Patent Application
20200397523
Certain embodiments generally pertain to micromotors with imaging contrast agent(s) and cargo such as, for example, therapeutic drugs.
Microrobots and nanorobots have drawn recent attention for their promise of enabling biomedical applications such as disease diagnosis, targeted drug delivery, and minimally-invasive and precise microsurgery. Some examples of microrobots/nanorobots can be found in Li, J., Esteban-Fernandez de Avila, B., Gao, W., Zhang, L., Wang, J., “Micro/nanorobots for biomedicine: Delivery, surgery, sensing, and detoxification,” Sci. Robot. 2, eaam 6431 (2017), Paxton, W. F., Kistler, K. C., Olmeda, C. C., Sen, A., St. Angelo, S. K., Cao, Y., Mallouk, T. E., Lammert, P. E., Crespi, V. H., “Catalytic nanomotors: Autonomous movement of striped nanorods,” J. Am. Chem. Soc. 126, 13424-13431 (2004), Hu, W., Lum, G. Z., Mastrangeli, M., Sitti, M., “Small-scale soft-bodied robot with multimodal locomotion,” Nature 554, 81-85 (2018), Fan, D., Yin, Z., Cheong, R., Zhu, F. Q., Cammarata, R. C., Chien, C. L., Levchenko, A., “Subcellular-resolution delivery of a cytokine through precisely manipulated nanowires,” Nat. Nanotechnol. 5, 545-551 (2010), Yan, X., Zhou, Q., Vincent, M. Deng, Y. Yu, J., Xu, J., Xu, T. Tang, T. Bian, L., Wang, J. Kostarelos, K. Zhang, L., “Multifunctional biohybrid magnetite microrobots for imaging-guided therapy,” Sci. Robot. 2, eaaq1155 (2017), and Hu, C., Pane, S., Nelson, B. J., “Soft micro- and nanorobotics,” Annu. Rev. Control. Robot. Auton. Syst. 1, 53-75 (2018), which are hereby incorporated by reference in their entireties.
A microrobotic device, comprising one or more micromotors and a microcapsule encapsulating the one or more micromotors. Each micromotor comprises a reactive particle and a partial coating disposed on the reactive particle. The partial coating comprises an imaging contrast layer, a cargo layer, and an encapsulation layer.
A method of fabricating a microrobotic device, the method comprising fabricating one or more micromotors, each micromotor fabricated by depositing a partial coating on a reactive particle, the partial coating comprising an imaging contrast material and cargo, the partial coating having one or more areas open to the reactive particle; and encapsulating the one or more micromotors in a microcapsule.
An image-guided microrobotic method, comprising using one or more images to determine that a microrobotic device is at or near a target region, wherein the microrobotic device comprises one or more micromotors encapsulated in a microcapsule, at least one of the micromotors comprising a partial coating disposed over a reactive particle, the partial coating comprising an imaging contrast material and cargo; and inducing disintegration of at least a portion of the microcapsule.
These and other features are described in more detail below with reference to the associated drawings.
Different aspects are described below with reference to the accompanying drawings. The features illustrated in the drawings may not be to scale. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the presented embodiments. The disclosed embodiments may be practiced without one or more of these specific details. In other instances, well-known operations have not been described in detail to avoid unnecessarily obscuring the disclosed embodiments. While the disclosed embodiments will be described in conjunction with the specific embodiments, it will be understood that it is not intended to limit the disclosed embodiments. For example, while certain techniques are described with reference to biomedical applications, it would be understood that these same techniques can be used to address environmental remediation, micro/nanofabrication, and detoxification. As another example, while certain techniques are described with reference to techniques that image and control micromotors, it would be understood that these same techniques can be used to image and control other microrobots such as magnetic propellers and also nanorobots.
Chemically-powered micromotors with autonomous propulsion and/or versatile functions in biofluids might prove to be particularly useful for in vivo applications. Some examples of conventional chemically-powered micro/nano motors can be found in Sanchez, S., Soler, L., and Katuri, J., “Chemically powered micro- and nanomotors,” Angew. Chem. Int. Ed. 54, 1414-1444 (2015), Tu, Y., Peng, F., Sui, X., Men, Y., White, P. B., van Hest, J. C. M., and Wilson, D. A., “Self-propelled supramolecular nanomotors with temperature-responsive speed regulation,” Nat. Chem. 9, 480 (2016), Esteban-Fernandez de Avila, B., Angsantikul, P., Li, J., Lopez-Ramirez, M. A., Ramirez-Herrera, D. E., Thamphiwatana, S., Chen, C., Delezuk, J., Samakapiruk, R., Ramez, V., Zhang, L., and Wang, J., “Micromotor-enabled active drug delivery for in vivo treatment of stomach infection,” Nat. Commun. 8, 272 (2017), Wang, J., Gao, W., “Nano/microscale motors: biomedical opportunities and challenges,” ACS Nano 6, 5745-5751 (2012), Gao, W., Dong, R., Thamphiwatana, S., Li, J., Gao, W., Zhang, L., and Wang, J., “Artificial micromotors in the mouse's stomach: A step toward in vivo use of synthetic motors,” ACS Nano 9, 117-123 (2015), which are hereby incorporated by reference in their entireties. Discussion of recent progress in micromotors can be found in Li, T., Chang, X., Wu, Z., Li, J., Shao, G., Deng, X., Qiu, J., Guo, B., Zhang, G., He, Q., Li, L., and Wang, J., “Autonomous collision-free navigation of microvehicles in complex and dynamically changing environments,” ACS Nano 11, 9268-9275 (2017), Sitti, M., “Miniature soft robots-road to the clinic,” Nat. Rev. Mater, 3, 74-75 (2018), Medina-Sanchez, and M. S., Schmidt, O. G., “Medical microbots need better imaging and control,” Nature 545, 406-408 (2017), Vilela, D., Cossío, U., Parmar, J., Martinez-Villacorta, A. M., Gomez-Vallejo, V., Llop, J. Sanchez, S., “Medical imaging for the tracking of micromotors,” ACS Nano 12, 1220-1227 (2018), which are hereby incorporated by reference in their entireties.
