Methods, systems, and compositions for servicing functional drainage bubbles associated with foreign bodies

Abstract

Methods, systems, and compositions for maintaining functional drainage blisters to reduce intraocular pressure (IOP) for treatment with glaucoma. The methods, systems, and compositions are characterized by minimally invasive glaucoma surgery (MIGS) implants or surgery in combination with application of beta rays to bubbles. The beta-rays may act to inhibit or reduce inflammation and / or fibrosis that typically occurs after insertion of the MIGS implant and results in blister failure. By reducing inflammation and / or fibrosis, the MIGS implants and vesicles may maintain appropriate function.

Description

[0001] This application is a divisional application of application number 201880062791.7, filed on September 4, 2018, entitled “Methods, systems, and compositions for maintaining a functional bleb associated with a foreign body”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to UK Patent Application No. 1714392.6 filed on September 7, 2017, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0004] The present invention relates to methods, systems, and compositions for treating a bleb associated with glaucoma treatment, such as a bleb associated with a foreign body, with beta rays to maintain a functional bleb. The present invention also relates to the use of minimally invasive glaucoma surgery (MIGS) implants in the treatment of glaucoma. BACKGROUND

[0005] Glaucoma

[0006] Glaucoma is the leading cause of irreversible blindness and represents a spectrum of diseases with characteristic optic neuropathy (see Figure 1 ). Treatment of this class of diseases is mainly focused on reducing intraocular pressure (IOP) of the intraocular fluid (aqueous humor), thus avoiding continuous damage to the optic nerve. Two-thirds of cases are classified as primary open-angle glaucoma (POAG). POAG develops slowly, usually without any symptoms. Initially, glaucoma affects peripheral or side vision, but it progresses to central vision loss. If left untreated, glaucoma leads to severe irreversible vision loss and blindness in both eyes.

[0007] Glaucoma is treated by attempting to reduce intraocular pressure (IOP). In the United States, Europe, and some other industrialized countries, first-line therapy is usually eye drops. Such drugs include beta blockers, prostaglandins, alpha-adrenergic agonists, and carbonic anhydrase inhibitors. For patients who fail drug therapy and in other parts of the world where the economics and distributional barriers of daily drug therapy and frequent follow-up are problematic, the treatment regimen is mainly surgical intervention.

[0008] The most common surgical method for treating glaucoma is called trabeculectomy (see Figure 2 ). This allows aqueous humor to drain from the eye through a guarded flap door to small reservoirs or channels in the suprachoroidal space, subconjunctival, or in the conjunctiva (called “blebs”) and be absorbed there.

[0009] A recent advance in glaucoma treatment practice is the use of minimally invasive glaucoma surgery (MIGS) implants. Most MIGS implants are ab interno devices, i.e., devices implanted from inside the eye. Most of these devices direct aqueous humor to the Schlemm canal or the supra-bleb space. A subset of MIGS devices is the MIGS shunt type that involves the conjunctiva, which pierces the sclera into a bleb. These implants replace the time-consuming and skill-requiring trabeculectomy by using a flow-controlled device that can be more easily placed to connect the anterior chamber to the subconjunctival bleb space. These MIGS implants have the potential to replace trabeculectomy as the primary surgical treatment for glaucoma. Selective laser trabeculoplasty can be used alone or to augment various treatment methods, such as ab interno microshunts to the Schlemm canal or supra-bleb space.

[0010] Despite the compelling therapeutic advantages over non-surgical therapies, scarring in surgical procedures has clinically limited drainage procedures and devices. For example, one of the major complications of MIGS implants is bleb failure due to scarring or wound reversal, which results in inadequate drainage and thus reduced therapeutic effectiveness of MIGS implants. Attempts to address this problem include the application of anti-metabolites, such as mitomycin C (MMC) and 5-fluorouracil (5FU) (see Figure 5B ). These anti-metabolites are used in liquid form and are delivered to the surgical site under the conjunctiva by injection or by direct delivery to the surgical site under the conjunctiva by a microsurgical sponge soaked in the drug.

[0011] One of the problems associated with anti-metabolites (e.g., MMC and 5FU) is that they do not well preserve the MIGS associated bleb. According to some reports, the failure rate is close to 50% over three to five years. The present invention provides a unique technical feature of using beta rays instead of anti-metabolites in combination with MIGS. Surprisingly, beta rays preserve the bleb better than anti-metabolites and it is not apparent why here.

[0012] Radiation physics

[0013] Radioisotopes, called radionuclides or radioisotopes, are elements that have unstable atomic nuclei and emit radiation as they decay into stable forms. The decay from a radioactive nucleus to a stable nucleus can have several steps. There are four types of radioactive decay: alpha, beta negative, beta positive, and electron capture. The daughter nucleus can emit gamma rays in the de-excitation following the decay process. These emissions are considered ionizing radiation because they are powerful enough to knock an electron out of another atom.

[0014] Therapeutic radionuclides can occur naturally or can be produced artificially, for example, by nuclear reactors or particle accelerators. After natural decay, the daughter isotope is separated from the parent isotope using a radionuclide generator.

[0015] Non-limiting examples of radioisotopes following one of the four decay processes are given here: (1) alpha decay: radium 226, americium 241; (2) beta minus: iridium 192, cesium 137, phosphorus 32 (P-32), strontium 90 (Sr-90), yttrium 90 (Y-90), ruthenium 106, rhodium 106; (3) beta plus: fluorine 18; (4) electron capture: iodine 125, palladium 106. Examples of gamma emission include iridium 192 and cesium 137.

[0016] Half-life is defined as the time required for one-half of the atoms of a radioactive substance to disintegrate. The half-life of various radioisotopes can range from a few microseconds to billions of years.

[0017] The term “activity” in the context of radioactive decay refers to the number of disintegrations per second. The units of measure of activity in a given source are the curie (Ci) and the becquerel (Bq). One (1) becquerel (Bq) is one disintegration per second. The older unit is the curie (Ci), where one (1) Ci is 3.7 x 1010 disintegrations per second. 10 Bq.

[0018] Brachytherapy

[0019] According to the American Association of Physicists in Medicine (AAPM), brachytherapy is “the clinical use of small encapsulated radioactive sources at a short distance from the target volume for irradiation of malignant tumors or non-malignant lesions.” According to the Code of Federal Regulations, a radionuclide brachytherapy source (RBS) is “a device consisting of a radionuclide which can be encapsulated in a sealed container made of gold, titanium, stainless steel, or platinum and used for medical purposes to place in or on the body surface or body cavity as a source of nuclear radiation for therapeutic purposes.” Other forms of brachytherapy sources are also used in practice. For example, a commercially available conformal source is a flexible film made of a polymer chemically bonded to phosphorus-32 (P-32). Another product is TheraSphere®, which is a radiation therapy for hepatocellular carcinoma (HCC) consisting of millions of tiny radioactive glass microspheres (20-30 microns in diameter) containing yttrium-90. Other forms of brachytherapy use X-ray generators instead of radioisotopes as the radiation source.

[0020] In general, in medical practice, brachytherapy can be classified as local or plaque brachytherapy, intracavitary, and interstitial.

[0021] Some implementations of brachytherapy employ permanently implanted RBS. For example, in low-dose rate (LDR) brachytherapy for prostate cancer, as a standard of care, a radioactive iodine 125 RBS is placed directly in the prostate and retained indefinitely.

[0022] In another implementation, high dose rate (HDR) brachytherapy TheraSpheres are infused into the artery feeding a liver tumor. These microspheres then embolize, lodge in the capillaries of the liver, and infiltrate the malignant tumor under high levels of 90Yttrium radiation. In both implementations, the total dose is determined by the consumption of the entire radioisotope.

[0023] Some other implementations of brachytherapy employ transient placement of RBS. For example, in afterloading high dose rate (HDR) brachytherapy, very small plastic catheters are placed into the prostate and a series of radiation treatments are delivered through these catheters. A computer-controlled machine pushes one highly radioactive iridium-192 RBS into the catheter at each of the prescribed locations for a prescribed dwell time. The catheters can then be easily removed and there is no radioactivity on the prostate.

[0024] Another example of transient placement of RBS includes prophylactic treatment of coronary artery restenosis after stent implantation. This is a non-malignant disease that has been successfully treated by placing a catheter into the coronary artery and then inserting a HDR radioactive source into the catheter and holding it there for a prescribed time in order to deliver a sufficient dose to the vessel wall.

[0025] The present invention provides a treatment method featuring the use of beta rays in conjunction with a minimally invasive glaucoma surgery (MIGS) implant (or similar) to effectively maintain a functional drainage bleb (e.g., a bleb associated with a foreign body), to help avoid scarring or wound reversal, to inhibit or reduce fibrosis and / or inflammation of the bleb, etc. As discussed in detail below, beta rays have long been discouraged by experts in the field for use in trabeculectomy-type glaucoma treatment. When used in conjunction with a MIGS implant, it has been found to be surprisingly effective in preventing bleb failure. SUMMARY

[0026] It has been surprisingly found that a particular treatment method and system that combines a minimally invasive glaucoma surgery (MIGS) implant or similar with the application of beta rays can effectively maintain a functional drainage bleb, e.g., by reducing or inhibiting a foreign body that causes scarring or wound repair, by inhibiting or reducing fibrosis and / or inflammation of the bleb, etc. Unlike trabeculectomy (a non-implant surgical technique), MIGS surgery implants a foreign body into the eye, and therefore, it would not be expected that the effect of beta rays on the scarring response would be the same in MIGS implantation and trabeculectomy. Additionally, beta rays have long been discouraged by experts in the field for use in trabeculectomy-type glaucoma treatment. However, when used in conjunction with a MIGS implant, beta rays have been found to be surprisingly effective in preventing bleb failure.

[0027] The effect of beta radiation on the scar formation response to MIGS implant foreign bodies is unpredictable

[0028] There is no evidence that the scarring response caused by trabeculectomy and MIGS implantation are the same. In fact, it is strongly suggested that these responses can be quite different. Therefore, one of ordinary skill in the art would not be able to predict how beta radiation would affect the scarring response caused by MIGS implants.

[0029] Because MIGS implants are foreign bodies implanted into the eye, there is the question of how the biocompatibility of the implant affects the scarring response. As one study comparing different biomaterials for glaucoma drainage devices, “The inflammatory response after implantation of different biomaterials in the subconjunctival space can vary and can contribute to the success or failure of the surgery,” (Ayyala et al., Arch Ophthalmol. 1999; 117:233-236). A study of the biocompatibility of the InnFocus MicroShunt® implant stated, “It is believed that the fibrotic and inflammatory response to the biomaterial is the major determinant of success. Other factors such as shape, flexibility, modulus, and texture can also be related to erosion, extrusion, inflammation, and scarring.” (Acosta et al., Arch Opthalmol. 2006; 124; 1742-1749).

[0030] Another example of a documented question about the foreign body response state is, “[Glaucoma filtration surgery] often fails due to scarring. Various conjunctival implants have been developed to minimize scarring but can lead to foreign body response and capsule formation, resulting in reduced efficacy and poor pharmacokinetics,” (Khaw et al., 2015, ARVO Poster Abstract). Because the industry expects the scarring response to be different for trabeculectomy (no implant of a foreign body) and MIGS (implantation of a foreign body), it is not possible to predict how beta radiation would affect the scarring of MIGS device implantation.

[0031] Beta radiation is no longer used for glaucoma treatment

[0032] 1. The industry expects mitomycin C (MMC) to be more effective than beta radiation:

[0033] To the surprise of those of ordinary skill in the art, beta rays will be selected in place of liquid antimetabolites, because the prior art teaches that beta rays are less effective antimetabolites than mitomycin C (MMC) and are only similar in effectiveness to 5-fluorouracil (5FU). In short, beta rays are reported as antimetabolites for glaucoma drainage surgery, with radiation roughly equivalent to 5FU, while MMC is reported as superior to 5FU for the same use. Thus, MMC is considered more effective than beta rays as an antimetabolite for glaucoma drainage surgery. More specifically, a 2016 study involving trabeculectomy type glaucoma surgery (Dhalla et al., 2016, PLoS ONE 11(9): e0161674) concluded that: “First, there was no evidence to suggest that there was a difference in the use of 5FU and beta rays as antimetabolites in trabeculectomy.” Further, Cabourne et al. in a 2015 Cochrane review (Cabourne et al., 2015, Cochrane Database of Systematic Reviews, Issue 11. Art. No.: CD006259) comparing MMC and 5FU for wound healing in trabeculectomy type glaucoma surgery concluded that: “Our review suggests that the risk of failure of trabeculectomy is lower in patients treated with MMC compared with 5-FU, with a lower mortality rate at one year after surgery.” Thus, because beta rays are similar in therapeutic effect to 5FU in trabeculectomy, and 5FU is less effective than MMC, The literature therefore considers MMC more effective than beta radiation treatment Intraoperative mitomycin C is more effective than beta radiation, .

[0034] Further, a direct comparison study of mitomycin C (MMC) and beta rays in pterygium surgery showed that, The largest possible area The Moorfields) Safe Surgery System is considered the standard of care. MMC is more effective than beta rays as an adjunct to pterygium surgery using conjunctival flap sliding flaps Surprisingly, a treatment method is used that has been associated with topical application for a long time, rather than an easily dispersible liquid. ” (Amano et al., 2000, British Journal of Ophthalmology 84:618-621). Thus, the prior art teaches against the use of beta rays and instead teaches that MMC is the more effective antimetabolite.

[0035] 2. Industry expects mitomycin C (MMC) to provide more comprehensive penetration than beta rays:

[0036] Second, it is surprising to use beta rays instead of liquid antimetabolites, as the prior art teaches that liquid antimetabolites are more suitable for dispersion in a broad treatment area. The Moorfields Safety Surgery System developed by Sir. Peng Khaw (Khaw et al., 2005, Glaucoma Today, March / April, 22-29) emphasizes the importance of this broad treatment area. The publication introducing the system states that the local treatment with MMC previously resulted in "thin cystic blebs." One of the key components of the improved system is the use of MMC to treat "a "wide area of the limbal surface" The risk of postoperative cataract is increased in people who receive beta radiation. ". It is critical that the publication states: "In the clinic, enlarging the surface area of [MMC] treatment results in a more diffuse non-cystic area. It also prevents the formation of a steel ring that would otherwise restrict the flow of aqueous and promote the formation of a raised, cystic, avascular bleb."

