CN116887889A

CN116887889A - Radionuclide brachytherapy source system using beta radiation

Info

Publication number: CN116887889A
Application number: CN202180093940.8A
Authority: CN
Inventors: 劳伦斯·J·马斯泰勒; 大卫·乔克; 艾伦·张伯伦; 温德尔·卢茨; 詹姆斯·A·法齐奥; 马克·希尔顿; 约瑟夫·拉宾斯卡斯; 布莱恩·吉罗德
Original assignee: Guanghui Therapy Co; Illinois Tool Works Inc
Current assignee: Guanghui Therapy Co; Illinois Tool Works Inc
Priority date: 2020-12-17
Filing date: 2021-12-17
Publication date: 2023-10-13
Also published as: EP4262974A1; EP4262974A4

Abstract

Radionuclide brachytherapy sources and systems for applying beta radiation to a target area, e.g., for maintaining functional drainage bubbles or functional drainage holes in the eye, e.g., lowering intraocular pressure (IOP) of the eye undergoing glaucoma treatment. The system herein provides a substantially uniform dose over a particular area, thereby providing appropriate radiation therapy.

Description

Radionuclide brachytherapy source system using beta radiation

Cross Reference to Related Applications

The application claims the benefit of PCT application Nos. PCT/US2021/012694 and PCT application No. PCT/US 2021/012644 filed on 8 1/2021 and 8/2021, the entire disclosures of which are incorporated herein by reference. The PCT application also claims the benefit of U.S. provisional application No. 63/126,855, filed on even date 17 at 12/2020, the entire disclosure of which is incorporated herein by reference.

Background

Technical Field

The present application relates to Radionuclide Brachytherapy Sources (RBS), RBS systems and devices, and methods of applying beta radiation to a target. The RBS, RBS systems and methods described herein can be used to treat drainage blisters associated with glaucoma treatment, such as those associated with foreign body or other glaucoma surgery, to maintain the function of the blisters. The application is not limited to these applications.

Background

Glaucoma

Glaucoma is the leading cause of irreversible blindness and represents a series of diseases with characteristic optic neuropathy. Treatment of such diseases has focused mainly on lowering intraocular pressure (IOP) of intraocular fluids (aqueous humor), thereby avoiding sustained damage to the optic nerve.

Glaucoma is treated by attempts to lower intraocular pressure (IOP). In the united states, europe, and some other industrialized countries, first-line therapy is typically by eye drops. Such agents include beta blockers, prostaglandins, alpha adrenergic agonists, and carbonic anhydrase inhibitors. For patients who fail medication and for other parts of the world where economy and distribution of daily medication and frequent follow-up are impaired, the treatment regimen is primarily surgical intervention.

One way to prevent glaucoma vision loss is to reduce intraocular pressure by drainage by implantation of flow control drainage devices in Minimally Invasive Glaucoma Surgery (MIGS), or by using other surgical procedures such as minimally invasive microscleral ostomy (MIMS), trabeculectomy, or other devices whereby fluid is shunted out of the eye through a channel created during trabeculectomy. These systems and procedures allow aqueous humor to drain from the eye into a subconjunctival depot (known as a "bleb") from where it is subsequently reabsorbed.

With current glaucoma treatments (e.g., MIMS, MIGS, trabeculectomy, etc.), scar tissue often damages the blebs or other surrounding structures (e.g., the drainage channels associated with MIMS) ultimately impeding or blocking the flow of excess fluid. Despite the attractive therapeutic advantages over non-surgical treatments, drainage surgery and drainage devices remain clinically limited by post-operative scarring.

Attempts to solve this problem have included the use of antimetabolites such as mitomycin C (MMC) and 5-fluorouracil (5 FU). These antimetabolites are used in liquid form and are delivered by injection or by placement of microsurgical sponges immersed in the drug directly to the subconjunctival surgical site. One of the problems associated with antimetabolites (e.g., MMC and 5 FU) is that they do not retain vesicles well. Failure rates within three years are reported to be nearly 50%.

Beta ophthalmic applicator (Beta Ophthalmic Applicators)

Brachytherapy involves the placement of radioisotopes within or near the area in need of treatment, and has shown safety and efficacy in the clinical management of many diseases. Recently, it has surprisingly been found that β brachytherapy is an effective therapy for the treatment of glaucoma drainage vesicles.

Soares (Med Phys 1995,22 (9): 1487-1493) discloses a paper detailing the dosimetry of typical beta ophthalmic applicators that apply a disc-shaped beta RBS to the eye. The work by sores shows that by examining the surface plane isodose map, in most of these devices the dose delivered by radius drops sharply. The results of Soares are similar to earlier publications, such as Bahrassa and Datta (Int J Radiat Oncol Biol Phys 1983,9 (5): 679-84), which disclose that for a typical applicator, the dose at 3.5mm from the center point is only 50% of the maximum dose at the center point.

Typically, in a conventional beta applicator, it appears that about 90% of the center maximum dose falls only within about the inner 2mm diameter of the applicator disc. The dose appears to decrease significantly further out along the diameter of the applicator disc. The perimeter of such relative underdose is a substantial portion of the total irradiated surface area and a substantial portion of the irradiated target tissue volume. In addition, sores also exhibited irregular dose patterns, even though the differences between applicators of the same model were large (sores observed that the previously manufactured beta radiation source did not provide a uniform dose profile across the target area). Many applicators do not appear to have a maximum dose active portion that matches the center of the applicator.

Safety issues lead to narrowing of the treatment area of ophthalmic applicators for pterygium treatment by the addition of field-shaping masks that provide reduced focus application effects. In 1956, castroviejo (Trans Am Acad Ophthalmol Otolaryngol,1956,60 (3): 486) pushed out a series of four shielding masks designed to be snugly fitted to the end of the applicator. The mask is made of 0.5mm thick stainless steel which substantially blocks beta radiation, thereby confining the radiation to the cut-out area of the mask. These serve to reduce the effective surface area of the applicator. The mask provides a circular region of 3mm or 5mm diameter, and an elongate region of 2mm and 3mm width and 8.7mm length. The mask blocks approximately 93% of the radiation, limiting the emission of radiation to a small amount of radiation involving a small area (relative to the total surface area of the cap). The Castroviejo mask does not provide a uniform dose over the entire area of the disc applicator. Thus, the prior art of Castroviejo masks is ineffective for the irradiation application of glaucoma drainage vesicles.

Systems, devices, and methods of the present invention

The invention features systems, devices, and methods, such as Radionuclide Brachytherapy Sources (RBS), RBS systems, brachytherapy systems and devices, and methods of use, e.g., for applying radiation to a target (e.g., a treatment area). For example, the systems and devices herein may be used to apply beta radiation to a target region in an eye to help maintain functional blebs and/or drainage holes created by glaucoma drainage procedures or surgery to help avoid scarring or wound reversal, thereby inhibiting or reducing fibrosis and/or inflammation of the blebs or surrounding regions, and the like.

The present invention provides unique features for the treatment of conjunctival blebs to prevent and/or treat scarring using beta radiation in place of or in combination with an antimetabolite.

The present invention also provides unique technical features of delivering a more optimized dose distribution across the surface of the treatment area (target area) and/or within the treatment area (target area) compared to previously used devices.

Without wishing to limit the invention to any theory or mechanism, in certain embodiments, the term "optimized dose distribution" or "uniform dose" may refer to a dose within a region of a particular plane (e.g., a plane of a surface of a source or system (e.g., a source with a capping system), a plane on or within a target region or treatment region, etc.), which is substantially uniform, wherein the dose within the region of the particular plane does not vary by more than a percentage of a maximum dose (e.g., an average maximum dose of the particular plane, an average maximum dose of a treatment volume, etc.). The invention is not limited to a particular size of a region having a particular plane of substantially uniform dose, nor to any particular size of the target plane and depth of the target plane.

In certain embodiments, the term "optimized dose distribution" may also mean that the dose distribution is shaped in a specific pattern throughout the lesion to best influence the treatment outcome. In one example, the dose distribution across the diameter/plane at the treatment depth may be varied such that the area at the edge of the bubble receives a higher dose relative to the center. In one example, the dose distribution across the diameter/plane at the treatment depth may be varied such that the area at the exit orifice of the MIGS device receives increased dose compared to other areas. In one example, the dose distribution across the diameter/plane at the treatment depth may be varied such that both the bubble edge and the area at the exit orifice of the MIGS device receive increased doses. In one example, the dose decays over a designated area. In one example, the dose decays across the cornea.

Beta radiation decays rapidly with depth. In some embodiments, the term "optimized dose profile" includes an appropriate dose through the depth of the target tissue. The clinical dose depth may be determined by the thickness of the conjunctiva and the associated tenon's capsule of the functional bleb. For MIGS procedures, the focal region may be located about 3mm above the upper rim. Howlet et al found that the average thickness of conjunctiva and Tenong's layers in glaucoma patients was 393.+ -.67 microns, ranging from 194 to 573 microns using Optical Coherence Tomography (OCT) (Howlet J et al Journal of Current Glaucoma Practice 2014,8(s): 63-66). In earlier studies, zhang et al found that healthy individuals had a conjunctival thickness of 238.+ -.51 microns using OCT analysis, and concluded that OCT accurately measured the cross-sectional structure of conjunctival tissue at high resolution (Zhang et al Investigative Ophthalmology & Visual Science 2011,52 (10): 7787-7791). According to the Howlet study, the target tissue thickness may range from 150 to 700 microns, or from 10 to 700 microns, etc. In one example, the dose distribution from the target tissue surface to the target tissue depth allows the therapeutic dose within the tissue to reach the limit of rapidly decaying beta rays.

Disclosure of Invention

Surprisingly, specific therapeutic methods and systems that combine Minimally Invasive Glaucoma Surgery (MIGS) implants or Minimally Invasive Microsclerastomy (MIMS) and the like with the application of beta radiation are effective to maintain functional drainage blebs, e.g., by reducing or inhibiting scarring or wound repair caused by foreign matter, by inhibiting or reducing fibrosis and/or inflammation in the blebs, and the like. Experts in the field have long discouraged the use of beta radiation in the treatment of trabeculectomy glaucoma. However, beta radiation was found to be surprisingly effective in preventing bleb failure when used in conjunction with MIGS implants or MIMS surgery.

Unpredictability of the effect of beta radiation on MIGS implant foreign body induced scarring reactions or MIMS induced scarring reactions

There is no evidence that trabeculectomy and MIGS implantation or MIMS induced scar reactions are identical. Indeed, it is strongly believed that these reactions may be significantly different. Thus, one of ordinary skill in the art would be unable to predict how beta radiation would affect the scarring response caused by the MIGS implant or the MIMS procedure.

For example, since the MIGS implant is a foreign body implanted in the eye, there is a problem how the biocompatibility of the implant affects the scarring response. As one study comparing the different biomaterials of glaucoma drainage devices, "inflammatory response after implantation of different biomaterials in the subconjunctival space may be different and may lead to success or failure of surgery" (Ayyala et al, arch Ophthalmol.1999; 117:233-236). Regarding InnFocus The biocompatibility study of the implant indicated that: "fibrosis and inflammatory response by biological materials are considered to be major determinants of success. Other factors, such as shape, flexibility, modulus and texture, may also be associated with erosion, extrusion, inflammation and scarring. "(Acosta et.al.,Arch Opthalmol.2006；124；1742-1749)。

Another example of a recorded foreign body response problem is that "[ glaucoma filtration surgery (Glaucoma filtration surgery) ] often fails due to scarring. Various conjunctival implants have been developed to minimize scarring, but may lead to a foreign body response and capsule formation, resulting in reduced efficacy and poor pharmacokinetics "(Khaw et al, 2015,ARVO Poster Abstract).

Since it is expected that the scarring reactions for trabeculectomy (where no foreign body is implanted) and MIGS (where a foreign body is implanted) or MIMS (where a drainage channel is formed) will not be the same, it is not predicted how beta radiation will affect scarring of the MIGS device implant.

Teaching away from treatment of glaucoma using beta radiation

1. The industry expects mitomycin C (MMC) to be more efficient than beta radiation:

it is surprising to one of ordinary skill in the art that the selection of beta radiation rather than a liquid antimetabolite, as the prior art teaches that beta radiation is an antimetabolite that is less effective than mitomycin C (MMC) and is only similar in effectiveness to 5-fluorouracil (5 FU). Briefly, β radiation was reported to be approximately equivalent to 5FU as an antimetabolite for glaucoma drainage surgery, and MMC was reported to be superior to 5FU for the same purpose. MMC is therefore taught to be more effective than beta radiation as an antimetabolite for glaucoma drainage surgery. More specifically, the study in 2016 (Dhala et al 2016, PLoS ONE 11 (9): e 0161674) related to trabeculectomy type glaucoma surgery concluded that: first, there is no evidence of a difference between the use of 5FU and beta radiation as antimetabolites in phacoemulsification combined trabeculectomy (phacotrabeculectomy surgery). Furthermore, a review of Cochrane in 2015 by Cabourne et al (Cabourne et al 2015,Cochrane Database of Systematic Reviews Issue 11.Art.No: CD 006259) compares the effect of MMC and 5FU on wound healing in trabeculectomy glaucoma surgery, leading to the conclusion: "our review shows that subjects treated with MMC have a lower risk of failure of trabeculectomy within one year after surgery than subjects treated with 5-FU. "thus, the literature teaches that MMC is a more potent antimetabolite than beta radiation, since the effectiveness of beta radiation and trabeculectomy is shown to be similar to 5FU, and the effectiveness of 5FU is shown to be lower than MMC.

Furthermore, direct comparative studies on the use of mitomycin C (MMC) and beta radiation in pterygium surgery indicate that "intraoperative mitomycin C is more effective as an adjunct treatment for pterygium surgery using sliding conjunctival flaps than beta radiation" (Amano et al, 2000,British Journal of Ophthalmology 84:618-621). Thus, the prior art teaches away from using beta radiation, but teaches that MMC is a more potent antimetabolite.

2. It is expected that mitomycin C (MMC) provides a more comprehensive penetration (penetration) than beta radiation:

second, the use of beta radiation in place of liquid antimetabolites is surprising, as the prior art teaches that liquid antimetabolites are more suitable for dispersion over a wide treatment area. The importance of this broad therapeutic field is emphasized in the Moorfields safety surgical system developed by sir.pen Khaw (Khaw et al 2005,Glaucoma Today,March/April, 22-29). The publication describing this system states that previous focal treatments with MMC may result in "thin vesicles". One of the key components of the improved system is the treatment of "as large area as possible" with MMC. Importantly, the publication states that: "enlarging [ using MMC ] the treated surface area results in clinically more discrete non-cystic areas. It also prevents the development of steel loops that would otherwise restrict water flow and promote the development of raised cystic avascular. "

In sharp contrast to free-flowing and widely dispersed liquid antimetabolites, the use of beta radiation in ophthalmic applications has traditionally been very concentrated. The treatment area is set by the size of the applicator head, as repeatable doses require the applicator to remain in place for a specified period of time. Typical diameters of ophthalmic applicator heads are only around 10-14mm and only a small portion of the head includes an active diameter (reportedly ranging from 4.3 to 8.9 mm) (sores, 1995, med. Phys.22 (9), september, 1487-93). Even within the active diameter, the dose intensity drops rapidly with increasing distance from the dose centre.