To date, optical imaging is widely used for biomedical applications owing to its high spatiotemporal resolution and molecular contrasts. However, applying conventional optical imaging to deep tissues is hampered by strong optical scattering, which inhibits high-resolution imaging beyond the optical diffusion limit (˜1-2 mm in depth) as discussed in Ntziachristos, V., “Going deeper than microscopy: the optical imaging frontier in biology,” Nat. Methods 7, 603-614 (2010), which is hereby incorporated by reference in its entirety. Fortunately, photoacoustic (PA) tomography (PAT), detecting photon-induced ultrasound, achieves high-resolution imaging at depths that far exceed the optical diffusion limit as discussed in Razansky, D., Distel, M., Vinegoni, C., Ma, R., Perrimon, N., Koster, R. W., Ntziachristos, V., “Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo,” Nat. Photonics 3, 412-417 (2009), which is hereby incorporated by reference in its entirety. In PAT, the energy of photons absorbed by chromophores inside the tissue is converted to acoustic waves, which are subsequently detected to yield high-resolution tomographic images with optical contrasts. Leveraging the negligible acoustic scattering in soft tissue, PAT has achieved superb spatial resolution at depths, with a depth-to-resolution ratio of ˜200, at high imaging rates, as discussed in Wang, L. V., Hu, S., “Photoacoustic tomography: in vivo imaging from organelles to organs,” Science 335, 1458-1462 (2012), which is hereby incorporated by reference in its entirety.
Also, photoacoustic computed tomography (PACT) has been able to attain high spatiotemporal resolution (125-μm in-plane resolution and 50-μs frame−1 data acquisition), deep penetration (48-mm tissue penetration in vivo), and anatomical and molecular contrasts as discussed in Li, L., Zhu, L., Ma, C., Lin, L., Yao, J., Wang, L., Maslov, K., Zhang, R., Chen, W., Shi, J., “Single-impulse panoramic photoacoustic computed tomography of small-animal whole-body dynamics at high spatiotemporal resolution,” Nat. Biomed. Eng. 1, 0071 (2017), Li, L., Shemetov, A. A., Baloban, M., Hu, P., Zhu, L., Shcherbakova, D. M., Zhang, R., Shi, J., Yao, J., Wang, L. V., Verkhusha, V. V., “Small near-infrared photochromic protein for photoacoustic multi-contrast imaging and detection of protein interactions in vivo,” Nat. Commun. 9, 2734 (2018), Yao, J., Kaberniuk, A. A., Li, L., Shcherbakova, D. M., Zhang, R., Wang, L., Li, G., Verkhusha, V. V., Wang, L. V., “Multiscale photoacoustic tomography using reversibly switchable bacterial phytochrome as a near-infrared photochromic probe,” Nat. Methods 13, 67 (2015), which are hereby incorporated by reference in their entireties.
Previously, small-animal whole-body imaging typically relied on non-optical approaches such as, e.g., X-ray computed tomography (X-ray CT), magnetic resonance imaging (MRI), positron emission tomography (PET) or single-photon emission computed tomography (SPECT), and ultrasound imaging (USI) as discussed in Ntziachristos, V., “Going deeper than microscopy: the optical imaging frontier in biology,” Nat. Methods 7, 603-614 (2010), which is hereby incorporated by reference in its entirety. Although these non-optical techniques provided deep penetration, they suffer from significant limitations. For example, microscopic MRI requires a long data acquisition time, ranging from seconds to minutes, too slow for imaging dynamics as discussed in Wu, D., Zhang, J., “In vivo mapping of macroscopic neuronal projections in the mouse hippocampus using high-resolution diffusion MRI,” NeuroImage 125, 84-93 (2016) and Alomair, O. I., Brereton, I. M., Smith, M. T., Galloway, G. J., Kurniawan, N. D., “In vivo high angular resolution diffusion-weighted imaging of mouse brain at 16.4 Tesla,” PloS One 10, e0130133 (2015), which are hereby incorporated by reference in their entireties. More importantly, MRI, requiring a strong magnetic field, is incompatible with magnetically driven or guided micromotors as discussed in Yan, X., Zhou, Q., Vincent, M. Deng, Y. Yu, J., Xu, J., Xu, T. Tang, T. Bian, L., Wang, J. Kostarelos, K. Zhang, L., “Multifunctional biohybrid magnetite microrobots for imaging-guided therapy,” Sci. Robot. 2, eaaq1155 (2017), which is hereby incorporated by reference in its entirety. X-ray CT has poor contrast of the micromotors made of biocompatible/biodegradable metals as discussed in Vilela, D., Cossío, U., Parmar, J., Martinez-Villacorta, A. M., Gomez-Vallejo, V., Llop, J. Sanchez, S., “Medical imaging for the tracking of micromotors,” ACS Nano 12, 1220-1227 (2018) and Schambach, S. J., Bag, S., Schilling, L., Groden, C., Brockmann, M. A., “Application of micro-CT in small animal imaging,” Methods 50, 2-13 (2010), which are hereby incorporated by reference in their entireties. PET/SPECT alone suffers from poor spatial resolution. In addition, X-ray CT and PET/SPECT employ ionizing radiation, which inhibits longitudinal monitoring as discussed in Brenner, D. J., Hall, E. J., “Computed tomography—an increasing source of radiation exposure,” N. Engl. J. Med 357, 2277-2284 (2007), which is hereby incorporated by reference in its entirety. USI does not image extravascular molecular contrasts as discussed in Brenner, D. J., Hall, E. J., “Computed tomography—an increasing source of radiation exposure,” N. Engl. J. Med 357, 2277-2284 (2007), which is hereby incorporated by reference in its entirety. In addition, the microcapsules (MCs) of certain aspects described herein are mainly by mass composed of gelatin, which has almost the same acoustic impedance as soft tissue as discussed in Lai, P., Xu, X., Wang, L. V., “Dependence of optical scattering from Intralipid in gelatin-gel based tissue-mimicking phantoms on mixing temperature and time,” J Biomed. Opt. 19, 035002 (2014), which is hereby incorporated by reference in its entirety. Thus, USI cannot image microcapsules with sufficient contrast in vivo. Optical imaging uses non-carcinogenic electromagnetic waves to provide extraordinary molecular contrasts with either endogenous or exogenous agents at high spatiotemporal resolution. Unfortunately, the strong optical scattering of tissue hampers the application of conventional optical imaging technologies to small-animal whole body imaging at high spatial resolution as discussed in V. Ntziachristos, Going deeper than microscopy: the optical imaging frontier in biology. Nat. Methods 7, 603-614 (2010), which is hereby incorporated by reference in its entirety. On the other hand, photoacoustic tomography (PAT) can break the optical diffusion limit (as discussed in D. Razansky, M. Distel, C. Vinegoni, R. Ma, N. Perrimon, R. W. Koster, V. Ntziachristos, “Multispectral opto-acoustic tomography of deep-seated fluorescent proteins in vivo,” Nat. Photonics 3, 412-417 (2009), which is hereby incorporated by reference in its entirety) on penetration and achieves high-resolution imaging in deep tissues with optical contrasts.