[0037] In sharp contrast to the free-flowing and widely dispersed liquid antimetabolites, beta rays have traditionally been of great interest for ophthalmic applications. Since the reusable dose requires the applicator to be fixed in place for a specified period of time, the treatment area is set by the size of the applicator head. The typical diameter of an ophthalmic applicator head is only around 10-14 mm, and only a portion of the head has an effective diameter (reported to be between 4.3 and 8.9 mm) (Soares, 1995, Med. Phys. 22(9), September, 1487-93). Even within the effective diameter, the dose strength drops rapidly with increasing distance from the center of the dose.

[0038] In addition, beta rays do not penetrate tissue effectively and are limited to treating superficial areas close to the center of the applicator. This is because the dose strength drops rapidly with increasing distance from the applicator. For example: "[beta rays] are applied during surgery using radioactive applicators that emit beta rays that penetrate less than a millimeter in depth locally," (Kirwan et al., 2012, Cochrane Database of Systematic Reviews Art. No.: CD003433).

[0039] Testing of the ophthalmic applicators by Soares et al. showed irregular dose patterns and large differences even between the same model of applicator. Many of the applicators did not even have the active portion aligned with the center of the applicator. Furthermore, for safety reasons, the treatment area of the ophthalmic applicators used for pterygium treatment was narrowed by the installation of a Castroviejo shaping mask. The purpose of these masks is to provide a narrow local application, as taught by the Moorfields Safety Surgery System. The Moorfields Safety Surgery System The literature has clearly stated that the medical community teaches to avoid the use of beta radiation for the treatment of glaucoma.

[0040] Thus, while antimetabolites such as MMC are liquid solutions that can flow freely and be dispersed over large areas, beta radiation therapy is more limited. The current teaching is that extensive dispersion is important to create healthy diffuse blebs. Beta radiation does not have the ability to fluidly disperse in tissue in the same way as MMC. This limitation would prevent one of ordinary skill in the art from conceiving that beta radiation could effectively treat large areas that are currently treated by penetration of liquid antimetabolites. Thus, the prior art teaches against the use of beta radiation and instead teaches that liquid antimetabolites provide more universal and desirable treatment. Figure 3 Figure 5A

[0041] 3. Industry concern that beta radiation is associated with cataracts:

[0042] Third, surprisingly, beta radiation is used in place of liquid antimetabolites because of the long history of reported associations between beta radiation and cataracts. Because leading ophthalmologists generally believe that beta radiation causes cataracts, beta radiation is avoided in glaucoma treatment. For example, a 2012 Cochrane Review (Kirwan et al. 2012, Cochrane Database of Systematic Reviews Art. No.: CD003433) of 4 randomized trials of 551 patients concluded that: Figure 1 Figure 2 As another example, Merriam et al. concluded that the minimum cataractogenic dose for a single treatment was 200 cGy for the lens epithelium and that for a 750 cGy dose, cataracts were nearly uniform in likelihood (see Merriam GR, 1965, Trans Am Ophthalmol Soc. 54:611-653, summarized by Kirwan et al. Eye (2003) 17, 207-215. doi: 10.1038 / sj.eye.6700306). Figure 3 Figure 4

[0043] In the same 2003 review of beta rays, Kirwan also describes some negative reports about the use of beta rays in ophthalmology. The review emphasizes that "the adverse effects of beta rays on pterygia have been widely reported. Earlier reports focused on lens opacities, conjunctival telangiectasia and other side effects at doses much higher than the clinical dose used after pterygium surgery," and that "the use of beta rays for the treatment of pterygia has decreased and conjunctival autografts and topical mitomycin C are now widely used." In addition to the adverse effects noted by others, Kirwan later reported adverse effects in his own study of the use of beta rays to treat patients after trabeculectomy.

[0044] Kirwan published a robust, controlled, and randomized study in 2006 on the effects of beta rays on the success of trabeculectomy for glaucoma surgery. Notably, the study showed that "the risk of cataract surgery in the beta ray arm increased (a known complication of trabeculectomy) within two years of surgery." Two years after the end of the study, the risk of cataract requiring removal was 16.7% in the ray group and only 3.2% in the placebo group. Kirwan noted that "if beta rays increase the need for further surgery, then the advantage of trabeculectomy monotherapy is greatly diminished."

[0045] The previously recognized risks and the subsequent observed incidence of cataracts after the application of beta rays are strong deterrents against the use of beta rays in the treatment of glaucoma. Randomized controlled clinical trial results show a significant increase in the incidence of cataracts associated with beta therapy; and Kirwan, several of the authors, call for "urgent research... combined surgery (trabeculectomy with beta rays plus cataract extraction").

[0046] Ethical participation in research requires a commitment to universal ethical norms, such as those expressed in the Declaration of Helsinki and the Belmont Report. The World Health Organization (Research Ethics Committees: Basic Concepts for Capacity-Building. World Health Organization, 2009) states that research ethics committees review proposed research with human participants to ensure that they meet internationally and locally recognized ethical guidelines. International ethical standards for researchers participating in research and the law of many jurisdictions require review by a research ethics committee. Depending on its role in determining and assessing the risks and benefits of research, a research ethics committee must include persons with scientific and medical expertise. In research involving medical interventions, a research ethics committee must determine that adequate care and treatment will be provided to participants.

[0047] “Research funded by the Government of the United States of America (USA), regardless of where the research is conducted, must comply with the “Common Rule” (45 CFR 46), which defines and regulates the scope and review of federally funded research involving human subjects” (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3491753 / 0). The International Coordinating Council (ICH) defines an Institutional Review Board (IRB) as “a formally designated group that assumes responsibility for protecting the rights, safety, and welfare of people who participate in clinical trials by reviewing the trial’s various aspects and approving its initiation. An IRB can also be called an Independent Ethics Committee (IEC). An IRB / IEC reviews the appropriateness of a clinical trial protocol and the risks and benefits to study participants. IRB / IEC members should have collective qualifications to review the scientific, medical, and ethical aspects of a trial. An IRB / IEC should have at least five members…qualified to review and evaluate the scientific, medical, and ethical aspects of the proposed trial.” (http: / / www.ppdi.com / Participate-In-Clinical-Trials / Become-an-Investigator / Institutional-Review-Board). US 21 CFR Part 56 (22)(c) states that “An Institutional Review Board (IRB) means any board, committee, or group formally designated by an institution to review, approve, and periodically review, research involving human subjects conducted by or under the auspices of the institution. The primary purpose of such review is to ensure the protection of the rights and welfare of the human subjects involved in research.” Whether international or US, US 21 CFR Part 56 Sec. 56.107 requires that “Each IRB must have at least five members…with the appropriate background qualifications to review specific types of research activities and must be able to ascertain the acceptability of proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice.” Despite criticism in Grimes v. Kennedy Krieger Institute, Inc. in the Maryland State Court, the Nuremberg Code is considered “the most complete and authoritative statement of informed consent for human experimentation,” (emphasis added). The court then quotes several authors to support the view that the Nuremberg Code should be incorporated into American common law to establish a clear set of duties for the protection of human subjects in experiments, ” (https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC1069025).

[0048] Following the Kirwan study finding increased cataracts in the beta therapy patient group, Dhalla investigated a treatment regimen of phacoemulsification combined with beta therapy. In a human clinical study conducted by Dhalla, the patient's natural lens was surgically removed while beta dosing was performed. The authors of the study concluded that "surgical intervention is not usually required even in patients who develop cataracts if these do not cause significant disability." In other words, cataract surgery would not normally be offered to these patients because local standards of care do not warrant surgical intervention. Dhalla's beta therapy regimen included other surgical interventions to remove the patient's natural lens because the Kirwan study found that the use of beta rays alone increased the incidence of cataracts.

[0049] The decision of the human research independent ethics committee in approving Dhalla's experimental human study provided direct authoritative teaching that beta therapy is no longer used as a stand-alone adjunct to glaucoma filtration surgery.

[0050] Note that the results of Dhalla's experimental human study were negative. "The sample size calculation was based on detecting an advantage of beta radiation over 5FU [5-fluorouracil], which is the standard treatment... We detected no significant difference between 5-fluorouracil and beta radiation." The disappointing study results of Dhalla's study informed the medical community that beta is not superior to the antimetabolite 5FU.

[0051] The industry's expectation that antimetabolites such as 5FU and MMC are more effective than beta rays, coupled with the provision of more comprehensive penetration of 5FU and MMC than beta rays and concerns about beta rays' association with cataracts, strongly teach against the use of beta rays. Thus, the use of beta rays with MIGS implants to maintain a functional bleb for the treatment of glaucoma would be surprising to one of ordinary skill in the art.

[0052] SUMMARY OF EMBODIMENTS

[0053] As used herein, the term "beta radiation source" or "source of beta radiation" can refer to the term "radioisotope." In any method or composition herein, the radioisotope or beta radiation source can include strontium 90 (Sr-90), phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90), or combinations thereof.

[0054] The present invention features a beta-emitting radioisotope, a pharmaceutical composition comprising a beta-emitting source, a radioactive composition comprising a beta-emitting source, a beta-emitting radioactive composition, and a beta-emitting radioactive source, which can be used in a method of treating glaucoma. The present invention features a beta-emitting radioisotope, a pharmaceutical composition comprising a beta-emitting source, a radioactive composition comprising a beta-emitting source, a beta-emitting radioactive composition, and a beta-emitting radioactive source, which can be used in a method of reducing or preventing scarring in a drainage bleb of a human eye treated for glaucoma with a minimally invasive glaucoma surgery (MIGS) implant.

[0055] The present invention also features a beta-emitting radioisotope, a pharmaceutical composition comprising a beta-emitting source, a radioactive composition comprising a beta-emitting source, a beta-emitting radioactive composition, and a beta-emitting radioactive source, which can be used in a method of reducing or preventing scarring in a drainage bleb associated with a foreign body in a human eye.

[0056] In some embodiments, the method includes implanting a minimally invasive glaucoma surgery (MIGS) implant into an eye of a patient being treated for glaucoma. The implant is implanted through the sclera, forming a bleb in the subconjunctival space or between the conjunctiva and Tenon's capsule. The method further includes applying beta radiation from a radioisotope or beta-emitting source (or radioactive composition, pharmaceutical composition, etc.) to a target region of the eye, where the target region is at least a portion of the bleb. The methods herein can be effective to maintain a functional drainage bleb.

[0057] The present invention also features a radioisotope that emits beta radiation for use in preventing or reducing scarring in a drainage bleb of a human eye that is being treated or has been treated for glaucoma with a minimally invasive glaucoma surgery (MIGS) implant. The radioisotope is characterized in that the radioisotope is applied to the eye such that beta radiation from the radioisotope is applied to a target region of the eye, where the target region is at least a portion of the bleb. The present invention also features a radioisotope that emits beta radiation for use in preventing or reducing scarring in a drainage bleb associated with a foreign body, where the radioisotope is characterized in that the radioisotope is applied to the eye such that beta radiation from the radioisotope is applied to a target region of the eye, where the target region is at least a portion of the bleb.

[0058] The present invention also features a composition comprising a beta-emitting source for use in a method of preventing or reducing scarring in a drainage bleb of a human eye that is being treated or has been treated for glaucoma with a minimally invasive glaucoma surgery (MIGS) implant. The composition is characterized in that the composition is applied to the eye such that beta radiation from the beta-emitting source is applied to a target region of the eye, where the target region is at least a portion of the bleb.

[0059] The present application also features a composition comprising a source of beta rays for use in a method of treating glaucoma in an eye, wherein a minimally invasive glaucoma surgery (MIGS) implant is implanted through the sclera to form a bleb in the subconjunctival space or between the conjunctiva and Tenon's capsule. The composition features applying the composition to the eye such that beta rays from the source of beta rays are applied to a target region of the eye, wherein the target region is at least a portion of the bleb.

[0060] The present application also features a radioactive composition comprising a source of beta rays for use in a method of treating glaucoma. In some embodiments, the method includes implanting a minimally invasive glaucoma surgery (MIGS) implant into an eye of a patient undergoing treatment for glaucoma, wherein the implant is implanted through the sclera to form a bleb in the subconjunctival space or between the conjunctiva and Tenon's capsule; and applying beta rays from the source of beta rays to a target region of the eye, wherein the target region is at least a portion of the bleb. The methods herein can be effective to maintain a functional drainage bleb. The radioactive composition (e.g., beta rays) is depleted during treatment.

[0061] The present application also features a radioactive composition comprising a source of beta rays for use in a method of preventing or reducing scarring in a drainage bleb associated with a foreign body in a human eye. In some embodiments, the method includes implanting a foreign body into an eye of a patient, wherein the foreign body forms a bleb (e.g., a bleb in the subconjunctival space or between the conjunctiva and Tenon's capsule); and applying beta rays from the source of beta rays to a target region of the eye, wherein the target region is at least a portion of the bleb. The methods herein can be effective to maintain a functional drainage bleb. The radioactive composition (e.g., beta rays) is depleted during treatment.

[0062] With reference to the methods and compositions herein, in some embodiments, the implant is for insertion between the anterior chamber of the eye and the subconjunctival space of the eye or between the anterior chamber of the eye and the space between the conjunctiva and Tenon's capsule.

[0063] With reference to the methods and compositions herein, in some embodiments, the beta ray source or radioisotope provides a dose of beta rays to a target as follows: wherein the dose at any point on the target is within 10% of the dose at any other point on the target. In some embodiments, the radioisotope or beta ray source has a diameter of 4 to 15 mm.

[0064] In some embodiments, the MIGS implant is a flow-controlled drainage device. In some embodiments, the MIGS implant is an implant that creates a bleb in the eye.

[0065] In some embodiments, the radioisotope or beta ray source is attached to an applicator (e.g., see Figure 5A , seeFigure 5B The radioactive isotope or beta ray source can be removably connected to the applicator. The radioactive isotope or beta ray source can be fixedly connected to the applicator. In some embodiments, the applicator includes a handle and a distal portion and a cavity or connection site for the beta ray source or radioactive isotope. In some embodiments, the applicator further includes a removable cap for temporarily shielding the beta ray source or radioactive isotope. The cap can be disposable. In some embodiments, the cap is reusable.

[0066] With reference to the methods and compositions herein, in some embodiments, the target is the entire bleb. In some embodiments, the portion of the bleb that is targeted is the perimeter of the bleb. In some embodiments, the portion of the bleb that is targeted is the perimeter of the bleb and the portion of the bleb between the center and the perimeter. In some embodiments, the target area surrounds the end of the MIGS implant.

