In some examples, the biomarker sensitive hydrogel comprises an elongate shape between <NUM>-<NUM> thick and <NUM>-<NUM> long, and the one or more dimensional changes of the biomarker sensitive hydrogel comprise a change in the volume of the biomarker sensitive hydrogel. The change in volume causes a detectable change in the length of the biomarker sensitive hydrogel, which correlates with the concentration of predefined biomarkers interacting with the biomarker sensitive hydrogel.

In some examples, the one or more characteristics of the biomarker sensitive hydrogel comprise first and second sets of characteristics of the biomarker sensitive hydrogel. The first set of characteristics of the biomarker sensitive hydrogel correspond to a first view of the biomarker sensitive hydrogel within the in vivo environment, and the second set of characteristics of the biomarker sensitive hydrogel correspond to a second view of the biomarker sensitive hydrogel within the in vivo environment where the second view is substantially orthogonal to the first view.

One or more examples can include a system for detecting a concentration of one or more biomarkers within an in vivo environment. The system can include (i) an ultrasound transducer, (ii) a sleeve that selectively surrounds at least a distal end of the ultrasound transducer, and (iii) a computer system in electrical communication with the ultrasound transducer. The sleeve comprises a hydrogel resonator sheet configured to absorb a subset of ultrasonic frequency bands emitted by the ultrasound transducer. The hydrogel resonator sheet comprises a biomarker sensitive hydrogel arranged in an array of acoustic resonators that undergo one or more physical changes in response to a selective association with the one or more biomarkers. The computer system includes one or more processors and is configured to receive one or more characteristics of at least a portion of the array of acoustic resonators from the ultrasound transducer and to determine, at the one or more processors, one or more changes of the hydrogel resonator sheet based on the received one or more characteristics of the portion of the array of acoustic resonators.

In some examples, the computer system is additionally configured to receive a plurality of ultrasound frequencies from the ultrasound transducer that are outside the subset of ultrasonic frequency bands, and by processing at least a portion of the plurality of ultrasound frequencies outside the subset of ultrasonic frequency bands, the computer system is configured to construct an image the in vivo environment using the one or more processors.

In some examples, the one or more characteristics received from the ultrasound transducer comprise a shift in a frequency position of the maxima of the absorption (or any other significant point of the frequency spectrum) for the portion of the array of resonators, and as determined by the shift in the frequency position of the maxima of the absorption for the portion of the array of resonators, the one or more changes of the hydrogel resonator sheet comprise a swelling or a shrinking of at least the portion of the array of resonators.

In some examples, the hydrogel resonator sheet is spatially associated with a contrast structure, and the computer system is additionally configured to receive spatial information associated with the contrast structure from the ultrasound transducer. Additionally, the computer system can determine the dimensional changes of the biomarker sensitive hydrogel based on the spatial information associated with the contrast structure and the received one or more characteristics between a first point in time and a second point in time.

In some examples, the array of acoustic resonators comprises a periodic array of same-sized acoustic resonators.

In some examples, the array of acoustic resonators comprises a repeated pattern of cylindrical ultrasonic resonators to enable selective harmonic suppression. The repeated pattern can include, in a first direction, a central cylindrical ultrasonic resonator having a first size alternating with a second cylindrical ultrasonic resonator having a second size. The repeated pattern can additionally include, in a second direction, the central cylindrical ultrasonic resonator alternating with a third cylindrical ultrasonic resonator having a third size.

In some examples, the sleeve further includes a control array of resonators that do not undergo one or more physical changes in response to interaction with predefined biomarkers. The ultrasound transducer is configured to identify control characteristics of the control array of resonators, and the computer system is further configured to receive, from the ultrasound transducer, the control characteristics and determine changes, at the one or more processors, based on differences between the characteristics of the portion of the array of acoustic resonators and the control characteristics of the control array of resonators.

One or more examples can include a biosensor that provides an ultrasound-dependent readout of biomarker concentration within an in vivo environment. The biosensor can include a chip having a contrast structure disposed on a bottom portion and a hydrogel resonator sheet configured to absorb a subset of ultrasonic frequency bands emitted by an ultrasound transducer. The hydrogel resonator sheet can be associated with a top portion of the chip and positioned above the contrast structure. The contrast structure additionally includes a plurality of spatially rigid reference points for comparing dimensional changes of the hydrogel resonator sheet.

One or more examples can include a computer-implemented method for using ultrasound to identify one or more changes in a biomarker sensitive hydrogel positioned within an in vivo environment. The computer-implemented method can include receiving data from an ultrasound receiver at a first time, the data comprising one or more characteristics of the biomarker sensitive hydrogel, and determining one or more of a volume or length of the biomarker sensitive hydrogel based on the one or more characteristics. The computer-implemented method can additionally include receiving additional data from the ultrasound receiver at a second time, the additional data comprising one or more updated characteristics of the biomarker sensitive hydrogel, and determining one or more of an updated volume or an updated length of the biomarker sensitive hydrogel based on the one or more updated characteristics. Based on the volume, the length, the updated volume, and the updated length, the computer-implemented method can additionally include calculating the dimensional changes of the biomarker sensitive hydrogel.

Accordingly, systems for identifying one or more changes in a biomarker sensitive hydrogel positioned within an in vivo environment are disclosed.

This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an indication of the scope of the claimed subject matter.

Additional features and advantages of the disclosure will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the disclosure. The features and advantages of the disclosure may be realized and obtained by means of the instruments and combinations particularly pointed out in the appended claims. These and other features of the present disclosure will become more fully apparent from the following description and appended claims, or may be learned by the practice of the disclosure as set forth hereinafter.

In order to describe the manner in which the above recited and other advantages and features of the disclosure can be obtained, a more particular description of the disclosure briefly described above will be rendered by reference to specific embodiments thereof, which are illustrated in the appended drawings. It is appreciated that these drawings depict only typical embodiments of the disclosure and are not therefore to be considered to be limiting of its scope.

In the drawings, multiple instances of an element may each include separate letters appended to the element number. For example, two instances of a particular element "<NUM>" may be labeled as "100a" and "100b. " In that case, the element label may be used without an appended letter (e.g., "<NUM>") to generally refer to every instance of the element, while the element label will include an appended letter (e.g., "100a") to refer to a specific instance of the element. Similarly, a drawing number may include separate letters appended thereto. For example, <FIG> may include Figure 2A and Figure 2B. In that case, the drawing number may be used without the appended letter (e.g., <FIG>) to generally refer to every instance of the drawing, while the drawing label will include an appended letter (e.g., Figure 2A) to refer to a specific instance of the drawing. The disclosure will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:.

Before describing various embodiments of the present disclosure in detail, it is to be understood that this disclosure is not limited to the parameters of the particularly exemplified systems, methods, apparatus, products, processes, and/or kits, which may, of course, vary. Thus, while certain embodiments of the present disclosure will be described in detail, with reference to specific configurations, parameters, components, elements, etc., the descriptions are illustrative and are not to be construed as limiting the scope of the claimed invention. In addition, the terminology used herein is for the purpose of describing the embodiments, and is not necessarily intended to limit the scope of the claimed invention.

As discussed above, medical imaging devices are generally limited in the kind information that can be reported. Ultrasound, for example, generally relies on sonically reflective surfaces to produce an image and provides little information outside of image data. Particularly, ultrasound lacks the resolving power to identify the presence or absence-let alone the concentration-of biomarkers within the body. Other advancements, however, can be adapted for this purpose. One such example includes hydrogels.

