Method for eye lens removal using cavitating microbubbles

A surgical method of cataract fragmentation and extraction via microbubble cavitation is described. In particular, gas-filled microbubbles are injected into a lens capsule of a subject's eye, and cavitation of the microbubbles is activated by applied ultrasound energy. The ultrasound energy can be applied from an external device. The cavitation fragments cataract tissues without damaging other tissue, such as the lens capsule. Fragmented lens material is then aspirated from the lens capsule. The method can be used alone or in conjunction with other methods, such as phacoemulsification.

BACKGROUND

1. Field of the Invention

The present application generally relates to cataract extraction surgery. Specifically, it relates to cataract fragmentation and extraction using microbubble cavitation, which may be augmented by ultrasound energy.

2. Description of Related Art

A cataract is the opacification of the natural phakic lens in the eye. Cataracts occur most commonly due to aging, but can also be secondary to congenital defect, trauma, medication, systemic disease or ocular surgery. Cataracts are the leading cause of visual impairment in the United States, and the most common cause of blindness in the developing world. Virtually all people who live long enough eventually require cataract surgery to maintain good vision. Cataract surgery is one of the most commonly performed surgeries in the United States, with over 3.6 million procedures performed in 2015.

Conventional phacoemulsification methods for surgical cataract extraction are effective at fragmenting and emulsifying the lens but have significant safety drawbacks. Possible vision-threatening complications can occur in approximately 1% to 4% of phacoemulsification procedures, for patients who would otherwise have excellent post-operative vision. Accordingly, cataract surgical training is the key and one of the most important components of a 3-year ophthalmic surgery residency. Moreover, even in an uncomplicated surgery with skilled hands, the energy produced by the phacoemulsification process may lead to a loss of corneal endothelial cells. This can lead to prolonged healing times and ultimately to corneal decompensation with irreversible clouding, necessitating corneal surgery.

Besides the human toll of the safety drawbacks, conventional phacoemulsification often requires significant equipment expenditure both in capital expenditure and ongoing costs for the disposable supplies.

Thus, there is a need for another method of cataract extraction capable of augmenting or replacing conventional high-energy phacoemulsification techniques.

BRIEF SUMMARY

A surgical method of cataract fragmentation and extraction via microbubble cavitation is described. In particular, the cavitation of injected microbubbles is activated by ultrasound energy. The cavitation can efficiently fragment cataracts without damaging other tissue, such as the subject's lens capsule. The method can also be used to augment phacoemulsification.

Gas-filled microbeads are applied into a lens capsule holding the cataract. Ultrasound energy is directed at the microbeads, inducing cavitation. The cataractous lens material is fragmented, while the lens capsule is preserved. The fragmented lens material is aspirated from the capsule.

In one aspect of this disclosure, a method for removing a lens from an eye comprises providing gas-filled microbeads having an outside diameter less than 500, 250, or 100 microns. The method further comprises injecting the microbeads into an eye, wherein the eye contains a cataractous lens of a subject. For example, the microbeads may be injected into a lens capsule of the subject holding the cataractous lens. The method further comprises directing ultrasound energy at the injected microbeads sufficient to cause the microbeads to undergo cavitation. The method further comprises fragmenting lens material with the cavitation while preserving the posterior lens capsule. The method further comprises aspirating the fragmented lens clumps from the lens capsule.

In some embodiments, the method further comprises repeating the injecting, directing, fragmenting, and aspirating to remove the entire cataractous lens from the subject.

In some embodiments, each of the microbeads is comprised of a phospholipid shell and a fluorinated alkane gas inside the shell.

In some embodiments, the fluorinated alkane gas is selected from the group consisting of perfluoropropane and butane.

In some embodiments, each of the microbeads is comprised of a multiphase polymer shell and air inside the shell.

In some embodiments, the microbeads are coated with a targeting moiety configured to bind to lens material. The method may further comprise binding the microbeads to lens material of the cataractous lens. In various embodiments, the lens material may be lens fiber protein, or another lens material, and is not limited by the present disclosure.

In some embodiments, the targeting moiety comprises polypeptides or acidic groups.

In some embodiments, the method further comprises performing a capsulorhexis on the anterior lens capsule. The method may further comprise hydrodissecting the cataractous lens from the lens capsule. The method may further comprise inserting an artificial intraocular lens into the lens capsule.

In some embodiments, the microbeads are injected along with hydrodissecting liquid.

In some embodiments, the microbeads are injected into or around the cataractous lens.

In some embodiments, the microbeads are in a liquid suspension, and the injecting includes injecting the liquid suspension into the lens capsule.

In some embodiments, the liquid suspension is used to irrigate the lens capsule.

In some embodiments, the ultrasound energy reaches the microbeads by being transmitted through biological tissue from outside of the lens capsule.

In some embodiments the ultrasound energy originates outside of the eye.

In some embodiments, the ultrasound energy is transmitted from within the lens capsule using an ultrasonic tip.