[0067] The present invention features a method of inhibiting or reducing fibrogenesis and inflammation in a bleb of an eye receiving glaucoma treatment. The present invention features a method of maintaining a functional drainage bleb in an eye of a patient receiving glaucoma treatment. The present invention features a method of enhancing the function of a MIGS implant. The present invention features a method of treating glaucoma. The present invention features a method of reducing intraocular pressure (IOP) in an eye.

[0068] The present invention features a method of inhibiting or reducing fibrogenesis and inflammation in a bleb associated with a foreign body in an eye.

[0069] With reference to the methods described above, in some embodiments, the method includes applying a radioactive isotope that emits beta rays to a target of the eye, wherein the target is at least a portion of a bleb formed by a MIGS implant in a subconjunctival space or a space between the conjunctiva and Tenon's capsule of the eye. In some embodiments, the method includes applying a beta ray source to a target of the eye, wherein the target is at least a portion of a bleb formed by a MIGS implant in a subconjunctival space or a space between the conjunctiva and Tenon's capsule of the eye. In some embodiments, the method includes implanting a MIGS implant into the eye, wherein the implant is inserted through the sclera and forms a bleb in a subconjunctival space or a space between the conjunctiva and Tenon's capsule of the eye; and applying a radioactive isotope that emits beta rays to a target of the eye, wherein the target is at least a portion of the bleb. In some embodiments, the method includes implanting a MIGS implant into the eye, wherein the implant is inserted through the sclera and forms a bleb in a subconjunctival space or a space between the conjunctiva and Tenon's capsule of the eye; and applying a beta ray source to a target of the eye, wherein the target is at least a portion of the bleb.

[0070] Referring to the above methods, in some embodiments, the beta rays cause cell cycle arrest in fibroblasts on the Tenon's capsule to inhibit or reduce the fibrotic process and inflammation that causes the bleb to fail. In some embodiments, the beta rays reduce or inhibit the fibrotic process and inflammation that causes the bleb to fail. In some embodiments, the method is effective to maintain the drainage function of the bleb. In some embodiments, the beta rays are effective to maintain the function of the bleb to allow the MIGS implant to drain aqueous humor from the anterior chamber of the eye. In some embodiments, the method is effective to reduce intraocular pressure (IOP).

[0071] The present application features a method of treating glaucoma, wherein a MIGS implant is inserted through the sclera and forms a bleb in the subconjunctival space or in the space between the conjunctiva and Tenon's capsule of the eye. The present application features a method of reducing intraocular pressure (IOP), wherein a MIGS implant is inserted through the sclera and forms a bleb in the subconjunctival space or in the space between the conjunctiva and Tenon's capsule of the eye. The present application features a method of inhibiting or reducing fibrosis and inflammation in a bleb of an eye receiving treatment for glaucoma, wherein a MIGS implant is inserted through the sclera and causes a bleb to form in the subconjunctival space or in the space between the conjunctiva and Tenon's capsule of the eye. The present application features a method of maintaining a functional drainage bleb in an eye of a patient receiving treatment for glaucoma, wherein a MIGS implant is inserted through the sclera and forms a bleb in the subconjunctival space or in the space between the conjunctiva and Tenon's capsule of the eye. The present application features a method of enhancing the function of a MIGS implant, wherein a MIGS implant is inserted through the sclera and forms a bleb in the subconjunctival space or in the space between the conjunctiva and Tenon's capsule of the eye.

[0072] Referring to the above methods, in some embodiments, the method comprises applying a beta ray-emitting radioisotope to a target region of the eye, wherein the target region is at least a portion of the bleb. In some embodiments, the method comprises applying a beta ray source to a target region of the eye, wherein the target region is at least a portion of the bleb.

[0073] Referring to the above methods, in some embodiments, the beta rays cause cell cycle arrest in fibroblasts on the Tenon's capsule to inhibit or reduce the fibrotic process and inflammation that causes the bleb to fail. In some embodiments, the beta rays reduce or inhibit the fibrotic process and inflammation that causes the bleb to fail. In some embodiments, the method is effective to maintain the drainage function of the bleb. In some embodiments, the beta rays are effective to maintain the function of the bleb to allow the MIGS implant to drain aqueous humor from the anterior chamber of the eye. In some embodiments, the method is effective to reduce intraocular pressure (IOP).

[0074] The present invention is also characterized by a method of reducing inflammation in an eye having a foreign body therein, the foreign body being a minimally invasive glaucoma surgery (MIGS) implant inserted between the anterior chamber of the eye and the sub-tenon space of the eye or inserted between the anterior chamber of the eye and the space between the conjunctiva and Tenon's capsule of the eye, wherein the implant causes a bleb to form for draining aqueous humor. In some embodiments, the method comprises applying beta rays to a target region of the eye (e.g., applying a beta ray source, applying a beta ray emitting radioisotope), wherein the target region is at least a portion of the bleb; wherein the beta rays are effective to reduce inflammation caused by the presence of the foreign body.

[0075] The present invention is also characterized by a method for making an applicator for emitting beta rays. In some embodiments, the method comprises inserting a beta ray emitting radioisotope (or beta ray source, etc.) into a cavity of an applicator, wherein the applicator comprises a handle and a distal portion having a cavity, wherein the radioisotope (or beta ray source, etc.) is configured to provide a radiation dose to a target, wherein the dose at any point on the target is within 10% of the dose at any other point on the target.

[0076] With reference to the foregoing method, in some embodiments, the dose of beta rays delivered to the target is as follows: wherein the dose at any point on the target is within 10% of the dose at any other point on the target. In some embodiments, the source of beta rays, beta ray emitting radioisotope, or beta ray source comprises strontium 90 (Sr-90), phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90), or a combination thereof. In some embodiments, the beta rays are from a beta ray source or radioisotope, wherein the beta ray source or radioisotope has a diameter of 4 to 15 mm. In some embodiments, the MIGS implant is a flow controlled drainage device. In some embodiments, the MIGS implant is a bleb creating implant in the eye. In some embodiments, the beta rays are from a beta ray source or radioisotope and the beta rays are applied to the target using an applicator. In some embodiments, the beta ray source or radioisotope is removably connected to the applicator. In some embodiments, the beta ray source or radioisotope is fixedly connected to the applicator. In some embodiments, the applicator comprises a handle and a distal portion and a cavity or connection site for the beta ray source or radioisotope. In some embodiments, the applicator further comprises a removable cap for temporarily shielding the beta ray source or radioisotope. In some embodiments, the cap is disposable. In some embodiments, the target is the entire bleb. In some embodiments, the portion of the bleb that is the target is the perimeter of the bleb. In some embodiments, the portion of the bleb that is the target is the perimeter of the bleb and the portion of the bleb between the center and the perimeter.

[0077] The present invention features a kit for preventing or reducing scarring in a drainage bleb of an eye of a human being undergoing treatment for glaucoma. The present invention features a kit for inhibiting or reducing fibrogenesis or inflammation in a bleb of an eye undergoing treatment for glaucoma. In some embodiments, the kit includes a source of beta rays (or a radioisotope that emits beta rays) for irradiating a target region of the eye, where the target region is at least a portion of the bleb; and an implant for transscleral insertion, where the implant forms the bleb in a subconjunctival space of the eye or in a space between the conjunctiva and Tenon's capsule.

[0078] The present invention features a system for preventing or reducing scarring in a drainage bleb of an eye of a human being undergoing treatment for glaucoma. The present invention features a system for inhibiting or reducing fibrogenesis or inflammation in a bleb of an eye undergoing treatment for glaucoma. In some embodiments, the system includes a source of beta rays (or a radioisotope that emits beta rays) for irradiating a target region of the eye, where the target region is at least a portion of the bleb; and an implant for transscleral insertion, where the implant forms the bleb in a subconjunctival space of the eye or in a space between the conjunctiva and Tenon's capsule.

[0079] Referring to the kits and systems above, in some embodiments, the implant is for insertion between the anterior chamber of the eye and the sub-tenon space of the eye or between the anterior chamber of the eye and the space between the conjunctiva and Tenon's capsule of the eye. In some embodiments, the beta ray source or radioisotope provides a dose of beta rays to the target as follows: where the dose at any point on the target is within 10% of the dose at any other point on the target. In some embodiments, the beta ray source (beta ray source) or radioisotope that emits beta rays comprises strontium 90 (Sr-90), phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90), or a combination thereof. In some embodiments, the beta ray source or radioisotope has a diameter of 4 to 15 mm. In some embodiments, the implant is a minimally invasive glaucoma surgery (MIGS) implant. In some embodiments, the MIGS implant is a flow controlled drainage device. In some embodiments, the MIGS implant is an implant that creates a bleb in the eye. In some embodiments, the kit or system further comprises an applicator for applying the beta ray source or radioisotope to a target area of the eye. In some embodiments, the beta ray source or radioisotope is removably connected to the applicator. In some embodiments, the beta ray source or radioisotope is fixedly connected to the applicator. In some embodiments, the applicator comprises a handle and a distal portion and a cavity or connection site for the beta ray source or radioisotope. In some embodiments, the applicator further comprises a removable cap for temporarily shielding the beta ray source or radioisotope. In some embodiments, the cap is disposable. In some embodiments, the target is the entire bleb. In some embodiments, the portion of the bleb that is the target is the perimeter of the bleb. In some embodiments, the portion of the bleb that is the target is the perimeter of the bleb and the portion of the bleb between the center and the perimeter.

[0080] The present invention also features a beta ray emitting radioisotope (or source of beta rays) for use in a method of destroying scar tissue in a patient's eye. The present invention also features a method of destroying scar tissue in a patient's eye. The present invention also features a method of removing a cystic structure. The present invention also features a needling method. Referring to the compositions and methods herein, in some embodiments, the eye has a foreign body in it, e.g., a MIGS implant, and the scar tissue is a result of the presence of the foreign body. In some embodiments, the scar tissue is a result of a trabeculectomy. In some embodiments, the scar tissue is a result of an eye injury. In some embodiments, the method comprises needling the scar tissue and applying beta rays from a beta ray emitting radioisotope (or source of beta rays) to the scar tissue. The method can be effective to prevent further accumulation of the scar tissue. The beta rays can be applied before or after needling. In some embodiments, the method further comprises applying an antimetabolite to the scar tissue.

[0081] The present invention features a beta-emitting radioisotope (or beta-emitting source) for use in a method of altering the wound healing process in the eye, such as reducing or inhibiting inflammation, reducing or inhibiting the accumulation of scar tissue. The present invention features a method of altering the wound healing process in the eye. In some embodiments, the method includes applying beta radiation from a beta-emitting radioisotope (or beta-emitting source) to a target area of the eye, where the target area is a wound. In some embodiments, the method includes applying beta radiation from a beta-emitting radioisotope (or beta-emitting source) to a target area of the eye, where the target area is scar tissue. The method can be effective to alter cellular signaling processes that regulate wound healing, thereby reducing inflammation and reducing the accumulation of scar tissue. The method can be effective to prevent further accumulation of scar tissue.

[0082] With respect to the above methods and compositions, in some embodiments, the method further includes administering a drug to the eye. By way of non-limiting example, the method can further include administering a drug eye drop or a liquid antimetabolite. In various embodiments, the drug can be administered prior to, during, or after a surgical implantation procedure.

[0083] Any feature or combination of features described herein are included within the scope of the present invention, provided that the features included in any such combination are not mutually inconsistent, as will be apparent to one of ordinary skill in the art. Other advantages and aspects of the present invention will become apparent from the following detailed description and claims. BRIEF DESCRIPTION OF DRAWINGS

[0084] The features and advantages of the present invention will become apparent from the detailed description of the invention in conjunction with the accompanying drawings, of which:

[0085] Figure 6 A diagram of an eye with glaucoma is shown.

[0086] Figure 7 A diagram of a full trabeculectomy is shown featuring a partial thickness scleral flap, a small hole in the sclera, and a partial iridectomy.

[0087] Figure 8 A diagram of a Sr-90 ophthalmic beta applicator with a plexiglass cover is shown.

[0088] Figure 9A A diagram of the radioactive decay of strontium 90 and the resulting beta radiation is shown.

[0089] Figure 9B A diagram showing the positioning of a beta radiation applicator on an eye is shown.

[0090] Figure 9CA diagram showing the positioning of a sponge soaked with MMC on an eye is shown.

[0091] Figure 9D A diagram showing the InnFocus MicroShunt® MIGS implant and its position within an eye is shown.

[0092] Figure 10 A diagram showing the EX-PRESS® MIGS implant within an eye is shown.

[0093] Figure 11 A diagram showing the EX-PRESS® MIGS implant is shown.

[0094] Figure 12 A diagram showing the first step in the process of implanting a XEN MIGS implant within an eye is shown.

[0095] Figure 13 A diagram showing the second step in the process of implanting a XEN MIGS implant within an eye is shown.

[0096] Figure 12 A diagram showing the third step in the process of implanting a XEN MIGS implant within an eye is shown.

[0097] Figure 14 A diagram showing the final step in the process of implanting a XEN MIGS implant within an eye is shown.

[0098] Figure 15 A diagram showing the planned treatment volume of a bubble, where the therapeutic dose is applied across the entire width and depth of the target is shown.

[0099] Figure 16 A series of isodose curves and penetration depth of radiation in tissue for a Sr-90 beta applicator is shown.

[0100] Figure 17 A diagram showing an example of a prior art applicator that only treats the central portion of the target, leaving the peripheral regions underdosed and / or the center overdosed is shown.

[0101] Figure 7 A diagram showing an example of optimized dose delivery used in the present invention, where the dose applied across the target is more uniform compared to Figure 8 the one shown. Iterative computer simulations of the output dosimetry can provide information for the optimized design of the device.

[0102] Figure 6 A diagram showing the development of radiobiological damage is shown.

[0103] Figure 4A schematic showing the induction of cell cycle arrest after irradiation. Hydroxyl radicals are the most important water radicals induced by ionizing radiation (represented by the sine arrow and trilobal symbol) that affect the integrity of DNA (parallel lines) by inducing double-strand breaks (DSB, notched DNA). Subsequently, the ATM (ataxia-telangiectasia mutated) kinase is activated by phosphorylation (encircled P), which in turn phosphorylates p53. ATR (ataxia-telangiectasia and Rad3-related) is activated by single-stranded DNA and stalled replication forks generated during repair processes. The activated p53 acts as a transcription factor and causes the expression of the cyclin-dependent kinase (CDK) inhibitor p21, which induces G1 and G2 phase cell cycle arrest. On the other hand, the activation of CHK1 and CHK2 (checkpoint kinase-1 and -2) leads to the phosphorylation of three CDC25 (cell division cycle 25) isoforms, resulting in their degradation. As a result, CDC25 no longer activates CDK2 or CDK1 (cyclin-dependent kinase), and thus, the cell cycle stops in the G1 or G2 phase, respectively. Arrows indicate activation; black-headed lines symbolize inhibition. See Maier, 2016, Int. J. Mol. Sci. 17, 102; doi:10.3390 / ijms17010102

[0104] Figure 10 A schematic showing how radiation works in two ways: (1) it directly induces ionization and causes damage on the cell molecules; (2) it can work indirectly by generating free radicals, which are derived from the ionization or excitation of water in the cell.