Hydrogels are objects consisting of hydrophilic cross-linked networks of polymer that have both liquidlike and solidlike properties. Smart hydrogels characteristically experience a change in their volume and mechanical properties in response to the presence of a specific stimulus or analyte. As used herein, the term "analyte" includes any substance that can itself be identified or measured or of which a chemical or physical property thereof can be identified or measured. Analytes include, for example, nucleic acids, proteins, chemicals, or other compounds. In some instances, analytes serve as a physiologic, pathologic, or environmental marker of a known or unknown phenomenon (e.g., insulin levels can serve as a biomarker for diabetes). Hydrogels that are responsive to one or more biomarkers are termed "biomarker sensitive hydrogels," and although much of the disclosure herein particularly recites "a biomarker sensitive hydrogel," it should be appreciated that the disclosed embodiments apply generally to smart hydrogels that are responsive to any analyte.

Hydrogels can also respond to the presence of an environmental stimulus (e.g., temperature, pH, gas, osmolarity, humidity, etc.) and can additionally serve to indicate particular state data of an aqueous solution, such as pH. That is, hydrogels can change their volume and mechanical properties in response to the level of salinity or acidity in an aqueous solution.

<FIG> illustrates the characteristic change in volume exhibited by hydrogels. As shown, a hydrogel can transition from a collapsed or shrunken state <NUM> to a swollen state <NUM> in response to the presence of a specific analyte <NUM>. Although seemingly depicted as a binary transition-from a shrunken state <NUM> to a swollen state <NUM>-the change in volume exhibited by hydrogels is typically not binary, just as a change in analyte availability is also often not represented as a binary modality. As shown, the concentration <NUM> of the analyte <NUM> can span any point along a spectrum from low to high concentration. Advantageously, hydrogels respond to variable analyte concentrations in a similar graded fashion. Instead of being a binary readout of the presence or absence of an analyte or stimulus, hydrogels experience a change in volume that correlates with the concentration of analyte interacting with the hydrogel.

Hydrogels can sense analytes and/or stimuli using a variety of recognition domains, and the binding specificity and fidelity can be tuned to various sensitives, often depending on the type of recognition domain utilized. <FIG> illustrates a generalized method <NUM> of molecular imprinting that can be used to manufacture hydrogels with specificity for a given analyte. Molecular imprinting relies on a combination of reversible binding and shape complementarity to specifically recognize target analytes. Referring to <FIG>, the first step of the illustrated method <NUM> is allow functional monomers <NUM> to interact with and self-assemble about a print molecule <NUM>. The print molecule <NUM> includes the same desired shape as the target analyte such that when the functional monomers <NUM> self-assemble and are polymerized, the resulting molecular imprinted polymer <NUM> includes a cavity <NUM> that is complementary in size and shape to the print molecule. The print molecules can be removed from the molecular imprinted polymer <NUM>, leaving the cavity <NUM> to function as a selective binding site for the specific analyte.

Hydrogels can be made to include a variety of additional or alternative analyte recognition domains, such as antibodies nucleic acid based aptamers. Antibodies traditionally demonstrate a high level of specificity for targets and are good receptors for biomarkers. Advantageously, antibody binding of biomarkers is a reversible process, and when incorporated into a hydrogel, the resultant biomarker sensitive hydrogel can dynamically respond to changes in biomarker concentration and thereby dynamically change its volume (e.g., shrinking or swelling) in response to increased or decreased concentrations of available biomarker. As shown in <FIG>, antibodies <NUM> can be added to a pre-polymerized hydrogel solution <NUM>, and following polymerization, the antibodies <NUM> are positioned within the resultant biomarker sensitive hydrogel <NUM> so as to interact with biomarkers <NUM>. In some instances, lithography or similar manufacturing methods can be used to first form a foundation of polymerized hydrogel-into which the antibodies are arranged-followed by polymerization of the remaining hydrogel.

As additionally illustrated in <FIG>, the biomarker sensitive hydrogel <NUM> is configured to swell (e.g., as shown by swollen biomarker sensitive hydrogel <NUM>) in response to interacting with additional biomarkers <NUM> and shrink (e.g., as shown in biomarker sensitive hydrogel <NUM>) in response to a lower concentration of available biomarkers <NUM>. Accordingly, the biomarker sensitive hydrogel <NUM> is configured to reach an equilibrium <NUM> between swollen and shrunken states based on the amount or concentration of biomarker <NUM> available to interact with the antibodies <NUM> within the biomarker sensitive hydrogel <NUM>. In doing so, the biomarker sensitive hydrogel <NUM> acts as a biosensor for the amount or concentration of biomarker <NUM> in the vicinity of the biomarker sensitive hydrogel <NUM>, and by determining the volume of the biomarker sensitive hydrogel <NUM>, the amount or concentration of biomarker can be determined.

The possibility to tailor hydrogel responses to different analytes or stimuli has made hydrogels an attractive material for applications like drug delivery, sensing, actuation, and implants. Hydrogels, particularly biomarker sensitive hydrogels, are additionally attractive as a material for biosensing and as an implant due to its inherent biocompatibility, failure to elicit an immune response, and dynamic ability to correlate biomarker concentrations.

However, the ability to obtain a real-time, visual readout of hydrogel responses to analytes or other stimuli has proven problematic, particularly when the hydrogel is implanted in vivo. Noninvasive medical imaging techniques would be an ideal method to obtain a real-time, visual readout of hydrogel responses in vivo, but hydrogels are nearly invisible to most medical imaging devices-including ultrasound-making it difficult to determine any response of the hydrogel to surrounding analytes and/or stimuli. Thus, even though hydrogels represent a promising material for biomedical and biotechnological applications, their lack of visibility and concomitant lack of ability to be tracked in real time using current imaging devices and techniques renders their potential a moot point.

Embodiments of the present disclosure enable the use of ultrasonic imaging to accurately measure changes in the volume and shape of biomarker sensitive hydrogels due to exposure to various biomarkers and thereby determine the concentration of biomarkers within an in vivo environment. Practicing the disclosed embodiments advantageously allows the use of existing, comparably cheap medical imaging technology to noninvasively obtain a real-time, visual readout of hydrogel swelling. Because biomarker sensitive hydrogels are biocompatible and essentially immunologically inert and because the specificity of biomarker sensitive hydrogels can be adapted to sense a variety of biomarkers, embodiments of the present disclosure advantageously enable the use and readout of long-term implants that can provide meaningful information about biomarker concentrations at an in vivo site. Further, the use of ultrasound to identify dimensional changes in a biomarker sensitive hydrogel placed within, for example, the human body is advantageous over optical sensing techniques, as ultrasound allows for a deeper reach into tissue.

Referring now to <FIG>, illustrated are exemplary biomarker sensitive hydrogels associated with a variety of ultrasound markers and/or contrast agents. The associated ultrasound markers and/or contrast agents provide at least a twofold benefit. First, the ultrasound markers and/or contrast agents associated with the biomarker sensitive hydrogel allow the biomarker sensitive hydrogel to be easier to locate in vivo and can even be used to define the general contour of the biomarker sensitive hydrogel with respect to surrounding structures. Second, the ultrasound markers and/or contrast agents associated with the biomarker sensitive hydrogel allow detection of dimensional changes within the biomarker sensitive hydrogel (e.g., swelling as a result of sensing a specified biomarker). In some embodiments, the addition of ultrasound markers and/or contrast agents to the biomarker sensitive hydrogel does not substantially interfere with or otherwise hinder the swelling and shrinking of the hydrogel in response to sensing an increase or decrease in the amount or concentration of specific biomarkers.