Similarly, photoacoustic computed tomography (PACT) can attain high spatiotemporal resolution, deep penetration, and anatomical and molecular contrasts. Typically when implementing PACT to image tissue, a laser pulse is used to broadly illuminate the whole tissue sample to be imaged. As photons propagate inside the tissue, some are absorbed by molecules, and their energy is partially or completely converted into heat, creating a temperature rise through nonradiative relaxation. The local temperature rise induces a pressure rise through thermoelastic expansion. The pressure rise propagates, at a speed of roughly 1500 m s−1, inside the tissue as a photoacoustic wave, and is detected outside the tissue by an ultrasonic transducer or transducer array. The detected photoacoustic signals are processed by a computing device to form an image, which maps the original optical energy deposition in the biological tissue. Because ultrasound scattering in soft tissue is about three orders of magnitude weaker than light scattering on a per unit path length basis in the ultrasonic frequency of interest, PACT may achieve superb spatial resolution at depths by detecting ultrasound.
Drug delivery through the gastrointestinal (GI) tract serves as a convenient and versatile therapeutic tool, owing to its cost-effectiveness, high patient compliance, lenient constraint for sterility, and ease of production as discussed in Bellinger, A., et al. “Oral, ultra-long-lasting drug delivery: application toward malaria elimination goals,” Sci. Transl. Med. 8, 365ra157 (2016) and Koziolek, M., et al., “Navigating the human gastrointestinal tract for oral drug delivery: Uncharted waters and new frontiers,” Adv. Drug Delivery Rev. 101, 75-88 (2016), which are hereby incorporated by reference in their entireties. Drug absorption of conventional micro/nanoparticle-based drug delivery systems is inefficient due to the limited intestinal retention time as discussed in Soppimath, K. S., Kulkarni, A. R., Rudzinski, W. E, Aminabhavi, T. M., “Microspheres as floating drug-delivery systems to increase gastric retention of drugs,” Drug Metab. Rev. 33, 149-160 (2001), which is hereby incorporated by reference in its entirety. Passive diffusion-based targeting strategies have been explored to improve delivery efficiency, but they suffer from low precision, size restraint and specific surface chemistry as discussed in Rosenblum, D., Joshi, N., Tao, W., Karp, J. M., Peer, D., “Progress and challenges towards targeted delivery of cancer therapeutics,” Nat. Commun. 9, 1410 (2018), which is hereby incorporated by reference in its entirety. Also, conventional microrobotic systems do not have precise control of microrobots in vivo as discussed in Yang, G.-Z., et al. “The grand challenges of science robotics,” Sci. Robot. 3, eaar7650 (2018) and Medina-Sanchez, M. S., Schmidt, O. G., “Medical microbots need better imaging and control,” Nature 545, 406-408 (2017), which are hereby incorporated by reference in their entireties. Additionally, biodegradability and biocompatibility are required, and an ideal microrobotic system is expected to be cleared safely by the body after completion of the tasks as discussed in Yan, X., Zhou, Q., Vincent, M. Deng, Y. Yu, J., Xu, J., Xu, T. Tang, T. Bian, L., Wang, J. Kostarelos, K. Zhang, L., “Multifunctional biohybrid magnetite microrobots for imaging-guided therapy,” Sci. Robot. 2, eaaq1155 (2017), Abdelmohsen, L. K. E. A., Peng, F., Tu, Y., Wilson, D. A., “Micro- and nano-motors for biomedical applications,” J. Mater. Chem. B 2, 2395-2408 (2014), and Wang, H., Pumera, M., “Fabrication of micro/nanoscale motors,” Chem. Rev. 115, 8704-8735 (2015), which are hereby incorporated by reference in their entireties.
Certain aspects pertain to image-guided microrobotic techniques (e.g., systems, methods, and devices) that employ imaging to navigate microrobots, such as micromotors, in deep tissue at high spatiotemporal resolution and high contrast, and with precise on-demand control of the microrobots, particularly in in vivo applications. In one aspect, for example, photoacoustic computed tomography (PACT) is employed to monitor and navigate micromotors in vivo, e.g., through the intestines. Some examples of PACT systems and methods that can be employed are described in U.S. patent application Ser. No. 16/798,204, titled “PHOTOACOUSTIC COMPUTED TOMOGRAPHY (PACT) SYSTEMS AND METHODS,” filed on Feb. 21, 2020 and Lin, L., Hu, P., Shi, J. et al., “Single-breath-hold photoacoustic computed tomography of the breast,” Nat. Commun. 9, 2352 (2018), which are hereby incorporated by reference in their entireties. Owing to the high spatiotemporal resolution, non-invasiveness, molecular contrast, and deep penetration aspects of PACT, it can be an attractive tool for imaging and navigating micromotors in deep tissue in vivo. Other examples of imaging techniques that can be used to image and guide micromotors are ultrasound, magnetic resonance imaging (MRI), X-ray computed tomography (CT), positron emission tomography (PET), diffuse optical tomography (DOT), photoacoustic microscopy (PAM), optical coherent tomography (OCT).
Certain implementations pertain to image-guided microrobotic devices. An image-guided microrobotic device includes, at least in part, one or more micromotors and a microcapsule (also sometimes referred to herein as “micromotor capsule”) enveloping the one or more micromotors. Once released from the microcapsule, the micromotor(s) can exhibit propulsion in various fluids such as, e.g., biofluids. In one aspect, the image-guided microrobotic device is spheroid or spherical and has a diameter in the range of about 20 μm to about 1000 μm.
In certain implementations, a micromotor includes a partial coating deposited on or otherwise disposed on a reactive particle or other form of reactive material(s) (also sometimes referred to herein as a “reactive core”). Although the reactive particle is generally spheroid or spherical, other shapes can be used such as oblong or cylinder. Some examples of reactive materials that can be used include magnesium, zinc, sodium carbonate. Some examples of the rough diameters of an approximately spherical reactive particle include 20±5 μm, 60±10 μm, 3±0.5 μm, and 100±20 μm. In one aspect, the rough diameter of an approximately spherical reactive particles is in a range of 20 μm to 60 μm. In one aspect, the reactive core is a magnesium microparticle. An example of a suitable commercially-available magnesium microparticle is the magnesium microparticle with a diameter of 20±5 μm sold by TangShan WeiHao Magnesium Powder. The partial coating of a micromotor includes one or more material layers that have imaging contrast agent(s) and a cargo carrier material with cargo such as, e.g., one or more therapeutic drugs, imaging contrast agents, photodynamic particles, and/or magnetic particles. In one aspect, at least one material layer of the partial coating that has both an imaging contrast agent(s) and cargo. In contrast with conventional microrobots, micromotors of certain implementations described herein employ a biocompatible propulsion mechanism, e.g., from a reaction between magnesium and water, to implement efficient and biocompatible self-propulsion in various biofluids such as gastric and intestinal fluids.