In some embodiments, the method further comprises inserting a phacoemulsification handpiece tip into the lens capsule. The method may further comprise emulsifying, during or after the fragmenting, the lens material using emulsifying ultrasonic energy transmitted from the phacoemulsification handpiece tip within the lens capsule. Less emulsifying ultrasonic energy from the phacoemulsification handpiece tip inside the lens capsule may be required to remove the cataractous lens than if the fragmenting with the cavitation were not performed.

In some embodiments, the subject is a mammal, such as a human, a dog, or a rabbit.

DETAILED DESCRIPTION

The disclosed system and method of cataract fragmentation and extraction improves over conventional phacoemulsification techniques.

Technical advantages of some of the system and method embodiments include improved safety and efficiency of cataract removal surgery, reduced costs associated with phacoemulsification, and lowered training requirements or less of a learning curve for ophthalmological surgical residents.

I. Cataract Surgery and Potential Complications

The goal of cataract surgery is to extract a cataractous lens and implant an artificial lens in its place. The standard modern technique for cataract extraction relies on phacoemulsification (also referred to as “phaco”), or fragmenting the cataract, emulsifying it with irrigating fluid, and aspirating the emulsified cataract from the eye. The basis for fragmenting and emulsifying the cataract is that removing the cataract in pieces, rather than en bloc, permits surgery through a corneal incision significantly smaller than the diameter of the lens. This can minimize ocular trauma and post-operative defects, such as astigmatism.

FIG. 1Aillustrates an example cataract surgery100incorporating traditional phacoemulsification of the prior art. The phacoemulsification handpiece102is inserted through a corneal incision and the opening in the capsular bag to engage the cataractous lens104. There, through a combination of pulsed ultrasonic energy emitted by the phacoemulsification handpiece102and mechanical separating techniques using a second rigid instrument106, also referred to as a ‘chopper,’ lens104is fragmented and emulsified to the point it can be aspirated through the small opening of the phacoemulsification handpiece102. In this example, lens104is already partially fragmented, and has a missing fragment108.

In standard phacoemulsification techniques for cataract extraction, a surgeon or nurse dilates the patient's pupil. Next, the surgeon makes an incision at the limbus of the cornea and performs capsulorhexis, or incises a small opening in the surface of the capsular bag (also referred to as the lens capsule), a thin membrane housing phakic lens104. Frequently the surgeon will then inject liquid between the lens and capsule to separate, or hydrodissect, them apart. The surgeon then uses the phaco handpiece102to perform ultrasonic phacoemulsification, that is, to deliver ultrasonic waves that fragment the cataractous lens104. The handpiece also aspirates and removes the emulsified cataractous lens104from the eye while irrigating, to maintain a stable volume of fluid in the eye. The surgeon then deposits an artificial intraocular lens into the capsular bag.

FIG. 1Billustrates a potential complication in an example cataract surgery130of the prior art. Although the phacoemulsification method for cataract extraction is very effective for fragmenting and emulsifying the lens132, it has considerable safety drawbacks. One common complication, capsular bag rupture134, can permanently damage a structure within the eye. Learning to avoid capsular bag rupture necessitates extensive surgical training before ophthalmological surgeons are qualified to perform cataract removal.

The human eye's phakic, or natural, lens132is situated within a very thin (tapering from approximately 5 μm to 15 μm) membrane posterior to the iris called the capsular bag136(also referred to as the lens capsule), and is supported for 360 degrees with zonular fibers. Rupture of the capsular bag can occur when the sharp needle tip138of phaco handpiece140breaks the capsular bag136. Because needle tip138moves quickly during surgery, and fluids such as the irrigation fluid may be flowing rapidly, it is challenging for a surgeon to avoid inadvertently contacting capsular bag136with needle tip138. Moreover, during aspiration of the emulsified cataract, membrane136can be drawn toward tip138, increasing the risk of inadvertent contact. Thus, capsular bag rupture134can happen very quickly and abruptly if the surgeon accidentally contacts or aspirates the capsular bag136, with little opportunity to correct such an error. This can result in a large hole134in capsular bag136, which may immediately become unusable once damaged.

Phacoemulsification can also lead to other serious complications. For example, the sharp tip138of phaco handpiece140can also inadvertently damage many other delicate and critical structures in the eye, including the cornea and iris. Its ultrasound energy may cause wound burns, as described further below.

FIG. 1Cillustrates aspects160of conventional, prior art phacoemulsification procedures that have the potential to cause complications, damage, or discomfort. As described in the example ofFIG. 1Babove, capsular bag rupture is a somewhat common and serious complication. However, there are a number of other complications, sources of discomfort, or impracticalities that sometimes arise in conventional phacoemulsification. Some complications may be mild (requiring medication), while others may require additional surgery and/or engender long term inflammation, retinal detachment, infection, or permanent vision loss or blindness. Studies suggest the total complication rate for phacoemulsification is approximately 1-4%. In this example, the contributing factors or potential sources of such complications, discomfort, and impracticalities are described.