<FIG> illustrates an exemplary biomarker sensitive hydrogel 406a having a plurality of microbubbles <NUM> dispersed throughout the biomarker sensitive hydrogel 406a. In some embodiments, the microbubbles <NUM> are filled with gas, such as air. In some embodiments, the gas is a perfluorocarbon (e.g., a perfluoroalkane such as perfluoropropane). The microbubbles <NUM> are infused within the biomarker sensitive hydrogel 406a and act to reflect ultrasound waves emitted from an ultrasound transducer. Thus, the diffuse microbubbles <NUM> provide ultrasound contrast to a volume of space that is substantially coexistent with the biomarker sensitive hydrogel 406a, thereby allowing the hydrogel 406a to be more easily viewed using ultrasound. In some embodiments, one or more dimensional changes associated with the biomarker sensitive hydrogel 406a can be determined by tracking respective spatial locations of two or more microbubbles <NUM> or by comparing an average density of microbubbles within a given viewing window (e.g., as shown and described below with respect to <FIG>).

In some embodiments, the diameter of the microbubbles is greater than <NUM> in diameter but less than <NUM> in diameter, greater than <NUM> in diameter but less than <NUM> in diameter, greater than <NUM> in diameter but less than <NUM> in diameter, greater than <NUM> in diameter but less than <NUM> in diameter, greater than <NUM> in diameter but less than <NUM> in diameter, greater than <NUM> in diameter but less than <NUM> in diameter, greater than <NUM> in diameter but less than <NUM> in diameter, or the diameter of the microbubbles is selected within a range defined by any of the foregoing upper and lower bounds.

<FIG> illustrates an exemplary biomarker sensitive hydrogel 406b having a plurality of barber pole stripes <NUM> disposed along the biomarker sensitive hydrogel 406b. In some embodiments, the barber pole stripes <NUM> include a metal film or wire (e.g., microwires or nanowires) disposed on top of, around, or inside the biomarker sensitive hydrogel 406b. The metal can be chosen from any sonically reflective metal that is at least somewhat biocompatible or non-toxic including, for example, gold, palladium, platinum, or silver. In some embodiments, the metal film or wire is helically disposed along or within the biomarker sensitive hydrogel 406b and is flexible along its helical axis such that volumetric changes of the biomarker sensitive hydrogel 406b cause elongation or constriction of the helix. Accordingly, volumetric changes within the biomarker sensitive hydrogel 406b can be tracked by measuring the distance between two or more barber pole stripes (e.g., two adjacent operable stripes).

In some embodiments, the hydrogel 406b is formed around the metal film or wire that comprises the plurality of barber pole stripes <NUM>. For example, a helical metal film can be placed within a mold and a pre-polymerized solution of hydrogel can be poured over the helical metal film followed by polymerization of the hydrogel solution, thereby incorporating the helical metal film therein. In some embodiments, metal film or wire is added to the biomarker sensitive hydrogel 406b after the hydrogel is been manufactured. For example, the metal film or wire may be wound about a discrete portion of manufactured hydrogel to create the plurality of barber pole stripes <NUM>. In some embodiments, the biomarker sensitive hydrogel 406b is manufactured using lithography, and the plurality of barber pole stripes <NUM> are generated during this process. In some embodiments, the biomarker sensitive hydrogel is fabricated, dried out and the plurality of barber pole stripes added by lithography based techniques for metallic thin film fabrication.

Referring now to <FIG>, illustrated is an exemplary biomarker sensitive hydrogel 406c having a sonically reflective and elastic sleeve <NUM> associated therewith. For example, the sleeve <NUM> may include an elastic material such as nitinol. Additionally, or alternatively, the sleeve <NUM> can be geometrically patterned (e.g., honeycombed or like chicken wire) to permit expansion or deformation in one or more spatial directions. The sonically reflective characteristics and elasticity of nitinol along with the defined geometric pattern of the sleeve <NUM> permit volumetric changes within the hydrogel 406c will also tracking such changes. For example, as the volume of the biomarker sensitive hydrogel 406c increases, the sleeve <NUM> elastically expands and distends one or more dimensions of the geometric shapes (e.g., the hexagonal honeycomb) that comprise the sleeve <NUM>. These changes can be tracked and processed to determine an amount or concentration of biomarker.

Referring now to <FIG>, illustrated is an exemplary biomarker sensitive hydrogel 406d having a plurality of nanoparticles <NUM> overlain on the surface of the biomarker sensitive hydrogel 406d. It should be appreciated that <FIG> illustrates a planar front view of the biomarker sensitive hydrogel 406d, making it appear that the plurality of nanoparticles <NUM> are aligned in a single line or plane. In some embodiments, the plurality of nanoparticles are indeed aligned in a single line across the surface of the biomarker sensitive hydrogel. In other embodiments, the plurality of nanoparticles are dispersed across at least one surface of the biomarker sensitive hydrogel. In some embodiments, the plurality of nanoparticles are dispersed across more than one surface (or all surfaces) of the biomarker sensitive hydrogel. The plurality of nanoparticles <NUM> can include any sonically reflective nanoparticles, such as polystyrene nanoparticles, gold nanoparticles, silver nanoparticles, or combinations thereof. In some embodiments, the nanoparticles are equally distributed across the whole volume of the biomarker sensitive hydrogel.

Similar to the microbubbles of <FIG>, the sonically reflective nanoparticles <NUM> of <FIG> can be used to determine volumetric changes in the biomarker sensitive hydrogel 406d. For example, the distance between two or more nanoparticles <NUM> or an average density of nanoparticles on the surface of the biomarker sensitive hydrogel 406d taking at two time points can be used to identify volumetric changes in the associated biomarker sensitive hydrogel 406d. It should be appreciated that coating only a single surface of the hydrogel with sonically reflective nanoparticles may dictate or at least limit the angles at which the ultrasound can reveal the most informative data about the spatial relationships between nanoparticles on the surface of the hydrogel. For example, if the ultrasound was taken at an angle that yields the biomarker sensitive hydrogel 406d illustrated in <FIG>, less information can be accurately and consistently gleaned than if the ultrasound was taken at an angle orthogonal to the top surface of the biomarker sensitive hydrogel 406d.

Further, imaging only a single angle of the hydrogel yields a two-dimensional object from which three-dimensional volumetric data is extrapolated. In some embodiments, a second view of the hydrogel is obtained that is rotationally different than the first view to provide additional dimensional data for computing volumetric changes. In some embodiments, the two views are substantially orthogonal to one another. In some embodiments, more than two views are used (e.g., three views, four views, five views, six views, or more). It should be appreciated that in any of the foregoing and forthcoming embodiments where two-dimensional images are used to determine three-dimensional characteristics, it can be beneficial to obtain a second image that is taken in a different rotational plane (e.g., substantially orthogonal) than the first image.

Referring now to <FIG>, illustrated is an exemplary biomarker sensitive hydrogel 406e having a pair of contrast laden foci <NUM> disposed on opposite ends of the biomarker sensitive hydrogel 406e. In some embodiments, the foci <NUM> include any of the foregoing ultrasound markers and/or contrast agents disclosed in <FIG>. In some embodiments, the biomarker sensitive hydrogel 406e is extruded during manufacturing, and the initial N-terminal points of extrusion coincide with application of an ultrasound marker and/or contrast agent. In some embodiments, a volumetric change of the biomarker sensitive hydrogel 406e can be determined based on the difference between the foci <NUM>.