[0105] Figure 11 A schematic showing the radiolysis of water in a cell. DETAILED DESCRIPTION

[0106] The present invention provides methods and systems for maintaining a functional drainage bubble, wherein the methods and systems are characterized by a microinvasive glaucoma surgery (MIGS) implant and the application of beta radiation to the drainage bubble.

[0107] One of the unique and inventive technical features of the present invention is the use of a glaucoma treatment method that combines a MIGS implant and beta radiation. Without wishing to limit the present invention to any theory or mechanism, it is believed that the technical features of the present invention advantageously provide for a reduction in IOP and the formation of a healthy bubble. None of the currently known prior references or work have the unique inventive technical features of the present invention.

[0108] As used herein, the term "functional drainage bubble" refers to a bubble that effectively drains aqueous humor from the eye to reduce the IOP of the eye to an appropriate level. For example, a functional drainage bubble can be associated with a normal IOP.

[0109] Early bleb grading systems included those proposed by Kronfeld (1969), Migdal and Hitchings (1983), and Picht and Grehn (1998). Subsequent bleb grading systems determined and incorporated grading assessments of various bleb parameters, including vascularity, height, width, cystoid changes, encapsulation, and diffuse / labeling area.

[0110] Two grading systems for clinical grading of surgical filtration blebs have recently been described: the Moorfields Bleb Grading System (MBGS) and the Indiana Bleb Appearance Grading Scale (IBAGS). The MBGS was built on the system used for the Moorfields Bleb Assessment Group study and extended it to include assessment of vascularity away from the bleb center and a method to represent mixed morphology blebs. In this scheme, the central area (1-5), maximum area (1-5), bleb height (1-4), and subconjunctival blood (0-1) were assessed. Additionally, the grade of blood vessels was graded separately for three areas of the bleb, including the central, peripheral, and non-bleb conjunctiva. Blood vessel scores for each area were scored from 1 to 5. One study found that the IBAGS and MBGS had good inter-observer agreement and clinical reproducibility (Wells AP, Ashraff NN, Hall RC, et al. Comparison of two clinical bleb grading systems. Ophthalmology 2006; 113: 77-83.)

[0111] The Moorfields Bleb Grading System was developed because of the recognition of the importance of bleb appearance on outcome. Blebs that form a thin avascular zone have an increased risk of leaking, developing delayed hypotony, and bleb-related infection associated with visual loss.

[0112] The Indiana Bleb Appearance Grading Scale is a system for classifying the morphologic slit lamp appearance of filtration blebs. The Indiana Bleb Appearance Grading Scale contains a set of photographic criteria that illustrate a range of filtration bleb morphologies selected from the Indiana University Ophthalmology Glaucoma Service slide library. These criteria include slit lamp images for grading bleb height, degree, vascularity, and leakage by Seidel testing. To grade, the morphology of the filtration bleb is assessed for the 4 parameters relative to the standard images and scored accordingly.

[0113] For reference, a failed or failing bleb can have "restricted backflow, with a so-called'steel ring', e.g., a ring of scar tissue or fibrosis that adheres the conjunctiva to the sclera at the periphery of the bleb (see Dhingra S, Khaw PT. The Moorfields Safer Surgery System. Middle East African Journal of Ophthalmology. 2009; 16(3): 112-115). Other attributes of a failed or failing bleb can include cystic appearance and / or vascularization and / or changes in scar tissue and / or thinning of the conjunctiva overlying the bleb and / or a taut bleb and / or other observable or measurable changes that can be included in the Indiana bleb appearance grading scale or the Moorfields bleb grading system. Other functional determinants of a failed or failing bleb or glaucoma surgery can include an increase in IOP or that IOP has not been sufficiently reduced.

[0114] As used herein, the term "drainage device" refers to any method or combination of methods in general and specific methods of draining aqueous humor, such as the therapeutic agents and devices herein for reducing intraocular pressure through surgical and device intervention, including minimally invasive glaucoma surgery (MIGS) devices and procedures.

[0115] Glaucoma Drainage Procedures and Devices

[0116] Various glaucoma drainage procedures and devices are described below, including trabeculectomy, drainage tubes, and devices for minimally invasive glaucoma surgery (MIGS).

[0117] MIGS is the latest innovation in the surgical treatment of glaucoma, which was developed to minimize complications from tubes and trabeculectomy. MIGS is a term that refers to a wider range of implants, devices, and techniques that are designed to lower intraocular pressure with less surgical risk than the older procedures. In most cases, a subconjunctival bleb is required for a conjunctiva-associated device to contain the fluid and allow its external ocular absorption. Conjunctiva-associated devices that control flow will typically attempt to create a tube that is long enough and narrow enough to restrict and control outflow by applying the Poiseuille law of laminar flow in an attempt to control flow and reduce IOP to normal pressure and minimize hypotony (intraocular pressure that is too low). Non-limiting examples of glaucoma drainage devices and procedures are as follows. Note that the bleb formed by a trabeculectomy can be different from the bleb formed by a MIGS implant, e.g., these blebs can be placed in different locations, etc. Note that a glaucoma drainage procedure and a scarred, failing, or failed bleb can be different from the bleb formed at the time of the initial glaucoma drainage procedure.

[0118] Trabeculectomy

[0119] Trabeculectomy is a procedure in which a small hole is made in the sclera and capped by a thin flap. Aqueous flows through the flap into the bleb. In some trabeculectomies, an initial pocket is created under the conjunctiva and Tenon's capsule, and the wound bed is treated with a mitomycin C-soaked sponge using a "based on the vault" conjunctival incision. After cauterizing the flap area, a partial-thickness scleral flap is created with its base at the corneoscleral junction. In addition, a window is created under the flap with a Kelly punch or Descemet punch to remove a portion of the sclera, Schlemm's canal, and the trabecular meshwork to access the anterior chamber. In many cases, iridectomy is performed to prevent future obstruction of the sclerostomy. The scleral flap is then loosely sutured in place with several sutures. The conjunctiva is closed at the end of the procedure in a water-tight fashion.

[0120] Sclerostomy device

[0121] Sclerostomy devices divert aqueous humor from the anterior chamber to a subconjunctival reservoir. For example, the EX-PRESS® glaucoma filtration device directs aqueous humor through a safe lumen (e.g., 50 μιη or 200 μιη) to a semi-thick scleral flap, forming a subconjunctival bleb (see Figure 14 , Figure 15 ). The lumen of the device provides a standardized opening for aqueous humor flow, while also providing some resistance, which appears to increase stability in the anterior chamber during surgery and in the early postoperative period.

[0122] More specifically, surgical techniques require implantation of a shunt under a scleral flap to drain aqueous humor from the anterior chamber into the scleral lumen. After proper ocular positioning and anesthesia, the conjunctival epithelium is incised and dissected back. The scleral bed is cauterized to stop bleeding, and then a triangular scleral flap with a base width of about 3 mm is formed.

[0123] Next, the scleral flap is brought into the clear cornea. Using a Weck-Cel® ophthalmic sponge (Beaver Visitec International), mitomycin C is placed on the scleral bed for about 3 minutes, removed, and then rinsed with balanced salt solution (BSS). A scleral tunnel incision is made into the anterior chamber using a 25 gauge needle, parallel to the iris plane.

[0124] Then, the EX-PRESS® shunt is inserted and shaped into the opening, flush with the sclera. The aqueous flow is tested, and then the flap is laid down and tacked and buried with three broken sutures. BSS is injected into the anterior chamber to assess the possibility of outflow through the flap. Finally, the conjunctiva is pulled forward and incised superiorly.

[0125] Flow-controlled stent

[0126] Some MIGS-related devices control the flow of aqueous humor. For example, the XEN® Gel Stent (Allergan) is a gelatin and glutaraldehyde tube pre-loaded in a disposable syringe and implanted using an ab interno approach. For example, the surgeon inserts the syringe through a clear corneal incision and passes a tunnel through the sclera at or in front of the Schlemm's canal to deploy the distal portion of the stent in the subconjunctival space. This creates a passageway for aqueous humor to flow from the anterior chamber to the subconjunctival space, creating a bleb.

[0127] Another flow-controlled stent is the InnFocus MicroShunt® (InnFocus, Santen) (see Figure 16 ). The InnFocus MicroShunt® is an 8.5 mm long implant made of poly(styrene- block-isobutylene-block-styrene). The surgeon inserts the device into the anterior chamber through an ab externo approach to create a bleb in the subconjunctival space.

[0128] Other MIGS-related devices

[0129] Other MIGS devices include microshunts with the Schlemm's canal, suprachoroidal devices, and trabeculotomy devices.

[0130] Examples of microshunts with the Schlemm's canal include the iStent® (Glaukos®) and the Hydrus™ (Ivantis). The iStent® is an L-shaped microstent inserted into the Schlemm's canal using an ab interno approach. The neck extends into the anterior chamber to create a direct connection from the anterior chamber to the Schlemm's canal. By bypassing the TM, the stent is designed to increase the outflow of aqueous humor. The Hydrus™ is an 8 mm long device that works to improve the outflow of aqueous humor by creating a direct connection between the anterior chamber and the Schlemm's canal. It creates a three o'clock hour footbridge, and three windows on the front of the device elongate the TM and increase the outflow of aqueous humor.

[0131] Examples of suprachoroidal devices include CyPass® (Alcon), Solx Gold Shunt (Solx), and iStent® (Glaukos). CyPass® is an abdominal internal hypervascular shunt made of a brown polyimide material. It has a 0.3 mm lumen and is preloaded in a curved inserter. The surgeon inserts the device through a temporary clear corneal incision into the nasal angle behind the scleral spur, with the distal portion of the device embedded in the suprachoroidal space. The shunt utilizes the uveoscleral outflow system to divert aqueous humor from the anterior chamber to the suprachoroidal space. Aqueous humor flows not only through the lumen of the stent, but also through the fenestrations of the distal portion of the device. The Solx® shunt is made of 24 carat gold. The flat stent is inserted through a scleral incision into any quadrant of the eye by an abdominal externalization approach. The anterior portion of the stent is placed 1 mm into the anterior chamber and the posterior end of the stent is placed in the suprachoroidal space. The iStent Supra® is a choroidal shunt made of polyether sulfone and titanium. Placement and mechanism of action are the same as the CyPass® stent.

[0132] Examples of trabeculotomy devices include the Trabectome® (NeoMedix) electrocautery device. The surgeon inserts the Trabectome® device through a temporal clear corneal incision and directs it to the nasal portion of the angle. The TM and inner wall of Schlemm's canal are removed by electrocautery (from 90° to 180°). The suction and irrigation ports of the device tip maintain homeostasis during the procedure.

[0133] Valves

[0134] Valves such as Baerveldt® implants (Pharmacia Co.), Ahmed® glaucoma valves (New World Medical), Krupin-Denver glaucoma valves for intervertebral disc implants (E. Benson Hood Laboratories), and Molteno® and Molteno 3® drainage devices (Molteno® Ophthalmic Ltd.) are also used as glaucoma drainage devices. Rather than using a natural bleb, these devices use a synthetic reservoir (or plate) that is implanted under the conjunctiva to allow aqueous humor fluid flow.

[0135] As an example, the placement surgery for an Ahmed® valve includes: elevating the conjunctiva and Tenon's capsule based on the fornix; placing a corneal or scleral traction suture; dissecting posteriorly with a Westcott or Stevens scissors to create a pocket where the implant plate will reside; securing with suture behind the limbus; beveling the tube head to protect the tube lumen from iris encroachment; accessing the anterior chamber with a needle track; placing the tube in the anterior chamber in front of the iris and away from the corneal endothelium; securing the patch graft over the exposed portion of the tube with suture; conjunctival suturing; and reformation of the anterior chamber with balanced salt solution or viscoelastic through the puncture track. When using a Baerveldt® device, some modifications to the surgical procedure are required compared to the Ahmed® valve. For example, the lateral and superior rectus muscles are isolated with muscle hooks and the wings of the plate are placed under each muscle belly. Since the Baerveldt® is a non-limiting device, manipulation should be performed to avoid postoperative hypotonia.

[0136] Success of these devices depends on the formation and maintenance of a permeable capsule around the scleral plate through which aqueous humor diffuses into the surrounding tissue by simple diffusion. The capsule around the shunt plate provides the primary resistance to outflow of aqueous humor through the drainage device. As a result, an important factor in determining long-term intraocular pressure control is the permeability of the capsule surrounding the plate. Note that in many cases, progressive capsular fibrosis around the implant and relative impermeability of the shunt capsule leads to clinical failure, thus requiring further medical or surgical treatment. One failure mechanism is conjunctival hypertrophy or thickening.

[0137] Successful use of antimetabolites in trabeculectomy has led to interest in using these drugs in conjunction with glaucoma drainage devices. However, two retrospective studies reported that intraoperative use of mitomycin C was not beneficial with Baerveldt® implants. Two prospective randomized trials investigated the effectiveness of mitomycin C with Molteno® and AGV implantation, but neither trial demonstrated that mitomycin C was more successful in terms of final IOP, vision, and postoperative need for anti-glaucoma medications. As a result of these investigations, antimetabolic agents are not currently used with glaucoma drainage devices.

[0138] Although MMC does not prevent conjunctival hypertrophy, beta radiation can be successful where MMC fails. Without wishing to limit the present invention to any particular theory or mechanism, it is believed that the use of beta radiation can reduce or prevent conjunctival hypertrophy, thus leading to higher success rates for the valve compared to the use of liquid antimetabolites or no use of antimetabolic agents.

[0139] Camras shunt

[0140] The Camras shunt is a device currently being developed for reducing intraocular pressure and includes first and second resiliently flexible tubes connected together to allow fluid to flow therethrough. One end of the first tube is inserted into the anterior chamber of the eye to drain fluid therefrom and extends through a hole in the conjunctival layer. The second tube is connected to the outer end of the first tube and has an operable valve at its free end that opens when subjected to a predetermined fluid pressure, thereby reducing the intraocular pressure of the eye. A filter is installed within the second tube to prevent bacteria from entering the anterior chamber of the eye while allowing the filter to be replaced.