First, the phacoemulsification handpiece162combines several functions, including emitting ultrasound energy164to fragment cataract166, mechanically cutting the cataract166, and aspirating the emulsified cataract. Thus, phaco handpiece162is a relatively large instrument, requiring a corneal limbal incision168of over 2 mm. In fact, the size of phaco handpiece162is often the limiting factor in the required corneal incision size during cataract surgery. Such a corneal incision poses dangers of eye trauma or wound leak.

Within eye170, the phacoemulsification handpiece162requires a sharp metal tip to insert into the cataractous lens and effectively deliver the pulsed ultrasonic energy164. During the course of surgery, this sharp tip can inadvertently damage many of the delicate and critical structures in the eye, including the cornea, iris, and the lens capsule, as described in the example ofFIG. 1Babove. Note that phacoemulsification is a mature technique that has already been optimized extensively, yet previous techniques have failed to make the needle tip smaller and safer. Furthermore, the manipulation of the lens166required in phacoemulsification can stress and tear the lens capsule and zonules.

In addition, because ultrasound energy164is poorly targeted to lens168, the dose of ultrasound energy164delivered into eye170may be substantially larger than the mechanical energy needed to fragment cataract168. Such a large dose potentially causes complications and side effects160. For example, if there is any disruption to the cooling irrigation mechanism of the phacoemulsification handpiece162while producing the large dose of ultrasound energy164, handpiece162can produce damaging wound burns in the surrounding tissue near the insertion site of probe162. These burns may frequently lead to reoperation, infection, and potentially blinding complications. The disclosed system and methods can lower the risk of such burns, both by reducing the ultrasound dose, and, in some embodiments, by generating the ultrasound outside of eye170.

Likewise, the dispersion and reflection of poorly-targeted ultrasound waves164delivers significant energy to tissues of eye170away from the desired target, cataract166, thereby potentially damaging vital structures or tissues. Even in uncomplicated surgery, the ultrasound energy164in phacoemulsification has been shown to lead to damage and loss of corneal endothelial cells in a dose-related fashion. The loss of these corneal endothelial cells can lead to prolonged healing times and ultimately corneal decompensation with irreversible clouding. This may necessitate additional corneal surgery. Beyond surgical complications, phacoemulsification also faces several practical issues: for example, the need to sterilize all the instruments involved in the procedure and the need to replace disposable phaco “packs” after each procedure.

Likewise, phacoemulsification carries significant equipment expenses. For example, disposable supplies such as the phaco “packs” may cost $100 to $200 per procedure, and capital expenditure such as a phaco machine may cost $50,000 to $100,000.

Because complications160, including possibly vision-threatening ones, can occur in patients who would otherwise have excellent post-operative vision, cataract surgical training is currently the key and one of the most important components during the 3-year ophthalmic surgery residency. Thus, by simplifying current surgical procedures and techniques, the disclosed system and methods can both benefit patients and also improve ophthalmology training.

An alternative or complementary method for cataract fragmentation and extraction is disclosed herein. The disclosed system fragments the cataract primarily by means of microbubble cavitation. Cavitation is the process by which a microbubble expands and collapses, with a resultant micro jet causing damage to surrounding matter. It is known well for surface pitting in metal marine propellers. In some embodiments, the energy required for the expansion is provided by ultrasound radiation.

Generally, microbubbles may form spontaneously, and may subsequently undergo cavitation spontaneously, in areas of rapid flow change (e.g., the phaco needle tip, propellers, pipe areas of changing diameter). However, the disclosed system and methods may instead make use of chemically or physically stabilized microbubbles. Moreover, these stabilized microbubbles can be activated by external energy sources providing sufficient activation energy, and once active, can undergo cavitation at a controlled rate. For example, the microbubbles can be activated by low-energy ultrasound waves or electromagnetic radiation, which can be applied either ab interno or ab externo.

FIG. 2Aillustrates an example microbubble200, in accordance with embodiments. Microbubble200may include an outer shell202and an interior core204. Interior core204may contain gas206or liquid with a lower boiling-point from the surrounding aqueous environment208. Shell202may protect interior core204from the aqueous environment208.

In some embodiments, the microbubble200used may be a DEFINITY® microbead produced by Lantheus Medical Imaging, Inc. of North Billerica, Mass., USA. U.S. Pat. No. 8,658,205 to Hui et al. and U.S. Pat. No. 10,220,104 to Robinson et al. describe such microbubbles and uses for cardiac imaging. Note that the DEFINITY® microbeads may be used with moderately higher-energy ultrasound than would be used for a contrast agent in cardiac imaging applications, but still significantly lower-energy ultrasound than in conventional phacoemulsification. In some embodiments, the microbubbles may be created or modified to target particular matter. U.S. Pat. Nos. 10,149,906 and 10,357,565 to Grubbs et al. describe modifications for biological targets. In some embodiments, other microbubbles may be used, and are not limited by the present disclosure.

Moreover, in some embodiments, the system may include a related apparatus or system used for mixing or agitating a precursor substance in order to form the microbubbles, such as the VIALMIX® activation device for use with DEFINITY® microbeads, also produced by Lantheus Medical Imaging, Inc. In some embodiments, the system may include a related microbubble apparatus.