Although the image-guided microrobotic techniques described herein are mainly described with reference to micromotors, it would be understood that these techniques apply to other microrobots such as acoustically powered microrobots. Some examples of materials that can be employed as an imaging contrast agent include, for example, micro/nanoparticles, organic dyes, reporter gene proteins, microbubbles, fluorescent molecules, quantum dots, and metals. Some examples of materials that can be employed as a controllable cargo carrier include, for example, mesoporous silica, metal of framework, microcapsule, and polymersome.
In certain implementations, a micromotor includes a reactive particle at least partially coated by: 1) an imaging contrast layer, 2) a cargo layer, and/or 3) an encapsulation layer. The imaging contrast layer includes one or more imaging contrast agents. Some examples of imaging contrast agents include metals such as gold (Au), an organic dye, reporter gene protein, micro/nanoparticles, and/or microbubbles. In one example, the imaging contrast layer is a layer of gold (Au) having an approximate thickness of 50 nm. In one aspect, the thickness of the imaging contrast layer is in a range of 1 μm and 20 μm. In another aspect, the thickness of the imaging contrast layer is in a range of 10 μm and 20 μm. The imaging contrast layer may be used to increase optical absorption of the micromotor for imaging purposes (e.g., for photoacoustic imaging) and/or increase the reaction rate of the reactive core for efficient propulsion. For example, employing an Au layer as the imaging contrast layer over a magnesium particle can both increase the optical absorption of the micromotor for photoacoustic imaging and increase the reaction rate of the magnesium particle for efficient propulsion simultaneously. The material composition of the cargo layer may be designed to increase the loading capacity of the functional components (also referred to herein as “cargo”) such as, e.g., therapeutic drugs and imaging contrast agents. The cargo layer includes a cargo carrier material and cargo. The material composition of the encapsulation layer may be designed to maintain the geometry of the micromotor during propulsion. For example, the encapsulation layer may include parylene.
The partial coating of the micromotor includes one or more areas open to the reactive particle, which allow ingress of fluid that may react with the reactive particle. In certain implementations, the one or more open areas are located on one side (e.g., a portion of an outer surface of the micromotor that is facing substantially one direction) of the microrobot. For example, the micromotor may have a partial coating with one or more open areas on one side that are open to a reactive magnesium particle at the center of the micromotor. In one aspect, the size of an open area in a partial coating is in a range of 5 μm2 to 500 μm2. In one aspect, the size of the open area in a partial coating is less than 100 μm2. According to implementations where micromotors are released into a body e.g. into the intestines, when the micromotors are released from the microcapsule, biofluids can pass through an open area to the reactive core (e.g., magnesium particle) and gas bubbles may be generated and/or cargo released. As gas bubbles exit the open area on one side, a propulsion force is created in a direction opposite the direction that the side faces.
In another aspect, micromotors may have a geometry that can generate directional bubbles to provide propulsion force in one direction without implementing a partial coating. For example, a micromotor may have a cylindrical structure with an asymmetrical opening on end of the cylindrical structure. A catalyst encapsulated in inside the structure can react with fluid to generate the bubbles that exit the open end providing the propulsive force.
In certain aspects, an image-guided microrobotic device includes one or more micromotors and a microcapsule that envelopes the one or more micromotors. The microcapsule may be formed from material(s) that are stable and protect the one or micromotors from the environment outside the microcapsule while the image-guided microrobotic device is travelling to the region being targeted for deployment. For example, the microcapsule may include a protective material that is capable of being stable in gastric fluids in the stomach while the image-guided microrobotic device travels to the intestines. Some examples of materials that may be used to form the microcapsule include, for example, gelatin material, enteric polymer, and/or parylene.
In one implementation, the partial coating of a micromotor includes a magnetically-charged material such as, e.g., iron oxide, nickel, and/or iron. In this case, the direction of the micromotor can be magnetically controlled by using external alternative magnetic field. An example of using magnetic control to control a microrobot can be found in Servant, A. et al. “Controlled in vivo swimming of a swarm of bacteria-like microrobotic flagella,” Advanced Materials 27, 2981-2988(2015), which is hereby incorporated by reference in its entirety.
In one exemplary method, one or more image-guided microrobotic devices, each with one or more micromotors encapsulated in a microcapsule, are ingested, injected, or otherwise introduced into the specimen. The material composition the microcapsule is stable in the environment into which it is introduced such as, e.g., in the gastric fluids of the stomach if ingested. The migration of the one or more image-guided microrobotic devices toward the targeted region (e.g., through the intestines to a tumor) can been visualized in real time in vivo by PACT or another imaging method. Once it is determined, using the images acquired, that the one or more microcapsules have arrived at or near the targeted region, a release trigger, such as, e.g., near-infrared light irradiation, high-intensity focused ultrasound, and/or magnetic field, induces disintegration or collapse of the one or more microcapsules to discharge the cargo-loaded micromotors. Once released, the reactive cores of the one or more micromotors are exposed to the biofluids or other fluids that may produce gases that generate propulsion when exiting through one or more open areas in the micromotors. The propulsion of the microrobots may effectively prolong the retention of the one or more micromotors in the specimen, and more particularly, in the targeted area. The image-guided microrobotic method may enable deep imaging and precise control of the one or more micromotors in vivo for biomedical applications such as, e.g., drug delivery and microsurgery.
Certain aspects pertain to imaging-guided microrobotic devices, systems, and methods that allow deep tissue navigation and placement of micromotors with enhanced retention in vivo. The imaging-guided microrobotic devices may be ingestible or injectable in some cases. For example, some image-guided microrobotic techniques may be operable to directly visualize the dynamics of one or more micromotors with high spatiotemporal resolution in vivo at the whole-body scale to provide real-time visualization and guidance of the one or more micromotors. In addition to high spatiotemporal resolution, these image-guided microrobotic techniques may also provide deep penetration and molecular contrast. According to one aspect, an image-guided microrobotic technique implements photoacoustic computed tomography (PACT) to visualize and/or guide a plurality of micromotors in one or more microcapsules to a targeted region. According to one aspect, the imaging-guided microrobotic devices, systems, and methods enable controlled propulsion of micromotors and prolonged cargo retention in vivo.