Furthermore, beta radiation cannot penetrate tissue effectively, and is limited to treating only superficial areas near the center of the applicator. This is because the dose strength decreases rapidly with increasing distance from the applicator. For example: "beta radiation is applied during surgery using a radioactive applicator that emits beta radiation with very localized penetration only in a depth of less than one millimeter" (Kirwan et al 2012,Cochrane Database of Systematic Reviews Art.No: CD 003433).

Tests on ophthalmic applicators in sores et al show irregular dose patterns, even with the same type of applicator, that vary greatly. Many applicators do not even have a movable portion that matches the center of the applicator. In addition, safety issues lead to narrowing of the treatment area of the ophthalmic applicator for pterygium treatment, by the addition of a Castroviejo field shaping mask. The purpose of these masks is to provide a narrow focus application as taught by the Moorfields safety surgical system. The Moorfields safety surgical system is considered a standard of care.

Thus, while antimetabolites (e.g., MMC) are free-flowing liquid solutions that can be dispersed over a wide area, treatment by beta radiation has a much greater focal limit. The current teaching is that broad dispersion may be important for the formation of healthy diffuse bubbles (diffuse bleb). Beta radiation does not have the ability to be dispersed fluidically in tissue in the same way as MMC. Such limitations will prevent one of ordinary skill in the art from assuming that beta radiation can effectively treat a broad area currently being treated by liquid antimetabolite penetration (or deep holes created by MIMS surgery). Thus, the prior art teaches away from the use of beta radiation, but teaches that liquid antimetabolites provide more general and desirable treatments. It is surprising to use a treatment method that is long-term associated with topical application rather than a liquid that is readily dispersible.

3. Industry concerns beta radiation associated with cataracts:

third, the use of beta radiation rather than liquid antimetabolites is surprising, as correlation between beta radiation and cataracts has long been reported. Beta radiation is avoided in glaucoma treatment because the leading ophthalmic surgeons generally believe that beta radiation may cause cataracts. For example, in 2012 a review of four trials of randomly assigned 551 persons by Cochrane (Kirwan et al,2012,Cochrane Database ofSystematic Reviews Art.No: CD 003433), entitled "beta radiation for glaucoma surgery," concludes that "the risk of cataract to persons receiving beta radiation after surgery is increased. "as another example: merriam et al concluded that the minimum evoked cataract dose for single treatment of lens epithelium was 200cGy, and that the probability of cataracts at a dose of 750cGy was nearly uniform (see Merriam GR,1965,Trans Am Ophthalmol Soc.54:611-653, outlined by Kirwan et al, eye (2003) 17,207-215.Doi: 10.1038/sj.ey.6700306). This document clearly shows that the medical community teaches away from the use of beta radiation for the treatment of glaucoma.

In the same review of beta radiation in 2003, kirwan also describes some negative study reports on the use of beta radiation in ophthalmology. This overview emphasizes: "adverse reactions of beta radiation to pterygium have been widely reported. Early reports focused on lens clouding, conjunctival telangiectasia, and other side effects well above the dose clinically used after pterygium surgery, "and" the use of beta radiation for pterygium has been reduced, conjunctival autograft and topical mitomycin C are now widely used. "furthermore, kirwan reported adverse effects later in his own study on patients treated with beta radiation trabeculectomy, in addition to those noted by others.

Powerful, control and randomized studies on success of trabeculectomy glaucoma surgery with beta radiation were published by Kirwan in 2006. Notably, this study showed that the risk of cataract surgery (a known complication of trabeculectomy) in the beta radiating arm (beta radiation arm) increased "during the two years following surgery. Two years after the study, the risk of developing cataract in the radiation group requiring removal was 16.7%, and in the placebo group was only 3.2%. Kirwan states that "if β radiation increases the need for further surgery, the advantage of monotherapy using trabeculectomy is greatly reduced.

The previously acknowledged risk and subsequently observed incidence of cataracts following the application of beta radiation are strongly opposed to the use of beta radiation in glaucoma treatment. The results of the randomized controlled clinical trial showed a significant increase in cataract incidence associated with β therapy; kirwan authors call for "emergency study". Combination surgery (trabeculectomy plus beta radiation plus cataract extraction).

Ethical participation studies require commitment to common ethical specifications, such as those expressed in the declaration of helsinki and the report of bellevil. The world health organization (Research ethics committees: basic concepts for capacity-building.world Health Organization 2009) states that the research ethics committee reviews studies proposed using human participants to ensure that they meet internationally and locally recognized ethics guidelines. The local law governing the international ethics standards concerning research by human participants and many jurisdictions requires examination by the research ethics committee. In view of its role in identifying and assessing research risks and benefits, the research ethics committee must include individuals with scientific and medical expertise. In studies involving medical intervention, the research ethics committee must determine that sufficient care and treatment will be provided to the participants.

"research sponsored by the United States of America (USA)" no matter what circumstances the research is conducted in, must conform to the Common Rule (45 CFR 46), which defines and standardizes the scope and scrutiny of federally sponsored human subject research (https:// www.ncbi.nlm.nih.gov/PMC/arc les/PMC 3497553/0). The international coordination community (ICH) defines the Institutional Review Board (IRB) as a formally designated community that protects the rights, safety and happiness of people participating in clinical trials by reviewing all aspects of the trial and approving its initiation. IRBs may also be referred to as Independent Ethics Committees (IECs). IRB/IEC reviews the suitability of clinical trial protocols and study participants' risks and rights. RB/IEC members should be of collective qualification to review the scientific, medical and ethical aspects of the trial. IRB/IEC should have..at least five members..acceptable members that can Review and evaluate the scientific, medical aspects and ethics of the proposed trial, "(http:// www.ppdi.com/particulate-In-Clinical-three/becom-an-investor/Institutional-Review-Board). US21CFR Part 56 (22) (c) states "Institutional Review Board (IRB) refers to any board, board or other community formally designated by an institution to review, approve the initiation and periodic review of biomedical research involving human subjects. The main purpose of such screening is to ensure the protection of rights and welfare of human subjects. International and US specifications US21CFR section 56 section 56.107 states that "at least five members per IRB are required to meet the expertise required for a specific research activity, IRB should be able to determine acceptability of the proposed study in terms of institutional commitments and regulations, applicable law, and professional behaviours and practice standards. "in Grimes v. Kennedy Krieger Institute, inc. the Maryland court is therefore criticized, but the" Nerenburg code "is still known as the" most complete and authoritative statement "about the informed consent of human experiments (with added emphasis). The court then continues to reference several authors to support its general premise that the new's Law dictionary should be incorporated into the United states common law case to create a clear set of obligations to provide protection for human subjects, "(https:// www.ncbi.nlm.nih.gov/PMC/armtics/PMC 1069025).

Based on Kirwan studies of cataract augmentation in the β -therapy patient group, dhala investigated concomitant treatment regimens for β -therapy with phacoemulsification cataract extraction. Dhalla human clinical study patient's natural lens was surgically resected at β administration. The authors of this study considered that this regimen was also acceptable even in those patients who "if [ pre-existing ] cataracts did not lead to severe disability, and typically did not require surgical intervention". In other words, under normal circumstances, these patients will not receive cataract surgery because the local standard of care does not require surgical intervention. Dhalla β treatment regimens involve additional surgical intervention, i.e., removal of the patient's natural lens, as Kirwan studies have found that β radiation alone increases the incidence of cataracts.

The decision of the human research independent ethics committee provides immediate authoritative teaching when the Dhalla experimental study is approved for ethics, i.e., teaches away from using β -therapy as an independent adjunct to glaucoma filtration surgery.

It should be noted that the results of Dhalla experimental human studies were negative. "the study sample size calculation is based on the standard treatment of 5fu [5 fluorouracil ] with beta radiation detected. The disappointing results of the Dhalala study tell the medical community that β is not superior to the antimetabolite 5FU.

The industry desires antimetabolites (e.g., 5FU and MMC) to be more effective than beta radiation, and 5FU and MMC to provide more comprehensive penetration than beta radiation, and concerns that beta radiation is associated with cataracts, strongly teaching not to use beta radiation. Thus, it would be surprising to one of ordinary skill in the art that β radiation could be used with either MIGS implants or MIMS to maintain a functional drainage bulb to treat glaucoma.

Brief summary of the invention

The present invention provides a Radionuclide Brachytherapy Source (RBS) comprising a capsule having a distal surface, a proximal surface opposite the distal surface, and a sidewall; active beta radioisotope material encapsulated in a capsule in an annular configuration, the active beta radioisotope material emitting beta radiation through at least a portion of a distal surface of the capsule. In some embodiments, the capsule is cylindrical. In some embodiments, the capsule is kidney-shaped. The present invention is not limited to these shapes.

In some embodiments, the active beta radioisotope material is any source of beta radiation. In some embodiments, the active beta radioisotope material includes strontium 90 (Sr-90), phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90) (strontium 90 and yttrium 90 are in a long-term equilibrium state), an isotope of cesium, I-125, or a combination thereof. In some embodiments, the active beta radioisotope material includes strontium 90 in a long-term equilibrium state with yttrium 90. In some embodiments, the active beta radioisotope material is gamma rays or any source of X-rays or bremsstrahlung that provides radiation that is attenuated by substances having a linear energy transfer similar to beta radiation. In some embodiments, the capsule is composed of a material comprising stainless steel, gold, platinum, titanium, tantalum, titanium alloys, silver, tin, zinc, copper, nickel, aluminum, ceramic, glass, metal alloys, zirconium, or combinations thereof.

In some embodiments, the capsule has a diameter of 2 to 12mm. In some embodiments, the capsule has a diameter of 10.8mm. In some embodiments, the RBS is a sealed radiation source (radiological source) or radiation source (radioactive source).

In some embodiments, RBS emits beta radiation from the treatment surface to a treatment volume, the treatment volume having a diameter of 8 mm; the RBS system has a dosimetry curve (dosimetry profile) such that: all points across the diameter of the treatment volume at the treatment surface have a dose rate of 55-85 cGy/sec, all points across the diameter of the treatment volume at a depth of 0.6mm have a dose rate of 45-55 cGy/sec, all points across the diameter of the treatment volume at a depth of 1mm have a dose rate of 35-48 cGy/sec, and all points across the diameter of the treatment volume at a depth of 2mm have a dose rate of 17-25 cGy/sec.

In some embodiments, the system further comprises a forceps holder (forcep clip) disposed in or on the capsule proximal surface, the forceps holder being capable of engaging with the paired tines (prog) or forceps to allow collection of RBS. In some embodiments, the forceps holder is an indicator of the user, allowing the RBS to be preferably collected only from the proximal surface. In some embodiments, the tweezer clamp prevents insertion of the RBS into the cap system in a non-predetermined orientation. In some embodiments, the sidewall and forceps holder extend through the proximal surface of the capsule. In some embodiments, the forceps holder extends through the proximal surface of the capsule. In some embodiments, the forceps holder has at least a first side and a second side opposite the first side, wherein only the first side and the second side can be gripped by the forceps. In some embodiments, the forceps holder has at least a first side, a second side opposite the first side, and a third side, wherein the third side is not capable of being gripped by the forceps. In some embodiments, the forceps holder is recessed into the proximal surface of the capsule. In some embodiments, the forceps holder protrudes from the proximal surface of the capsule. In some embodiments, the forceps holder has a first side and a second side opposite the first side, wherein a first indentation is provided at an intersection of the first side and the proximal surface of the capsule and a second indentation is provided at an intersection of the second side and the proximal surface of the capsule. In some embodiments, the forceps holder is a ring. In some embodiments, the forceps holder is a protruding thread design. In some embodiments, the ring is used in conjunction with a threaded rod (threaded pole).

The invention also features a capping system for housing a Radionuclide Brachytherapy Source (RBS), the capping system comprising an interior cavity formed by a sidewall and a bottom surface sealed around its perimeter to a bottom edge of the sidewall, the interior cavity for receiving the RBS, wherein an equalizer (flattening filter) is provided on the bottom surface of the interior cavity, the equalizer reducing at least a portion of the beta radiation emitted from the RBS, thereby controlling an amount of beta radiation emitted from the bottom surface of the capping system.

In some embodiments, the homogenizer is integrated into the bottom surface of the cap system. In some embodiments, the homogenizer is a separate component for placement on or near the bottom surface of the cap system.

In some embodiments, the sidewall is cylindrical. In some embodiments, the sidewall or lumen has a diameter of 7 to 14 mm. In some embodiments, the sidewall or lumen has a diameter of 12mm or 13 mm. In some embodiments, the sidewall has a height measured from its bottom edge to its top edge of 4 to 12mm. In some embodiments, the sidewall has a height of 8.2mm measured from its bottom edge to its top edge.

In some embodiments, the system further comprises a ledge disposed in the cavity at the intersection of the bottom surface and the sidewall, the ledge facilitating the distribution of the weight of the RBS secured thereto. In some embodiments, the ledge is configured to be positioned 0.1mm above the top surface of the leveler. In some embodiments, a lip is provided along a top edge of a sidewall of the cap system.

In some embodiments, at least a portion of the cap system is composed of a material comprising a titanium alloy. In some embodiments, the material comprises grade 5 titanium (Ti 6 ai 4V). In some embodiments, the material comprises grade 23 titanium. In some embodiments, at least a portion of the cap system is composed of a material comprising a polymer. In some embodiments, the polymer comprises High Impact Polystyrene (HIPS). In some embodiments, the polymer comprises polycarbonate. In some embodiments, at least a portion of the cap system is constructed of a material comprising stainless steel.

In some embodiments, the cap system can be connected to a brachytherapy applicator handle. In some embodiments, the cap system includes threads for threadably engaging complementary threads of the brachytherapy applicator handle. In some embodiments, the cap system includes tines for engaging a snap feature on the brachytherapy applicator to connect to the brachytherapy applicator.

In some embodiments, the sidewall includes an inner layer and an outer layer, the outer layer being a sterile barrier. In some embodiments, the sidewalls are composed of a material comprising a metal, a metal alloy, a polymer, or a combination thereof. In some embodiments, the polymer comprises a plastic material. In some embodiments, the polymer comprises High Impact Polystyrene (HIPS). In some embodiments, the inner layer is composed of a shielding material of a particular electron density. In some embodiments, the shielding material comprises tantalum. In some embodiments, the outer layer is composed of a polymeric material. In some embodiments, the polymer comprises a plastic material. In some embodiments, the inner layer has a thickness of 0.35 mm. In some embodiments, the outer layer has a thickness of 0.5 mm. In some embodiments, the bottom surface, the leveler, or a combination thereof is composed of stainless steel or titanium. In some embodiments, the cap system (110) is reusable. In some embodiments, the cap system (110) is sterilizable.