FIG. 2Billustrates an example microbubble microscopic structure250, in accordance with embodiments. In an embodiment, the outer shell of the microbubble may comprise phospholipids252, and the interior core254may be filled with fluorinated gas. In particular, microbubble structure250may comprise phospholipids252with an inter phase254of a fluorinated alkane, such as perfluoropropane or butane. For example, the microbubbles may comprise a synthetic phospholipid shell filled with octafluoropropane gas.

In some embodiments, the microbubble shell may be formed from block copolymers or functionalized natural polymers and fluorocarbons, and is not limited by the present disclosure. Additionally, other classes of bubbles can be formed by multiphase polymerization of styrene or similar monomers that trap a center core254of air.

In some embodiments, the phospholipids252may comprise anchoring and/or targeting moieties, such as hydrophobic tails256, oriented toward the interior254of the bubble structure. Thus, structure250may facilitate the microbubbles' stability over long periods of time. Accordingly, unlike spontaneously-formed bubbles in a high-pressure fluid, chemically stabilized microbubble250may require the input of activation energy before it undergoes cavitation. The disclosed microbubbles thus act like a potential energy storage reservoir, forming stable low-pressure regions or voids254in the surrounding ocular fluid and/or irrigation fluid. When activation energy is provided and these voids are filled by the surrounding fluid, the fluid's motion can initiate cavitation microjets, releasing sufficient mechanical energy to fragment the cataract. Thus, chemical stabilization enables the disclosed system and methods to target a cataract preferentially, since the disclosed microbubbles can remain stable until they are deposited and activated near the cataract.

This improves over conventional techniques for cataract fragmentation because the microbubbles can more precisely target the cataract than can ultrasound waves, which are subject to dispersion, reflection, etc. Accordingly, the disclosed system and methods can significantly lower the eye's exposure to waste mechanical energy, and improve efficiency and safety of the cataract fragmentation process.

In some embodiments, microbubble250can have an average diameter (wherein “average diameter” refers to the largest dimension for non-spheroidal shapes) between 0.1 μm and 10 μm, or between 0.5 μm and 10 μm, or between 1 μm and 10 μm. In some embodiments, the average diameter is between 0.5 μm and 3 μm, or between 1 μm and 2 μm. In some embodiments, the microbubble250has an average diameter less than 10 μm, or less than 5 μm, or less than 1 μm, or less than 0.5 μm, or less than 0.1 μm. In some embodiments, microbubble250has an average diameter greater than 0.1 μm, or greater than 0.5 μm, or greater than 1 μm, or greater than 5 μm, or greater than 10 μm. Synthetic processes allow the production of bubbles of various sizes and materials.

The term “microbubbles” may be used interchangeably herein with “bubbles,” and it will be appreciated that use of the term “microbubbles” is not intended to limit the size of the bubbles to any particular range (e.g., micron diameters).

Because the eye's lens is typically bare, the microbubbles may be able to bind to the cataractous lens without being tagged. Accordingly, in some embodiments, the microbubbles are not tagged to a lens protein in order to bind to the lens. In some embodiments, the microbubbles may be tagged and/or coated with a targeting moiety to bind to the lens protein.

After introduction of the bubbles and attachment or association of the bubbles with the target, cavitation may be initiated by a variety of methods. In some embodiments, this may involve application of activation energy, as described above. The activation energy may be generated ex vivo, for example, by the application of directed ultrasound and/or radio waves. In one example, electromagnetic (EM) energy of a frequency between 400 kHz and 10 MHz is suitable because it propagates through tissue without strong interactions (due to low electrical conductivity). In another example, standard ultrasound units are applied, either within or adjacent to the patient's body, with sufficient power to initiate cavitation of the pre-positioned bubbles. Activation of the microbubbles by applying energy is described further herein below.

FIG. 3illustrates an example cavitation process300, as described in “High speed observation of damage created by a collapse of a single cavitation bubble,” Wear 418-419 (2019) by M. Dular et al., and in accordance with embodiments of the present disclosure. Cavitation is the process by which a microbubble310expands and collapses with a shock wave, causing pitting of a solid surface315. In this example, a vapor microbubble310can form within a high-pressure fluid. For example, the microbubble can form spontaneously in a region of rapid flow change in the fluid. In this example, the microbubble may form spontaneously as the fluid flows around a surface, such as surface315, especially if the surface's motion or acceleration creates large pressure gradients (e.g., in the vicinity of the phaco needle tip, propellers, or pipe areas of changing diameter). Such a surface315may be pitted by the cavitation process300. Note that surface315may also play a role in the bubble's collapse and subsequent cavitation.

