ULTRASOUND AND MICROBUBBLES IN OCULAR DIAGNOSTICS AND THERAPIES

Abstract

The present disclosure described methods, systems, and techniques for applying contrast-enhanced ultrasound to locate areas of blockage within retinal vessels and to break up clots that are causing damage. In addition to identifying the damaged area, the researchers anticipate that the initial image may serve as a baseline for monitoring the effect of treatment on the vessel, which may be achieved in multiple ways. The vibration effect of the ultrasound itself may suffice to dislodge clots. The microbubbles may also be coated or filled with medication, with ultrasonic shock waves activating the coating or causing mini explosions to release the medicine. Loading the microbubbles with a therapeutic agent, visualizing their presence at the diseased site using the ultrasound diagnostic mode, and then activating the microbubbles to release their contents at the targeted lesion could be a powerful and effective way to reverse occlusion without harming other areas of the eye or body.

Claims

1. A method of treating blood vessel blockage, comprising: applying ultrasound energy to locate one or more areas of blockage within one or more blood vessels; directing microbubbles to an area of blockage; and breaking up clots that are causing damage within the one or more areas of blockage.

2-38. (canceled)

Description

BRIEF DESCRIPTION OF DRAWINGS

[0014] Aspects of the disclosure may be more fully understood from the following description when read together with the accompanying drawings, which are to be regarded as illustrative in nature, and not as limiting. The drawings are not necessarily to scale, emphasis instead being placed on the principles of the disclosure. In the drawings:

[0015] FIG. 1 depicts application of ultrasound energy from an ultrasound probe systems to release drugs from microbubbles to effect treatment of a tumor, e.g., as located in a patient's eye, in accordance with exemplary embodiments of the present disclosure;

[0016] FIG. 2 depicts a application of ultrasound energy (beam) from an external or intraocular probe to an area of blockage within a retinal vessel and at a location including microbubble contrast agents, according to an exemplary embodiment of the present disclosure; and

[0017] FIG. 3 depicts a block diagram of a method 300 of therapy with microbubbles in accordance with exemplary embodiments of the present disclosure.

[0018] While certain embodiments are depicted in the drawings, one skilled in the art will appreciate that the embodiments depicted are illustrative and that variations of those shown, as well as other embodiments described herein, may be envisioned and practiced within the scope of the present disclosure.

DETAILED DESCRIPTION

[0019] Aspects of the present disclosure combine ultrasound with ultrasound contrast agents, known as microbubbles, to treat selected regions of a patient by what the inventors refer to as Contrast Enhanced Ultrasound Therapy.

[0020] Microbubbles are tiny, gas-filled lipid, or fat, bubbles that can be injected into the bloodstream, where they remain inactive unless stimulated. In conjunction with the utilization of such microbubbles, aspects and embodiments of the present disclosure utilize ultrasonic energy or ultrasound. High-frequency ultrasound has been used to create images of bone, tissue and other structures within the body by measuring the speed and intensity with which sound waves bounce off these objects and return as an echo. Ultrasound waves directed at microbubbles cause them to vibrate and return a unique echo within the bloodstream that produces a dramatic distinction, or high contrast, between blood vessels and surrounding tissue, thus enabling clinicians to visualize areas of restricted blood flow. Specialized Doppler ultrasound, which measures the rate and volume of blood flow, can further pinpoint the extent and severity of blockage caused by blood clots.

[0021] Embodiments of the present disclosure utilize contrast-enhanced ultrasound to locate areas of blockage within retinal vessels and to break up clots that are causing damage. In addition to identifying the damaged area, the researchers anticipate that the initial image may serve as a baseline for monitoring the effect of treatment on the vessel, which may be achieved in multiple ways. The vibration effect of the ultrasound itself may suffice to dislodge clots.

[0022] The microbubbles may also be coated or filled with medication, with ultrasonic shock waves activating the coating or causing mini explosions to release the medicine. Loading the microbubbles with a therapeutic agent, visualizing their presence at the diseased site using the ultrasound diagnostic mode, and then activating the microbubbles to release their contents at the targeted lesion/region can be a powerful and effective way to reverse occlusion without harming other areas of the eye or body.

[0023] FIG. 1 depicts application 100 of ultrasound energy from an ultrasound probe system 102 to microbubbles 104 containing desired drugs 106 to effect treatment of a tumor 1 located in an eye 2, in accordance with exemplary embodiments of the present disclosure. Gas filled microbubbles (e.g., on the order of microns in size/diameter) can be visualized or imaged by ultrasound. Using specially designed probes, which have the ability to image and also activate the microbubbles, targeted therapies can be effected in the eye, while minimizing collateral damage. Such a probe is described in co-owned and co-pending U.S. patent application Ser. No. 12/061,120 filed 2 Apr. 2008 and entitled Thrombolysis In Retinal Vessels with Ultrasound, incorporated in its entirety herein by reference. A pulsed-wave Doppler system with a PMN-PT needle transducer has been developed to measure the blood flow velocity in selected retinal vessels. See, e.g., Emanuel J. Gottlieb, et al., PMN-PT High Frequency Ultrasonic Needle Transducers for Pulsed Wave Doppler In The Eye, 2005 IEEE Ultrasonics Symposium (IEEE 2005), the contents of which are incorporated herein by reference in their entirety.

[0024] Ultrasonic techniques have also been utilized in surgical procedures on the eye for imaging structure and/or tissue of a surgical site. See, e.g., U.S. Pat. No. 6,676,607 to de Juan, Jr. et al., the contents of which are incorporated herein by reference in their entirety.