In one implementation, an imaging-guided microrobotic system includes one or more imaging-guided microrobotic devices that are ingestible for imaging-assisted control in intestines. Each imaging-guided microrobotic device includes a microcapsule that encapsulates one or more micromotors. The encapsulated micromotors survive the erosion of the stomach fluid and to allow for release and propulsion in the intestines. In some cases, PACT is employed to non-invasively monitor the migration of one or more imaging-guided microrobotic devices and/or the released micromotors, and visualizes their arrival at targeted areas in vivo. Continuous-wave near infrared radiation (CW NIR) is directed toward the targeted region to induce disintegration of the microcapsules at or near the target region, which triggers the propulsion of the micromotors. For example, if the microcapsule is gelatin-based and the imaging contrast layer is an Au layer, the Au layer can convert the NIR light to heat resulting in gel-sol phase transition of the gelatin-based microcapsule. The mechanical propulsion provides a driving force for the micromotors to be able to bind to the intestine walls, which may result in prolonged retention of the micromotors and/or their cargo in the tissues of the targeted region.
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During image acquisitions operations of the PACT system 200, the light source 210 is triggered to emit light pulses and illumination is generated to illuminate the mouse specimen 12. As photons propagate inside the tissue, some are absorbed by molecules, and their energy is partially or completely converted into heat, creating a temperature rise through nonradiative relaxation. The local temperature rise induces a pressure rise through thermoelastic expansion. The pressure rise propagates inside the tissue as a photoacoustic wave 242, and is detected outside the tissue by the ultrasonic transducer array 240. The translational stage 270 may be moved to one or more elevational positions and held for a time period or scanned between two elevational positions during image acquisition to capture images at different planes. The detected photoacoustic signals are processed by the computing device (e.g., the computing device 480 shown in
In certain aspects, the imaging system such as a PACT system takes time-lapsed images as the image-guided microrobotic devices move to the targeted region. In one aspect, the time-lapsed images are taken periodically such as, e.g., about one image every 10 second, about one image every 1 second, about one image every 0.1 second, about one image every 0.001 second, about one image every 0.0001 second, about one image every 0.00001 second. In some cases, the time-lapsed images are taken in a range of 0.0001-10 second.
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The image-guided microrobotic system 400 includes a computing device 480 having one or more processors or other circuitry 482 and an internal non-transitory computer readable media (CRM) 484 in electrical communication with the processor(s) or other circuitry 782. The computing device 180 is also in electronic communication with the imaging subsystem 410 to send control signals and receive one or more photoacoustic images or data transmissions from the DAQ(s). The computing device 180 is also in electronic communication with the trigger device 410 to send control signals to activate the trigger device, e.g., when the computing device has executed instructions that determined that one or more image-guided microrobotic devices are at or near the target region. The processor(s) or other circuitry 482 of the computing system 480 of the image-guided microrobotic system 400 and, additionally or alternatively, other external processor(s) (e.g., a processor of the external computing system 489) can execute instructions stored on non-transitory computer readable media (e.g., internal non-transitory CRM 484 or optional external memory 492) to perform operations of the image-guided microrobotic system 400.
In certain implementations, an image-guided microrobotic system includes one or more processors and/or other circuitry that can execute instructions stored on a computer readable medium CRM to perform one or more operations of the image-guided microrobotic system and/or the imaging subsystem. In one aspect, the processor(s) and/or other circuitry and/or one or more external processors may execute instructions to perform: 1) determining and communicating control signals to system components, 2) performing algorithm(s) to reconstruct one or more images of the specimen acquire over time, e.g., reconstructing photoacoustic images from an acoustic signal received from the DAQ(s) of a photoacoustic imaging system such as the PACT system 200 in
According to certain implementations, the computing system of an image-guided microrobotic system can perform parallel image processing. To perform parallel image processing, the computing device generally includes at least one processor (or “processing unit”). Examples of processors include, for example, one or more of a general purpose processor (CPU), an application-specific integrated circuit, an programmable logic device (PLD) such as a field-programmable gate array (FPGA), or a System-on-Chip (SoC) that includes one or more of a CPU, application-specific integrated circuit, PLD as well as a memory and various interfaces.
The computing system of an image-guided microrobotic system may be in communication with internal memory device and/or an external memory device. The internal memory device can include a non-volatile memory array for storing processor-executable code (or “instructions”) that is retrieved by one or more processors to perform various functions or operations described herein for carrying out various logic or other operations on the image data. The internal memory device also can store raw image data, processed image data, and/or other data. In some implementations, the internal memory device or a separate memory device can additionally or alternatively include a volatile memory array for temporarily storing code to be executed as well as image data to be processed, stored, or displayed. In some implementations, the computing system itself can include volatile and in some instances also non-volatile memory.
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In some implementations, an image-guided microrobotic system includes a computing device configured or configurable (e.g., by a user) to: (i) output raw data, processed data such as image data, and/or other data over a communication interface to a display, (ii) output raw image data as well as processed image data and other processed data over a communication interface to an external computing device or system, (iii) output raw image data as well as processed image data and other data over a communication interface for storage in an external memory device or system, and/or (iv) output raw image data as well as processed image data over a network communication interface for communication over an external network (for example, a wired or wireless network). Indeed in some implementations, one or more of operations of an image-guided microrobotic system can be performed by an external computing device. The computing device may also include a network communication interface that can be used to receive information such as software or firmware updates or other data for download by the computing device. In some implementations, an image-guided microrobotic system further includes one or more other interfaces such as, for example, various Universal Serial Bus (USB) interfaces or other communication interfaces. Such additional interfaces can be used, for example, to connect various peripherals and input/output (I/O) devices such as a wired keyboard or mouse or to connect a dongle for use in wirelessly connecting various wireless-enabled peripherals. Such additional interfaces also can include serial interfaces such as, for example, an interface to connect to a ribbon cable. It should also be appreciated that one or more of components of the iSVS system can be electrically coupled to communicate with the computing device over one or more of a variety of suitable interfaces and cables such as, for example, USB interfaces and cables, ribbon cables, Ethernet cables, among other suitable interfaces and cables.
The described electrical communication between components of an image-guided microrobotic systems may be able to provide power and/or communicate data. The electrical communication between components of the image-guided microrobotic systems described herein may be in wired form and/or wireless form.
A. Methods of Fabricating Image-Guided Microrobotic Devices
Methods of fabricating at least one image-guided microrobotic device includes at least two operations: 1) fabricating one or more micromotors; and 2) encapsulating the one or more micromotors in at least one microcapsule.