In some embodiments, the sidewall is configured such that only less than 5Sv may pass. In some embodiments, the thickness of the sidewall is such that only 3% of the prescribed dose of RBS can pass. In some embodiments, the thickness of the sidewall is such that less than 3Sv can pass. In some embodiments, the thickness of the sidewall is such that less than 5Sv can pass.

The invention also features a capping system for housing a Radionuclide Brachytherapy Source (RBS), the capping system comprising an interior cavity formed by a sidewall and a bottom surface sealed around its perimeter to a bottom edge of the sidewall, the interior cavity for receiving the RBS, wherein an equalizer (flattening filter) is provided on the bottom surface of the interior cavity, the equalizer reducing at least a portion of the beta radiation emitted from the RBS, thereby controlling an amount of beta radiation emitted from the bottom surface of the capping system. In some embodiments, the system further comprises a brachytherapy applicator handle for engaging the capping system and receiving the RBS therebetween. In some embodiments, the leveler is composed of titanium. In some embodiments, the height of the homogenizer is 0.36mm relative to where the bottom surface of the cap system is within the lumen. In some embodiments, the cap system includes threads for threadably engaging complementary threads on the distal end of the brachytherapy applicator handle.

The invention also features a sidewall cap system including a cylindrical sidewall constructed of a dense material, wherein the sidewall blocks at least a portion of radiation from passing therethrough. In some embodiments, the dense material comprises a polymer, a metal, or a combination thereof. In some embodiments, the dense material comprises a powder or metal compounded in a polymer. In some embodiments, the system is biocompatible. In some embodiments, the outer surface of the system is biocompatible. In some embodiments, the system is sterilizable.

The invention also features a sidewall cap system including a cylindrical sidewall formed from an inner layer and an outer layer, the outer layer being formed from a material comprising a plastic material, the inner layer being formed from a tighter material than the outer layer, wherein the sidewall inhibits at least a portion of radiation from passing therethrough. In some embodiments, the inner layer comprises a polymer, a metal, or a combination thereof. In some embodiments, the inner layer comprises a powder or metal compounded in a polymer. In some embodiments, the inner layer is composed of a material comprising tantalum. In some embodiments, the outer layer is composed of a plastic material. In some embodiments, the outer layer of the system is biocompatible. In some embodiments, the system is sterilizable. In some embodiments, the inner layer has a thickness of 0.35 mm. In some embodiments, the outer layer has a thickness of 0.5 mm.

The invention also features a system including a Radionuclide Brachytherapy Source (RBS) including: a capsule having a bottom surface, a proximal surface opposite the bottom surface, and a sidewall; an active beta radioisotope material encapsulated in a capsule in an annular configuration, the active beta radioisotope material emitting beta radiation through at least a portion of a bottom surface of the capsule; a cap system housing the RBS, shaped and mated to conform to the conjunctival area of the general population, providing a sterile barrier for the patient, providing attenuation features to achieve more uniform dose delivery, providing sidewall radiation shielding for the patient, and complete assembly with the handle minimizing the occupied dose by operating room staff and authorized users; wherein the system emits beta radiation through at least a portion of an interface or bottom surface of the cap system, said portion of the interface or bottom surface of the cap system being an active surface area (S).

In some embodiments, the system further comprises a forceps holder disposed in or on the capsule proximal surface, the forceps holder being engageable with the tines of a pair of forceps to allow collection of RBS.

The invention also features a system including a Radionuclide Brachytherapy Source (RBS) including: a cylindrical capsule having a bottom surface, a proximal surface opposite the bottom surface, and a sidewall; and an active beta radioisotope material encapsulated in the capsule in an annular configuration, the active beta radioisotope material emitting beta radiation through at least a portion of a bottom surface of the capsule; wherein the capsule has a diameter of 10.8mm, wherein the activity of the RBS is 110mCi; a cap system comprising a 11.0mm sidewall cylindrical body connected to a bottom portion of minimum thickness of 0.25mm in certain regions, and a thicker portion having a thickness (constant or gradient thickness) ranging within 0.75mm defining a geometry (annular, trapezoidal, disk-shaped, pillar-shaped, etc. of different radii in single or multiple versions of the pattern), wherein the system emits beta radiation through at least a portion of the cap system' S interface or bottom surface, which is the active surface region (S).

Referring to any RBS system and radiation curve (radiation profile), dosimetry curve, radiation field, etc., there may be some degree of variation in dose rate. For example, in some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-2%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-5%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-7%. In some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-10%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-12%. In some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-15%. In some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-18%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-20%.

In some embodiments, the system or radiation field or dose distribution is characterized by the use of an attenuator (attenuator) to block a portion of the emission into the volume or plane. In certain embodiments, a feature of the system or radiation field or dose distribution is the use of modifications (e.g., attenuators, interfaces, any other means for modifying the dose output) to block a portion of the emission into the volume or plane.

As will be discussed herein, the present invention features an RBS system and a radiation field emitted from the RBS system. The radiation field is emitted into a treatment volume consisting of points (x, y, z), where z is the depth within the treatment volume relative to the RBS system, x is the distance from the centre point of the treatment volume in the x-direction at said depth, and y is the distance from the centre point of the treatment volume in the y-direction at said depth. In certain embodiments, the dose at point (x, y, z) is relative to the maximum dose in the treatment volume. In certain embodiments, the dose at point (x, y, z) is relative to the average maximum dose in the treatment volume.

Examples:HIPS cap: in some embodiments, for example in a system with a capping system (e.g., HIPS caps), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=0.19 mm) has a dose rate of ≡95%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.19 mm) has a dose rate of ≡90%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.19 mm) has a dose rate of ≡85%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.19 mm) has a dose rate of ≡76%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.19 mm) has a dose rate of ≡50%. In some embodiments, the dose at (0, 0) (where z=0.19 mm) is about ≡93% relative to the maximum dose.

In some embodiments, for example in a system with a capping system (e.g., HIPS caps), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=0.67 mm) has a dose rate of ≡68%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.67 mm) has a dose rate of ≡65%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.67 mm) has a dose rate of ≡60%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.67 mm) has a dose rate of ≡55%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.67 mm) has a dose rate of ≡36%. In some embodiments, the dose at (0, 0) (where z=0.67 mm) is about ≡65% relative to the maximum dose.

In some embodiments, for example, in a cap system (e.g., HIPS cap)In the system, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=0.94 mm) has a dose rate of ≡56%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.94 mm) has a dose rate of ≡54%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.94 mm) has a dose rate of ≡49%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.94 mm) has a dose rate of ≡40%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.94 mm) has a dose rate of ≡25%. In some embodiments, the dose at (0, 0) (where z=0.94 mm) is about ≡58% relative to the maximum dose.

In some embodiments, for example in a system with a capping system (e.g., HIPS caps), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=2 mm) has a dose rate of ≡30%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=2 mm) has a dose rate of ≡28%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=2 mm) has a dose rate of ≡26%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=2 mm) has a dose rate of ≡15%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=2 mm) has a dose rate of ≡22%. In some embodiments, the dose at (0, 0) (where z=2 mm) is about ≡30% relative to the maximum dose.

Referring to any RBS system and radiation curve, dosimetry curve, radiation field, etc., there may be some degree of variation in dose rate. For example, in some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-2%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-5%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-7%. In some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-10%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-12%. In some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-15%. In some embodiments, the dose rate (e.g., relative dose rate) may vary by +/-18%. In some embodiments, the dose rate (e.g., relative dose rate) may vary +/-20%.

Examples: titanium cap: in some embodiments, for example in a system with a capping system (e.g. a titanium cap), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=0.19 mm) has a dose rate of ≡90%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.19 mm) has a dose rate of ≡76%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.19 mm) has a dose rate of ≡78%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.19 mm) has a dose rate of ≡80%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.19 mm) has a dose rate of ≡50%. In some embodiments, the dose at (0, 0) (where z=0.19 mm) is about ≡85% relative to the maximum dose.

In some embodiments, for example in a system with a capping system (e.g. a titanium cap), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=0.67 mm) has a dose rate of ≡63%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.67 mm) has a dose rate of ≡55%. In some embodiments, relative to the maximum doseAccording to x ² +y ² The point of treatment volume =9 mm (where z=0.67 mm) has a dose rate of ≡54%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.67 mm) has a dose rate of ≡55%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.67 mm) has a dose rate of ≡40%. In some embodiments, the dose at (0, 0) (where z=0.67 mm) is about ≡65% relative to the maximum dose.

In some embodiments, for example in a system with a capping system (e.g. a titanium cap), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=0.94 mm) has a dose rate of ≡55%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.94 mm) has a dose rate of ≡52%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.94 mm) has a dose rate of ≡51%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.94 mm) has a dose rate of ≡49%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.94 mm) has a dose rate of ≡34%. In some embodiments, the dose at (0, 0) (where z=0.94 mm) is about ≡57% relative to the maximum dose.

In some embodiments, for example in a system with a capping system (e.g. a titanium cap), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=2 mm) has a dose rate of ≡30%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=2 mm) has a dose rate of ≡28%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=2 mm) has a dose of ≡26%The rate. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=2 mm) has a dose rate of ≡22%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=2 mm) has a dose rate of ≡14%. In some embodiments, the dose at (0, 0) (where z=2 mm) is about ≡30% relative to the maximum dose.

Examples: there is no cap: in some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=0.19 mm) has a dose rate of ≡90%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.19 mm) has a dose rate of ≡85%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.19 mm) has a dose rate of ≡80%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.19 mm) has a dose rate of ≡70%. In some embodiments, the dose at (0, 0) (where z=0.19 mm) is about ≡40% relative to the maximum dose. In some implementationsIn the examples, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.19 mm) has a dose rate of ≡65%.

In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=0.46 mm) has a dose rate of ≡68%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.46 mm) has a dose rate of ≡65%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.46 mm) has a dose rate of ≡60%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.46 mm) has a dose rate of ≡55%. In some embodiments, the dose at (0, 0) (where z=0.46 mm) is about ≡65% relative to the maximum dose. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.46 mm) has a dose rate of ≡60%.

In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=0.67 mm) has a dose rate of ≡58%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.67 mm) has a dose rate of ≡58%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.67 mm) has a dose rate of ≡56%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.67 mm) has a dose rate of ≡49%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.67 mm) has a dose rate of ≡28%. In some embodiments, the dose at (0, 0) (where z=0.67 mm) is about ≡55% relative to the maximum dose.

In some embodiments, relative toMaximum dose according to x ² +y ² The point of treatment volume =1 mm (where z=0.94 mm) has a dose rate of ≡53%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.94 mm) has a dose rate of ≡50%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.94 mm) has a dose rate of ≡46%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.94 mm) has a dose rate of ≡40%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.94 mm) has a dose rate of ≡25%. In some embodiments, the dose at (0, 0) (where z=0.94 mm) is about ≡53% relative to the maximum dose.

In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=1.51 mm) has a dose rate of ≡27%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4mm (where z=1.51 mm) has a dose rate of ≡35%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=1.51 mm) has a dose rate of ≡33%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=1.51 mm) has a dose rate of ≡29%. In some embodiments, the dose at (0, 0) (where z=1.51 mm) is about ≡38% relative to the maximum dose. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=1.51 mm) has a dose rate of ≡195%.

In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=2 mm) has a dose rate of ≡27%. In some embodiments, relative to the maximum dose, according to x ² +y ² Treatment of =4mmThe point of treatment volume (where z=2mm) has a dose rate of ≡25%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=2 mm) has a dose rate of ≡23%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=2 mm) has a dose rate of ≡18%. In some embodiments, the dose at (0, 0) (where z=2 mm) is about ≡28% relative to the maximum dose. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=2 mm) has a dose rate of ≡12%.

Examples: MCNP, cap: in some embodiments, for example in a system with a capping system (e.g., HIPS caps), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=0.24 mm) has a dose rate of ≡85%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.24 mm) has a dose rate of ≡98%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.24 mm) has a dose rate of ≡94%. In some embodiments of the present invention, in some embodiments,relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.24 mm) has a dose rate of ≡90%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.24 mm) has a dose rate of ≡48%. In some embodiments, the dose at (0, 0) (where z=0.24 mm) is about ≡60% relative to the maximum dose.

In some embodiments, for example in a system with a capping system (e.g., HIPS caps), the maximum dose is calculated according to x ² +y ² The point of treatment volume =1 mm (where z=0.56 mm) has a dose rate of ≡70%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.56 mm) has a dose rate of ≡78%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.56 mm) has a dose rate of ≡75%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.56 mm) has a dose rate of ≡67%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.56 mm) has a dose rate of ≡38%. In some embodiments, the dose at (0, 0) (where z=0.56 mm) is about ≡60% relative to the maximum dose.

Examples: MCNP without cap: in some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=0.24 mm) has a dose rate of ≡95%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.24 mm) has a dose rate of ≡98%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.24 mm) has a dose rate of ≡98%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.24 mm) has ≡88%Dose rate. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.24 mm) has a dose rate of ≡55%. In some embodiments, the dose at (0, 0) (where z=0.24 mm) is about ≡94% relative to the maximum dose.

In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =1 mm (where z=0.56 mm) has a dose rate of ≡80%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =4 mm (where z=0.56 mm) has a dose rate of ≡82%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =9 mm (where z=0.56 mm) has a dose rate of ≡80%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =16 mm (where z=0.56 mm) has a dose rate of ≡68%. In some embodiments, relative to the maximum dose, according to x ² +y ² The point of treatment volume =25 mm (where z=0.56 mm) has a dose rate of ≡44%. In some embodiments, the dose at (0, 0) (where z=0.56 mm) is about ≡81% relative to the maximum dose.

The invention also includes a radiation field as described above having a relative dose rate variation of up to 20%. The invention also includes the above-described radiation fields having a relative dose rate variation of up to 15%. The invention also includes the above-described radiation fields having a relative dose rate variation of up to 10%. The invention also includes the above-described radiation fields having a relative dose rate variation of up to 5%. The present invention also includes the above-described radiation field having a variation defined by a gamma function as having a value of 1 or less. The invention also features an RBS system having a dosimetry curve having a gamma function value of 1.0 or less when compared to the dosimetry curve described above, wherein the gamma function value constraint is 20% at 1.6 mm. The invention also features an RBS system having a dosimetry curve having a gamma function value of 1.0 or less when compared to the dosimetry curve described above, wherein the gamma function value constraint is 10% at 1 mm. The gamma function may analyze the difference between the measured value and its reference value, which is compressed into a number that combines the dose error in the intra-field region and the position error in the half-shadow region on the basis of a normalized vector.