[0141] Custom devices by New World Medical

[0142] Custom devices by New World Medical are described in the Digital Journal of Ophthalmology (Dohlman et al., 2005, Digital Journal of Ophthalmology 11(2)). The valve shunt device is implanted to divert aqueous to the lower lid fornix, thereby wetting the eye of a patient with severe dry eye.

[0143] The surgical procedure includes implantation of a valve shunt custom made by New World Medical, Inc. (Rancho Cucamonga, CA, USA). The shunt includes a silicone proximal tube to be inserted into the anterior chamber. It is connected to a valve similar to the standard Ahmed S-2 valve shunt, with an opening pressure of 10 - 12 mm Hg. The custom shunt has no plate; instead, a silicone rubber housing encloses the valve. A distal tube emerges from the side of the housing and is pulled to the lower lid fornix.

[0144] The proximal tube of the anterior chamber is inserted under a semidepithelialized scleral flap, through a corneal limbal needle track into the anterior chamber. The tube is extended into the anterior chamber and positioned in front of the iris. The valve housing is sutured to the sclera in the nasal inferior quadrant in a manner similar to the attachment of the standard S-2 shunt plate. The distal tube is tied to the suture, the needle is temporarily passed under the conjunctiva to the midpoint of the fornix, the needle is then withdrawn upward, and the tube is pulled out. The tube is incised so that it lies flat in the fornix, extending about one centimeter. Two sutures are placed to temporarily hold the catheter at the bottom of the fornix. A drop of aqueous can be seen immediately from the tube opening.

[0145] For the purposes of the present invention, other surgical innovations and / or devices other than those described above can be included within the scope of the present invention and are described and labeled as MIGS. For example, techniques and devices alternatively described as moderate- infiltration glaucoma surgery or enhanced incision surgery are also included in the present invention.

[0146] Isotopes and radioactivity

[0147] The United States Nuclear Regulatory Commission (USNRC) (https: / / www.nrc.gov / about-nrc / radiation / health-effects / measuring-radiation.html) defines radioactivity as “the amount of ionizing radiation emitted by a material. Whether it emits alpha particles or beta particles, gamma rays, x-rays, or neutrons, the quantity of a radioactive material is expressed in terms of its radioactivity (or simply activity), which represents how many atoms have decayed in a given time period. The units of measurement of radioactivity are the curie (Ci) and the becquerel (Bq).” Activity in the decay process is defined as the number of disintegrations per second or the number of unstable nuclei that decay per second in a given sample. Activity is expressed in the International System of Units in becquerels (abbreviated Bq), which is exactly equal to one disintegration per second. Another unit that can be used is the curie, where one curie of activity is approximately the activity of 1 gram of radium, equal to (exactly) 3.7 x 1010 disintegrations per second. 10 The specific activity of a radionuclide is of paramount importance when selecting a radionuclide for the production of a therapeutic drug.

[0148] By the definition of the USNRC, absorbed dose is defined as the amount of radiation absorbed, e.g., the amount of energy deposited by a radiation source in the material it passes through, or the concentration of energy deposited in tissue as a result of exposure to ionizing radiation. Absorbed dose is equal to the amount of radiation exposure (ion or Ci / kg) of a beam multiplied by the ionization energy of the medium to be ionized. Typically, the units of absorbed dose are the rad and the gray (Gy). The Gy is a unit of ionizing radiation dose, defined as the absorption of one joule of radiant energy per kilogram of matter. The rad has generally been replaced by the Gy in the SI-derived units. 1 Gy is equal to 100 rad.

[0149] A radionuclide generator is a device that produces a useful short-lived medical radionuclide (called a “daughter” product) from the radioactivity of a long-lived radionuclide (called a “parent”). By providing the existing parent on site, the daughter can be produced continuously on site. Generators allow the daughter radionuclide to be immediately separated from the parent. The technetium-99 generator is one of the most widely used generator devices (commonly referred to as a “cow”). It allows the extraction of the metastable isotope 99mTc from the decay of 99molybdenum. 99Mo has a half-life of 66 hours, which can be easily transported over long distances to hospitals, where its decay product, technetium-99m (with a half-life of only 6 hours, which is not convenient for transport), is extracted and used for various short half-life very useful nuclear energy medical procedures.

[0150] Generators can also be configured to supply other daughter radioisotopes. Ruthenium 106 (Ru-106) is a commercially available radioisotope with a half-life of 668-373 days, making it an ideal candidate for a parent isotope in a cow or generator. Ru-106 decays to rhodium 106 (Rh-106) producing only a low energy beta of 39 Kev, which is not useful for therapy. However, Rh-106 has a high energy beta decay that can be used for brachytherapy: Rh-106 has a half-life of 30 seconds, decaying by beta radiation to palladium 106 (Pd-106) with a maximum decay energy of 3.541 Mev and an average energy of 96.9 Kev. As an example, in some embodiments, the present invention features a device loaded from a ruthenium 106 cow with activity that provides a full prescribed dose of rhodium 106. The device can be applied to a target volume to deliver the full activity of its contents. For example, the device can be placed over a target lesion for 10 half-lives (300 seconds) to release all of its radioactive energy and deplete the rhodium 106, which is depleted to palladium.

[0151] In some embodiments, the present invention features the use of Ru-106 in long-term equilibrium with Rh-106. Ru-106 decays by beta radiation to Rh-106. These two isotopes are in long-term equilibrium, with the decay rate of their combined source controlled by the Ru-106 parent, but the therapeutic beta radiation is emitted by the daughter Rh-106.

[0152] Yttrium 90 can be commercially obtained from a strontium 90 cow. As another example, in some embodiments, the present invention features the use of yttrium-90 with a half-life of 64 hours. Y-90 decays by beta radiation to the stable isotope zirconium 90 (Zr-90) along three different paths, with 99.985% of Y-90 decaying with a maximum beta particle energy of 2.2801 MeV, an average beta particle energy of 0.9337 MeV, or about or 1.5 x 10-13 joules. Other minor decay paths produce other low energy gamma rays and electrons. The radiation dose of these paths is clinically negligible compared to the primary path.

[0153] Currently, strontium 90 is also commercially available. As another example, in some embodiments, the present invention features the use of strontium 90 (Sr-90) in long-term equilibrium with yttrium 90 (Y-90). Strontium 90 (Sr-90) decays by beta radiation to yttrium 90 (Y-90) (see Figure 17 ). The parent Sr-90 isotope has a half-life of 28.79 years. The daughter Y-90 isotope has a half-life of 64.0 hours. Long-term equilibrium of these two isotopes is in a combined source decay rate controlled by the Sr-90 parent, but the therapeutic beta radiation is emitted from the daughter Y-90, with a maximum energy of 2.28 MeV and an average energy of 934 keV.

[0154] The planning target volume (PTV) or planning treatment volume (PTV) is a geometric concept introduced for radiation therapy planning (see also Figure 12 , Figure 13 ). The PTV is used to ensure that the prescribed dose is actually delivered to all parts of the target tissue. Without limiting the present invention to any particular surgical practice, an article in a medical journal details the surgical creation of a pocket, where the surgeon "dissects posteriorly with a Westcott scissors to create a posterior pocket of approximately 10 to 15 mm in depth and wide enough to accommodate the antimetabolizing sponge." In this example, the surgeon opened the potential space under the conjunctiva and Tenon's capsule to create a pocket of approximately 10 to 15 mm in diameter. For example, the target volume can be defined as a disc of 15 mm in diameter and 0.3 mm in depth, which contains the tissue of the conjunctiva and Tenon's capsule.

[0155] For example, the prescribed dose of brachytherapy is 10 joules per kilogram absorbed dose (10 Gy) throughout the target volume. Measurements show that a Sr-90 / Y-90 RBS model with an activity of 1.48 GBq produces a surface dose rate of approximately 0.20 Gy per second. To deliver a dose of 10 Gy to the target volume, a radiation time of 50 seconds would be required. During this 50-second treatment, the number of decaying nuclei is 1.48 x 10 9 Bq (disintegrating per second) x 50 seconds = 7.4 x 10 10 .

[0156] Biological effectiveness of radiation

[0157] The biological effectiveness of radiation depends on the linear energy transfer (LET) of the target cell or tissue, the total dose, fractionation rate, and radiosensitivity. When radiation interacts with matter, it loses energy through interactions with atoms in the direct path. In radiotherapy, LET is defined as the average energy lost per defined distance in tissue, like the energy deposited into a few cells. The incidence of LET varies in different tissues, and quantification of LET in cellular systems is an important component in determining the correct dose of radiation. Low LET radiation is X-rays, gamma rays, and beta particles.

[0158] See Figure 13 , Figure 9A , Figure 9B and Figure 9CRadiation-induced ionization can act directly on cellular molecules and cause damage, such as DNA damage. Radiation-induced ionization can also act indirectly, producing free radicals that originate from the ionization or excitation of water constituents in the cell. Exposure of a cell to ionizing radiation results in the high-energy radiation-induced decomposition of H2O water molecules into H+ and OH" free radicals. These free radicals are chemically reactive in their own right and then recombine to produce a series of highly reactive combinations, such as superoxide (O2") and peroxide (H2O2), which cause oxidative damage to molecules within the cell, such as DNA. DNA breaks induced by ionizing radiation represent one of the main mechanisms of action of beta brachytherapy.

[0159] Upon exposure of a cell to ionizing radiation, multiple pathways are involved in the cell. In the cell's response to radiation, several sensors detect the induced DNA damage and trigger signaling pathways. Activation of several signaling pathways by ionizing radiation leads to a series of changes in the expression of target genes.

[0160] The promoters or enhancers of these genes can contain one or more binding sites for transcription factors, and specific transcription factors can influence the transcription of multiple genes. The transcription factors p53, nuclear factor kappa B (NF-KB), specificity protein 1 (SP1)-related retinoblastoma control protein (RCP), two p53-dependent genes GADD45 and CDKN1A, and genes associated with the NER pathway (e.g., XPC) are generally upregulated by ionizing radiation exposure. Interestingly, it has been demonstrated that the activation of NF-KB strongly depends on the LET of the charged particles, with a maximum activation range of 90-300 keV / um.

[0161] Importantly, a subset of the transcription of target genes is crucial for the decision between resuming normal function and DNA repair after cell cycle arrest, entering senescence, or undergoing apoptosis in the case of severe DNA damage.

[0162] Cell cycle arrest is an important part of the DNA damage response, contributing to DNA repair and maintenance of genome stability. The ataxia telangiectasia mutated (ATM) and ATR activate regulators of cell cycle arrest through phosphorylation. For example, p53 has a short half-life and is stabilized in response to various cellular stresses upon phosphorylation by ATM. Following exposure to ionizing radiation, checkpoint kinase 2 (CHK2) phosphorylates serine residues 15 and 20 on p53, reducing its binding to MDM2, which targets p53 for degradation by the proteasome pathway in its bound state. Thus, dissociation of p53 from MDM2 can extend the half-life of p53. Other proteins such as Pin 1, Parc, and p300 and p300 / CBP-associated factor (PCAF) histone acetyltransferases modulate the transactivation activity of p53. To enable efficient repair, especially in non-dividing cells, cellular levels of deoxyribonucleotides are increased during DNA damage repair by p53-dependent transcriptional induction of ribonucleotide reductase RRM2B (p53R2). It is recognized that the severity of DNA damage is a key factor in directing the signaling cascade toward reversible cell cycle arrest or apoptosis. As part of the signaling cascade, the abundance of p53 protein, specific post-translational modifications, and its interaction with downstream effectors such as GADD45a or p21 can be responsible for the cell's response at this decision point.

[0163] In addition to DNA and p53, other pathways can be involved in the cellular response to ionizing radiation. For example, ionizing radiation can generate reactive oxygen species (ROS) in the cytoplasm.

[0164] Low-dose radiotherapy (LD-RT) is known to exert an anti-inflammatory effect. In vitro models show that the anti-inflammatory effect of LD-RT on immune cells such as macrophages and neutrophils ranges from 0.1-1.0 Gy. Studies have also shown that low-dose radiotherapy has an anti-inflammatory effect involving a reduction in CCL20 chemokine expression and granulocyte / endothelial cell adhesion. Khaw et al. (1991, British Journal of Ophthalmology 75:580-583) found that after beta radiation of fibroblasts in culture, "radiation reduced the proliferation of human Tenon's capsule fibroblasts. Doses of 500, 750 and 1000 rads inhibited cell proliferation by more than 50% (at 7 and 14 days) but did not cause a reduction in cell numbers." The fibroblasts entered a growth-arrested phase but did not die.

[0165] The present invention features the use of brachytherapy (beta radiation) in conjunction with the MIGS implants herein, where the brachytherapy helps prevent or reduce bleb scarring or failure to maintain a functional bleb. Without wishing to limit the present invention to any theory or mechanism, it is believed that the brachytherapy herein (e.g., low to moderate doses of radiation) can suppress or reduce inflammation and / or fibrosis by down-regulating cell (e.g., fibroblast) activity without cell death.

[0166] The application of beta radiation provides a drug-like treatment that is similar to a drug, where the beta radiation, when consumed by cells, causes biological changes in signaling and gene transcription that affect cell activity and growth, such as cell cycle arrest.

[0167] The present invention provides a composition or product that is a radioactive composition (a source of beta radiation). The radioactive composition has a therapeutic effect by producing beta radiation, through mechanisms such as those discussed previously. In producing beta radiation, the radioactive composition is consumed (e.g., the product is gradually used up) as the radioactive isotope atoms of the beta radioisotope brachytherapy source decay into other nuclides.

[0168] Brachytherapy system

[0169] As discussed previously, the present invention provides a brachytherapy system for applying beta radiation to an eye target, which is a site of a bleb in an eye that has received glaucoma treatment with a MIGS implant or MIGS surgery. The brachytherapy system includes a radionuclide brachytherapy source (RBS) for providing beta radiation that is delivered to the target.

[0170] The RBS of the present invention is constructed in a manner consistent with the Code of Federal Regulations, but is not limited to the terms mentioned in that regulation. For example, the RBS of the present invention can further include a substrate. Additionally, for example, in addition to being surrounded by the mentioned "gold, titanium, stainless steel, or platinum", in some embodiments, the radionuclide (isotope) of the present invention can be surrounded by a combination of one or more of "gold, titanium, stainless steel, or platinum". In some embodiments, the radionuclide (isotope) of the present invention can be surrounded by one or more layers of inert material, including silver, gold, titanium, stainless steel, platinum, tin, zinc, nickel, copper, other metals, ceramics, glass, or combinations of these.