In some embodiments, the biomarker sensitive hydrogel can be elongate in shape such that the width or diameter of the hydrogel is disproportionate to its length. In such embodiments, a volumetric change in the elongate hydrogel translates more noticeably into a change in length of the hydrogel. In some embodiments, the thickness to length ratio is no greater than <NUM>/<NUM> : <NUM> and/or no less than <NUM>/<NUM>,<NUM> : <NUM>. In some embodiments, and subject to the foregoing, the elongate biomarker sensitive hydrogel can have a thickness greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, or a thickness selected from a range consisting of any of the foregoing upper and lower bounds. For example, an elongate biomarker sensitive hydrogel can have a thickness between <NUM>-<NUM>. In some embodiments, and subject to the foregoing, an elongate biomarker sensitive hydrogel can have a length greater than <NUM>, greater than <NUM>, greater than <NUM>, dated and <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, or a length selected from a range consisting of any of the foregoing upper and lower bounds. For example, an elongate biomarker sensitive hydrogel can have a length between <NUM>-<NUM>.

For example, as shown in <FIG>, an elongate biomarker sensitive hydrogel <NUM> can increase in volume upon interaction with a higher concentration one or more specific biomarkers <NUM>, similar to those hydrogels described above. Similarly, the elongate biomarker sensitive hydrogel <NUM> can decrease in volume upon interaction with a lower concentration of one or more specific biomarkers <NUM>.

In some embodiments, the volumetric change in the elongate hydrogel is roughly proportional to a change in length, as shown in <FIG>. In such embodiments, it may be beneficial to apply an ultrasound marker and/or contrast agent in the same or similar manner as illustrated by the biomarker sensitive hydrogel 406e of <FIG>. That is, having two foci <NUM> positioned at opposite ends of an elongate biomarker sensitive hydrogel can quickly and easily identify changes in length, and in embodiments where volumetric changes are proportional to changes in length, a single image can be used to approximate or determine volumetric changes (and therefore an amount or concentration of biomarker). In some embodiments, this can save a significant amount of time and computing resources and can enable faster decision-making or increased availability of up-to-date information related to the amount or concentration of biomarker within an in vivo environment.

As alluded to above, an average density of ultrasound markers and/or contrast agents (e.g., microbubbles, sonically reflective nanoparticles, etc.) can be used to determine one or more dimensional changes of the hydrogel. <FIG> illustrates one method for determining the average density of ultrasound markers and/or contrast agents between two time points. As illustrated, an image of a biomarker sensitive hydrogel <NUM> having a plurality of discrete ultrasound markers and/or contrast agents <NUM> can be taken at a first time point. At a second time point, the biomarker sensitive hydrogel <NUM> has interacted with one or more predefined biomarkers, becoming a swollen biomarker sensitive hydrogel <NUM> having a plurality of discrete ultrasound markers and/or contrast agents <NUM>. It should be noted that the total number of discrete ultrasound markers and/or contrast agent <NUM> remains the same between the two time points. However, the density of such discrete ultrasound markers and/or contrast agents <NUM> differs as the same number of discrete ultrasound markers and/or contrast agents <NUM> exist in a larger volume of space.

In some embodiments, and as depicted in <FIG>, the density of discrete ultrasound markers and/or contrast agent <NUM> can be measured by overlaying a measurement window <NUM> of a predefined area onto images of the hydrogel <NUM>, <NUM> taken at both time points. The number of discrete ultrasound markers and/or contrast agents <NUM> touching or within the area defined by the measurement window <NUM> can be counted, recorded or compared between the two time points. In some embodiments, an average number of discrete ultrasound markers and/or contrast agents <NUM> is determined based on sampling, at multiple locations, the number of discrete ultrasound markers and/or contrast agents <NUM> touching or within the area defined by the measurement window <NUM> and dividing by the total number of samples taken. These averages can be compared to determine volumetric changes (and therefore an amount or concentration of biomarker) between the biomarker sensitive hydrogel <NUM> and the swollen biomarker sensitive hydrogel <NUM>.

Referring now to <FIG>, illustrated are exemplary ultrasound images depicting a biomarker sensitive hydrogel being viewed using standard ultrasound equipment. As shown in <FIG>, for example, a biomarker sensitive hydrogel associated with gold nanoparticles can be viewed using a Siemens® 18L6 HD transducer emitting at <NUM>, well within diagnostic frequencies. Similarly, as shown in <FIG>, differently spaced nanowires associated with a biomarker sensitive hydrogel can be viewed using a Siemens® 18L6 HD transducer emitting at <NUM>. It should be appreciated that although not shown, the different ultrasound markers and/or contrast agents discussed and illustrated in <FIG> can also enable a biomarker sensitive hydrogel to be viewed using ultrasound at a clinically relevant frequencies.

Referring now to <FIG>, illustrated are systems for identifying one or more changes in a biomarker sensitive hydrogel positioned within an in vivo environment (e.g., inside the human body). <FIG>, for example illustrates a diagram of an exemplary system <NUM> for identifying changes in a biomarker sensitive hydrogel <NUM>, <NUM> over time. The system <NUM> includes a biomarker sensitive hydrogel positioned within an in vivo environment <NUM>, an ultrasound transducer <NUM>, and a computing system <NUM> in electrical communication with the ultrasound transducer <NUM>. At a first time, the ultrasound transducer <NUM> locates the biomarker sensitive hydrogel <NUM> within the in vivo environment <NUM>. In some embodiments, the biomarker sensitive hydrogel <NUM> is associated with an ultrasound marker and/or contrast agent (as described above), which may assist in locating the biomarker sensitive hydrogel <NUM> within the in vivo environment <NUM>. The computing system <NUM> can identify and/or record one or more characteristics the biomarker sensitive hydrogel <NUM> at the first time point (t<NUM>). In some implementations, and for the purposes of <FIG>, the biomarker sensitive hydrogel <NUM> can reach a physiologic equilibrium with one or more stimuli (e.g., pH, osmolarity, temperature, etc.) and the basal levels (or non-existence) of biomarker within the in vivo system <NUM> prior to identifying and/or recording one or more characteristics of the biomarker sensitive hydrogel <NUM> at the first time point (t<NUM>).

At a second time point (t<NUM>)-the second time point coming chronologically after the first time point (t<NUM>)-the ultrasound transducer <NUM> again locates biomarker sensitive hydrogel <NUM> in the in vivo environment <NUM>, and the computing system <NUM> identifies and/or records one or more updated characteristics of the biomarker sensitive hydrogel <NUM>. As shown in <FIG>, the biomarker sensitive hydrogel <NUM> is swollen compared to the biomarker sensitive hydrogel <NUM> at the first time point (t<NUM>). In some embodiments, the second time point (t<NUM>) can occur during or after an event that causes an increase in the amount or concentration of the specific biomarker. The increase in the amount or concentration of the specific biomarker can cause swelling of the biomarker sensitive hydrogel <NUM> (similar to that shown in <FIG>).