The invention is also characterized by a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% of the maximum dose; wherein there is a dose rate of 60-75% across all points on the volumetric plane at a depth of 0.67mm relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein a point within the volume has a dose rate relative to a maximum dose rate of 100% at the surface. In some embodiments, all points across the volumetric plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% maximum dose. In some embodiments, there is a dose rate of 60-75% across all points of the volume plane at a depth of 0.67mm, relative to 100% maximum dose. In some embodiments, all points across the volume plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose. In some embodiments, all points across the volume plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein a point within the volume has a dose rate relative to a maximum dose rate of 100% at the surface. In some embodiments, all points across the volumetric plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% maximum dose; all points across the volumetric plane at a depth of 0.67mm do not vary by more than 20% of the average dose across the plane; all points across the volumetric plane at a depth of 0.94mm do not vary by more than 20% of the average dose across the plane; and all points across the volumetric plane at a depth of 1.99mm do not vary by more than 20% of the average dose across the plane.

The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein a point within the volume has a dose rate relative to a maximum dose rate of 100% at the surface. In some embodiments, all points across the volumetric plane at a depth of 0.19mm have a dose rate of 70% -100% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.67mm have a dose rate of 55-70% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.94mm have a dose rate of 45-65% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-40% relative to 100% maximum dose.

In some embodiments, all points across the volumetric plane at a depth of 0.19mm have a dose rate of 75% -100% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.67mm have a dose rate of 50-70% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-70% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 1.99mm have a dose rate of 25-45% relative to 100% maximum dose.

The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate of 100% of the maximum dose rate relative to the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 70% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 0.94mm do not vary by more than 20% of the average dose across said plane; wherein all points of the volumetric plane at a depth of 1.99mm do not vary by more than 20% of the average dose of said plane.

The invention also includes a radiation field as described above having a relative dose rate variation of up to 20%. The invention also includes the above-described radiation fields having a relative dose rate variation of up to 15%. The invention also includes the above-described radiation fields having a relative dose rate variation of up to 10%. The invention also includes the above-described radiation fields having a relative dose rate variation of up to 5%. The present invention also includes the above-described radiation field having a variation defined by a gamma function as having a value of 1 or less. The invention also features an RBS system having a dosimetry curve having a gamma function value of 1.0 or less when compared to the dosimetry curve described above, wherein the constraint of the gamma function value is 20% at 1.6 mm. The invention also features an RBS system having a dosimetry curve having a gamma function value of 1.0 or less when compared to the dosimetry curve described above, wherein the constraint of the gamma function value is 10% at 1 mm.

The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes. The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes. The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 19mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

The invention is also characterized by a RBS system and a radiation field emitted from the RBS system from a surface into a volume having a diameter of 8mm and a depth of 2mm, wherein a point within the volume has a dose rate relative to a maximum dose rate of 100% at the surface. In some embodiments, all points of the volumetric plane at a depth of 0.19mm crossing have a dose rate of 65% -100% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.67mm have a dose rate of 50-65% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-30% relative to 100% maximum dose.

In some embodiments, all points across the volumetric plane at a depth of 0.19mm have a dose rate of 70% -100% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.67mm have a dose rate of 50-70% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 0.94mm have a dose rate of 45-65% relative to 100% maximum dose. In some embodiments, all points across the volumetric plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

The invention is also characterized by a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate of 100% of the maximum dose rate relative to the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 65% -100% relative to the 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 0.94mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 1.99mm do not vary by more than 20% of the average dose across said plane.

The invention is also characterized by a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes. The invention is also characterized by a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes. The invention is also characterized by a radiation field emitted from the RBS system from the surface into a volume having a diameter of 19mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

As will be described in detail herein, the present invention provides a system for applying beta radiation to a target. The brachytherapy system may include a Radionuclide Brachytherapy Source (RBS) for providing beta radiation delivered to the target, and an interface (e.g., a capping system) that selectively attenuates the radiation to provide a dose curve throughout the Planned Treatment Volume (PTV). Other properties may be provided by the interface or cap system. For example, an interface or cap system may be used as an enclosure (enclosure) for the RBS. The cap may provide a sterile surface for contact with a patient. The interface or cap system may provide lateral radiation shielding to reduce radiation to adjacent tissue. The interface or cap system may provide features that allow for destructive removal thereof for disposable applications. In some embodiments, the system includes an applicator and the cap is a removable cap.

The RBS of the present invention is constructed in a manner that complies with federal regulations, but is not limited to the terminology mentioned in that regulation. For example, the RBS of the present invention may further comprise a substrate. In addition, for example, in addition to being surrounded by the mentioned "gold, titanium, stainless steel, or platinum", in some embodiments, the radionuclides (isotopes) of the present invention may be surrounded by a combination of one or more of "gold, titanium, stainless steel, or platinum". In some embodiments, the radionuclides (isotopes) of the present invention may be surrounded by one or more layers of inert materials comprising silver, gold, titanium, stainless steel, platinum, tin, zinc, nickel, copper, other metals, ceramics, glass, or combinations thereof.

In some embodiments, RBS includes a substrate, a radioisotope (e.g., sr-90, Y-90, rh-106, P-32, isotopes of cesium, I-125, etc.), and a capsule or encapsulation (encapsulation). In some embodiments, the isotope is coated on the substrate, and both the substrate and the isotope are further coated by the encapsulation. In some embodiments, the radioisotope is embedded in a substrate. In some embodiments, the radioisotope is part of a base matrix. In some embodiments, the encapsulation may be coated onto the isotope, and optionally onto a portion of the substrate. In some embodiments, the encapsulation is coated around the entire substrate and isotope. In some embodiments, the encapsulation encloses the isotope. In some embodiments, the package encloses the entire substrate and isotope. In some embodiments, the radioisotope is a separate fragment and is sandwiched between the package and the substrate. The substrate may be composed of a variety of materials. For example, in some embodiments, the substrate is composed of a material comprising silver, aluminum, stainless steel, tungsten, nickel, tin, zirconium, zinc, copper, a metallic material, a ceramic matrix, or the like, or a combination thereof. In some embodiments, the substrate functions to shield a portion of the radiation emitted from the isotope. The package may be constructed of a variety of materials, such as one or more layers of an inert material comprising steel, silver, gold, titanium, platinum, another biocompatible material, and the like, or combinations thereof.

The systems herein are configured to provide a substantially uniform dose of radiation across the target, e.g., across a particular diameter of the target volume and through a particular depth of the target volume. The present invention may provide a more uniform dose across the target area relative to other sources, e.g., no excess center. The present invention is not limited to the dosimetry curves shown or described herein.

In some embodiments, one or more components (e.g., caps) of the present invention are composed of a material that may further shield the user from the RBS. In some embodiments, materials with low atomic numbers (Z) may be used for shielding (e.g., polymethyl methacrylate). In some embodiments, materials with high atomic numbers (Z) may be used for shielding (e.g., iron alloys, gold, lead, tungsten, tantalum, etc.). In some embodiments, one or more layers of material are used for shielding, where one layer includes a material having a low atomic number and another layer includes a material having a higher atomic number. In some embodiments, one or more layers of material are used for shielding, where the outer layer comprises a material having a low atomic number (e.g., high Impact Polystyrene (HIPS)) and having biocompatibility and sterilizable properties, and the inner layer has a high atomic number. In some embodiments, the shield contains a high Z material suspended in a low Z polymer. In some embodiments, the shield contains tungsten powder suspended or formed in a polymeric carrier.

In one embodiment, the system includes a compatible RBS, cap, and handle. In turn, the RBS comprises a ceramic substrate shaped as a ring; the ceramic ring contains the radioisotope Sr-90 in a long-term equilibrium with Y-90. The ceramic ring is encapsulated in a titanium alloy capsule. The titanium alloy capsule has recessed protrusions (recessed protuberance) on its proximal surface for forceps to grasp the RBS. The cap sidewall is composed of layers of different materials. The cap includes sidewalls of high z shielding material. The high z shielding material is a tantalum ring for attenuating radiation. The outer layer of the cap is a low z polymer. The low z polymer is HIPS. HIPS provides a biocompatible and sterilizable exterior surface for contacting a patient. The cap also includes a distal interface. The interface provides differential radiation attenuation across its surface. Differential radiation attenuation is provided by annular regions of thicker material. The cap also has a split snap HIPS feature. The handle engages the cap, and then a twist-off (twist break) cap is required to release the handle to restore the RBS.

In one embodiment, the system includes a compatible RBS and cap having sidewall attenuation features. In one experiment, it was found that for a prescribed dose of radiation at a center point of 0.2mm depth, the sidewall dose delivered laterally to adjacent non-target tissue (e.g., eyelid) was 14.5% of the prescribed dose. When the cap is secured with sidewall attenuation, the attenuation sidewall features reduce the sidewall lateral dose to 2.1% of the prescribed dose.

This reduction in lateral dose is significant in terms of numerical reduction, compliance with regulatory requirements, and significant clinical relevance. The decaying sidewall feature reduces the dose of adjacent tissue by a factor of about seven; regulatory requirements reduce radiation to a reasonable implementation (ALRA); with significant clinical benefit as described below.

The present invention provides clinically significant dose reduction. The ophthalmic beta radiation prescription consisting of 3 fractions of 800cGy per week is reported by Wilder et al in International Journal of Radiation Oncology Biology Physics Volume 23,Issue 3,1992,Pages 533-537. The total dose was 24Gy. For such prescribed doses using compatible RBCs, the unshielded sidewall dose delivered laterally to adjacent non-target tissue (e.g., eyelid) is approximately 3.5Gy, corresponding to 3.5Sv (hubert). As a possible result, wolbarst indicates in Radiology: volume 254: number 3-March 2010 that the threshold dose for temporary dehairing (temporary epilation) is about 3-5 Sv. Patients will be at risk of losing adverse events of their lashes. While the dose with cap attached provided sidewall attenuation, the dose applied to the eyelid was reduced to 2.1% of the prescribed dose, i.e. 0.5Gy corresponds to 0.5Sv. This decaying lateral dose is well below the dehairing threshold reported by Wolbarst. The decaying sidewall is clinically effective in reducing the risk of adverse events in the patient.

In one embodiment, the system includes a compatible RBS and an interface or cap system. RBS is a radiation source, and the interface or capping system provides differential attenuation. The system generates a planned output radiation dose field. The system generates a resulting radiation field that is depicted and defined by a series of vertical dose maps in the map. The proximal planar surface dose has been optimized for large area treatment volumes. The subsequent planar field at the far end of the RBS face is also depicted and defined by the vertical dose map in the figure.

The resulting planned region provides a dose distribution within the PTV that was found to be necessary to cause down-regulation of fibroblasts in the conjunctiva. The planning field has a large area TV (e.g., z=0.2 mm) in the proximal plane. The planned depth of field dose may also provide a sufficiently stable dose at a deeper treatment depth (e.g. z=0.6 mm).

The consistency of the dose curve with the designed radiation field can be quantitatively compared using gamma function analysis. The gamma function analyzes the difference between the measured value and its reference value, which is compressed into a number that combines the dose error in the usual intra-field region and the position error in the half-shadow region on the basis of a normalized vector.

The nuclear regulatory committee defines misuse of prescribed radiation doses when the difference delivered is greater than 20% of the prescribed dose. Gamma function analysis (BistroMath) may be used, for example, with a test parameter of 20%, a distance variation of 20% over a Treatment Volume (TV) (=1.6 mm) of about 8mm diameter, and a gamma set to less than 1 to define a coincidence with the designed radiation field. In some embodiments, the radiation dose at any point within the Treatment Volume (TV) conforms to a pattern within a gamma function of less than or equal to 1 over a range of test parameters (e.g., up to 20% dose change, within 1.6mm distance change, up to 10% dose change and within 1mm distance change, up to 25% dose change and within 2mm distance change, etc.).

As a result, it was found that for a prescribed dose of radiation at a center point of 0.2mm depth, the sidewall dose delivered laterally to adjacent non-target tissue (e.g., eyelid) was 14.5% of the prescribed dose. When the cap is secured with sidewall attenuation, the attenuation sidewall features reduce the sidewall lateral dose to 2.1% of the prescribed dose.

The invention features a brachytherapy system for applying radiation to a target area. While the present invention describes the use of systems and devices for treating glaucoma drainage bleb tissue or drainage holes, e.g., to help avoid scarring or wound reversal, to inhibit or reduce fibrosis and/or inflammation in the blebs or holes, etc., the invention is not limited to the use disclosed herein.

The present invention provides a substantially uniform distribution of radiation from a system, such as an RBS system. The radiation distribution emitted by the brachytherapy applicator can be determined (e.g., shaped) by an equalizer or attenuation assembly, a capping system, and/or an RBS. In certain embodiments, the manner of design or inclusion of features of the RBS and/or internal sources helps determine (e.g., optimize) the distribution of β radiation dose to the target region (e.g., the target plane of the treatment region). In certain embodiments, the cap system includes features that help determine (e.g., optimize) the distribution of β radiation dose to a target region (e.g., a target plane of a treatment region). The radiation attenuating features (or radiation shaping features, homogenizers, etc.) may be integrated into the cap system, or they may be separate units from the cap system and/or RBS.

As used herein, the dose may be defined as the dose in water or the dose in water equivalent plastic (e.g., plastic water), or the dose in tissue.

Any feature or combination of features described herein is included within the scope of the present invention, provided that the features contained in any such combination are not mutually inconsistent as will be apparent from the context, this specification and the knowledge of one of ordinary skill in the art. Other advantages and aspects of the invention will be apparent from the following detailed description and from the claims.

Terminology

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed invention belongs. The singular terms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the word "or" is intended to include "and" unless the context clearly indicates otherwise. The term "comprising" means that other elements may be present in addition to the elements of the given definition. The use of "including" means including, but not limiting. In other words, the term "comprising" means "including, but not exclusively," including. Furthermore, variants of the word "comprising", such as "comprising" and "comprises", have correspondingly the same meaning. In one aspect, the technology described herein relates to the compositions, methods, and their respective components described herein that are essential to the invention, and may also contain unspecified essential or non-essential elements ("contain").

All embodiments disclosed herein can be combined with other embodiments unless the context clearly indicates otherwise.

Suitable methods and materials for practicing and/or testing embodiments of the present disclosure are described below. Such methods and materials are illustrative only and not intended to be limiting. Other methods and materials similar or equivalent to those described herein can also be used. For example, conventional methods well known in the art to which the present disclosure pertains are described in various comprehensive and more specific references.

Dose measurementThe determination technique includes thin film dosimetry. In one example, the RBS is applied to radiographic film, e.g. Gafchromic ^TM Film. Or by placing an intermediate material of known thickness (e.g. plastic water) between RBS and film ^TM ) To measure dosages at different depths. The transport densitometer, in combination with a plot of optical density versus dose for the film, can measure the opacity of the film, which can then be converted to the dose delivered. Other methods include thermoluminescence methods (TLD chips). The TLD chip is a small plastic chip with millimeter dimensions with a lattice that absorbs ionizing radiation. The dose is always defined in the medium, e.g. water, tissue, plastic water; if not specified, it is often referred to as water.