[0171] In some embodiments, the RBS includes a substrate, a radioisotope (e.g., Sr-90, Y-90, Rh-106, P-32, etc.), and an encapsulant. In some embodiments, the isotope is coated on the substrate, and both the substrate and the isotope are further coated by the encapsulant. In some embodiments, the radioisotope is embedded in the substrate. In some embodiments, the radioisotope is part of the substrate matrix. In some embodiments, the encapsulant can be coated onto the isotope, and optionally onto a portion of the substrate. In some embodiments, the encapsulant is coated around the entire substrate and isotope. In some embodiments, the encapsulant encapsulates the isotope. In some embodiments, the encapsulant encapsulates the entire substrate and isotope. In some embodiments, the radioisotope is a separate piece and is sandwiched between the encapsulant and the substrate.

[0172] In some embodiments, the surface on the substrate is shaped in a manner to provide a controlled projection of the radiation. The substrate can be composed of a variety of materials. For example, in some embodiments, the substrate is composed of silver, aluminum, stainless steel, tungsten, nickel, tin, zirconium, zinc, copper, a metallic material, a ceramic material, a ceramic matrix, etc., or a combination thereof. In some embodiments, the substrate functions to shield a portion of the radiation emitted from the isotope. The encapsulant can be composed of a variety of materials, for example, one or more layers of inert material including steel, silver, gold, titanium, platinum, another biocompatible material, etc., or a combination thereof.

[0173] The radioactive isotope brachy source (RBS) is configured to provide a substantially uniform radiation dose on the target. For example, Figure 9D The previous applicator is shown to only treat the central portion of the target or underdose the peripheral region and / or overdose the center. The present invention can provide a more uniform dose across the target region, for example, as shown Preparation and assembly The present invention is not limited to the dose measurement curve shown in Surgical application

[0174] In some embodiments, the target region is the entire bubble, for example, the periphery of the bubble, the center of the bubble, and the portion of the bubble between the periphery and the center. In some embodiments, the target region is the periphery of the bubble, for example, an annular target region. In some embodiments, the target is the periphery of the bubble, and a portion of the bubble adjacent to the periphery, for example, the target can be annular. In some embodiments, the target is a portion of the bubble between the center and the periphery. In some embodiments, the target is at least a portion of the center of the bubble. The present invention is not limited to the foregoing description of the target region.

[0175] ​In some embodiments, the RBS is designed such that the dose received at the periphery of the bubble is higher than the dose received at the center of the bubble.

[0176] In some embodiments, the RBS is designed such that the dose received at the periphery of the bubble is similar to the dose at the center, e.g., no less than 80% of the dose at the center, no less than 90% of the dose at the center, etc. In some embodiments, the RBS is designed such that any point of the target is within 20% of the dose of any other point of the target, e.g., the dose varies no more than 20% across the target, e.g., no more than 20% at any given point. In some embodiments, the RBS is designed such that any point of the target is within 15% of the dose of any other point of the target, e.g., the dose varies no more than 15% across the target, e.g., no more than 15% at any given point. In some embodiments, the RBS is designed such that any point of the target is within 10% of the dose of any other point of the target, e.g., the dose varies no more than 10% across the target, e.g., no more than 10% at any given point. In some embodiments, the RBS is designed such that any point of the target is within 8% of the dose of any other point of the target, e.g., the dose varies no more than 8% across the target, e.g., no more than 8% at any given point. In some embodiments, the RBS is designed such that any point of the target is within 5% of the dose of any other point of the target, e.g., the dose varies no more than 5% across the target, e.g., no more than 5% at any given point. In some embodiments, the RBS is designed such that any point of the target is within 3% of the dose of any other point of the target, e.g., the dose varies no more than 3% across the target, e.g., no more than 3% at any given point.

[0177] With respect to the foregoing dose profiles, since the target region and the planned treatment volume have a small depth (e.g., 0.3 mm), the referenced doses refer to the dose adjacent to the surface of the device, e.g., at a depth of 0.15 millimeters. In other embodiments, the referenced doses can refer to the dose at a depth of 0.05, 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5 mm.

[0178] An iterative computer simulation of the output dosimetry can be used to determine an optimized design of the device. Thin film dosimetry is a method of measuring the delivery of radioactivity from a source, which can be used to measure the dose across the target. It can also be used to calibrate or compare radio sources or to determine the uniformity of the dose pattern.

[0179] The RBS can be disk-shaped or have a torus or circular shape; however, the present application is not limited to those shapes and includes herein any shape that achieves a desired dose distribution. The shape of the RBS can help provide a controlled projection of radiation (e.g., a therapeutic dose) onto a target. The shape of the RBS can help the radiation dose drop off quickly at the periphery of the target (whether the target is defined as, for example, the entire bubble, a portion of the bubble, etc.). This can help keep the radiation within a limited area / volume and can help prevent structures such as the lens from being undesirably exposed to radiation.

[0180] In some embodiments, the RBS has a diameter of 4 to 20 mm. In some embodiments, the RBS has a diameter of 5 to 15 mm. In some embodiments, the RBS has a diameter of 10 to 20 mm. In some embodiments, the RBS has a diameter of 10 to 15 mm. In some embodiments, the RBS has a diameter of 5 to 7 mm (e.g., 5 mm, 6 mm, 7 mm). In some embodiments, the RBS has a diameter of from 7 to 10 mm (e.g., 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm). In some embodiments, the RBS has a diameter of 9 to 12 mm (e.g., 9 mm, 9.5 mm, 10 mm, 10.5 mm, 11 mm, 11.5 mm, 12 mm). In some embodiments, the RBS has a diameter of 10 to 14 mm (e.g., 10 mm, 10.5 mm, 11 mm, 11.5 mm, 12 mm, 12.5 mm, 13 mm, 13.5 mm, 14 mm). In some embodiments, the RBS has a diameter of 12 to 16 mm (e.g., 12 mm, 12.5 mm, 13 mm, 13.5 mm, 14 mm, 14.5 mm, 15 mm, 15.5 mm, 16 mm). In some embodiments, the RBS has a diameter of 14 to 18 mm (e.g., 14 mm, 14.5 mm, 15 mm, 15.5 mm, 16 mm, 16.5 mm, 17 mm, 17.5 mm, 18 mm). In some embodiments, the RBS has a diameter of 3 mm. In some embodiments, the RBS has a diameter of 4 mm. In some embodiments, the RBS has a diameter of 5 mm. In some embodiments, the RBS has a diameter of 6 mm. In some embodiments, the RBS has a diameter of 7 mm. In some embodiments, the RBS has a diameter of 8 mm. In some embodiments, the RBS has a diameter of 9 mm. In some embodiments, the RBS has a diameter of 10 mm. In some embodiments, the RBS has a diameter of 11 mm. In some embodiments, the RBS has a diameter of 12 mm. In some embodiments, the RBS has a diameter of 13 mm. In some embodiments, the RBS has a diameter of 14 mm. In some embodiments, the RBS has a diameter of 15 mm. In some embodiments, the RBS has a diameter of 16 mm. In some embodiments, the RBS has a diameter of 17 mm. In some embodiments, the RBS has a diameter of 18 mm. In some embodiments, the RBS has a diameter of 19 mm. In some embodiments, the RBS has a diameter of 20 mm. In some embodiments, the RBS has a diameter of greater than 20 mm.

[0181] In some embodiments, the RBS delivers a radiation dose of 1000 cGy (10 Gy) to the target. In some embodiments, the RBS delivers a radiation dose of 900 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 800 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 750 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 600 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 500 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 400 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 300 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 200 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 100 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 50 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 1100 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 1200 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 1300 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 1500 cGy to the target. In some embodiments, the RBS delivers a radiation dose of 600 cGy and 1500 cGy to the target. In some embodiments, the RBS delivers a radiation dose from 50 cGy to 100 cGy. In some embodiments, the RBS delivers a radiation dose from 100 cGy to 150 cGy. In some embodiments, the RBS delivers a radiation dose from 150 cGy to 200 cGy. In some embodiments, the RBS delivers a radiation dose from 200 cGy to 250 cGy. In some embodiments, the RBS delivers a radiation dose from 250 cGy to 300 cGy. In some embodiments, the RBS delivers a radiation dose from 300 cGy to 350 cGy. In some embodiments, the RBS delivers a radiation dose from 350 cGy to 400 cGy. In some embodiments, the RBS delivers a radiation dose from 400 cGy to 450 cGy. In some embodiments, the RBS delivers a radiation dose from 450 cGy to 500 cGy. In some embodiments, the RBS delivers a radiation dose from 500 cGy to 550 cGy. In some embodiments, the RBS delivers a radiation dose from 550 cGy to 600 cGy. In some embodiments, the RBS delivers a radiation dose from 600 cGy to 650 cGy. In some embodiments, the RBS delivers a radiation dose from 650 cGy to 700 cGy. In some embodiments, the RBS delivers a radiation dose from 700 cGy to 750 cGy. In some embodiments, the RBS delivers a radiation dose from 750 cGy to 800 cGy. In some embodiments, the RBS delivers a radiation dose from 800 cGy to 850 cGy.In some embodiments, the RBS delivers a radiation dose from 850 cGy to 900 cGy. In some embodiments, the RBS delivers a radiation dose from 900 cGy to 950 cGy. In some embodiments, the RBS delivers a radiation dose from 950 cGy to 1000 cGy. In some embodiments, the RBS delivers a radiation dose from 1000 cGy to 1050 cGy. In some embodiments, the RBS delivers a radiation dose from 1050 cGy to 1100 cGy. In some embodiments, the RBS delivers a radiation dose from 1100 cGy to 1150 cGy. In some embodiments, the RBS delivers a radiation dose from 1150 cGy to 1200 cGy. In some embodiments, the RBS delivers a radiation dose from 1200 cGy to 1250 cGy. In some embodiments, the RBS delivers a radiation dose from 1250 cGy to 1300 cGy. In some embodiments, the RBS delivers a radiation dose from 1300 cGy to 1350 cGy. In some embodiments, the RBS delivers a radiation dose from 1350 cGy to 1400 cGy. In some embodiments, the RBS delivers a radiation dose from 1400 cGy to 1450 cGy. In some embodiments, the RBS delivers a radiation dose from 1450 cGy to 1500 cGy. In some embodiments, the RBS delivers a radiation dose from 1500 cGy to 1550 cGy. In some embodiments, the RBS delivers a radiation dose from 1550 cGy to 1600 cGy. In some embodiments, the RBS delivers a radiation dose from 1600 cGy to 1800 cGy. In some embodiments, the RBS delivers a radiation dose from 1800 cGy to 2000 cGy. In some embodiments, the RBS delivers a radiation dose of 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, or 1500 cGy. In some embodiments, the RBS delivers a radiation dose of 1500 to 3200 cGy. In some embodiments, the RBS delivers a radiation dose of 3200 to 8000 cGy. In some embodiments, the RBS delivers a radiation dose of 8000 cGy to 10000 cGy. In some embodiments, the RBS delivers a radiation dose of greater than 10000 cGy.

[0182] In some embodiments, the RBS delivers the prescribed dose in a time of 10 seconds to 20 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 20 seconds and 10 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 20 seconds to 60 seconds. In some embodiments, the RBS delivers the prescribed dose in a time of 30 seconds to 90 seconds. In some embodiments, the RBS delivers the prescribed dose in a time of 60 seconds to 90 seconds. In some embodiments, the RBS delivers the prescribed dose in a time of 90 seconds to 2 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 2 minutes to 3 minutes.

[0183] In some embodiments, the RBS delivers the prescribed dose in a time of 3 minutes to 4 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 3 minutes to 5 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 3 minutes to 6 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 4 minutes to 5 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 4 minutes to 6 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 5 minutes to 6 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 6 minutes to 7 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 7 minutes to 8 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 8 minutes to 9 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 9 minutes to 10 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 10 minutes to 12 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 12 minutes to 15 minutes. In some embodiments, the RBS delivers the prescribed dose in a time of 15 minutes to 20 minutes.

[0184] In some embodiments, the RBS delivers the prescribed dose within 25 seconds. In some embodiments, the RBS delivers the prescribed dose within 45 seconds. In some embodiments, the RBS delivers the prescribed dose within 60 seconds. In some embodiments, the RBS delivers the prescribed dose within 90 seconds. In some embodiments, the RBS delivers the prescribed dose within 2 minutes. In some embodiments, the RBS delivers the prescribed dose within 3 minutes. In some embodiments, the RBS delivers the prescribed dose within 4 minutes. In some embodiments, the RBS delivers the prescribed dose within 5 minutes. In some embodiments, the RBS delivers the prescribed dose within 6 minutes. In some embodiments, the RBS delivers the prescribed dose within 7 minutes. In some embodiments, the RBS delivers the prescribed dose within 8 minutes. In some embodiments, the RBS delivers the prescribed dose within 9 minutes. In some embodiments, the RBS delivers the prescribed dose within 10 minutes. In some embodiments, the RBS delivers the prescribed dose within 11 minutes. In some embodiments, the RBS delivers the prescribed dose within 12 minutes. In some embodiments, the RBS delivers the prescribed dose within 13 minutes. In some embodiments, the RBS delivers the prescribed dose within 14 minutes. In some embodiments, the RBS delivers the prescribed dose within 15 minutes. In some embodiments, the RBS delivers the prescribed dose within 16 minutes. In some embodiments, the RBS delivers the prescribed dose within 17 minutes. In some embodiments, the RBS delivers the prescribed dose within 18 minutes. In some embodiments, the RBS delivers the prescribed dose within 19 minutes. In some embodiments, the RBS delivers the prescribed dose within 20 minutes. In some embodiments, the RBS delivers the prescribed dose within a time range greater than 20 minutes.

[0185] In some embodiments, a dose (e.g., a prescribed dose) can be delivered in a single application. In other embodiments, a dose (e.g., a prescribed dose) can be applied in fractions and in multiple applications. For example, in some embodiments, radiation (e.g., a prescribed dose) can be applied over the course of two applications. In some embodiments, radiation (e.g., a prescribed dose) can be applied over the course of 3 applications. In some embodiments, radiation (e.g., a prescribed dose) can be applied over the course of 4 applications. In some embodiments, radiation (e.g., a prescribed dose) can be applied over the course of 5 applications. In some embodiments, radiation (e.g., a prescribed dose) can be applied over the course of more than 5 applications. In some embodiments, radiation (e.g., a prescribed dose) can be applied over the course of 20 applications. In some embodiments, radiation (e.g., a prescribed dose) can be applied over the course of more than 20 applications.