Returning to operation 520 in the flowchart 500 shown in
In one aspect, the image-guided microrobotic devices can be fabricated to have a particular approximate diameter by setting the rotational speed of the magnetic stirring.
Performance
For deep tissue imaging in vivo, image-guided microrobotic devices according to one aspect have higher optical absorption than the blood in the specimen. Using a PACT system, the photoacoustic performance of ingestible Mg-based image-guided microrobotic devices fabricated using the operations described in
To evaluate the stability of the image-guided microrobotic devices under pulsed NIR photoacoustic excitation, the PA signal fluctuation of the image-guided microrobotic devices was measured during photoacoustic imaging using PACT.
Maximum detectable depth of image-guided microrobotic devices using PACT was evaluated.
B. Methods of Navigating and Activating Image-Guided Microrobotic Devices
Each image-guided microrobotic device includes a partial coating disposed over a reactive particle. The partial coating includes at least one area that exposes the reactive particle to ingress by fluid that can cause a reaction that releases gases that when exiting the at least one area cause autonomous propulsion. The partial coating may include an imaging contrast agent and cargo such as, e.g., therapeutic drugs. The one or more images may be generated by an imaging subsystem or a separate imaging system that employs, e.g., PACT, ultrasound, magnetic resonance imaging, X-ray CT, PET, DOT, PAM, OCT.
In one implementation, PACT is used such as by employing the PACT system 200 shown in
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In Vitro Evaluation
To evaluate the dynamics of image-guided microrobotic techniques of certain implementations, photoacoustic imaging experiments were conducted in vitro, where silicone rubber tubes (e.g., silicone rubber tubes with an inner diameter of 0.5 mm sold by Dow Silicones) modeled intestines.
Triggering Collapse of Microcapsule(s)
In addition to tracking image-guided microrobotic devices, propulsion of the micromotors upon unwrapping from the microcapsules can be activated on demand by applying high power CW NIR irradiation and/or other triggering mechanisms.
In one implementation, CW NIR-activated propulsion of the micromotors is employed. To evaluate the CW NIR-activated propulsion, a PBS solution of 30 μL mixed with image-guided microrobotic devices was dropped on a piece of gene frame and a glass coverslip was placed over the gene frame. A CW NIR laser (e.g., 808 nm, 2 W CW NIR laser with a focal diameter of about 0.8 cm) was used to irradiate the image-guided microrobotic devices obliquely (e.g., at an angle of 45 degree) with the light beam aligned to the focus of a microscope. The image-guided microrobotic devices were irradiated before they completely sank to the bottom of the glass slide. The disintegration of the image-guided microrobotic devices occurred within 0.1 s exposure of the CW NIR light. In addition, during each respiration cycle, the resting time (the duration free of respiration motion) is typically longer than 0.3 s as discussed in Li, L., et al., “Single-impulse panoramic photoacoustic computed tomography of small-animal whole-body dynamics at high spatiotemporal resolution,” Nat. Biomed. Eng. 1, 0071 (2017). Thus, once the real-time PACT detects that image-guided microrobotic devices have reached the targeted area, the CW NIR light can trigger the release during the resting time, avoiding the influence of respiration motion. The process of the NIR-triggered disintegration of the image-guided microrobotic devices and the propulsion of the micromotors was captured using a high-speed camera (e.g., Axiocam 720 mono) at 100 and 25 frames s−1, respectively.
By implementing an enteric coating and gelatin encapsulation, an image-guided microrobotic device can have long-term stability in both gastric acid and intestinal fluid.
In certain aspects, micromotors exhibit gas bubble propulsion in various biofluids.
Bare Mg particles exhibit negligible propulsion in neutral media (e.g., intestinal fluid) and disordered propulsion in acidic conditions.
Although CW-NIR irradiation is used in many examples herein to trigger collapse of the microcapsule(s), it would be understood that other triggering mechanisms in biomedicine, such as magnetic or ultrasonic fields, can also be employed to activate propulsion of the micromotors as discussed in Tay, Z. W., et al. “Magnetic particle imaging-guided heating in vivo using gradient fields for arbitrary localization of magnetic hyperthermia therapy,” ACS Nano 12, 3699-3713 (2018), which is hereby incorporated by reference in its entirety.
In Vivo Evaluation
The movement of a swarm of image-guided microrobotic devices according to one implementation was monitored in vivo using PACT (e.g., the PACT system 200 in
The moving speed of the swarm image-guided microrobotic devices in the intestines and the movements induced by respiratory motion were quantified. To quantify the speed of migration of the image-guided microrobotic devices, the acquired frames were first averaged to project the trajectories of the image-guided microrobotic devices. The migration paths of image-guided microrobotic devices were manually identified from the averaged image. Time traces at points along the migration paths were then extracted, forming images in which one dimension was the distance along the migration paths (x) and the other dimension was the elapsed time (t). Median filter (3×3 pixels) was then used to smooth the x-t images. Applying a threshold (⅓ of the maximum) segmented out the pixels containing image-guided microrobotic devices. The center positions of image-guided microrobotic devices along the path were estimated by calculating the geometric centers of the segmented pixels for given times. The center positions at the elapsed time points were fitted linearly to compute the migration speeds.
Retention Evaluation
The propulsion of cargo-loaded micromotors described herein may provide a mechanical driving force that can enhance their retention and delivery of cargo at or near targeted areas. In one aspect, the amount of NIR activation power needed to disintegrate the microcapsules may be adjusted by controlling the synthesis process and composition of the microcapsules. The amount of NIR activation power is depending on the mechanical properties of the microcapsule while the mechanical property could be controlled by the parameters during synthesis of the microcapsules.
Of particular biomedical significance is the retention of cargo-loaded micromotors in a targeted region of the intestines. The biofluid-driven propulsion of active micromotors described herein may prolong retention in intestine walls. When the image-guided microrobotic devices approach the targeted areas of the intestines, the collapse of the microcapsules can be triggered and the propulsion of the micromotors activated on demand.
To investigate the use of the image-guided microrobotic methods for targeted delivery, melanoma cells were grown in mouse intestines and the intestines were coated with tissues as the model ex vivo colon tumor. Due to the high optical absorption of melanoma cells in the NIR wavelength region, colon tumors can be clearly resolved by PACT. After injection into the intestines, the image-guided microrobotic devices migrated toward the targeted colon tumor. A syringe pump was also connected to drive the image-guided microrobotic devices.