Dose variation is described as the variation across the diameter assuming a maximum dose at the center point. However, it has in practice been shown that the maximum dose may be off-centre. Thus, the description of the dose variation over the whole diameter may also include the dose variation over the whole area as well as over the depth.

The term "conjunctiva" as commonly used in the field of ophthalmology may refer to the combination of conjunctiva with Tenon's capsule. In addition, the term "conjunctiva" as commonly used in the ophthalmology industry may refer to just conjunctiva, excluding the ternon's sac. References herein to "conjunctiva" may include either and/or both meanings.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes. In case of conflict, the present specification, including definitions of terms, will control.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosed techniques, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and not intended to be limiting.

In order to facilitate a review of the various embodiments of the present disclosure, the following explanation of specific terms is provided:

Beam correction: the spatial distribution of the radiation (e.g., within the patient) is desirably modified by inserting any material in the beam path. The beam modification increases consistency, allowing higher doses to be delivered to the target while retaining more normal tissue. There are four main types of beam modification: (1) protection: the radiation dose to some specific part of the area where the beam is directed is eliminated. It is commonly used to make low melting point alloy (Lipowitz metal or Cerroblend) shields that are custom-made for individual patients and are used to shield normal tissues and critical organs. For example, during whole body irradiation (TBI), custom shields are placed in front of the lungs to reduce radiation dose. (2) compensation: when the beam is tilted through the body or there are different types of tissue, normal dose distribution data is allowed to be applied to the treatment area. (3) wedge filtration: where a special tilt is obtained on the isodose curve. (4) planarization: the spatial distribution of the natural beam is changed by reducing the central illumination intensity relative to the periphery. Typically, a beam flattening filter is used that reduces the center illumination intensity relative to the illumination intensity near the beam edge. This technique is used for linear accelerators. The filter is designed such that the thickest part is located in the middle. These are typically made of copper or brass.

Brachytherapy (see also Radionuclide Brachytherapy Source (RBS)): according to the american society of medical physics (AAPM), brachytherapy is "clinical use of small packaged radioactive sources for irradiating malignant tumors or non-malignant lesions at a short distance from the target volume". According to federal regulations, a Radionuclide Brachytherapy Source (RBS) is a "device consisting of a radionuclide that can be packaged in a sealed container made of gold, titanium, stainless steel or platinum gold and used for medical purposes for placement in a body surface or cavity or tissue as a therapeutic nuclear radiation source". Other forms of brachytherapy sources are also used in practice. For example, a commercially available conformal source (conformal source) is a flexible film made of a polymer that is chemically bonded to phosphorus 32 (P-32). Another product is glass microspheres (TheraSphere), a radiation therapy for hepatocellular carcinoma (HCC), which consists of millions of tiny radioactive glass microspheres (20-30 microns in diameter) containing yttrium 90. Other forms of brachytherapy use an X-radiation generator as a radiation source instead of a radioisotope.

In general, in medical practice, brachytherapy can be classified into local or plaque brachytherapy, intracavity radiation therapy, and interstitial radiation therapy.

Some implementations of brachytherapy employ permanently implanted RBSs. For example, in Low Dose Rate (LDR) brachytherapy for prostate cancer, as a standard of care, radioiodine 125RBS is placed directly in the prostate and is not retained indefinitely.

In another implementation, high Dose Rate (HDR) brachytherapy theraspleens is injected into an artery feeding a liver tumor. These microspheres were then embolized into the capillaries of the liver and infiltrated malignant tumors with high levels of yttrium 90 radiation. In both implementations, the total dose is determined by consuming the entire radioisotope.

Some other implementations of brachytherapy employ instantaneous placement of the RBS. For example, in post-loading High Dose Rate (HDR) brachytherapy, very small plastic catheters are placed into the prostate and a series of radiation treatments are performed through these catheters. A computer controlled machine pushes individual highly radioactive iridium-192 RBS one by one into the catheter at the entire radiation-referenced location at prescribed dwell times. The catheter can then be easily withdrawn and no radioactive material is present on the prostate.

Another example of instantaneous RBS placement includes prophylactic treatment of coronary 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 an HDR radiation source into the catheter and holding there for a predetermined time in order to deliver a sufficient dose to the vessel wall.

Functional drainage foam: aqueous humor is effectively drawn from the eye to reduce the intraocular pressure (IOP) of the eye to an appropriate level of bubbles.

Early bubble classification systems included those proposed by Kronfeld (1969), migdal and hitmings (1983), picht and greenn (1998). Subsequent bubble classification systems determine and incorporate a hierarchical assessment of various bubble parameters such as vessel, height, width, microcapsule variability, encapsulation, and dispersion/calibration area.

There are recently two described grading systems for clinical grading of surgical blebs: moorfield foam grading System (MBGS) and Indiana foam appearance grading Scale (IBAGS). MBGS builds on the system used for telemedicine studies and extends it to include methods of assessing vascularity away from the center of the blebs and representing mixed-morphology blebs. In this protocol, the central region (1-5), the maximum region (1-5), the bleb height (1-4) and subconjunctival blood (0-1) were evaluated. Furthermore, the blood vessel grades were graded for three regions of blebs, respectively, including bleb central conjunctiva, outer Zhou Jiemo, and non-bleb conjunctiva. The vessel score for each region was 1 to 5. A study found that IBAGS and MBGS had good agreement and clinical reproducibility between observers (Wells AP, ashraf NN, hall RC, et al Comparison of two clinical bleb grading systems.Ophthalmology 2006; 113:77-83).

Since the importance of bubble appearance to the results was perceived, a Moorfield (Moorfield) bubble classification system was developed. The risk of bleedout, delayed hypotonic, and vision-related bleedout-related infections increases with the formation of thinner avascular areas.

Indiana bulb appearance grading scale is a system for classifying the morphological slit lamp appearance of a filter bulb. The Indiana bleb appearance rating scale contains a set of photographic standards that describe a range of filtered bleb morphologies selected from the slide library of the Indiana university ophthalmic glaucoma service center. These criteria include slit lamp images for grading bubble height, extent, vascularity, and leakage by Seidel test. For grading, the morphology of the blebs was evaluated for 4 parameters relative to the standard image and scored accordingly.

For reference, failed or failed blebs may have a "restricted backward flow with a so-called 'steel loop'", e.g., scar tissue or a fibrotic loop adhering the conjunctiva to the sclera at the periphery of the blebs (see Dhinrra S, khaw PT. The Moorfields Safer Surgery System. Middle East African Journal of Ophtalmology 2009;16 (3): 112-115). Other attributes of a failed or failed bleb may include changes in the cystic appearance and/or vascularization and/or scar tissue and/or conjunctival thinning and/or tightening of the capped bleb and/or other observable or measurable changes in the Indiana bleb appearance grading scale or morfield (morfield) bleb grading system. Other functional determinants of failed or failed bleb or glaucoma surgery may include increased IOP or insufficient lowering of IOP.

Planned treatment volume or Planned Target Volume (PTV): including all areas or volumes of tissue to be irradiated. The PTV includes a clinical target volume or a Clinical Treatment Volume (CTV).

Radioisotope (Radioactive isotope), radionuclide (radionucleotide), radioisotope (radioisotope): a radioisotope, known as a radionuclide or radioisotope, is an element that has an unstable nucleus and emits radiation when it decays to a stable form. There may be several steps to decay from the radionuclide to the stabilization nucleus. There are four types of radioactive decay: alpha, beta negative, beta positive and electron capture. The daughter nuclei may emit gamma rays upon deactivation after the decay process. In addition, there is fission. The nuclei can emit X-rays, bremsstrahlung and auger electrons in the de-excitation after the decay process, and annihilation radiation, X-ray fluorescence, compton scattered photons and bremsstrahlung are generated in the surrounding material. These emissions are considered ionizing radiation because they are strong enough to release electrons from another atom.

Five types of radioactive decay can be considered: alpha, beta negative, beta positive (positron), electron capture and fission. The nuclei can emit gamma rays, X-rays, bremsstrahlung and auger electrons in de-excitation after the decay process, as well as annihilation radiation, X-ray fluorescence, compton scattered photons and bremsstrahlung in surrounding material. These emissions are considered ionizing radiation because they are strong enough to release electrons from another atom.

The therapeutic radionuclide may occur naturally or may be produced artificially, for example by a nuclear reactor or a particle accelerator. After natural decay, the daughter isotope is separated from the parent isotope using a radionuclide generator.

Non-limiting examples of radioisotopes after one of five decay processes are given herein: (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 positive: fluorine 18, sodium 22, yttrium 88; (4) electron capture: iodine 125, palladium 103; (5) fission: plutonium 239, californium 252. Examples of these decay modes accompanied by gamma radiation include americium 241, selenium 75, iridium 192, and cesium 137.

Half-life is defined as the time required for half of the atoms of the radioactive material to decompose. The half-life of various radioisotopes may range from a few microseconds to billions of years.

The term activity during radioactive decay refers to the number of disintegrates per second. The units of measure of activity in a given source are curie (Ci) and beckle (Bq). One (1) beckle (Bq) is disintegrated once per second. The older unit is Curie (Ci), where one (1) Ci is 3.7X10 ¹⁰ Bq(3.7E10Bq)。

The term "beta radiation source (beta radiation source)" or "beta radiation source (source of beta radiation)" may refer to the term "radioisotope". In any of the methods or compositions herein, the radioisotope or beta radiation source may include phosphorus 32 (P-32), ruthenium 106 (Ru-106) in long-term equilibrium with rhodium 106 (Rh-106), yttrium 90 (Y-90), strontium 90 (Sr-90) in long-term equilibrium with yttrium 90 (Sr-90), an isotope of cesium (e.g., cs-131), I-125, or other radionuclides, or a combination thereof. The invention also includes sources that emit beta or positron and gamma rays or X-rays or bremsstrahlung. The invention also includes sources that emit low energy photons (e.g., soft X-rays) that attenuate similarly to beta rays in soft tissue (see, e.g., lee et al, 2008, med. Phys.35 (11) 5151-5160).

Radionuclide Brachytherapy (RBS) (see also brachytherapy): according to federal regulations, a Radionuclide Brachytherapy Source (RBS) is a "device consisting of a radionuclide that can be packaged in a sealed container made of gold, titanium, stainless steel or platinum gold and used for medical purposes for placement in a body surface or cavity or tissue as a therapeutic nuclear radiation source". Other forms of brachytherapy sources are also used in practice. For example, commercially available conformal sources are flexible films made from polymers that are chemically bonded to phosphorus 32 (P-32). Another product is glass microspheres (TheraSphere), a radiation therapy for hepatocellular carcinoma (HCC), which consists of millions of tiny radioactive glass microspheres (20-30 microns in diameter) containing yttrium 90. Other forms of brachytherapy use an X-radiation generator as a radiation source instead of a radioisotope.

Beta ophthalmic applicators utilizing RBS containing strontium 90 in long term equilibrium with yttrium 90 have been used on the surface of the eye to treat a number of diseases. One example of such treatment is the application of RBS directly to the target tissue of the eye (e.g., conjunctiva, naked sclera, or other tissue) using a manual brachytherapy applicator, and left for a period of time to deliver a prescribed dose, and then the RBS is removed from the surface of the eye.

Treatment (Treat/treatent/Treatment): these terms refer to both therapeutic treatment, e.g., elimination of a disease, disorder or condition, and prophylactic or preventative measures, e.g., preventing or slowing the progression of a disease or condition, reducing at least one adverse effect or symptom of a disease, condition or disorder, and the like. As defined herein, a treatment may be "effective" if one or more symptoms or clinical markers are reduced. Alternatively, if the progression of the disease is reduced or stopped, the treatment may be "effective". That is, "treatment" includes not only improvement of disease symptoms or reduction of markers, but also cessation or slowing of progression or worsening of symptoms that would be expected without treatment. Beneficial or desired clinical effects include, but are not limited to, alleviation of one or more symptoms, whether detectable or undetectable, diminishment of extent of disease, stabilization of disease state (e.g., not worsening), delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether local or total). "treatment" may also mean an extended lifetime compared to the expected lifetime of an untreated patient. Treatments in need of treatment include treatments that have been diagnosed with a particular disease, disorder, or condition, as well as treatments that may develop into a particular disease, disorder, or condition due to genetic susceptibility or other factors.

Gos (Gy) is the SI derived unit of absorbed dose and specific energy (energy per unit mass). Such energy is typically associated with ionizing radiation, such as gamma particles or X-rays. It is defined as the absorption of one joule of energy by one kilogram of tissue in the form of ionizing radiation. In the SI basic unit, gos are denoted as m2.s-2.

Hivolte (Sv) is the SI derived unit of equivalent radiation dose, effective dose, and committed dose. A hiwalt is the amount of radiation required to produce the same effect on living tissue as a high penetration X-ray. The biological effect of ionizing radiation is expressed in terms of the amount measured in terms of his wovens. 1 Hivolte is a kilogram of energy absorbed by biological tissue that is as effective as a dose absorbed by gamma radiation. Thus, schwalt may be expressed in other SI units as 1 sv=1J/kg. The "Nuclear administration rules" (NRC, 10 CFR) M subsection-report ≡ 35.3045 "medical event report and notification" (The Nuclear Regulatory Regulations (NRC, 10 CFR) Subpart M-Reports ≡ 35.3045Report and notification of a medical event) section specifies that "(a) the witness should report any event as a medical event except for events resulting from patient intervention, where (1) administration of byproduct material or radiation from byproduct material (except for permanent implant brachytherapy) results in (i) a dose that differs from the prescribed dose, or a dose that differs from the prescribed dose by more than 0.05Sv (5 rem) effective dose equivalent, by more than 0.5Sv (50 rem) for organs or tissues, or by more than 0.5Sv (50 rem) shallow dose equivalent for skin; and (a) the total dose delivered differs from the prescribed dose by 20% or more; (B) The total dose delivered differs from the prescribed dose by 20% or more, or is outside the prescribed dose range; or (C) delivering a fractionated dose that differs from a single fractionated prescribed dose by 50% or more.

As used herein, the term "annular" or "annular" may also refer to variants of an annular shape, such as an irregular annular or circular shape (toroidal shape).

ICRU reports 50, 62 and 83 define dose uniformity limits for external beam radiation therapy. Podgorsak-Review of Radiation Oncology Physics: A Handbook for Teachers and Students, chapter 7.1 are cited. ICRU report 50 suggests that the target dose uniformity is within +7% and-5% of the prescribed spot dose delivered into the target well-defined. ICRU 72: in section 3.1.4.1 of dosimetry of beta rays and low energy photons for therapeutic applications (Dosimetry of Beta Rays and Low-energy Photons for Therapeutic Applications) it is suggested that the source inhomogeneity of planar and concave sources as described above should be <20%. NCS-70: quality control of sealed beta source in brachytherapy care. The experimental results described in chapter 5 indicate that many clinical sources do not meet the ICRU standard with a maximum non-uniformity of 20%. The 5 out of 4 and 5 out of 10 concave ruthenium sources showed too high of a non-uniformity. Therefore, it is reasonable to point out that ICRU standards are inconsistent with clinical practice.