In embodiments of the present disclosure, rather than forming spontaneously, the microbubbles may be chemically stabilized (e.g., they may comprise phospholipid shells with anchoring and/or targeting moieties, such as hydrophobic tails, in the interior of the bubbles). Accordingly, the microbubbles may require activation energy to undergo cavitation, rather than cavitating spontaneously. This stabilization and activation allows the disclosed system and methods to target the cataract preferentially, thereby significantly lowering the eye's exposure to waste mechanical energy, and improving efficiency and safety of the cataract fragmentation process. As described above, such stabilized microbubbles may be formed from a precursor substance using a mixing or agitating apparatus. In some embodiments, the microbubbles may form and/or cavitate spontaneously, and are not limited by the present disclosure.

The microbubble can subsequently reach its peak or maximum size and begin to implode at a susceptible point320under pressure from the fluid. In this example, the region322(shown in projection view as the top of microbubble320) of microbubble320farthest from surface315may collapse faster than the region324closest to the surface (shown as the bottom of microbubble320). In particular, during implosion, the high-pressure fluid surrounding region322may accelerate into the void previously formed by the microbubble. Accordingly, the implosion can trigger a jet330(also referred to as a microjet) of the high-pressure fluid, which can divide and annihilate the microbubble. The jet330may reach very high speeds, such as hundreds of meters per second.

Moreover, the jet can deform340nearby surface315. In embodiments of the present disclosure, the surface315can be the cataractous lens. The microbubbles can be designed to preferentially damage stiff surfaces, such as the cataract, while preserving pliable tissue, such as the lens capsule. Upon collision with the surface315, jet330can be deflected350along surface315, possibly forming eddies355. Such eddies355can form secondary microbubbles360, which may be smaller than the original bubble. Due to their very small size, secondary microbubbles360may have sufficient surface tension to remain spherical while imploding, thereby producing shock waves370which can further damage surface315.

In embodiments of the present disclosure, directed cavitation enables the selective fragmentation of objects in vivo while preserving adjacent tissues. The cavitation effect is related to the stiffness of the material. In embodiments of the present disclosure, the cataract can have a higher stiffness than the surrounding tissue of the lens capsule. Therefore, it can be damaged and destroyed by cavitation, while the lens capsule and surrounding tissues are preserved. This selectivity can be further augmented by tagging the surface of the microbubbles with a targeting moiety or reagent that specifically binds to the phakic lens. Such tags can include polypeptides or acidic groups.

FIGS. 4-6illustrate damage to a sample by successive cycles of microbubble cavitation. In some embodiments, multiple cycles of microbubble cavitation may be performed during the course of the cataract removal surgery. A respective cycle may include injecting or otherwise inserting bubbles to a small area inside the lens capsule, applying ultrasound energy, assessing damage to the lens, and optionally vacuuming, aspirating, or removing debris. In the example ofFIG. 4, after a first cavitation cycle, the sample remains largely intact, but shows some chipping402and404, and loss of mass. InFIG. 5, subsequent to a second cavitation cycle, the sample is significantly notched432, rounded at edges434and436, and scuffed, with jagged edges. InFIG. 6, subsequent to another cavitation cycle, the sample has fractured, with a broken chip462visible.

FIG. 7is a chart illustrating measured damage to a sample's mass vs. ultrasound exposure time, in accordance with an embodiment. In this example, the sample has an initial mass of approximately 143 μg. With subsequent ultrasound insonation of cavitating microbubbles, its mass is reduced linearly with time. Note that, in this example, after sufficient insonation time, the sample can be reduced to nearly zero mass. Accordingly, the results shown inFIG. 7demonstrate that the disclosed cavitation process is effective and can fully and completely fragment a cataract.

The disclosed system and methods can use cavitating microbubbles, such as those in the examples ofFIGS. 2A and 2Babove, to fragment and extract cataracts more expediently, efficiently, and safely than conventional phacoemulsification. In some embodiments, the disclosed system for cataract fragmentation has two primary components: first, microbubbles formed by the techniques described above; and second, an ultrasonic transducer. As demonstrated in the examples ofFIGS. 4-7, the cavitating microbubbles can efficiently and fully fragment the cataract, without damaging the lens capsule.

In accordance with embodiments of the present disclosure, the microbubbles may first be injected into or around the cataractous lens intraoperatively. In particular, the microbubbles may either be admixed into the irrigating solution (as described, for example, inFIG. 11Abelow), or be injected directly (i.e., in a separate syringe) into the eye. These microbubbles can either be tagged to a lens protein or untagged.

Next, the microbubbles can be stimulated via ultrasound to induce cavitation, either from a probe external to the eye or ab interno, from an instrument inserted into the eye. In some embodiments, the ultrasound probe may be a relatively small external wand. In some embodiments, electromagnetic (EM) energy, such as radio waves of frequencies between 400 kHz and 10 MHz may be used to stimulate the microbubbles to induce cavitation, and is not limited by the present disclosure. In particular, such EM energy can propagate through tissue without strong interactions (due to low electrical conductivity). In some embodiments, other frequencies of radiation may be used, e.g. radio waves of frequencies greater than 10 MHz, and are not limited by the present disclosure.