The system <NUM> of <FIG> is similar in many respects to the system <NUM> of <FIG>. For example, the system <NUM> includes an ultrasound transducer <NUM> in electronic communication with a computer system <NUM>. The ultrasound transducer <NUM> is configured to transmit and receive ultrasonic signals for identifying and/or monitoring a biomarker sensitive hydrogel <NUM> within the in vivo environment <NUM> and for identifying one or more characteristics of the biomarker sensitive hydrogel <NUM>. As opposed to system <NUM> of <FIG>, which relied on implanting a single biomarker sensitive hydrogel <NUM>, <NUM> and identifying differences over time, system <NUM> of <FIG> utilizes a control hydrogel <NUM> to establish a baseline of comparison for one or more characteristics of the biomarker sensitive hydrogel <NUM>. In some embodiments, the control hydrogel <NUM> is made of the same or substantially the same polymerized material but is configured not to interact with the predefined biomarker associated with the biomarker sensitive hydrogel <NUM>. In some embodiments, the control hydrogel <NUM> may still be capable of swelling in response to environmental stimuli such as pH and osmolarity so that the control hydrogel <NUM> can more accurately represent a baseline swelling or other dimensional or material properties that should be similarly exhibited by the biomarker sensitive hydrogel <NUM>. Accordingly, at any given time the differences in one or more characteristics between the biomarker sensitive hydrogel <NUM> and the control hydrogel <NUM> are indicative and/or caused by the biomarker sensitive hydrogel <NUM> interacting with one or more predefined biomarkers.

In some embodiments, the control hydrogel <NUM> includes one or more of the same ultrasound markers and/or contrast agents as the biomarker sensitive hydrogel <NUM>. In some embodiments, the control hydrogel <NUM> and the biomarker sensitive hydrogel <NUM> include different ultrasound markers and/or contrast agents. In still further embodiments, the control hydrogel <NUM> and the biomarker sensitive hydrogel <NUM> may each have specificity for a different biomarker. For example, the control hydrogel <NUM> may be sensitive for a biomarker that should not be present within the in vivo environment (e.g., peptidoglycan, viral capsid proteins, or other indications of infection at a typically sterile site), thereby acting as a control in almost every situation but simultaneously having an alarm function for the presence of potentially deleterious biomarkers.

Although the in vivo environment <NUM> is generically depicted in <FIG> as being within the human body, it should be appreciated that the in vivo environment can include any number or types of locations within the human body. For example, the biomarker sensitive hydrogel can be placed within the bloodstream to identify an amount or concentration of thrombin, clotting cascade factors, interleukins, cytokines, chemokines, C-reactive protein, or other biomarker associated with clotting processes and/or pro-inflammatory/anti-inflammatory responses. Such a biomarker sensitive hydrogel can be useful, for example, to monitor healing of the patient after trauma or surgery, and because the hydrogel can be read out using ultrasound techniques, such information can be obtained on demand and noninvasively.

Other implementations within the blood include monitoring a biomarker sensitive hydrogel that is specific for peptidoglycan, mycolic acid, viral capsid proteins, or other bacterial and/or viral specific antigens as a means of noninvasively monitoring the patient for bacteremia, viremia, or other blood-based infection. This can increase the reaction time of attending medical professionals to potentially life-threatening conditions, particularly in immunocompromised patients, so that the infection can be caught and treated early on where the prognosis for recovery is best. This can be particularly impactful, for example, in patients at risk for septicemia, where survival rates are inversely and exponentially correlated with the number of hours the patient is septicemic.

Yet other implementations within the blood include monitoring a biomarker sensitive hydrogel within a diabetic patient or pregnant individual where the hydrogel is specific for blood glucose or insulin. The hydrogel can thereby act as a mechanism by which the individual can quickly and noninvasively monitor their blood glucose levels and/or insulin levels to more effectively and efficiently manage and/or track their condition.

Still yet other implementations within the blood include monitoring a biomarker sensitive hydrogel within patients under general anesthesia. The hydrogel can be specific for one or more active components of the anesthesia or metabolic derivatives thereof, allowing an anesthesiologist or other healthcare provider to more accurately monitor the amount or concentration of anesthesia in the patient's bloodstream and to adjust one or more drugs according to the patient's individual ability to metabolize and/or filter the drugs from their system. A similar approach can be adapted for use in patients prescribed restricted drugs or drugs associated with a high incidence of abuse and/or addiction (e.g., opioids, amphetamines, etc.). The amount or concentration of the prescribed medication can be monitored to ensure compliance and/or to prevent abuse.

In some implementations, the in vivo environment for placement and monitoring of a biomarker sensitive hydrogel can include the bladder (e.g., for monitoring biomarkers correlating with organ failure, infection, eating disorders, preeclampsia, etc.), the vagina (e.g., for monitoring pH, hormones, biomarkers associated with pregnancy, etc.), liver, kidney, or deep tissue area.

It should be appreciated that while the foregoing disclosure has focused mainly on humans, the same or analogous biomarker sensitive hydrogels can be used within in vivo environments of nonhuman animals.

Additionally, or alternatively, implementations can include the use of analyte sensitive hydrogels within environmental locations. This may be particularly advantageous when monitoring, for example, water lines for the presence of pollutants (e.g., toxic metals, known carcinogens, etc.), microbial contamination, or additives (e.g., fluoride). Multiple analyte sensitive hydrogels can be placed at critical points within a supply line and quickly and noninvasively monitored using ultrasound. In some implementations, strategic placement of analyte sensitive hydrogels within environmental locations (e.g., along a water way or within a water line) can assist in and/or expedite identification of contaminating source or other issue. In some implementations, the analyte sensitive hydrogel can be multifaceted such that it will swell in response to interaction with any one of the plurality of analytes. This may be advantageous, for example, in situations where the analyte sensitive hydrogel identifies pollutants or contaminants, any of which alone may be cause for concern and/or the confluence of all should be below the prescribed threshold. In this way, a single hydrogel can be placed and monitored as opposed to deploying a plurality of individually specific analyte sensitive hydrogels to accomplish the same or similar purpose. As such, the foregoing implementations can save time and provide a more effective use of resources.

Referring now to <FIG>, illustrated is an exemplary system <NUM> for identifying one or more changes in a biomarker sensitive hydrogel <NUM> that is positioned within an in vivo environment <NUM>. As illustrated, the system <NUM> includes a computer system <NUM> in communication with an ultrasound transducer <NUM> which can communicate with the in vivo environment <NUM>. From the perspective of the computer system <NUM>, location data and/or data associated with characteristics of a biomarker sensitive hydrogel <NUM> and optionally the control hydrogel <NUM> are received through ultrasound transducer <NUM>. At the processor <NUM>, the received data is analyzed to determine changes, if any, in the characteristics of the biomarker sensitive hydrogel <NUM> between successive time points and/or between analogous characteristics received for the control hydrogel <NUM>. Any changes identified can be used to determine one or more dimensional changes of the biomarker sensitive hydrogel <NUM>, which in turn can be used to determine an amount or concentration of analyte(s) <NUM> within the in vivo environment <NUM>. The computer system <NUM> can additionally process image data received from the ultrasound transducer <NUM> using image processor <NUM> and display the processed image data at display <NUM>. In some embodiments, the computer system <NUM> can display any of the amount or concentration of analyte <NUM>, the determined dimensional changes of the biomarker sensitive hydrogel <NUM>, and/or the identified characteristics of biomarker sensitive hydrogel <NUM> and/or control hydrogel <NUM>.