[0025] Procedures/techniques according to the present disclosure, e.g., as depicted and described for FIG. 1, can be expanded to other ocular disorders as well. The same techniques may also be applied to ocular tumors, such as retinoblastoma in children, for which systemic treatment is associated with potentially devastating side effects, but for which drugs delivered directly to the tumor could be safe and very effective. The same principle may also apply to tumors in other parts of the body such as breast, kidney, liver, brain etc.

[0026] Moreover, the tumor does not have to have a blood clot (and they usually don't). The ultrasound breaks up the microbubbles and results in the release of the drug they carry. As long as the drug is loaded on the microbubble it does not have any effect (good or bad). The ultrasound enables one to focally release the drug in the tumors or other desired location. As a result, there is a high concentration of the active drug in the tumor or location (e.g., a clot) for destruction of such. Despite the presence of the drug in the blood, however, the other tissues in the body are spared because the drug is attached to the microbubbles and is inactive. The drug delivery for tumors can be independent of the presence of a blood clot.

[0027] FIG. 2 depicts a application 200 of ultrasound energy (or beam) 202 from a ultrasound source, e.g., an external or intraocular probe, to an area or volume of blockage 1 within a retinal vessel 2 and at a location including microbubble contrast agents 204, according to an exemplary embodiment of the present disclosure.

[0028] The gas filled microbubbles 204 can be easily visualized using the ultrasound probe. Exemplary imaging or visualization techniques are described in co-owned and co-pending U.S. patent application Ser. No. 12/061,147 filed 2 Apr. 2008 and entitled Preoperative and Intra-Operative Lens Hardness Measurement by Ultrasound; U.S. Patent Application No. 12/061,120 filed 2 Apr. 2008 and entitled Thrombolysis In Retinal Vessels with Ultrasound; and U.S. Patent Application 12/102,293 filed 14 Apr. 2008 and entitled Intraocular Doppler Techniques; the contents of all of which are incorporated herein by reference.

[0029] The microbubbles 204 can be ruptured or activated to release their content by slightly altering the ultrasound mode. By loading these microbubbles with a specific therapeutic agent, visualizing their presence at the diseased area, and then activating the microbubbles to release their contents at the target lesion, side effects of this therapeutic agent can be limited by delivering it only to the needed site (or substantially so).

[0030] Moreover, the use of ultrasound and microbubbles in itself has the potential to dislodge blood clots, as shown in FIG. 2, with empty microbubbles rupturing and dislodging broken pieces of blood clots la after application of suitable ultrasound energy 202. By visualizing the microbubbles, and then activating them inside the diseased blood vessel at the site of the clot, therapy for retinal vascular occlusions can be effected.

[0031] FIG. 3 depicts a block diagram of a method 300 of therapy with microbubbles in accordance with exemplary embodiments of the present disclosure. For method 300, a desired quantity/volume of microbubbles can be introduced to a desired location of a patient, as described at 302. For example, microbubbles can be injected into the eye (vitreous cavity, subretinal, or anterior chamber) or may be injected intravascularly. Ultrasound techniques can be used to image or visualize the microbubbles at the desired location in the patient, as described at 304.

[0032] Continuing with the description of method 300, suitable ultrasound energy can be applied to the microbubbles to cause them to rupture or activate (meaning cause them to release drugs), as described as 306. In exemplary embodiments, the microbubbles can be filled or loaded with a desired drug before introduction into the patient as described at 308.

[0033] In exemplary embodiments, method 300 can include: using an ultrasound system configured and arranged to produce an ultrasound output; and supplying ultrasound contrast agents configured and arranged as microbubbles to a tumor wherein the microbubbles are loaded with chemotherapeutic drug that is active against the tumor, and wherein the ultrasound is used to localize the tumor and activate the microbubbles within the tumor to visualize and activate the release of drug within the tumor. The treated tumor can be an intraocular choroidal melanoma, and the drug can be labeled to attach to the blood vessels of the tumor selectively. The tumor can be a ciliary body melanoma or a retinoblastoma or an iris tumor. The microbubbles can be loaded with a therapeutic agent active against subretinalneovascularization in the back of the eye.

[0034] The drug/s inside the microbubbles can, in exemplary embodiments, be labeled to attach to the blood vessels of newly formed blood vessels, and the ultrasound output is used to activate the microbubbles focally to release the therapeutic agent. An optically labeled microbubble can be loaded with a therapeutic agent and visualized optically, then activated by ultrasound to release the therapeutic agent within the subretinalneovascular complex. The microbubbles can be loaded with genetic material. The method of claim 24, wherein the disease is retinitis pigmentosa and the genetic material is able to correct the genetic defect. The treated disease can be diabetic retinopathy, and the drug or genetic material can reverse the vascular defect in abnormal blood vessels of the diseased retina. The drug can be labeled to attach to the optic nerve, and the ultrasound output can be used to activate the microbubbles focally to release the therapeutic agent. The therapeutic agent can be a nerve growth factor or a vascular growth factor or an anti-cancer agent against an optic nerve tumor.

[0035] The ultrasound energy can be applied externally from outside the eye globe or internally from inside the eye. The treatment can be directed at the cornea, the front most layer of the eye. The treatment enhances therapy of corneal disease. The microbubbles can contain a therapeutic agent against a corneal disease or infection. The microbubbles can be applied to the surface(s) of the eye that is/are loaded with drugs and the ultrasound treatment facilitates entry of the drug(s) into the anterior chamber of the eye, delivering therapeutics to the interior of the eye.

[0036] While certain embodiments have been described herein, it will be understood by one skilled in the art that the methods, systems, and apparatus of the present disclosure may be embodied in other specific forms without departing from the spirit thereof.

[0037] Accordingly, the embodiments described herein, and as claimed in the attached claims, are to be considered in all respects as illustrative of the present disclosure and not restrictive.