Subsequently, the microbubbles in and around the lens can cavitate (i.e., undergo cavitation) in response to ultrasonic stimulation, and the resultant microjets can preferentially fragment the lens. This cavitation can fragment the cataractous lens, minimizing or eliminating the need for high-energy phacoemulsification. In particular, by minimizing phacoemulsification energy, use of microbubbles reduces such complications as: rupture of the thin protective posterior capsule, vitreous loss, damage to the endothelial cells, corneal edema, delayed healing, and corneal decompensation. Finally, the fragmented lens can be aspirated, and this process can be repeated in multiple cycles until the cataract is fully removed (as illustrated in the examples ofFIGS. 4-6above).

In some embodiments, the procedure may be preceded by making a small opening in the anterior surface of capsular bag (capsulorhexis), and may further include irrigation of fluid around the lens to mobilize it (hydrodissection), and removing the cataract from the eye. Subsequently, an artificial lens can be inserted into the lens capsule.

FIG. 8illustrates injection of microbubbles802about a cataract804, in accordance with external activation embodiments of the present disclosure. In this example, after capsulorhexis and hydrodissection of the lens, the surgeon may inject microbubbles802, such as the microbubbles ofFIGS. 2A and 2B, in and/or around the cataractous intraocular lens804. In this example, microbubbles802are injected directly using syringe806into the eye800. In some embodiments, the microbubbles may instead be admixed into the irrigating solution. In this example, microbubbles802are arranged around cataract804and in proximity to it. An ultrasonic probe (not shown) may also be positioned externally to the eye, by contrast with the surgically inserted phacoemulsification probe of conventional methods, so as to activate cavitation of the microbubbles.

Note that injection of the microbubbles802does not require as large an incision in the cornea808as would normally be required in conventional phacoemulsification. In this example, injection of a thin needle tip806suffices to position microbubbles802precisely, prior to cavitation. Moreover, the other surgical instruments, such as aspiration and/or irrigation instruments, also do not require large incisions. Thus, in embodiments where the microbubbles are admixed in the irrigating solution, the incision can still be significantly smaller than in phacoemulsification. Such a smaller incision may improve the safety, healing time, and stability of the disclosed method, as well as enabling a broader choice of artificial lens, and broader choices of other aspects of the surgery.

In external activation embodiments, cavitation of the microbubbles802, activated by directed ultrasound energy as described herein below, may be the primary source of mechanical energy used to fragment cataract804. Thus, in external activation embodiments, the ultrasound acts essentially as a trigger that activates the cavitation, rather than directly fragmenting the cataract. In some embodiments, a surgical ‘chopper’ instrument, and/or conventional phacoemulsification ultrasound energy, may also be used to augment the fragmentation.

FIG. 9illustrates activation of microbubbles902to cavitate904, in accordance with external activation embodiments of the present disclosure. In this example, low energy ultrasound may be directed from the ultrasonic probe906to the microbubbles902surrounding the crystalline lens908. The microbubbles902can be activated by the ultrasound energy910, thereby inducing them to undergo cavitation904.

In this example, the cavitation904, rather than the direct action of the ultrasound, fragments the cataractous lens908. The ultrasound energy910may be lower-power, less sharp, and/or more directional than in conventional phacoemulsification, thereby being safer to surrounding tissue and targeting the microbubbles902far more precisely than conventionally. In conventional phacoemulsification methods, by contrast, a higher level of ultrasound energy is propagated much more broadly throughout the surgical region, so as to fragment the cataract by its direct action. Accordingly, the disclosed system and methods can use lower energy and provoke fewer complications than conventional phacoemulsification.

The injection and/or cavitation of microbubbles can be repeated in multiple cycles, as necessary, in order to fragment the lens thoroughly. Such fragmentation allows for aspiration of the emulsified cataract using standard irrigation/aspiration instrumentation. As described in the examples ofFIGS. 4-6above, each cycle can significantly damage the cataract, leading eventually to complete extraction and removal. In particular, cycles may include injecting bubbles to a small area inside the lens capsule, applying ultrasound energy, assessing damage to the lens, and optionally vacuuming or removing debris. Such cycles are described further in the example flow ofFIG. 13below.

FIG. 10illustrates activation of microbubbles1002to cavitate1004, in accordance with internal activation embodiments of the present disclosure. In this example, after capsulorhexis and hydrodissection of the cataractous lens1006, an internal microbubble activation instrument1008may be introduced, which combines the functions of irrigation and aspiration with those of an ultrasonic probe. By contrast with a conventional phacoemulsification handpiece, microbubble activation instrument1008would not require a sharp tip, making it safer. Moreover, microbubble activation instrument1008may be smaller than a conventional phacoemulsification handpiece, and therefore may be inserted using a significantly smaller corneal incision than the phacoemulsification handpiece, as in the example ofFIG. 9above. The instrument1008may irrigate the lens with a microbubble solution. Instrument1008may also emit ultrasonic waves from its tip to activate microbubbles in its proximity, triggering focal cavitation and lens fragmentation. The instrument may then perform aspiration to remove the ensuing lens fragments. In an embodiment, a so-called IA (Irrigation and Aspiration) tip may be used.