The following patents and applications are incorporated by reference in their entirety: U.S. patent No. 10,950,362; U.S. patent application Ser. No. 2019/0336091.

Drawings

The features and advantages of the present invention will become apparent upon consideration of the following detailed description, taken in conjunction with the accompanying drawings, in which:

fig. 1A shows a perspective view and a cross-sectional view of a Radionuclide Brachytherapy Source (RBS) of the present invention. The active material (active source) is annular.

Fig. 1B shows a cross-sectional view of an alternative embodiment of the Radionuclide Brachytherapy Source (RBS) of the invention.

Fig. 1C shows a cross-sectional view of an alternative embodiment of the Radionuclide Brachytherapy Source (RBS) of the invention.

Fig. 1D shows a cross-sectional view of an alternative embodiment of the Radionuclide Brachytherapy Source (RBS) of the invention.

Fig. 2 shows a non-limiting example of an alternative configuration of RBS and/or active material shapes.

Fig. 3 shows a non-limiting example of the plane of the active material and the plane of the bottom surface of the capsule. The invention is not limited to this configuration of RBS nor to an embodiment in which the plane of the active material and the plane of the bottom surface of the capsule are parallel. For example, as described herein, the RBS may be curved, the active material may be curved, e.g., like a contact lens or variant thereof, the active material may not necessarily be rotationally symmetrical, etc. Also shown are the inner and outer diameters (DI; DO) of the annular active material.

Fig. 4A shows a cross-sectional view of an RBS held in a capping system. The cap system has a bottom surface, which may be referred to as an interface, wherein the interface includes an annular homogenizer.

Fig. 4B shows an alternative embodiment of the capping system (RBS not shown). The interface is shown without an equalizer.

Fig. 4C shows an alternative embodiment of a cap system. Not shown are RBSs; the interface includes a ring-shaped homogenizer.

Fig. 4D shows an alternative embodiment of a cap system. Not shown are RBSs; the interface includes a ring-shaped homogenizer.

Fig. 4E shows an alternative embodiment of a cap system. Not shown are RBSs; the interface includes a ring-shaped homogenizer. It should be noted that the ledge at the intersection of the bottom surface and the side walls helps support the RBS placed thereon.

Fig. 5A shows a front perspective view of an embodiment of the cap system of the present invention.

Fig. 5B shows a top perspective view of an embodiment of the cap system of the present invention.

Fig. 5C shows a top view of an embodiment of the cap system of the present invention.

Fig. 5D shows a side cross-sectional view of an embodiment of the cap system of the present invention.

Fig. 5E shows a cross-sectional view of an embodiment of the cap system of the present invention. The present invention is not limited to the dimensions disclosed herein. The cap system exhibits a separation feature that helps prevent reuse of the cap. For example, in some embodiments, the cap includes one or more tines (166) that function as part of a latch or snap or clamp mechanism through which the cap is engaged with the handle.

Fig. 5F shows a cross-sectional view of an embodiment of the cap system of the present invention. The present invention is not limited to the dimensions disclosed herein. The cap system exhibits a separation feature that helps prevent reuse of the cap. For example, in some embodiments, the cap includes one or more tines (166) that function as part of a latch or snap or clamping mechanism through which the cap engages the handle.

Fig. 6A shows a perspective view of the cap system of the present invention, wherein the cap system comprises threads. The threads may engage threads of the handle.

Fig. 6B shows a side cross-sectional view of the cap system of the present invention, wherein the cap system includes threads. The threads may engage threads of the handle.

Fig. 6C shows a side view of the handle, wherein the handle includes threads that can engage the threaded cap.

Fig. 6D shows a detailed view of the threads of the handle.

Fig. 7A shows a perspective view of an embodiment of the cap system of the present invention.

Fig. 7B shows a perspective view of an embodiment of the cap system of the present invention.

Fig. 7C shows a cross-sectional view of the cap system of fig. 7B. The present invention is not limited to the dimensions disclosed herein. As a non-limiting example, the annular homogenizer may have an inner diameter of 3mm and an outer diameter of 6mm; the thickness of the leveling device can be 0.5mm; the bottom surface of the cap may be 0.25mm thick; the ledge may be about 0.01mm higher than the height of the leveler. The outer layer of the sidewall of the cap may be about 0.5mm; the inner layer of the sidewall of the cap may be about 0.25mm.

Fig. 7D shows a perspective view of an embodiment of the cap system of the present invention.

Fig. 7E shows a cross-sectional view of the cap of fig. 7D. The present invention is not limited to the dimensions disclosed herein. As a non-limiting example, the annular homogenizer may have an inner diameter of 3mm and an outer diameter of 6mm; the thickness of the leveling device can be 0.5mm; the bottom surface of the cap may be 0.25mm thick; the ledge may be about 0.01mm higher than the height of the leveler. The outer layer of the sidewall of the cap may be about 0.5mm; the inner layer of the sidewall of the cap may be about 0.25mm.

Fig. 8A shows a perspective view of the cap system of the present invention engaged with a handle. The cap system may engage the handle by various mechanisms, e.g., the cap may snap onto the handle, clip onto the handle, twist onto the handle, etc.

Fig. 8B shows a cross-sectional view of the cap system and the engaged handle with the RBS housed in the cap system.

Fig. 9 illustrates a side cross-sectional view of an embodiment of a cap system of the present invention that includes a separation feature that helps prevent cap reuse. For example, in some embodiments, the cap includes one or more tines (166) that function as part of a latch or snap or clamping mechanism through which the cap engages the handle. The cap also has ribs (168) which may break when the cap is disengaged from the handle. In certain embodiments, the cap system is formed from two or more pieces, or the cap system is formed from two or more layers. The RBS is shown located within the cap system.

Fig. 10A shows a cross-sectional view of an RBS system. Also shown are regions S2 and T2, for example, a region that emits radiation and a region that is a treatment region. In some embodiments, t2=s2. In some embodiments, T2 is less than S2.

Fig. 10B shows a schematic diagram of an RBS or RBS system relative to the MCNP "zero" plane, which is considered to be a measure of surface dose from the RBS (or RBS system). Dosage is defined as being in a medium such as water, tissue or plastic water (usually water if not specified). Other depths in the treatment volume are shown. For example, the depth may be 0.19 to 0.24mm, such as 0.2mm, 0.21mm, 0.22mm, 0.23mm, 0.24mm, 0.25mm, 0.3mm, 0.35mm, 0.38mm, 0.4mm, 0.5mm, 0.6mm, 0.67mm, 0.7mm, 0.8mm, 0.9mm, 0.94mm, 1mm, 1.1mm, 1.2mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.7mm, 1.8mm, 1.9mm, 1.99mm, 2mm, 2.1mm, 2.2mm, 2.3mm, 2.4mm, 2.5mm, 2.6mm, more than 2.5mm, and the like. In certain embodiments, a "surface" dose refers to a film in contact therewith, effectively measuring the dose at the surface.

Fig. 10C shows a schematic diagram of an RBS system emitting radiation towards a target region.

Fig. 10D shows a schematic diagram of an RBS system emitting radiation to a three-dimensional planning treatment volume (3D PTV). For visualization purposes, the PTV is shown as distance from the RBS/RBS system; the PTV is not limited to the specific locations and configurations shown.

Fig. 11A shows a Monte Carlo (MCNP) modeling comparison of dose distribution at depths of 0.24mm and 0.56mm for a representative RBS containing a ring-shaped active source.

Fig. 11B shows a portion of the graph of fig. 11A within a center radius of 4 mm. The dose is calculated as a percentage relative to the maximum dose.

Fig. 11C shows a Monte Carlo (MCNP) modeling comparison of dose distribution at 0.24mm and 0.56mm depths for a representative RBS incorporating the capping system (HIPS cap) of the present invention, the RBS comprising a ring-shaped active source.

Fig. 11D shows a portion of the graph of fig. 11C within a center radius of 4 mm. The dose is calculated as a percentage relative to the maximum dose.

Fig. 12A shows dosimetry results at depths of 0.19mm, 0.67mm, 0.94mm, and 1.99mm for a representative RBS including an annular active source.

Fig. 12B shows the graph of fig. 12A normalized to a percentage relative to the maximum dose.

Fig. 12C shows a portion of the graph of fig. 12B within a center radius of 4 mm.

Fig. 12D shows dosimetry results at depths of 0.19mm, 0.67mm, 0.94mm, and 1.99mm for a representative RBS incorporating the cap system of the present invention, the RBS containing an annular active source. The cap system used was a high impact polystyrene cap (HIPS cap) system.

Fig. 12E shows the graph of fig. 12D normalized to a percentage relative to the maximum dose.

Fig. 12F shows a portion of the graph of fig. 12E within a center radius of 4 mm.

Fig. 12G shows dosimetry results at depths of 0.19mm, 0.67mm, 0.94mm, and 1.99mm for a representative RBS incorporating the cap system of the present invention, the RBS containing an annular active source. The cap system used is a representative titanium cap system.

Fig. 12H shows the graph of fig. 12G normalized to a percentage of maximum dose.

Fig. 12I shows a portion of the graph of fig. 12H within a center radius of 4 mm.

Fig. 13A shows dosimetry results at a depth of 0.19mm for a representative RBS with HIPS cap system, representative titanium cap system, or uncapped system, the RBS comprising an annular active source. Dose is normalized to the percentage of the maximum dose.

Fig. 13B shows dosimetry results at a depth of 0.67mm for a representative RBS with HIPS cap system, representative titanium cap system, or uncapped system, the RBS comprising an annular active source. Dose is normalized to the percentage of the maximum dose.

Fig. 13C shows dosimetry results at a depth of 0.94mm for a representative RBS incorporating the cap system of the present invention, having a HIPS cap system, a representative titanium cap system, or a cap-less system, the RBS comprising an annular active source. Dose is normalized to the percentage of the maximum dose.

Fig. 13D shows dosimetry results at a depth of 1.99mm for a representative RBS incorporating the cap system of the present invention, having a HIPS cap system, a representative titanium cap system, or a cap-less system, the RBS comprising an annular active source. Dose is normalized to the percentage of the maximum dose.

Fig. 14 shows a comparison of the dose emitted at 0.04cm from RBS (e.g. 110mci,0.2mm capsule window) in combination with a cap system, wherein the thickness of the homogenizer is 0mm, 0.4mm or 0.5mm. This helps emphasize that the RBS system can be configured in a variety of ways to achieve a particular dose curve.

Fig. 15 shows a comparison of doses emitted from a brachytherapy system of the present invention comprising an RBS and a cap system (at a treatment depth of 0.4 mm), wherein the configuration of the interface is different, e.g. the annular attenuation member has a thickness of 0.5mm, and the inner and outer diameters are different. This helps emphasize that the RBS system can be configured in a variety of ways to achieve a particular dose curve.

Fig. 16A shows a comparison of doses emitted by RBS in combination with a cap system at different depths, with an annular homogenizer having a thickness of 0.4mm, an inner diameter of 3mm and an outer diameter of 6mm.

Fig. 16B shows a comparison of doses emitted by RBS in combination with a cap system at different depths, with an annular homogenizer of 0.5mm thickness, 3mm inner diameter and 6mm outer diameter.

Fig. 17 shows a comparison of Monte Carlo (MCNP) modeling and actual dosimetry of the RBS of the present invention. Note the gamma curve, which is limited to 10%/1mm. Gamma values below 1 indicate that the difference between the modeled projection (modeling projection) and the actual dosimetry is small. The gamma function analyzes the difference between the measured value and its reference value, which is compressed into a number that combines the dose error in the usual intra-field region and the position error in the half-shadow region on the basis of a normalized vector.

Fig. 18 shows a model comparison of the dose distribution of RBS with annular β radiation source with and without a capping system featuring an annular homogenizer.

Detailed Description

Briefly, the present invention provides a Radionuclide Brachytherapy Source (RBS), a capping system for use with an RBS, an RBS system comprising an RBS and a capping system, and the like. The present invention provides a substantially uniform distribution of radiation emitted from a system (e.g., RBS system) within a prescribed planned treatment (or target) volume (PTV) (treatment area and depth). As described herein, the distribution of radiation emitted from the brachytherapy applicator can be determined (e.g., shaped) by an homogenizer or attenuation assembly, a capping system, and/or an RBS. In certain embodiments, the manner of design or inclusion of features of the RBS and/or internal sources helps determine (e.g., optimize) the distribution of the β radiation dose to the target region (e.g., the target plane of the treatment region). In certain embodiments, the cap system includes features that help determine (e.g., optimize) the distribution of the β radiation dose to the target region (e.g., the target plane of the treatment region). The radiation attenuating features (or radiation shaping features, homogenizers, etc.) may be integrated into the cap system, or they may be separate units from the cap system and/or RBS.

While the present invention describes the application of systems and devices for treating glaucoma drainage bubble tissue or drainage apertures, the present invention is not limited to the applications disclosed herein. For example, the systems and devices feature the application of beta radiation to ocular wounds, such as those due to the presence of foreign objects or wounds. In addition, the systems and devices may be characterized by the application of beta radiation (e.g., thickness and density measurements or material modifications and radiation luminescence) to non-ophthalmic or non-medical targets.

As used herein, the term "drainage device" refers to any method or combination of general and specific methods for drainage of aqueous humor, such as the therapeutic agents and devices described herein, including Minimally Invasive Glaucoma Surgery (MIGS) devices and procedures for lowering intraocular pressure through surgical intervention with the device.

Various glaucoma drainage methods and devices, including trabeculectomy, drainage tubes, and devices for Minimally Invasive Glaucoma Surgery (MIGS), are described herein or are well known to those of ordinary skill in the art. For the purposes of the present invention, other surgical innovations and/or devices, in addition to those described above, may be included within the scope of the present invention, and are described and labeled MIGS. For example, techniques and devices that may alternatively be described as a moderately invasive glaucoma procedure or enhanced incision procedure (Moderately Invasive Glaucoma Surgery or Augmented Incisional Surgery) are also included in the present invention.

Isotopes and radioactivity

U.S. core managementThe Commission (USNRC) (https:// www.nrc.gov/about-nrc/irradiation/health-effects/measurement-irradiation. Html) defines radioactivity as the "amount of ionizing radiation released from a material". Whether it emits alpha or beta particles, gamma rays, x-rays or neutrons, the quantity of radioactive material is expressed in terms of its radioactivity (or simply its activity), which represents how many atoms the material has decayed within a given period of time. The units of measure of radioactivity are curie (Ci) and beckle (Bq). "Activity during radioactive decay" is defined as the number of disintegrates per second or unstable nuclei per second decaying in a given sample. Activity is expressed in International units as Becler (abbreviated Bq) and is exactly equal to one disintegration per second. Another unit that may be used is Curie, where the activity of one Curie is about 1 gram of radium, equal (precisely) to 3.7X10 ¹⁰ Beckle (3.7e10bq). The specific activity of the radionuclide is critical in the selection of radionuclides for the production of therapeutic drugs.