In some implementations, it may be useful to know and/or have access to information regarding site-specific concentrations of biomarkers, particularly during procedures that are already utilizing an ultrasound transducer to acquire image data. However, current ultrasound transducers lack the resolution or ability to identify individual biomarkers using the transducer alone. Embodiments of the present disclosure include hydrogel resonator sheets that can be adapted for use on a chip-based implant (as shown, for example, in <FIG>) or as part of a protective sleeve for ultrasound transducers (as shown, for example, in <FIG>). The hydrogel resonator sheets disclosed herein provide site-specific information regarding an amount or concentration of a biomarker and can do so, in some embodiments, independently from the use of an ultrasound marker and/or contrast agent.

<FIG> illustrates an exemplary hydrogel resonator sheet <NUM>, which includes a hydrogel base plate <NUM> and a biomarker sensitive hydrogel arranged in an array of resonators <NUM> that undergo one or more physical changes (e.g., swelling) in response to interacting with one or more predefined biomarkers. In some embodiments, the functional aspects of the hydrogel contained within the hydrogel resonator sheet <NUM> is the same and/or substantially similar to the hydrogels disclosed above. For example, the biomarker sensitive hydrogel used to form the resonators <NUM> can undergo volume changes in response to association with one or more predefined biomarkers, particularly in response to association with a higher concentration of the one or more predefined biomarkers. As above, the biomarker sensitive hydrogel used to form the resonators <NUM> can also decrease in volume in response to association with lower concentrations of the one or more biomarkers.

In some embodiments, the resonators <NUM> absorb certain ultrasound frequency bands. Accordingly, at some frequencies, particularly where the main mode or resonant frequency of the resonators <NUM> is located, resonators <NUM> can cause a signal reduction or "dip" in the intensity of the received ultrasonic waves. The signal reduction is a result of transmitted waves being absorbed by the resonators <NUM> instead of being reflected back to the transducer. This phenomenon occurs to a large extent at the main mode (the resonant frequency), and to a lesser extent at higher order harmonic frequencies (e.g., <NUM>nd and <NUM>rd harmonic frequencies), and is dependent upon the volume of the resonator <NUM>. It should be appreciated that in some embodiments the hydrogel array includes an array of sensors, and therefore, the resultant main mode observed is a collective effect achieved by the coupling of the main modes of all the resonators in the array. Further, the dimensions of the resonator can be tailored to a desired frequency range. Accordingly, as the resonator <NUM>, which is comprised of a biomarker sensitive hydrogel, swells or shrinks in response to interactions with predefined biomarkers, the volume of the resonator <NUM> increases and decreases. The increasing or decreasing spatial volume (and accompanying change in material properties) of the resonator <NUM> causes a shift in the resonant frequency of the resonator <NUM>.

Such a phenomenon is illustrated, for example in <FIG>. As shown, a <NUM>% expansion of the hydrogel comprising at least a portion of the resonator sheet has a defined kinetic energy profile along a frequency spectrum. Upon expansion (e.g., as a result of interaction with the hydrogel-specific stimulus/stimuli), the resonant frequency of the hydrogel shifts. The frequency shift of a <NUM>% expansion of the hydrogel is shown in <FIG>. In some embodiments, the frequency shift along a range of hydrogel expansion can be determined ahead of time, and by comparing the known frequency shift given a particular expanded state with the observed frequency shift, the degree of volumetric change can be determined. In some embodiments, comparing a known volumetric change resulting from interaction with a defined concentration of stimulus (e.g., biomarker) with the observed or determined volumetric change in the hydrogel sheet, the concentration of stimulus can be extrapolated.

By identifying a first frequency that corresponds to the resonator's <NUM> main mode (e.g., by scanning through a plurality of frequencies to find a significant signal reduction), changes in the main mode can be tracked (e.g., by following the frequency shift in the signal reduction). The tracked frequency changes in the main mode can be directly correlated to a volumetric change of the resonators <NUM>, and upon determining the volumetric change of the resonators <NUM>, a corresponding amount or concentration of biomarker can be determined. In this way, the disclosed hydrogel resonator sheets can indirectly utilize ultrasound to determine an amount or concentration of a biomarker within an in vivo environment.

With continued reference to <FIG>, the hydrogel baseplate can, in some embodiments, contribute to frequency absorption at the main mode. Additionally, or alternatively, the hydrogel baseplate can provide leverage and connectivity for manipulating the array of resonators both during manufacturing and/or molding as well as during manipulation of the hydrogel resonator sheet onto sensor arrays or other platforms. In some embodiments, the baseplate can be made from a differnet material (e.g., polyimide, silicone, etc.) to facilitate handling. In some embodiments, it is advantageous to make the baseplate from hydrogel because of ease of fabrication and because it likely does not obstruct the ultrasound waves outside the resonance band.

For example, as shown in <FIG>, a sensor array <NUM> can include a hydrogel resonator sheet <NUM> attached to a chip <NUM>. In some embodiments, the chip <NUM> is a silicone chip and includes a contrast structure <NUM> positioned beneath the hydrogel resonator sheet <NUM>. The contrast structure <NUM> can, in some embodiments, provide a spatially rigid reference for comparing swelling and/or shrinkage of the hydrogel resonator sheet (or components thereof) and which can additionally be seen using ultrasound. For example, the contrast structure <NUM> can include a plurality of evenly spaced ridges, which in some embodiments can be a metal or other sonically reflective material, to locate the hydrogel and to provide a contrast feature that can be used to observe the loss of contrast (=signal/intensity) to find the signal dip. The contrast structure is superior, in some embodiments, than using arbitrary body tissue to observe a loss of contrast. This can be used to identify shifts in the resonance frequency of the hydrogel and thereby determine volumetric changes in the hydrogel (and therefore an amount or concentration of biomarker).

Implementations of the chip-based sensor shown in <FIG> include in vivo implantation for any of the purposes described above and can additionally include placement within the environment, also as described above. Advantageously, the sensor can provide additional durability and can also be incorporated more rigidly into existing (or slightly adapted) sensors and/or implants.

Ultrasound transducers can be used internally to, for example, obtain different angled views of an internal structure and/or to provide better resolution images. Ultrasound transducers can also be used internally to guide minimally invasive procedures, including minimally invasive surgical procedures. In a very common procedure for pregnant women, an ultrasound transducer is positioned within the vaginal canal so the physician can get a proper angled and/or better image of various internal structures, such as, for example, the cervix, the uterus, the placenta, or the fetus. Before the procedure, the ultrasound transducer is often placed within a protective sleeve-both to protect the patient from possible infection and to protect the ultrasound transducer from potential contamination.

As illustrated in <FIG>, and ultrasound transducer <NUM> can be associated with a sleeve <NUM> in a similar fashion to that described above. However, the sleeve <NUM> additionally includes a plurality of resonators <NUM> that are the same as and/or substantially similar to the resonator structures <NUM>, <NUM> described above. In some embodiments, a gel acoustic coupling <NUM> can be applied between the ultrasound transducer <NUM> and the sleeve <NUM>, particularly that portion of the ultrasound transducer <NUM> beneath the resonators <NUM>. The gel acoustic coupling <NUM> can, for example, provide a medium through which ultrasound frequencies can be transmitted and received with higher fidelity.