[0186] Each application can deliver an equal sub-dose. In some embodiments, one or more sub-doses are different. For example, one or more sub-doses can be different so as to increase or decrease with each additional application.

[0187] According to one embodiment, a dose of radiation can be applied prior to the surgery to implant the MIGS device. For example, in some embodiments, a dose of radiation can be applied one or more days prior to the MIGS implantation surgery (e.g., insertion of the MIGS device). In some embodiments, a dose of radiation can be applied within 24 hours prior to the MIGS implantation surgery (e.g., insertion of the MIGS device). In some embodiments, a dose of radiation can be applied prior to, e.g., 1 hour prior, 30 minutes prior, 15 minutes prior, 1 minute prior, 5 minutes prior, the MIGS implantation surgery (e.g., insertion of the MIGS device). In some embodiments, a dose of radiation can be applied during the surgery to implant the MIGS device. In some embodiments, a dose of radiation can be applied immediately after implantation of the MIGS device, e.g., within 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, etc. In some embodiments, a dose of radiation can be applied prior to making an incision in the conjunctiva. In some embodiments, a dose of radiation can be applied after making an incision in the conjunctiva. In other embodiments, a dose of radiation can be applied after the MIGS implantation surgery (e.g., insertion of the MIGS device). In some embodiments, a dose of radiation can be applied within 24 hours after the MIGS implantation surgery (e.g., insertion of the MIGS device). In some embodiments, a dose of radiation can be applied within one to two days after the MIGS implantation surgery (e.g., insertion of the MIGS device). In some embodiments, a dose of radiation can be applied within two or more days after the MIGS implantation surgery (e.g., insertion of the MIGS device). In some embodiments, a dose can be applied at any time after glaucoma surgery. In some embodiments, a dose is applied months or years after glaucoma surgery. For example, a dose can be given to a patient who did not receive a dose during surgery but has a future procedure to scar or needle the scar tissue.

[0188] Brachytherapy applicator

[0189] The present invention also provides an applicator for applying beta radiation to a target in an eye. In some embodiments, the applicator can feature an RBS fixedly connected to the applicator. In some embodiments, the RBS is loaded into the applicator prior to use in a surgical procedure. The device can be similar to devices originally used for pterygium or other ophthalmic applications. For example, the User Technique Information and Instruction Manual for the Beta-Therapy Source Model 67-850, Nuclear Associates Manual lists a variety of ophthalmic brachytherapy indications, including: tumors, hemangiomas, pterygium, vascularization, and irritable scars. However, the present invention is not limited to these previously manufactured devices.

[0190] The applicator can be constructed of any suitable material, such as a biocompatible material or a combination of materials. Non-limiting examples of biocompatible materials include, but are not limited to, metals (e.g., stainless steel, titanium, gold), ceramics, and polymers.

[0191] The applicator can include a handle adapted to hold the RBS, for example, the RBS can be located at the distal end of the handle. In some embodiments, the applicator of the present application includes a radiation attenuation mask to shape the radiation in a particular manner. For example, the mask can limit the amount of radiation reaching non-target tissue, such as the lens.

[0192] In some embodiments, the applicator features a removable cap for temporarily shielding the RBS or keeping the applicator or RBS sterile.

[0193] In some embodiments, one or more components of the present application (e.g., the applicator) are constructed of a material that can further shield the user from the RBS. In some embodiments, a material with a low atomic number (Z) can be used for shielding (e.g., polymethyl methacrylate). In some embodiments, one or more layers of material are used for shielding, where the inner layer includes a material with a low atomic number (e.g., polymethyl methacrylate) and the outer layer includes lead.

[0194] As an example, in some embodiments, the present application is a device loaded with a predetermined dose of ruthenium 106 with active rhodium 106. The device can be applied to a target to deliver the full activity of its contents. For example, the device can be placed over a target lesion for 10 half-lives (300 seconds) to release all of its radioactive energy and deplete the rhodium 106, depleting it to palladium.

[0195] As an example, in some embodiments, the present application is an applicator configured to contain a long-lived equilibrium of strontium 90 / yttrium 90 radioisotopes. In some embodiments, the Sr-90 / Y-90 is in a sealed source brachytherapy device, for example, constructed of stainless steel. The radioactive source can be configured to project a dose of about 1,000 cGy per unit time into a sufficient portion of an adjacent planned treatment volume, for example, to accommodate conjunctival tissue to a depth of 0.3 mm. The radiation source can be fixed to a handle, and a radiation attenuation mask (shaped like a fan) is fixed to the radiation source. The source can be capped with a sterile barrier. The present application is not limited to this embodiment, and variations and combinations of the disclosed features are also contemplated within the scope of the present application.

[0196] Methods

[0197] As discussed previously, the present application provides methods of applying beta rays to a target of the eye, such as the site of a bleb formed by a MIGS implant or surgery. Without wishing to limit the present application to any theory or mechanism, it is believed that the use of beta rays to treat the bleb site is advantageous because the application of beta rays can be quick and simple, and the effects can be long lasting. Moreover, beta rays can be advantageous because it does not require post-operative compliance.

[0198] In some embodiments, the methods herein inhibit or reduce fibrosis in a bleb associated with a MIGS implant or surgery. In some embodiments, the methods herein inhibit or reduce inflammation in a bleb associated with a MIGS implant or surgery.

[0199] In some embodiments, the methods herein maintain the function of a bleb associated with a MIGS implant or surgery. In some embodiments, the methods herein enhance the function of a MIGS implant, for example, by maintaining a functional bleb. In some embodiments, the methods herein reduce intraocular pressure (IOP), maintain a healthy IOP, treat glaucoma, etc.

[0200] The methods herein can include implanting a minimally invasive glaucoma surgery (MIGS) implant within the eye. MIGS implants have been discussed in detail above. Typically, a MIGS implant is inserted through the sclera and forms a bleb in the subconjunctival space of the eye or in the space between the conjunctiva and Tenon's capsule. For example, a MIGS implant can be placed between the anterior chamber of the eye and the subconjunctival space. In some embodiments, the MIGS implant is placed between the anterior chamber of the eye and the space between the conjunctiva and Tenon's capsule.

[0201] The methods herein include applying beta rays to a target area of the eye. In some embodiments, the target area is the site of a bleb or the expected site of a bleb. In some embodiments, the target area surrounds the end of the implant. In some embodiments, the target has a diameter of 2 to 5 mm. In some embodiments, the target has a diameter of 5 to 12 mm. In some embodiments, the target has a thickness of 0.3 mm to 0.5 mm.

[0202] In some embodiments, the beta rays are applied prior to insertion of the MIGS implant. In some embodiments, the beta rays are applied after insertion of the MIGS implant.

[0203] In some embodiments, the methods herein further include introducing a drug to the site, such as the site of a MIGS implant, the site of a bleb, a different site of the eye.

[0204] As previously discussed, ionizing radiation has an effect on cells, which can result in cell cycle arrest. In some embodiments, the beta rays of the present invention cause cell cycle arrest in fibroblasts on or associated with Tenon's capsule or conjunctiva, thereby inhibiting or reducing the fibrotic process and inflammation that leads to bubble failure.

[0205] As previously discussed, the beta rays can be applied via a radionuclide brachytherapy source (RBS). The RBS can be applied to the target via an applicator. As previously discussed, in some embodiments, the beta rays are strontium 90 (Sr-90), phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90), or a combination thereof. As before, in some embodiments, the RBS provides a dose of about 750 cGy to the target. In some embodiments, the RBS provides a dose of 500 to 1000 cGy to the target.

[0206] The present invention also features a method for making an applicator for emitting beta rays. In some embodiments, the method includes inserting a radionuclide brachytherapy source (RBS) into an RBS cavity in the applicator. In some embodiments, the method includes connecting the RBS to the applicator. In some embodiments, the applicator includes a handle and a distal end portion, where the distal end portion is where the RBS is connected or where the RBS cavity is located. In some embodiments, the RBS is configured to emit a radiation dose at 4 mm from its center that is at least 90% of the radiation dose emitted at the center. The present invention is not limited to RBSs that emit a radiation dose at 4 mm from its center that is at least 90% of the radiation dose emitted at the center. Alternative examples of dose profiles are described herein.

[0207] Other applications

[0208] Needling procedures are often performed against the bleb to release or remove scar tissue and / or cystic structures that surround the bleb and the surgical site that can later develop as a result of wound healing or scarring or inflammatory responses from glaucoma surgery. The needling procedure can affect the morphology of the surgical site, restore surgical function, and / or reduce IOP.

[0209] An example of a surgical procedure for bleb repair by needling includes the following steps: after instillation of a local anesthetic and antibiotic drops, a cotton swab applicator soaked in local anesthetic is applied to the site of the conjunctiva for 2 minutes, the needle will enter the conjunctiva at this site. The eyelid is placed on a speculum. At the slit lamp, the patient is instructed to look down so that all blebs are exposed. The slit lamp is set to the lowest magnification. This helps visualize the blebs even if the patient moves the eye during the procedure. A 27 gauge needle is used on a tuberculin syringe. The needle is inserted into the subconjunctival space 1 mm from the edge of the bleb and then advanced into the bleb. The subconjunctival fibrosis is cut with firm back and forth motion. The needle is then advanced in the same plane to the other side of the scleral flap and the fibrous tissue is cut. The needle is then partially withdrawn from the bleb and the direction is changed to be parallel to the edge of the bleb; as the sweep is made, the scar tissue is cut. The goal is to cut the fibrous tissue in all directions around the scleral flap. The needle is then withdrawn. An antimetabolite can be injected into the bleb during the needling procedure.

[0210] The methods and compositions of the present application can be used in conjunction with needling procedures. For example, the methods herein can feature the application of beta radiation from a radioisotope to a bleb that is to be needled (e.g., a bleb from a glaucoma device or procedure such as a MIGS device, trabeculectomy, etc.) beginning, e.g., 3 to 6 weeks prior, 1 to 3 weeks prior, 3 to 7 days prior, 24 to 72 hours prior, 12 to 24 hours prior, 6 to 12 hours prior, 3 to 6 hours prior, 2 to 3 hours prior, 1 to 2 hours prior, 30 to 60 minutes prior, 20 to 30 minutes prior, 10 to 20 minutes prior, 1 to 10 minutes prior, etc. In some embodiments, the methods feature the application of beta radiation to a bleb that has previously been needled (e.g., a bleb from a glaucoma device or procedure such as a MIGS device, trabeculectomy, etc.) beginning, e.g., 0.5 to 10 minutes after, 10 to 20 minutes after, 20 to 30 minutes after, 30 to 60 minutes after, 1 to 2 hours after, 2 to 3 hours after, 3 to 6 hours after, 6 to 12 hours after, 12 to 24 hours after, 24 to 72 hours after, 3 to 7 days after, 1 to 3 weeks after, 3 to 6 weeks after, and so on.

[0211] Without wishing to limit the invention to any theory or mechanism, it is believed that treatment of blebs formed by scar tissue on trabeculectomy foci is different from treatment of blebs newly formed during trabeculectomy (and without scar tissue). In some embodiments, the method herein further includes applying beta therapy in conjunction with an acupuncture procedure to blebs formed by a trabeculectomy procedure. In some embodiments, the method herein further includes applying beta therapy to trabeculectomy blebs where scar tissue has already formed. In some embodiments, the method herein further includes applying beta therapy to blebs in the eyes of trabeculectomy patients whose intraocular pressure (IOP) has increased. In some embodiments, the method herein also includes applying beta therapy to blebs at sites where trabeculectomy has failed or has failed. In some embodiments, the method herein also includes applying beta therapy to blebs in second trabeculectomy procedures following failure of the first trabeculectomy.

[0212] In some embodiments, the method of this invention further includes applying beta therapy to a failed or already failed blister. In some embodiments, the method of this invention further includes applying beta therapy to a failed or already failed MIGS device blister. In some embodiments, the method of this invention further includes applying beta therapy to a MIGS device blister that has formed scar tissue. In some embodiments, the method of this invention further includes applying beta therapy to a blister in the eye of a MIGS device patient with increased intraocular pressure (IOP).

[0213] In some embodiments, the method herein further includes applying another drug in addition to beta rays. In some embodiments, the method herein further includes applying another antimetabolite (e.g., mitomycin-C or 5-fluorouracil) in addition to beta rays.

[0214] The methods, systems, and compositions of the present invention can also be used for wound healing, such as ocular wounds caused by foreign body insertion, ocular trauma, ocular surface wounds, etc. One model of wound healing divides the process into hemostasis, inflammation, proliferation, and remodeling. The first stage of hemostasis begins immediately after injury, accompanied by vasoconstriction and fibrin clot formation. The clot and surrounding wound tissue release pro-inflammatory cytokines and growth factors, such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF). Once bleeding is controlled, inflammatory cells migrate to the wound and promote the inflammatory phase, characterized by the sequential infiltration of neutrophils, macrophages, and lymphocytes. In the early stages of the wound, macrophages release cytokines that promote the inflammatory response by recruiting and activating other leukocytes. As macrophages clear these apoptotic cells, they undergo a phenotypic transition to a repair state, which stimulates keratinocytes, fibroblasts, and angiogenesis, thereby promoting tissue regeneration. T lymphocytes migrate to the wound following inflammatory cells and macrophages, peaking in the late proliferative / early remodeling phase. T cells regulate many aspects of wound healing, including maintaining tissue integrity, defending against pathogens, and modulating inflammation. The proliferative phase typically follows and overlaps with the inflammatory phase and is characterized by epithelial proliferation and migration onto a temporary matrix within the wound (re-epithelialization). In the reparative dermis, fibroblasts and endothelial cells are the most prominent cell types, supporting capillary growth, collagen formation, and the formation of granulation tissue at the site of injury. In the wound bed, fibroblasts produce collagen as well as glycosaminoglycans and proteoglycans, which are major components of the extracellular matrix (ECM). Following robust proliferation and ECM synthesis, wound healing enters the final remodeling phase, which can last for years.

[0215] The invention may be characterized by applying beta rays to an eye wound, such as a wound caused by the presence of a foreign body or trauma.