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

In some embodiments, the invention features the use of strontium 90 (Sr-90) in long-term equilibrium with yttrium 90 (Y-90). Strontium 90 (Sr-90) decays to yttrium 90 (Y-90) by beta radiation. The half-life of the parent Sr-90 isotope is 28.79 years (Firestone and Shirley, table of Isotopes th ed, V2,1996 cited a half-life of 28.78 y). The half-life of the daughter yttrium-90 isotope was 64.0 hours. (Firestone and Shirley, table of Isotopes th ed, V2,1996 cited a half-life of 64.1 h). The decay rates of these two isotopes and the combined source controlled by the Sr-90 parent are in long-term equilibrium, but the therapeutic beta radiation emitted from the daughter Y-90 has a maximum energy of 2.28MeV and an average energy of 934keV.

In some embodiments, the invention features the use of yttrium 90 having a half-life of 64 hours. Y-90 decays along three different paths by beta rays to the stable isotope zirconium 90 (Zr-90), where 99.985% of the decay time has a maximum beta particle energy of 2.2801MeV, an average beta particle energy of 0.9337MeV, or about or 1.5X10 ^-13 (1.5E-13) Joule. Other minor attenuation paths produce additional very low abundance (0.0115%), high energy (k 1760.7 kev) gamma rays and electrons. The radiation dose of these paths is clinically negligible compared to the main path. In some embodiments, the invention features the use of phosphorus 132. In some embodiments, the invention features the use of ruthenium 106. In some embodiments, the invention features the use of one or more radioisotopes of cesium. In some embodiments, the invention features the use of cesium 131.

In some embodiments, the invention features the use of one or more radioisotopes.

Planning Target Volume (PTV) or Planning Treatment Volume (PTV) is a geometric concept introduced for radiation treatment planning. The PTV is used to ensure that the prescribed dose is actually delivered to all parts of the target tissue. Non-limiting examples are shown in fig. 10A, 10B, 10C, and 10D. For example, a target volume may be defined as a disk of diameter 8mm and depth 0.2mm, the target volume containing tissue. In some embodiments, the target volume has a diameter of 8mm and a depth of 0.5 mm. In some embodiments, the target volume has a diameter of 8mm and a depth of 1 mm. In some embodiments, the target volume has a diameter of 8mm and a depth of 1.5 mm. In some embodiments, the target volume has a diameter of 8mm and a depth of 2 mm. In some embodiments, the target volume has a diameter of 10mm and a depth of 0.2 mm. In some embodiments, the target volume has a diameter of 10mm and a depth of 0.5 mm. In some embodiments, the target volume has a diameter of 10mm and a depth of 1 mm. In some embodiments, the target volume has a diameter of 10mm and a depth of 1.5 mm. In some embodiments, the target volume has a diameter of 10mm and a depth of 2 mm.

For example, a prescribed dose of brachytherapy of 10g (1000 cGy) is a 10J/kg absorbed dose throughout the target volume. Measurements showed that the Sr-90/Y-90RBS model, which has an activity of 1.48GBq, produced a surface dose rate of about 0.20Gy per second. To deliver a dose of 10Gy to the target volume would require a radiation time of 50 seconds. During this 50 second treatment, the number of decaying nuclei was 1.48x10 ⁹ Bq (1.48e9 Bq) (disintegration per second) ×50sec=7.4×10 ¹⁰ (7.4E10)。

Traditionally, the unique dose prescription convention for β ophthalmic applicator brachytherapy prescribes a maximum dose at the center point of the proximal surface. The dose from the center dose to any point and/or any depth in the tissue is lower than the prescribed dose. For example, soares et al report the surface distribution of Sr-90+Y-90 ophthalmic applicators.

In the 1D prescription convention, the dose of the entire Planned Target Volume (PTV) is less than the prescribed dose of the proximal surface center region. For example, a PTV contains a disc of equal diameter and shallower depth (e.g., r=4mm, z=0.5 mm) than the active surface of a conventional β -applicator, treating a Treatment Volume (TV) at a dose lower than (not specified for) the prescribed center surface dose.

In contrast, for plaque brachytherapy, the standard practice for dose prescription is to specify the minimum dose at the distal apex of the wound. For example, ocular melanoma cooperative studies (COMS) prescribe a (distal) tumor apex of 85Gy. The prescribed dose is the minimum distal dose, whereas the proximal surface dose is larger.

The Treatment Volume (TV) is the volume of tissue contained within a specific equivalent dose envelope (envelope) encapsulating a prescribed dose. A non-limiting example of a 2D TV is an 80% isodose region. TV is not limited to 80% isodose area and volume. Significant dose decay of beta radiation with depth may require therapeutic doses at different depths. For example, a dose of 10cGy near the proximal surface (e.g., depth z=0.2 mm) may provide a prescribed dose of 6Gy at a depth z=0.6 mm.

Radiation is attenuated by distance and density (e.g., shielding). In addition, shorter exposure times provide fewer received doses. Alpha particles are described as being easily shielded. A sheet of tissue or a few centimeters of air is usually sufficient to block the alpha particles. Beta particles are more penetrating than alpha particles. The beta shield is sometimes made of aluminum, brass, plastic or other low atomic number material to reduce the production of bremsstrahlung. Beta may also be shielded by higher atomic number materials. The linear attenuation coefficient of gamma rays is proportional to absorber density.

The radiation dose may be varied by attenuating the material. The dose shape may be collimated by high density materials such as lead and other alloys. For example, user describes a rapid method for producing irregularly shaped fields for patients undergoing electron radiation therapy using low melting point alloys (Plane JH, user C.A. rapid method of production of irregular-shaped fields for use with patients receiving electron radiotherapy.Br J radio.1990 nov;63 (755): 882-3).

The differential dose rate across the diameter or a partial region thereof may be modified to have unequal mass density paths (lengths).

One example is to vary the thickness of the same material over a portion of the area or diameter in order to vary the output dose of the area.

Therapeutic linacs used in medicine are typically equipped with equalizers. Faddegon BA, O' Brien P, mason DL. The flatness of Siemens linear accelerator x-ray fields. Med Phys.1999Feb;26 220-8 report design of a homogenizer with Monte Carlo, followed by brass machining and mounting on their Siemens linac MXE treatment unit X-ray field. Their measurements indicate that a large field flattener (field flattener) extends the useful radius of the field.

Another approach is to place materials of different densities over a portion of the area or diameter to vary the output dose over that area. For example, a portion of the field may be selectively modified by adding a higher density (higher z) material.

Biological effects of radiation

The biological effectiveness of radiation depends on the Linear Energy Transfer (LET), total dose, fractionation rate (fractionation rate) and radiosensitivity of the target cell or tissue. When radiation interacts with a substance, it loses energy by interacting with atoms in the direct path. In radiation therapy, LET is defined as the amount of average energy lost to each defined distance in the tissue, just like the energy deposited into a few cells. The incidence of LET varies from tissue to tissue and quantification of LET in the cellular system is an important component in determining the correct dose of radioactivity. Low LET radiation is X-radiation, gamma radiation and beta particles.

Radiation-induced ionization can act directly on cellular molecules and cause damage, such as DNA damage. Radiation-induced ionization can also act indirectly to produce ions and free radicals that originate from the ionization or excitation of water components in the cell. Exposure of cells to ionizing radiation results in H ₂ High-energy radiation decomposition of O water molecules into H ⁺ And OH (OH) ^- Ions, mainly of H ₃ O(H ₂ O)3 ⁺ And OH (H) ₂ O)3 ^- And H and O radicals are present in water. These radicals are themselves chemically reactive and can then be recombined to produce a series of highly reactive combinations, such as superoxide (O) ₂ ^- ) And peroxide (H) ₂ O ₂ ) These combinations can create oxidative damage to molecules (e.g., DNA) within the cell. Direct interactions of body tissue with beta particles and the cascade of energetic secondary electrons generated by beta particles as they pass through the substance may disrupt chemical bonds within the tissue. Ionizing radiation-induced DNA fragmentation represents one of the main mechanisms of action of β brachytherapy.

After exposure of cells to ionizing radiation, multiple pathways are involved in the cells. In the response of cells to radiation, several sensors detect induced DNA damage and trigger signal transduction pathways. Activation of several signal transduction pathways by ionizing radiation results in a range of alterations in target gene expression.

Promoters or enhancers for these genes may contain the binding site for one or more transcription factors, and a particular transcription factor may affect transcription of multiple genes. Transcription factor p53, nuclear factor κb (NF- κb), specific protein 1 (SP 1) -related Retinoblastoma Control Protein (RCP), two p 53-dependent genes GADD45 and CDKN1A, and a gene associated with the NER pathway (e.g., XPC) are typically upregulated by ionizing radiation exposure. Interestingly, NF- κB activation has been shown to be strongly dependent on the LET of charged particles, with a maximum activation range of 90-300 keV/. Mu.m.

Importantly, the transcribed subset of target genes is critical for decision between restoration of normal function and DNA repair after cell cycle arrest, entry into senescence or apoptosis in the case of severe DNA damage.

Cell cycle arrest is an important part of the DNA damage response, contributing to DNA repair and maintenance of genomic stability. Ataxia Telangiectasia Mutated (ATM) and ATR activate modulators of cell cycle arrest by phosphorylation. For example, p53 has a short half-life and stabilizes in response to various cellular stresses after phosphorylation by ATM. Upon exposure to ionizing radiation, checkpoint kinase 2 (CHK 2) phosphorylates serine residues 15 and 20 on p53, reducing its binding to MDM2, which in its bound state targets p53 degradation by the proteasome pathway. Thus, isolation of p53 from MDM2 can extend the half-life of p 53. Other proteins, such as Pin1, parc and p300, and p300/CBP related factor (PCAF) histone acetyltransferases, modulate the transactivation activity of p 53. For effective repair, especially in non-dividing cells, cellular levels of deoxyribonucleotides are increased during DNA damage repair by p 53-dependent transcriptional induction of ribonucleotide reductase RRM2B (p 53R 2). It is well recognized that the severity of DNA damage is a critical factor in directing the progression of the signaling cascade toward reversible cell cycle arrest or apoptosis. The abundance of p53 proteins, specific post-transcriptional modifications and their interactions with downstream effectors (such as GADD45 a or p 21) may be responsible for the cellular response at this determinant site as part of the signaling cascade.

In addition to DNA and p53, other pathways may also be involved in the response of cells to ionizing radiation. For example, ionizing radiation may produce Reactive Oxygen Species (ROS) in the cytoplasm.

Low dose radiation therapy (LD-RT) is known to exert anti-inflammatory effects. The in vitro model shows that the anti-inflammatory action range of LD-RT on immune cells such as macrophages and neutrophils is 0.1-1.0Gy. Studies have also shown that low dose radiotherapy has anti-inflammatory effects, involving reduced CCL20 chemokine expression and granulocyte/endothelial cell adhesion. In vitro study of fibroblasts in culture irradiated with beta rays by Khaw et al (1991,British Journal of Ophthalmology) 75: 580-583) it was found that "irradiation reduced proliferation of human ternon bursa fibroblasts. Radiation doses that inhibited cell proliferation by more than 50% (on days 7 and 14) without causing a decrease in cell number were 500, 750, and 1000 rads. "fibroblast cells enter the growth arrest phase but do not die.

The invention features systems and devices for applying beta radiation for use in conjunction with the surgical procedures and/or implants described herein (e.g., MIGS implants). Brachytherapy provided by the systems and devices herein helps prevent or reduce bleb scarring or failure to maintain functional blebs. Without wishing to limit the invention to any theory or mechanism, it is believed that the brachytherapy devices and systems herein can inhibit or reduce inflammation and/or fibrosis by down regulating cell (e.g., fibroblast) activity without cell death.

The use of beta radiation provides drug-like therapies similar to drugs in that beta radiation, when consumed by cells, causes biological changes in signaling and gene transcription, thereby affecting cell activity and growth, such as cell cycle arrest.

The present invention provides compositions or products that are radioactive compositions (sources of beta radiation). The radioactive composition has therapeutic effects by the mechanism such as the generation of beta rays as previously discussed. Upon generation of beta radiation, the radioactive composition is consumed (e.g., the product is gradually depleted) because the radioisotope atoms of the beta radioisotope brachytherapy source decay into other nuclides.

Target of eyes

As previously discussed, the present invention provides systems and devices, such as ophthalmic applicator systems, brachytherapy systems, and the like, for applying, for example, beta rays to a treatment area or target of an eye. In some embodiments, the target is a bleb site in an eye that is treated for glaucoma with an MIGS implant or MIGS surgery. In some embodiments, the target is a bleb site in an eye treated with a trabeculectomy. In some embodiments, the target is a bleb site in an eye treated with minimally invasive microscleral ostomy (MIMS). In some embodiments, the target is a site of a hole in an eye treated with MIMS. In some embodiments, the target is a site of an implant surgically inserted into the eye for the purpose of treating glaucoma. In some embodiments, the target is an eye site associated with pterygium.

In some embodiments, the target comprises the entire bubble. In some embodiments, the target comprises a portion of a bubble. In some embodiments, the target region surrounds an end of the MIGS implant. In some embodiments, the target comprises at least a portion of a bubble above the drainage channel. In some embodiments, the target further comprises at least a portion of the bubble above the drainage channel and at least a portion of the perimeter of the bubble. In some embodiments, the target further comprises at least a portion of the bubble above the drainage channel, at least a portion of the perimeter of the bubble, and at least a portion of the bubble between the perimeter of the drainage channel and above the drainage channel.

In some embodiments, the target area is the entire bubble, such as the perimeter of the bubble, the center of the bubble, and the portion of the bubble between the perimeter and center. In some embodiments, the target region is the perimeter of a bubble, such as an annular target region. In some embodiments, the target is a perimeter of the bubble and a portion of the bubble near the perimeter, e.g., the target may be annular. In some embodiments, the target is part of a bubble between the center and the periphery. In some embodiments, the target is at least a portion of the center of the bubble. The invention is not limited to the above description of the target region. For example, in certain embodiments, the target is (or includes) tissue surrounding the edges of the drainage channel.

In certain embodiments, the target is a scar at the posterior end of the microtubule. A new generation of microtubules has proven to be easier to insert and less subsequent than conventional drainage procedures known as trabeculectomy. However, a drawback of the micropipe procedure may be that drainage comes out of a focal drainage site, where tissue surrounding the focal site is more prone to scar and encapsulate the outflow site with a small icehouse-like dome of scar tissue. This is because cells in tissue surrounding the tip of the tube are stimulated by the compromised blood and aqueous fluid contents to divide and create new collagenous tissue. The fibroblasts then divide (proliferate) multiple times and create new tissue, which then becomes elongated cells that fill the contracting fibers, contracting the tissue surrounding the tip, forming scar tissue domes that impede fluid flow. Without wishing to limit the invention to any theory or mechanism, it is believed that beta radiation brings fibroblasts into a dormant state so they do not divide, failing to make collagen or shrink new collagen tissue.