As shown in <FIG>, the ultrasound transducer <NUM> and associated sleeve <NUM> can be inserted into an in vivo environment <NUM> (particularly the vaginal canal <NUM>) where the ultrasound transducer <NUM> can be used to both image the in vivo environments <NUM> as well as monitor one or more biomarkers within the in vivo environment <NUM>. This is perhaps better illustrated in <FIG>, where the ultrasound transducer <NUM> is shown as emitting at least two ultrasound frequencies f<NUM> and f<NUM>. The first frequency (f<NUM>) is directed to the frequency of the main mode of the resonator <NUM>, and the second frequency (f<NUM>) can be directed to any other frequency used for ultrasound imaging that is not the main mode of the resonator <NUM>.

Accordingly, the ultrasound transducer <NUM> can perform to simultaneous functions. The ultrasound transducer <NUM> can function as an imaging device by transmitting and receiving a frequency (or frequencies) other than the frequency associated with the main mode of the resonators <NUM>. The data received from this transmission and reception frequencies can then be processed into one or more images <NUM>. The ultrasound transducer <NUM> can additionally perform the function of monitoring the frequency of the main mode associated with the resonators <NUM> and tracking any changes or shifts in the frequency of the main mode or other significant features of the frequency spectrum (e.g., higher modes can be advantageous for higher sensitivity). These data can be processed to determine a volumetric change in the resonators <NUM> and therefore an amount or concentration biomarker specific to the hydrogel comprising the resonators <NUM> (as shown in graph <NUM>). It should be appreciated that some embodiments, the shifting main mode frequency of the resonators <NUM> can indirectly be used to graph a change in concentration of analyte (e.g., a biomarker) over time.

The aforementioned processing steps can be performed, for example, by a computer system. For example, the computer system <NUM> that is in electrical communication with ultrasound transducer <NUM> of <FIG> can perform the processing steps to both display an ultrasound image and determine a biomarker concentration. In some embodiments, the computer system is a portable computer system or controller that is both electrically and physically coupled to the ultrasound transducer. In some embodiments, the computer system is an electronic mobile device (e.g., a tablet or smart phone) that either communicates directly with the ultrasound transducer or communicates with the ultrasound transducer (e.g., receiving information) through a cloud-based system. In other embodiments, the computer system is a desktop or laptop computer in electrical communication with the ultrasound transducer.

Illustrated in <FIG> is a system for detecting a concentration of one or more biomarkers <NUM> within an in vivo environment <NUM>. The system of <FIG> includes a computer system <NUM> and an ultrasound transducer <NUM> coupled to a sleeve <NUM>. The ultrasound transducer <NUM> and sleeve <NUM> are provided within an in vivo environment <NUM> and through transmitters <NUM> and receiver <NUM>, the ultrasound transducer <NUM> can obtain information related to physiologic structures <NUM> (e.g., imaging data) and biomarkers <NUM> (e.g., resonance frequency data and shifts associated therewith). This information can be received by the computer system <NUM> where the processors <NUM> determine a volumetric change of at least portions of the hydrogel resonator sheet <NUM> associated with the sleeve <NUM> based on one or more shifts in the main mode or resonant frequency of the hydrogel resonator sheet <NUM>. Based upon the volumetric change of at least portions of the hydrogel resonator sheet <NUM>, the processors <NUM> can determine an amount or concentration of biomarker <NUM> within the in vivo environment <NUM>. Any of the foregoing data-both received and determined-can be stored within hardware storage device <NUM>.

Additionally, the image processor <NUM> of the computer system <NUM> can receive the image data and generate one or more ultrasound images therefrom. The generated ultrasound images can be sent to and displayed on display <NUM> and/or stored within hardware stores device <NUM>.

In some embodiments, the ultrasound transducer <NUM> and sleeve <NUM> (and components associated therewith) can be sized and shaped to fit within a catheter <NUM> for transit to a surgical site <NUM>. In some embodiments, information received at the ultrasound transducer can be transmitted in real time to the computer system <NUM> where the data can provide relevant information to the medical service provider regarding the surgical site <NUM> or biomarker <NUM> associated therewith. As an illustrative example, an ultrasound transducer can be passed through a catheter to a distant surgical site where the sleeve associated with the ultrasound transducer includes resonators on the hydrogel resonator sheet that comprise a biomarker sensitive hydrogel specific to thrombin. As the surgery progresses, and the local concentrations of thrombin increase, these data can be obtained using ultrasound (as described above) and further elucidated using computer <NUM>. The real time or near real time thrombin concentration at the surgical site can be presented to the medical professional performing the surgery (e.g., at the display of the computer system). In some embodiments, the catheter-based ultrasound transducer can be associated with a sleeve having disposed thereon a biomarker sensitive hydrogel arranged within an array of resonators, and as described above, using ultrasound and the biomarker sensitive hydrogel, an amount or concentration of biomarker can be detected at or near the location of the ultrasound transducer. As a particular non-limiting example, the foregoing can be used in cardiac surgery, such as arterial fibrillation ablation surgery.

The resonator sheets described above can be incorporated into the sensors (as in <FIG>) and/or sleeves (as in <FIG>) as described. In some embodiments, however, alternative resonator arrays can be incorporated into the foregoing. For example, the alternative array structures depicted in <FIG> can be incorporated within embodiments disclosed herein to, for example, increase transmission in certain frequency bands and/or enable harmonic suppression. Importantly, the resonance frequency of resonators depends on the mechanical properties they exhibit in addition to the geometry of the resonators independently and collectively. Because hydrogels can experience a change in mechanical properties and volume (which are usually interconnected) when exposed to a stimulus or analyte, a sheet of stimuli responsive hydrogel resonators can be used together with ultrasound as a readout mechanism to create an analyte sensor. The resonators have different transmission and reflection values along a frequency range. In some embodiments, it is expected that the reflection of the hydrogel sheets will be low and ineffectual for detection. The detected dip in the signal is due in large part to the fact that these sheets absorb strongly at their resonance frequencies and do not absorb much at other frequency bands. The ultrasonic signal usually needs to be reflected from something else (e.g., tissue, contrast structure, etc.) in order to reach the transducer again. In many pulse echo modes of commercial ultrasound equipment, the waves also need to pass the resonators twice, thereby increasing their effect. Therefore, the ultrasonic waves produced by an actuator could be recorded after passing through or scattering from these resonators. The changes in resonance frequency of the structure changes the frequency response which could be quantified and translated into an amount or concentration of analyte.

As shown in <FIG>, one structure for the hydrogel resonator array is a repeated pattern of cylindrical ultrasonic resonators, each resonator having a diameter of <NUM>. In some embodiments, each resonator has a diameter greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, greater than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, less than <NUM>, or a diameter chosen from a range of diameters having a lower and upper bound selected from the foregoing. The illustrated array includes a main resonance peak (i.e., a main mode) and several other smaller peaks. At a resonance frequency, the hydrogel sheet absorbs more wave intensity and transmits less. Having a fewer number of resonance peaks can facilitate the detection of the main peak more easily and/or quickly. This, in turn, makes tracking the shifting main mode easier. Also, this can be used to clear more frequency band, the cleared frequency bands being able to be used for conventional ultrasound imaging.

As shown in <FIG>, an additional structure for a hydrogel resonator array is depicted. The design of this array utilizes additional resonators alongside the main resonators to enable harmonic suppression (e.g., the elimination of spurious resonance peaks). As shown, there are resonators having a <NUM> diameter, a <NUM> diameter, and a <NUM> diameter. In some embodiments, the diameter of the resonators within the array are between <NUM> - <NUM> and comprise any of two, three, or four different diameters arranged in a pattern about a central resonator and configured to suppress one or more resonance peaks.