As in the external activation embodiments described above, cavitation of the microbubbles1002and1004, activated by directed ultrasound energy emitted from instrument1008, may also be the primary source of mechanical energy used to fragment cataract1006in internal activation embodiments. Thus, in internal activation embodiments, the ultrasound energy from instrument1008acts to activate or trigger cavitation, rather than directly fragmenting cataract1006. Accordingly, the ultrasound can be low in energy and can be directed so as to target microbubbles1002and1004precisely, rather than being aimed broadly at cataract1006. In some embodiments, a surgical ‘chopper’ instrument may also be used to augment the cavitation.

Thus, instrument1008may be used in a similar manner to a conventional phacoemulsification handpiece, but instrument1008does not require a sharp tip, making the risk of complication far lower. In addition, as in the external activation embodiments described above, the ultrasound energy emitted by microbubble activation instrument1008may be significantly lower in energy and more precisely directed than in conventional phacoemulsification, lowering the risk of burns. The instrument1008can also be smaller and less sharp than a phacoemulsification handpiece, allowing for a smaller corneal incision, and can be less sharp. Moreover, combining the irrigation and aspiration functions with the ultrasound probe simplifies the procedure and reduces the number of instruments that must be inserted in the eye, potentially further lowering the complication risk.

FIG. 11Aillustrates an example surgical system1100, in accordance with phaco-augmentation embodiments of the present disclosure. Phaco-augmentation embodiments can make use of standard phacoemulsification systems and methods, augmented by the cavitation action of the activated microbubbles1102to fragment a cataractous lens. Thus, in phaco-augmentation embodiments, surgical system1100can be similar to a standard phacoemulsification system, but unlike a conventional system, system1100can include microbubbles1102.

In particular, in this example, microbubbles1102may be admixed into the irrigating fluid in irrigation bottle1104, which can comprise a balanced salt solution, as in a standard phacoemulsification system. Irrigation bottle1104may be of adjustable height in order to regulate the fluid pressure by gravity fluidics. Phaco machine1106may include pinch valve1108, which controls inflow1110of the irrigation fluid, and pump1112, which regulates outflow1114of aspirated fluid from the phaco handpiece1116during cataract removal surgery on eye1118. Thus, inflow1110of the irrigation fluid may transport microbubbles1102to the cataract within eye1118in a comparatively non-invasive manner. In some embodiments, the microbubbles may instead be injected directly via a syringe.

When pinch valve1108is open, the fluid in irrigation bottle1104can produce pressure in the anterior chamber of eye1118. During surgery, the aspirated fluid containing the emulsified cataract can be pumped1114from eye1118by pump1112. The height of irrigation bottle1104may be set to match the inflow1110of irrigation fluid to the outflow1114of aspirated fluid. Pump1112can include a flow pump, such as a peristaltic pump, and/or a vacuum pump, such as a venture pump. Phaco machine1106may filter waste, such as the emulsified cataract, from the aspirated fluid into waste bag1120.

FIG. 11Bis an inset view of activation of microbubbles1152to cavitate by a surgical system phaco tip1154ofFIG. 11A, in accordance with phaco-augmentation embodiments of the present disclosure. In this example, after capsulorhexis and hydrodissection of the cataractous lens1156, the cataract1156may be irrigated with microbubbles1152. As described in the example ofFIG. 11Aabove, the irrigation fluid used to replace the hydrodissected cataract may contain microbubbles1152, which can be deposited on and around cataract1156.

In phaco-augmentation embodiments, a standard phacoemulsification handpiece1154may be used to fragment the lens1156with mechanical ultrasound energy, augmented by the cavitation action of the activated microbubbles1152. In particular, the ultrasound energy from phaco handpiece1154can activate microbubbles1152, which can cavitate and help to fragment cataract1156.

By combining the fragmentation power of phacoemulsification and microbubble cavitation, the disclosed system and methods may require far less phacoemulsification energy compared to conventional phacoemulsification. Consequently, the procedure may cause fewer complications.

FIG. 12illustrates directionality of the ultrasound waves1202and precision of the targeted damage to the cataract1204, in accordance with embodiments of the present disclosure. As described above, the disclosed system and methods can improve significantly over conventional phacoemulsification techniques for cataract removal. In particular, the disclosed system and methods can improve safety and efficiency of cataract removal surgery, reduce costs associated with phacoemulsification, and lower training requirements for ophthalmological surgical residents. Whereas phacoemulsification surgical training is currently a key component of the 3-year ophthalmic surgery residency, in some embodiments, the disclosed procedures for cataract fragmentation based on microbubble cavitation could be taught to surgeons in much less time.