Once the image-guided microrobotic devices approached the targeted region, they were irradiated with CW NIR light to trigger a responsive release of the micromotors. The photoacoustic signals from the image-guided microrobotic devices in the intestines were prolonged upon the CW NIR irradiation, suggesting the release of the micromotors.
To evaluate retention of the micromotors in vivo, the micromotors encapsulated in enteric polymer-coated microcapsules and paraffin-coated passive Mg and Mg/Au particles (as Control 1 and Control 2 respectively) were orally administrated to three mouse groups. As the controls, paraffin-coated passive particles (Mg particles and Mg/Au particles as Control 1 and Control 2, respectively) were prepared by incubating 0.05 g particles with 1 g paraffin wax at 75° C. overnight and then sequentially washed with chloroform, acetone, and pure water as discussed in Hong, L., Jiang, S., Granick, S., “Simple method to produce Janus colloidal particles in large quantity,” Langmuir 22, 9495-9499 (2006), which is hereby incorporated by reference in its entirety. The intestines from the mice treated with micromotors retained a much higher number of micromotors than that with passive particles.
The images show hollow structures of the micromotors in the intestine before and after acid treatment. is a microscopic image of the micromotors attached to the intestines before the addition of 0.1 M gastric acid, according to an implementation.
Besides active propulsion, the enhanced retention in vivo may also be attributed to the elevated pH and Mg2+ concentration in the surrounding environment caused by Mg-water reactions in certain implementations. The enhanced retention of micromotors in vivo may be attributed to the interaction between micromotors and intestinal mucus. The chemical reaction of magnesium and water generated Mg2+ and elevated pH in local environment, which may trigger the phase transition of mucus according to Tay, Z. W., et al. “Magnetic particle imaging-guided heating in vivo using gradient fields for arbitrary localization of magnetic hyperthermia therapy,” ACS Nano 12, 3699-3713 (2018) and Bansil, R., Turner, B. S., “The biology of mucus: Composition, synthesis and organization,” Adv. Drug Deliv. Rev. 124, 3-15 (2018), which are hereby incorporated by reference in their entireties. High pH (˜8.2-12.0) could trigger a phase transition of the mucus and facilitate tissue penetration of the micro/nanoparticles as discussed in Tay, Z. W., et al. “Magnetic particle imaging-guided heating in vivo using gradient fields for arbitrary localization of magnetic hyperthermia therapy,” ACS Nano 12, 3699-3713 (2018), Bansil, R., Turner, B. S., “The biology of mucus: Composition, synthesis and organization,” Adv. Drug Deliv. Rev. 124, 3-15 (2018), Celli, J. P., et al., “Helicobacter pylori moves through mucus by reducing mucin viscoelasticity,” Proc. Natl. Acad. Sci. U.S.A 106, 14321-14326 (2009), Lai, S. K., Wang, Y.-Y., and Hanes, J., “Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues,” Adv. Drug Deliv. Rev. 61, 158-171 (2009), which are hereby incorporated by reference in their entireties.
To investigate the influence of the micromotors on the pH of the surrounding environment, the micromotors were dispersed in water with phenolphthalein as a pH indicator.
The enhanced diffusion of the micromotors in mucus was further investigated using a technique discussed in Kirch, J., et al., “Optical tweezers reveal relationship between microstructure and nanoparticle penetration of pulmonary mucus,” Proc. Natl. Acad. Sci. U.S.A 109, 18355-18360 (2012), which is hereby incorporated by reference in its entirety.
Encapsulation and Release of Drug from Micromotors
In one aspect, the encapsulation efficiency (EE) and release profile of DOX for image-guided microrobotic devices and micromotors can be increased using techniques described in Cui, Y., et al. “Transferring-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment,” Biomaterials 34, 8511-8520 (2013) and Gaihre, B., Khil, M. S., Lee, D. R., Kim, H. Y., “Gelatin-coated magnetic iron oxide nanoparticles as carrier system: Drug loading and in vitro drug release study,” Int. J. Pharm. 365, 180-189 (2009), which are hereby incorporated by reference in their entireties. To encapsulate DOX into the micromotors, 1.0 mL alginate solution (2%, w/v) with different concentrations of DOX were dropped onto the glass slides containing Au layer-coated Mg microparticles, and then a 1.0 mL CaCl2) solution was dropped onto the glass slide to cross-link alginate, followed by coating of a parylene layer and water rinse for 3 times. Micromotors without cross-linking were also prepared. The amount of DOX was measured through a UV-visible spectrophotometer at 485 nm. The EE of DOX on the micromotors can be determined using the following equation:
For the drug release study, ˜10 mg DOX-loaded micromotors were suspended in 5 mL PBS with magnetic stirring at 37° C. and 8000 rpm. At different time intervals, the supernatant was removed and replaced with fresh PBS. The concentration of DOX was determined by measuring its absorbance using a spectrophotometer at a wavelength of 485 nm.
Compared with the negligible diffusion of the control silica particles in the mucus, diffusion of the micromotors in the mucus shows a significantly enhanced profile within 40 minutes. To investigate the cargo release kinetics of the micromotors, a fluorescent anticancer drug, DOX, was encapsulated into the alginate layer of the micromotors. The release of DOX from the micromotors was characterized utilizing an ultra-violet/visible spectrophotometer. The cross-linking treatment of the hydrogel significantly improves the efficiency of DOX loading.
Biocompatability and Biodegradablity of Image-Guided Microrobotic Devices
The biocompatibility and biodegradability of the image-guided microrobotic devices are important for biomedical applications. The materials of the image-guided microrobotic devices, such as Mg, Au, gelatin, alginate, and enteric polymer are known to be biocompatible. To evaluate the toxicity profile of the image-guided microrobotic devices in vivo, healthy mice were orally administered with image-guided microrobotic devices or DI water once a day for two consecutive days. Throughout the treatment, no signs of distress, such as squinting of eyes, hunched posture, or lethargy, were observed in either group. Initially, the toxicity profile of the image-guided microrobotic devices in mice was evaluated through changes in body weight. During the experimental period, the body weights of the mice administered with image-guided microrobotic devices have no significant difference from those of the control group.
The components of micromotors described herein are widely used as therapeutic agents and in implantable devices have been studied to be safe for in vivo applications as discussed in Smith, B. R., Eastman, C. M., Njardarson, J. T., “Beyond C, H, 0, and Ni analysis of the elemental composition of U.S. FDA approved drug architectures,” J. Med. Chem. 57, 9764-9773 (2014) and Baheiraei, N., Azami, M., Hosseinkhani, H., “Investigation of magnesium incorporation within gelatin/calcium phosphate nanocomposite scaffold for bone tissue engineering,” Int. J. Appl. Ceram. Technol. 12, 245-253 (2015) and Sezer, N., Evis, Z., Kayhan, S. M., Tahmasebifar, A. Koç, M., “Review of magnesium-based biomaterials and their applications,” J. Magnesium Alloys 6, 23-43 (2018), which are hereby incorporated by reference in their entireties. The micromotors have been shown to be eventually cleared by the digestive system via excrement, without any adverse effects.