Referring now to <FIG>, the total kinetic energy of (i) a periodic array of resonators (like that shown in <FIG>; solid line) and (ii) an array that enables harmonic suppression (like that shown in <FIG>; broken line) are illustrated. As can be seen in the Figure, the total kinetic energy of the periodic array of resonators includes a main mode around <NUM> with multiple smaller harmonic peaks occurring around <NUM>, <NUM>, <NUM>, and <NUM>. By including resonators with different sizes and by placing them between the main resonators within the array (as shown in <FIG>), the main mode was maintained around <NUM>, but the next closest harmonic peak-expected to occur around <NUM>-was suppressed. In some embodiments, the sizes of the side resonators are tuned to suppress specific unwanted peaks.

Implementations of harmonic suppression hydrogel resonator arrays described above can advantageously eliminate or reduce the number and/or frequency of redundant resonance peaks, and in some embodiments, this can consequently make the resonance spectrum easier to track and can additionally clear frequency bands for conventional ultrasound imaging. Additionally, the reduction in the number of spurious peaks can beneficially mitigate the risk of misinterpreting the main resonance peak.

Referring now to <FIG>, illustrated is an embodiment of an optic fiber filament <NUM> associated with a biomarker sensitive hydrogel <NUM> that dynamically responds to an analyte concentration (e.g., a biomarker concentration) to undergo a volumetric change or a colorimetric change <NUM>. A volumetric change in the terminally tipped biomarker sensitive hydrogel <NUM> can act similar to an optical lens, distorting light entering the optic fiber filament <NUM>. The distorted light can be used as a readout for determining the volumetric change (and thereby the amount or concentration of biomarker interacting with the biomarker sensitive hydrogel <NUM>).

In some embodiments, the biomarker sensitive hydrogel <NUM> undergoes a colorimetric change <NUM>. The colorimetric change <NUM> causes a shift in the frequency of light entering the optic fiber filament <NUM>, and in embodiments where the colorimetric change (e.g., darker hue or color shift) is biomarker concentration dependent, the shift in light frequencies entering the optic fiber filament <NUM> correlates with the concentration of biomarker interacting with the biomarker sensitive hydrogel <NUM>.

The following discussion now refers to methods and method acts that may be performed.

Referring now to <FIG>, a method <NUM> is illustrated. The method <NUM> includes acts for using ultrasound to identify one or more changes in a biomarker sensitive hydrogel positioned within an in vivo environment. The method <NUM> includes receiving data from an ultrasound receiver, the data comprising one or more characteristics of the biomarker sensitive hydrogel (act <NUM>). For example, <FIG> illustrates a computer system <NUM> receiving data from an ultrasound receiver <NUM> comprising characteristics of a biomarker sensitive hydrogel <NUM>.

The method <NUM> further includes determining one or more of a volume or a length of the biomarker sensitive hydrogel based on the one or more characteristics (act <NUM>). For example, <FIG> illustrates representations of a computer system <NUM> determining the volume or length of the biomarker sensitive hydrogel <NUM>, <NUM> based on characteristics.

The method <NUM> further includes at a second time, receiving additional data from the ultrasound receiver, the additional data comprising one or more updated characteristics of the biomarker sensitive hydrogel (act <NUM>). For example, in <FIG>, the computer system <NUM> receives additional data from the ultrasound receiver <NUM> at a second time that comprises updated characteristics.

The method <NUM> may further include determining one or more of an updated volume or an updated length of the biomarker sensitive hydrogel based on the one or more updated characteristics. For example, in <FIG>, the computer system <NUM> determines an updated volume or an updated length of the biomarker sensitive hydrogel based on the one or more updated characteristics.

The method <NUM> may further include calculating the one or more dimensional changes of the biomarker sensitive hydrogel based on the volume, the length, the updated volume, and the updated length. For example, in <FIG>, the computer system <NUM> calculates dimensional changes of the biomarker sensitive hydrogel based on the volume, length, updated volume, and updated length.

When information is transferred or provided over a network or another communications connection (either hardwired, wireless, or a combination of hardwired or wireless) to a computer, the computer properly views the connection as a transmission medium. Transmissions media can include a network and/or data links which can be used to carry or desired program code means in the form of computer-executable instructions or data structures and which can be accessed by a general purpose or special purpose computer.

Any headings used herein are for organizational purposes only and are not meant to be used to limit the scope of the description or the claims.

Various aspects of the present disclosure, including devices, systems, and methods may be illustrated with reference to one or more embodiments or implementations, which are exemplary in nature. As used herein, the term "exemplary" means "serving as an example, instance, or illustration," and should not necessarily be construed as preferred or advantageous over other embodiments disclosed herein. In addition, reference to an "implementation" of the present disclosure or invention includes a specific reference to one or more embodiments thereof, and vice versa, and is intended to provide illustrative examples without limiting the scope of the invention, which is indicated by the appended claims rather than by the following description.

As used throughout this application the words "can" and "may" are used in a permissive sense (i.e., meaning having the potential to), rather than the mandatory sense (i.e., meaning must). Additionally, the terms "including," "having," "involving," "containing," "characterized by," as well as variants thereof (e.g., "includes," "has," "involves," "contains," etc.), and similar terms as used herein, including within the claims, shall be inclusive and/or open-ended, shall have the same meaning as the word "comprising" and variants thereof (e.g., "comprise" and "comprises"), and do not exclude additional un-recited elements or method steps, illustratively. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains.

Disclosure of certain features relative to a specific embodiment of the present disclosure should not be construed as limiting application or inclusion of said features to the specific embodiment. Rather, it will be appreciated that other embodiments can also include said features, members, elements, parts, and/or portions without necessarily departing from the scope of the present disclosure. Moreover, unless a feature is described as requiring another feature in combination therewith, any feature herein may be combined with any other feature of a same or different embodiment disclosed herein. Furthermore, various well-known aspects of illustrative systems, methods, apparatus, and the like are not described herein in particular detail in order to avoid obscuring aspects of the example embodiments. Such aspects are, however, also contemplated herein.

Claim 1:
A system (<NUM>, <NUM>) for identifying one or more changes in a biomarker sensitive hydrogel (<NUM>, <NUM>) based on changes in concentration of one or more biomarkers, the biomarker sensitive hydrogel being positioned within an in vivo environment (<NUM>, <NUM>), the system comprising:
a biomarker sensitive hydrogel (<NUM>) arranged in an array of acoustic resonators, the biomarker sensitive hydrogel being positioned within the in vivo environment and configured to dimensionally change, and thereby cause a volumetric change in the array of acoustic resonators, in response to interaction with one or more predefined biomarkers;
an ultrasound transducer (<NUM>, <NUM>) for locating the biomarker sensitive hydrogel within the in vivo environment and for identifying one or more characteristics of the biomarker sensitive hydrogel, including resonant frequencies of the array of acoustic resonators;
a computer system in electrical communication with the ultrasound transducer, the computer system having one or more processors and being configured to:
receive, from the ultrasound transducer, the one or more characteristics of the biomarker sensitive hydrogel, including a resonant frequency of the array of acoustic resonators;
determine, at the one or more processors, one or more dimensional changes of the biomarker sensitive hydrogel, including a volumetric change in the array of acoustic resonators, based on the received one or more characteristics of the biomarker sensitive hydrogel; and
determine concentration of the one or more biomarkers based on the one or more dimensional changes of the biomarker sensitive hydrogel.