As described in the example ofFIG. 1Babove, the complication of capsular bag rupture can happen easily, and is relatively common in phacoemulsification procedures. Accordingly, preventing capsular bag rupture is one of the principal components of the training requirements. By contrast, particularly in internal and external activation embodiments, the disclosed system and methods does not require relatively sharp instruments. As described in the example ofFIG. 10, even the internal microbubble activation instrument1008does not require a sharp tip. Likewise, in external activation embodiments, as in the example ofFIG. 12, the ultrasonic probe1206can be completely external to the eye1208. Accordingly, the risks of capsular bag rupture and/or damage to other structures in the eye, such as the cornea or iris, may be far lower using the disclosed system and methods, than with conventional phacoemulsification. Moreover, microbubbles1210may preferentially damage stiff surfaces, such as cataract1204, while preserving pliable tissue, such as the capsular bag. In this example, cataract1204is fragmented into multiple pieces, while the capsular bag remains intact.

In addition, as described above, the disclosed system and methods are particularly advantageous because less ultrasound and/or mechanical energy may be needed than in conventional phacoemulsification. This is true both because a smaller amount of energy is required to activate the microbubbles to cavitate (rather than directly fragmenting the cataract), and because the microbubbles themselves can more precisely target the cataract than can propagating ultrasound waves, which are subject to dispersion, reflection, etc. Accordingly, the eye is exposed to significantly less waste mechanical energy than in conventional methods, thereby improving efficiency and safety of the fragmentation process.

In particular, there is less danger of burns than in conventional phacoemulsification because less ultrasound energy1202is used, and because the ultrasonic probe1206can be external to eye1210. Moreover, the lower ultrasound dose than in conventional phacoemulsification can also reduce the risk of damage to corneal endothelial cells and other ocular structures and tissues.

In addition, the disclosed system and methods require much smaller incision than conventional phacoemulsification, at least in the internal and external activation embodiments. Such a smaller incision may improve the stability of the disclosed method, as well as enabling a broader choice of artificial lens.

IV. Method for Cataract Removal with Cavitating Microbubbles

FIG. 13is a flowchart illustrating process1300for cataract fragmentation and extraction via microbubble cavitation, in accordance with embodiments of the present disclosure.

Optionally, in operation1360, a capsulorhexis is performed on the anterior lens capsule.

Optionally, in operation1370, the cataractous lens is hydrodissected from the lens capsule. In some embodiments, the microbeads are injected with hydrodissecting liquid (in combination with operation1320below).

In operation1310, gas-filled microbeads are provided. The gas-filled microbeads can have an outside diameter less than 500 microns. In some embodiments, the outside diameter may be less than 250 microns or less than 100 microns. In some embodiments, each of the microbeads is comprised of a phospholipid shell and a fluorinated alkane gas inside the shell. In some embodiments, the fluorinated alkane gas is selected from the group consisting of perfluoropropane and butane. In some embodiments, each of the microbeads is comprised of a multiphase polymer shell and air inside the shell. In some embodiments, the microbeads are coated with a targeting moiety configured to bind to lens material (e.g., lens fiber protein or another lens material). The method may further comprise binding the microbeads to lens material of the cataractous lens. In some embodiments, the targeting moiety comprises polypeptides or acidic groups.

In operation1320, the microbeads are injected into a lens capsule that holds a cataractous lens of a subject. In some embodiments, the microbeads are in a liquid suspension, and the injecting includes injecting the liquid suspension into the lens capsule. In some embodiments, the liquid suspension is hydrodissecting liquid and/or is used to irrigate the lens capsule. In some embodiments, the subject is human. In others, the subject can be an animal, such as a dog, rabbit, or pig.

In operation1330, ultrasound energy is directed at the injected microbeads sufficient to cause the microbeads to undergo cavitation. In some embodiments, the ultrasound energy reaches the microbeads by being transmitted through biological tissue from outside of the lens capsule. In some embodiments, the ultrasound energy is transmitted from within the lens capsule using an ultrasonic tip.

In operation1340, lens material are fragmented in the lens with the cavitation while preserving the posterior lens capsule.

In operation1350, the fragmented lens clumps are aspirated from the lens capsule.

The injection and/or cavitation of microbubbles can be repeated in multiple cycles, as necessary, in order to fragment the lens thoroughly. Optionally, following operation1350, process1300may return to operation1310, and additional cycles of microbubble cavitation may be performed. Such cycles may repeat operations1310through1350, as needed to fragment the cataractous lens. In particular, cycles may include injecting bubbles to a small area inside the lens capsule, applying ultrasound energy, assessing damage to the lens, and optionally vacuuming or removing debris. As described in the examples ofFIGS. 4-6above, each cycle can significantly damage the cataract, leading eventually to complete extraction and removal.

Optionally, following operation1350and/or any additional cycles, in operation1380, an artificial intraocular lens is inserted into the lens capsule.

In some embodiments, the method further comprises inserting a phacoemulsification handpiece tip into the lens capsule. The method may further comprise emulsifying, during or after the fragmenting, the lens clumps using emulsifying ultrasonic energy transmitted from the phacoemulsification handpiece tip within the lens capsule. Less emulsifying ultrasonic energy from the phacoemulsification handpiece tip inside the lens capsule may be required to remove the cataractous lens than if the fragmenting with the cavitation were not performed.

The invention has been described with reference to various specific and illustrative embodiments. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the following claims.