To estimate the toxicity of the image-guided microrobotic devices in vivo, 5-6-week old nude mice were administered with 0.1 mL micromotor suspension via oral gavage. Healthy mice treated with DI water were used as a negative control. The body weight of mice was measured daily during the experiment. In order to prepare the intestine sample for histology investigation, the intestines were treated with 10% (v/v) buffered formalin for 15 hours. The intestines were cut to smaller sections as duodenum, jejunum, and distal colon. The longitudinal tissue sections were washed in tissue cassettes and embedded in paraffin. The tissue sections were sliced into 8-μm thick sections using a freezing microtome (Leica, CM1950) and stained with H&E assay. The samples were imaged with an optical microscope (Zeiss, AXIO).
Penetration Depth with Different Imaging Techniques
In human clinical applications, tissue penetration may be up to tens of centimeters. PACT can provide up to 7-cm tissue penetration, which is limited by photon dissipation. In some implementations, the image-guided microrobotic methods/systems employ imaging techniques that use excitation sources such as, e.g., microwave, acoustic detection, and thermoacoustic tomography (TAT) that are capable of tissue penetration for human clinical applications as discussed in Xu, Y., Wang, L. V., “Rhesus monkey brain imaging through intact skull with thermoacoustic tomography,” IEEE Trans. Ultrason. Ferroelectr. Freq. Control 53, 542-548 (2006) and Kruger, R. A., et al. “Thermoacoustic CT: imaging principles,” Proc. SPIE 3916, 150-160 (2000), which are hereby incorporated by reference in their entireties. In implementations that use a gold layer as the imaging contrast layer in the micromotor, the gold layer may provide an excellent microwave absorption contrast for TAT imaging owing to the high electrical conductivity, and thus greatly enhances the deep tissue imaging capability of the micromotors. Focused ultrasound heating may also increase the depths of thermally-triggered microrobot release to the whole-body level of humans.
Applications Other than Intestines
Passive diffusion-based targeting strategies have been explored to improve delivery efficiency, but they suffer from low precision, size restraint and specific surface chemistry as discussed in Rosenblum, D., Joshi, N., Tao, W., Karp, J. M., Peer, D., “Progress and challenges towards targeted delivery of cancer therapeutics,” Nat. Commun. 9, 1410 (2018), which is hereby incorporated by reference in its entirety.
Certain implementations of image-guided microrobotic techniques described herein enable micromotors to reach a targeted region in intestines with high precision. These techniques can be tailored to reactive particles of various sizes and can be applied to any biological media such as, for example, gastrointestinal tract, blood, urea, and interstitial fluid. In one aspect, reactive particles are in a range of 3 μm to 1 mm. In another aspect, reactive particles are in a range of 20 μm to 60 μm. The image-guided microrobotic techniques can implement micromotors with material that can carry various cargos such as, e.g., therapeutic agents and diagnostic sensors, with real-time feedback during delivery to the target region and activation.
Certain implementations of image-guided microrobotic techniques described herein pertain to an ingestible image-guided microrobotic device with high optical absorption for imaging-assisted control in, e.g., intestines. The encapsulated micromotors survive the erosion of the stomach fluid and permit propulsion in intestines. In one aspect, PACT non-invasively monitors the migration of the micromotors and visualizes their arrival at targeted areas in vivo. As the micromotors arrive at or near the targeted region, CW NIR irradiation may be used to induce a phase transition of the microcapsules and trigger the propulsion of the micromotors. The mechanical propulsion provides a driving force for the micromotors to bind to the intestine walls, resulting in an extended retention.
Modifications, additions, or omissions may be made to any of the above-described embodiments without departing from the scope of the disclosure. Any of the embodiments described above may include more, fewer, or other features without departing from the scope of the disclosure. Additionally, the steps of described features may be performed in any suitable order without departing from the scope of the disclosure. Also, one or more features from any embodiment may be combined with one or more features of any other embodiment without departing from the scope of the disclosure. The components of any embodiment may be integrated or separated according to particular needs without departing from the scope of the disclosure.
It should be understood that certain aspects described above can be implemented in the form of logic using computer software in a modular or integrated manner. Based on the disclosure and teachings provided herein, a person of ordinary skill in the art will know and appreciate other ways and/or methods to implement the present invention using hardware and a combination of hardware and software.
Any of the software components or functions described in this application, may be implemented as software code using any suitable computer language and/or computational software such as, for example, Java, C, C#, C++ or Python, LabVIEW, Mathematica, or other suitable language/computational software, including low level code, including code written for field programmable gate arrays, for example in VHDL. The code may include software libraries for functions like data acquisition and control, motion control, image acquisition and display, etc. Some or all of the code may also run on a personal computer, single board computer, embedded controller, microcontroller, digital signal processor, field programmable gate array and/or any combination thereof or any similar computation device and/or logic device(s). The software code may be stored as a series of instructions, or commands on a CRM such as a random access memory (RAM), a read only memory (ROM), a magnetic medium such as a hard-drive or a floppy disk, or an optical medium such as a CD-ROM, or solid stage storage such as a solid state hard drive or removable flash memory device or any suitable storage device. Any such CRM may reside on or within a single computational apparatus, and may be present on or within different computational apparatuses within a system or network. Although the foregoing disclosed embodiments have been described in some detail to facilitate understanding, the described embodiments are to be considered illustrative and not limiting. It will be apparent to one of ordinary skill in the art that certain changes and modifications can be practiced within the scope of the appended claims.
The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and can also cover other unlisted steps. Similarly, any composition or device that “comprises,” “has” or “includes” one or more features is not limited to possessing only those one or more features and can cover other unlisted features.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.
Groupings of alternative elements or embodiments of the present disclosure disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.
This application claims priority to and benefit of U.S. Provisional Patent Application No. 62/865,769, titled “Photoacoustic Computed Tomography Guided Microrobotic System” and filed on Jun. 24, 2019, which is hereby incorporated by reference in its entirety and for all purposes.
This invention was made with government support under Grant No. CA186567 & NS090579 & NS099717 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Number | Date | Country | |
|---|---|---|---|
| 62865769 | Jun 2019 | US |