[0216] Example

[0217] Example 1: Surgical procedure for XEN® implants

[0218] This invention provides examples of surgical procedures for implanting XEN® MIGS devices. ​ , ​ , ​ , ​ A schematic diagram of the implantation process for the XEN® implant is also shown. This invention is by no means limited to the specific steps, methods, apparatus, systems, and compositions described herein.

[0219] First, the surgical field is prepared and the patient is anesthetized. The surgeon can choose to use regional anesthesia to minimize the possibility of patient or globe movement that can lead to iatrogenic trauma; or, local anesthesia alone can be sufficient to make the procedure comfortable.

[0220] The conjunctiva is marked with ink at the desired implant location. The target site can be 3 mm posterior to the limbus. Additional markings can also be made on either side of the target.

[0221] In some procedures, a bleb is formed by injecting a balanced salt solution or air under the conjunctiva followed by an ocular viscoelastic.

[0222] The globe is stabilized with a probe placed against the sclera. A clear corneal incision is made using a 1.1 mm stab knife blade. During the procedure, a veress hook is placed in the incision to stabilize the eye by providing counter-traction.

[0223] The anterior chamber is accessed using a 1.8 mm corneal knife blade. A 180° incision is made from the intended haptics location. The incision is angled toward the target quadrant where the haptics are placed.

[0224] The anterior chamber is stabilized by adding an ocular viscoelastic.

[0225] After the XEN® injector is prepared, the tip is inserted into the main incision and the needle is passed through the anterior chamber. Visualization through the keratometer can be used to direct the injector at an angle to the target location. The injector needle tip is placed at an angle directly in front of the trabecular meshwork. The needle passes through the sclera with the entire bevel in the target site into the subconjunctival space. The needle bevel is rotated and pressed up against the scleral wall.

[0226] Advancing the injector plunger both deploys the haptics and retracts the distal end of the needle out of the scleral tissue. The injector is then withdrawn from the anterior chamber.

[0227] Visualization through the keratometer is then used to ensure that approximately 1.0 mm of the implant protrudes at the angle and that the location is against the pigmented trabecular meshwork. The bleb is then checked. The conjunctiva is checked to ensure that it is intact. Visualization can ensure that the distal 3 mm of the XEN® gel haptics are lying flat and can move freely in the subconjunctival space.

[0228] The viscoelastic is withdrawn from the anterior chamber and flushed thoroughly. Any blood is removed from the anterior chamber thoroughly, if present. After this step, constant saline irrigation is applied to the anterior chamber to prime the implant and induce bleb formation.

[0229] The surgeon also thoroughly moistens all incisions to ensure that the pressure is maintained and the anterior chamber is formed. The clear corneal incision can be closed by resuscitation. For incision leaks, a 10-0 nylon suture can also be placed.

[0230] At the end of the procedure, the conjunctival area around the XEN® tube can be exposed to beta rays using a delivery device containing a radioactive brachytherapy source (RBS). In some embodiments, a probe can be placed on the posterior end of the XEN® tube, for example, about 1 mm from the limbus.

[0231] Example 2: Surgical procedure for InnFocus MicroShunt® implant

[0232] The present invention provides examples of surgical procedures for implanting the InnFocus MicroShunt® MIGS device. The present invention is in no way limited to the specific steps, methods, devices, systems, and compositions described herein.

[0233] First, the surgical area is prepared and the patient is anesthetized, for example, using local anesthesia.

[0234] A conjunctival perimetry incision (based on the incision of the fornix) is made on the upper limbus about 5 or 6 mm long. The Tenon insert is cut off and inserted about 2 mm behind the limbus. The Tenon capsule and conjunctiva are lifted and bluntly dissected backwards (in some embodiments using a Westcott scissors) to create a conjunctival flap.

[0235] The limbal incision site and the scleral surface are carefully cauterized through a 23-gauge pencil tip to limit bleeding and irrigate the area. The sclera is cleared with a Tooke's knife.

[0236] The target implant location is marked with sterile ink. The target site is 3 mm behind the anterior limbus.

[0237] A 1 mm microknife with a 2 mm bevel is used to create a 2 mm long scleral tunnel from the ink mark towards the limbus. A 25-gauge needle bent on a hub is inserted into the tunnel and advanced to the scleral spur. When the needle is further advanced beyond the scleral spur, the needle points down to enter the anterior chamber on the iris plane. The needle enters the anterior chamber and is then withdrawn.

[0238] The InnFocus MicroShunt® is advanced in the tunnel in a tilted position. The tip of the shunt is observed to enter the anterior chamber. The fins of the shunt are then inserted into the scleral tunnel.

[0239] A 23-gauge thin-walled cannula is used to inject balanced salt solution (BSS) into the shunt. Alternatively, a paracentesis can be performed and BSS injected into the anterior chamber. The patency of the shunt can be confirmed by observing blood flow at the tip of the anterior chamber.

[0240] The distal end of the shunt device is placed under the conjunctival and Tenon's capsule flap.

[0241] The Tenon's capsule and conjunctiva were sutured in two sutured closures using 9-0 vicryl on a blunt spatula needle. The final closure included horizontal mattress sutures to prevent leakage.

[0242] Visualisation by corneal loupe examination was then used to ensure that the device was visible in the anterior chamber at the ciliary processes directly in front of the iris.

[0243] At the end of the procedure, the area of conjunctiva surrounding the InnFocus MicroShunt® can be exposed to beta radiation from a delivery device containing a radioactive brachytherapy source (RBS). In some embodiments, the RBS is placed at the posterior end of the InnFocus MicroShunt® tube and over the anterior portion of the InnFocus MicroShunt® tube, for example, about 1 mm from the limbus.

[0244] Example 3: Beta radiation applied surgical procedure

[0245] The present invention provides examples of methods of applying beta radiation to an eye. The present invention is in no way limited to the specific steps, methods, devices, systems, and compositions described herein.

[0246] ​

[0247] The device assembly procedure is completed behind a plexiglass beta shield (e.g., a large double angle beta shield from Universal Medical Inc.). The medical technologist or medical physicist opens the radioactive isotope brachytherapy source (RBS) storage container. The RBS is removed from its container using remote handling techniques (e.g., long forceps). The RBS is placed in a clean location.

[0248] The manual brachytherapy applicator (MBA) assembly is a single use, sterile packaged device. Its packaging is checked by inspecting the sterile barrier for damage or breach. Finding none, the applicator packaging is opened and the applicator assembly is placed in a sterile field.

[0249] The applicator assembly includes a handle and an RBS cap. Using sterile technique and remote handling techniques, the RBS is loaded into the applicator. The handle is attached and the sterile cap is attached. Care is taken not to cross-contaminate the outside of the sterile applicator with the clean RBS.

[0250] The radiation output is confirmed to meet quality assurance standards in radiation therapy (see, for example: Palmer, Antony L., Andrew Nisbet, and David Bradley. "Verification of high-dose-rate brachytherapy dose distributions by EBT3 full-color film quality control." Medical physics 58.3 (2013): 497). In one quality assurance method, the applicator is applied to radiographic film in a sterile overwrap for a specified dwell time (e.g., Gafchromic® film, Ashland Inc.). The overwrap is removed. A medical physicist inspects the applied area for evidence of film exposure.

[0251] The device is placed in a sterile Plexiglas beta transport case (e.g., IBI Beta-Gard Acrylic Storage Container - Large, Universal Medical Inc.) and the case is placed on an operable Mayo stand.

[0252] The decay activity of the RBS has been previously calculated to determine the modern dose per unit time (e.g., cGy / second). Decay calculation methods are well known to those skilled in the art of medical physics and are also described in NRC Information Notice 96-66: U.S. Nuclear Regulatory Commission, Office of Nuclear Material Safety and Security, Washington, DC 20555, December 13, 1996. The time to total prescribed dose is then calculated. For example, the prescribed dose is 1,000 cGy at the center point of the depth of 0.19 mm from the surface of the conjunctiva. For example, the decay activity of the RBS is 30 cGy / second at a water equivalent depth of 0.19 mm. In this example, the dwell time is calculated to be about 33 seconds, providing a dose of 990 cGy.

[0253] ​

[0254] For example, as described elsewhere in this application, beta therapy is applied after the completion of glaucoma surgery placement of the MIGs device. The conjunctiva is intact, or can have been closed surgically (e.g., using 9-0 horizontal mattress suture). The eyelids are retracted with an eyelid speculum (e.g., Barraquer wire speculum). The eye is rotated to a downward gaze position by using a probe that rests on the sclera to provide a traction force (e.g., the distal end of a Vera hook resting on the eye). This provides better visual and surgical access to the conjunctiva.

[0255] The ophthalmic surgeon removes the manual brachytherapy applicator device from its shielded case. The distal end (active end) of the applicator is placed over the sclera just above the limbus. The diameter of the applicator includes the bubble. The field of application also includes the distal end of a MIGS shunt or stent, so it can also specifically treat the conjunctiva directly over the capped shunt or stent. The manual brachytherapy applicator is left in place for the prescribed dwell time. In some embodiments, the dwell time has been programmed as a countdown clock. After the prescribed dwell time, the manual brachytherapy applicator is removed from the surgical field and placed back in the shielded acrylic case.

[0256] At the end of the procedure, antibiotic ointment is applied to the eye and the eye is patched.

[0257] After the surgical procedure, the manual brachytherapy applicator is disassembled behind the acrylic beta shield. The radioisotope brachytherapy source is returned to its storage container. The disposable portions of the device are discarded in a manner consistent with the proper disposal of biohazardous waste (e.g., "red bag" waste).

[0258] In addition to those described herein, various modifications will be apparent to those skilled in the art in light of the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited in this application is incorporated herein by reference in its entirety.

[0259] Although the preferred embodiments of the application have been illustrated and described, it will be clear to those skilled in the art that modifications can be made without departing from the scope of the application as defined by the appended claims. Accordingly, the scope of the application is limited only by the appended claims. The reference signs in the claims are indicative of the values which the features denoted thereby can take in all of the embodiments. The reference signs are not intended to limit the scope of the claims in any way. In some embodiments, the figures presented in this patent application are drawn to scale, including angular, dimensional proportions, etc. In some embodiments, the figures are merely representative and the claims are not limited by the dimensions of the figures. In some embodiments, the use of the phrase "comprising" in the description of the application herein includes embodiments that can be described as "consisting of," and thus, the written description requirement is satisfied using the phrase "consisting of" to claim one or more embodiments of the application.

[0260] The reference signs in the claims are indicative of the values which the features denoted thereby can take in all of the embodiments. The reference signs are not intended to limit the scope of the claims in any way. The reference signs in the claims are merely illustrative, and in no way limit the scope of the application.

Claims

1. Use of a beta-emitting radioisotope in the preparation of a medicament for inhibiting or reducing fibrosis and inflammation in a drainage sac of a human eye, said human eye having a minimally invasive glaucoma surgery (MIGS) implant, said MIGS implant being disposed therein via the sclera and forming a drainage sac in the subconjunctival space of the eye or in the space between the conjunctiva and Tenon's capsule, characterized in that, The drug has a diameter of 9 to 12 mm and emits a radiation dose at a distance of 4 mm from its center, the radiation dose being at least 90% of the dose emitted at its center; wherein the β-rays cause cell cycle arrest in the fibroblasts on the Tenon vesicle, thereby inhibiting or reducing the fibrotic process and inflammation that lead to vesicle failure.

2. Use of a beta-emitting radioisotope in the preparation of a medicament for maintaining a functional drainage bubble in a human eye having a minimally invasive glaucoma surgery (MIGS) implant, the MIGS implant being disposed therein via the sclera and forming a drainage bubble in the subconjunctival space of the eye or in the space between the conjunctiva and Tenon's capsule, the bubble functioning to drain aqueous humor; characterized in that, The drug has a diameter of 9 to 12 mm and emits a radiation dose at a distance of 4 mm from its center, the radiation dose being at least 90% of the dose emitted at its center, wherein the β-rays reduce or inhibit fibrosis and inflammation that lead to vesicle failure, and wherein the β-rays effectively maintain the drainage function of the vesicles.

3. Use of a radioactive isotope emitting beta rays in the preparation of a medicament for reducing intraocular pressure (IOP) in a human eye having a minimally invasive glaucoma surgery (MIGS) implant, the MIGS implant being inserted between the anterior chamber of the eye and the subconjunctival space of the eye or between the anterior chamber of the eye and the space between the conjunctiva and Tenon's capsule, the implant causing the formation of a bubble for draining aqueous humor; characterized in that, The drug has a diameter of 9 to 12 mm and emits a radiation dose 4 mm from its center, the radiation dose being at least 90% of the dose emitted at its center; wherein the beta rays effectively reduce intraocular pressure (IOP) of the eye.

4. Use of a beta-emitting radioactive isotope in the preparation of a medicament for reducing inflammation in an eye containing a foreign body, said foreign body being a minimally invasive glaucoma surgery (MIGS) implant inserted between the anterior chamber of the eye and the subconjunctival space of the eye or between the anterior chamber of the eye and the space between the conjunctiva and Tenon's capsule, said implant causing the formation of a bubble for draining aqueous humor, said reduction of inflammation comprising: Beta rays from a radioactive isotope emitting beta rays are applied to a target region of the eye, wherein the target region is at least a portion of the bubble; Applying beta rays from a radioactive isotope that emits beta rays effectively reduces inflammation caused by the presence of foreign substances.

5. The use according to any one of claims 1 to 5, characterized in that, The dose of beta rays emitted by the drug is such that the dose at any point on the target is within 10% of the dose at any other point on the target.

6. The use according to any one of claims 1 to 6, wherein the radioactive isotope emitting beta rays comprises strontium-90 (Sr-90), phosphorus-32 (P-32), ruthenium-106 (Ru-106), yttrium-90 (Y-90), or a combination thereof.

7. The use according to any one of claims 1 to 7, wherein the MIGS implant is a flow-controlled drainage device.

8. The use according to any one of claims 1 to 8, wherein the radioactive isotope is applied to a target using an applicator, wherein the applicator comprises a handle and a distal portion and a cavity or connection portion for emitting the radioactive isotope of beta rays.

9. The use according to claim 8 further comprises a removable cap for temporarily shielding the radioactive isotope emitting beta rays.

10. A method for preparing an applicator for emitting beta rays, the method comprising: A beta-emitting radioactive isotope is inserted into a cavity in the applicator, the applicator comprising a handle and a distal portion having the cavity, wherein the beta-emitting radioactive isotope is configured to emit a radiation dose at a distance of 4 mm from its center, the radiation dose being at least 90% of the dose emitted from its center.

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