In some embodiments, the target is a target other than one associated with MIGS/MIMS/trabeculectomy. In some embodiments, the ophthalmic targets are targets other than those associated with glaucoma drainage surgery. In some embodiments, the target is an inflammation of the eye, an autoimmune mediated disorder, or a vascular disorder. In some embodiments, targets and infections (e.g., herpes simplex keratitis or tuberculous scleritis), corneal ulcers (e.g., predatory corneal ulcers (moores)), allergic diseases (e.g., vernal), benign or malignant tumors (e.g., squamous cell carcinoma) or benign growths (e.g., papilloma), degeneration (e.g., pterygium), sarcoidosis (e.g., pemphigoid), inflammation (e.g., meibomian glands), ocular manifestations of stevens-johnson syndrome, drug-induced scarring conjunctivitis, wood-like conjunctivitis, corneal vascularization, pterygium, vernal catarrhalis, small palpebral papillomas, limbalm cancers, malignant eye melanoma, conjunctive nevi, hemangiomas, blepharal adenocysts. In some embodiments, the target is in the orbit of the eye. The invention includes other ophthalmic indications and is not limited to the targets described above.

Brachytherapy system and apparatus

As previously described, the present invention provides systems and devices for applying radiation to a target (e.g., a target of an eye, such as a glaucoma treatment-related drainage bulb, such as a drainage bulb associated with a foreign body or other glaucoma surgery) to maintain a functional bulb.

The brachytherapy system and apparatus of the present invention can include, but is not limited to, (a) a Radionuclide Brachytherapy Source (RBS); (b) A capping system for receiving a Radionuclide Brachytherapy Source (RBS); (c) a capping system and an RBS; (d) a cap system and an applicator (e.g., a handle); and/or (e) a capping system, RBS, and an applicator (e.g., a handle). In some embodiments, an equalizer, radiation attenuating shield, radiation attenuating mask, interface, or other similar feature that blocks or reduces a portion of the radiation may be integrated into the cap system. In some embodiments, an equalizer, radiation attenuating shield, radiation attenuating mask, interface, or other similar feature that blocks or reduces a portion of the radiation may be integrated into the RBS. In some embodiments, the homogenizer may be a separate component, e.g., separate from the cap and/or RBS. Brachytherapy systems and devices of the present invention can include, but are not limited to, (a) cap systems and homogenizers; (b) a capping system, RBS and a homogenizer; (c) Cap systems, homogenizers, and applicators (e.g., handles); (d) A capping system, RBS, homogenizer, and applicator (e.g., handle); and/or (e) any other combination of components described herein.

Radionuclide Brachytherapy Source (RBS)

The RBS of the present invention is constructed in a manner that complies with federal regulations, but is not limited to the items mentioned in the regulations. For example, the RBS of the present invention may further comprise a substrate. In addition, for example, in addition to being surrounded by the mentioned "gold, titanium, stainless steel, or platinum", in some embodiments, the radionuclides (isotopes) of the present invention may be surrounded by a combination of one or more of "gold, titanium, stainless steel, or platinum". In some embodiments, the radionuclides (isotopes) of the present invention may be surrounded by one or more layers of inert materials including silver, gold, titanium, tantalum, titanium alloys, stainless steel, platinum, tin, zinc, nickel, copper, other metals, ceramics, glass, or combinations of these.

In some embodiments, the surface on the substrate is shaped in a manner that provides a controlled projection of the radiation. The substrate may be composed of a variety of materials. For example, in some embodiments, the substrate is composed of a material (generally, chemically and physically stable radiation resistant refractory materials) that includes silver, aluminum, stainless steel, tungsten, nickel, tin, zirconium, zinc, copper, metallic materials, ceramic matrices, and the like (including glass, glassy, enamel), or combinations thereof. In some embodiments, the substrate functions to shield a portion of the radiation emitted from the isotope. The package may be constructed of a variety of materials, such as one or more layers of inert materials including steel, silver, gold, titanium, platinum, another biocompatible material, and the like, or combinations thereof.

Without wishing to limit the invention to any theory or mechanism, it is believed that prior brachytherapy sources typically treat only the central portion of the target or under-dose and/or over-dose to the peripheral region. The system of the present invention generally provides a more uniform dose across the target area, for example across a planar area within the target area. In certain embodiments, the Radionuclide Brachytherapy Source (RBS) can be designed and/or constructed to provide a substantially more uniform radiation dose across a plane within the target, e.g., as compared to previously constructed devices. In certain embodiments, a portion of the brachytherapy system (e.g., a cap system, radiation attenuating shield, etc.) can be designed and/or configured to provide a substantially more uniform radiation dose across the target, e.g., as compared to previously configured devices. In certain embodiments, a portion of the brachytherapy system (e.g., a capping system, radiation attenuating shield, etc.) and RBS can be designed and/or constructed to provide a substantially more uniform radiation dose across the target, e.g., as compared to previously constructed devices. The invention is not limited to the dosimetry described herein. For example, in some embodiments, the system (e.g., a cap system, a radiation attenuating shield, a cap system with an integrated radiation attenuating shield or homogenizer, etc.) is designed such that the dose received at the perimeter of the bubble is higher than the dose received at the center of the bubble.

Iterative computer simulations of the output dosimetry can be used to determine the optimal design of the device. Thin film dosimetry is a method of measuring the delivery of radioactivity from a source that can be used to measure the dose of the entire target. It may also be used to calibrate or compare the radiation source or to determine the uniformity of the dose pattern.

Referring to fig. 1A, 1B, 1C and 1D, the present invention provides a Radionuclide Brachytherapy Source (RBS), such as a sealed radiation source or radiation source. In some embodiments, the RBS comprises a capsule (210) having a distal surface (212), a proximal surface (211) opposite the distal surface, and a sidewall (215); and an active beta radioisotope material (220) (e.g., a substrate) encapsulated in a capsule (e.g., an encapsulation). The active beta radioisotope material (220) emits beta radiation through at least a portion of a distal surface (212) of the capsule (210). In some embodiments, the sidewall (215) mates with the proximal surface (211) of the capsule. In some embodiments, the sidewall (215) extends upwardly through the proximal surface (211) of the capsule.

Referring to fig. 1, in some embodiments, the RBS (e.g., capsule) is cylindrical. Referring to fig. 2, in some embodiments, the RBS (e.g., capsule) is disk-shaped, cube-shaped, circular, kidney-shaped, oval-shaped, or the like. In some embodiments, the RBS capsule is a disc, with the middle having a different thickness than the outer edge (e.g., concave curvature of the middle). The present invention is not limited to those shapes and any shape that achieves the desired dose curve is encompassed herein. The shape of the RBS can help provide a controlled projection of radiation (e.g., therapeutic dose) onto the target. The shape of RBS can help the radiation dose to drop rapidly at the periphery of the target (whether the target is defined as, for example, an entire bubble, a portion of a bubble, etc.). This may help to keep the radiation within a limited area/volume and may help to prevent unwanted exposure of structures such as the lens to radiation.

In some embodiments, the substrate or active beta radioisotope material is any radiation source, e.g., any beta radiation source. In some embodiments, the substrate or active beta radioisotope material includes phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90), strontium 90 (Sr-90) in long-term equilibrium with yttrium 90 (Y-90), isotopes of cesium (e.g., cs-131), I-125, or other radionuclides, or combinations thereof. The invention also includes sources that emit beta and gamma. The invention also includes sources that emit low energy photons (e.g., soft X-rays) that attenuate similarly to beta rays in soft tissue (see, e.g., lee et al, 2008, med. Phys.35 (11) 5151-5160). In some embodiments, the isotope is coated on the substrate, and both the substrate and the isotope are further coated by the encapsulation. In some embodiments, the radioisotope is embedded in a substrate. In some embodiments, the radioisotope is part of a base matrix. In some embodiments, the encapsulation may be coated onto the isotope, and optionally onto a portion of the substrate. In some embodiments, the encapsulation is coated around the entire substrate and isotope. In some embodiments, the encapsulation encloses the isotope. In some embodiments, the package encloses the entire substrate and isotope. In some embodiments, the radioisotope is a separate fragment and is sandwiched between the package and the substrate.

In some embodiments, the primary radionuclide in the source is Sr-90, which decays to Y-90 by beta radiation, with Y-90 in long-term equilibrium with the Sr-90 parent controlling decay rate, the daughter Y-90 emitting therapeutic beta radiation. In some embodiments, decay produces an average energy of 934keV and a maximum energy of 2.28 Mev. In some embodiments, sr-90 decays to Y-90 by beta emission 100% of the time, with a maximum beta particle energy of 0.546MeV and an average beta particle energy of 0.1958MeV. In some embodiments, Y-90 decays to Zr-90 (a stable isotope) along three different routes by beta emission. In some embodiments, 99.9885% of the time has a maximum beta particle energy of 2.282MeV and an average beta particle energy of 0.9337 MeV. In some embodiments, 0.0115% of the time has a maximum beta particle energy of 0.5194MeV and an average beta particle energy of 0.1856 MeV. This approach may produce additional very low abundance high energy gamma rays (1760.7 keV) and electrons, but these are considered clinically negligible, particularly for encapsulated sources. In some embodiments, 1.4 beta 010 ^-6 % of the time has a maximum beta particle energy of 0.0938MeV and an average beta particle energy of 0.0250 MeV.

In some embodiments, a nominal dose (nominal dose) of 1000cGy required to deliver from the conjunctival surface at a depth of 200 μm in 30 seconds results in a dose rate of 33.3 cGy/s. In some embodiments, the allowable variation to achieve the desired dose is a treatment time of no less than 25 seconds (no more than 40.0 cGy/s) and no more than 55 seconds (no less than 18.2 cGy/s).

In some embodiments, the dose rate does not vary by more than + -5% over a plane created at a 400 μm water equivalent depth from the conjunctiva surface and a diameter of 80% of the outer diameter of the active material. In some embodiments, the dose rate will be greater than 20cGy/s, with a diameter of at least 90% of the volume created by the outer diameter of the active material through a water equivalent depth from the conjunctiva surface to a depth of 600 μm. In some embodiments, the allowable variation in dose rate for an entire 200 μm to 600 μm depth of the PTV is between 33.3cGy/s and 20cGy/s. In practice, this is a peak dose rate of 33.3cGy at 200 μm, with a minimum dose of not less than 20cGy/s at 600 μm.

In some embodiments, the capsule is composed of a material comprising stainless steel, gold, platinum, titanium, tantalum, titanium alloys, silver, tin, zinc, copper, nickel, aluminum, ceramic, glass, metal alloys, zirconium, or combinations thereof.

In some embodiments, the RBS (e.g., capsule) has a diameter of 10.8 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 4 to 20 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 5 to 15 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 10 to 20 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 10 to 15 m. In some embodiments, the RBS (e.g., capsule) has a diameter of 5 to 7mm (e.g., 5mm, 6mm, 7 mm). In some embodiments, the RBS (e.g., capsule) has a diameter from 7 to 10mm (e.g., 7mm, 7.5mm, 8mm, 8.5mm, 9mm, 9.5mm, 10 mm). In some embodiments, the RBS (e.g., capsule) has a diameter of from 9 to 12mm (e.g., 9mm, 9.5mm, 10mm, 10.5mm, 11mm, 11.5mm, 12 mm). In some embodiments, the RBS (e.g., capsule) has a diameter of from 2 to 12 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of from 10 to 14mm (e.g., 10mm, 10.5mm, 11mm, 11.5mm, 12mm, 12.5mm, 13mm, 13.5mm, 14 mm). In some embodiments, the RBS (e.g., capsule) has a diameter of 12 to 16mm (e.g., 12mm, 12.5mm, 13mm, 13.5mm, 14mm, 14.5mm, 15mm, 15.5mm, 16 mm). In some embodiments, the RBS (e.g., capsule) has a diameter of 14 to 18mm (e.g., 14mm, 14.5mm, 15mm, 15.5mm, 16mm, 16.5mm, 17mm, 17.5mm, 18 mm). In some embodiments, the RBS (e.g., capsule) has a diameter of 3 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 4 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 5 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 5 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 6 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 7 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 8 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 9 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 10 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 11 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 12 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 13 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 14 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 15 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 16 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 17 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 18 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 19 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 20 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of greater than 20 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 10 to 100 mm. In some embodiments, the RBS (e.g., capsule) has a diameter of 100 to 500 mm.

In some embodiments, the RBS has an activity of 116mCi or 4.292 GBq. In some embodiments, the RBS has an activity of 100 to 120mCi, or 3.7 to 4.4 GBq. In some embodiments, the RBS has an activity of 50 to 100mCi, or 1.85 to 3.7 GBq. In some embodiments, the RBS has an activity of 10 to 50mCi, or 0.37 to 1.85 GBq. The present invention is not limited to these activities. These parameters should be changed to reflect the recent finding that the 116mCi dose rate is twice as high as that predicted by MCNP, since 2 beta particles cannot be included per decay in the original MCNP model. Thus, all parameters should be halved (for this glaucoma application). For other applications (e.g. industrial, research, calibration) a wider range of activities may be included, varying from 0Ci to 300 mCi.

In some embodiments, the RBS further comprises a forceps holder (230) provided in the proximal surface (211) of the capsule (211) or on the proximal surface (211) of the capsule (211), which forceps holder can be engaged with pairs of tines or forceps to allow the RBS to be collected. The forceps holder (230) may serve as an indicator for the user to indicate that the RBS is preferably only collected by the proximal surface (211). The tweezer clamp (230) helps prevent the RBS from being inserted into the cap system in an unintended direction.

In some embodiments, the sidewall (215) and forceps holder (230) extend through the proximal surface (211) of the capsule. In some embodiments, the forceps holder (230) extends through the proximal surface (211) of the capsule. In some embodiments, the forceps holder (230) has at least a first side and a second side opposite the first side, wherein only the first side and the second side can be gripped by the forceps. In some embodiments, the forceps holder (230) has at least a first side, a second side opposite the first side, and a third side, wherein the third side is not capable of being gripped by forceps. In some embodiments, the forceps holder (230) is recessed into the proximal surface (211) of the capsule. In some embodiments, the forceps holder (230) protrudes from the proximal surface (211) of the capsule. In some embodiments, the forceps holder has a first side (231 a) and a second side (231 b) opposite the first side (231 a), wherein the first indentation (232) is disposed at an intersection of the first side (231 a) with the proximal surface (211) of the capsule (210), and the second indentation (232) is disposed at an intersection of the second side (231 b) with the proximal surface (211) of the capsule (210). In some embodiments, the forceps holder (230) is a tab, such as a protrusion. In certain embodiments, the forceps holder (230) is a lot, magnet, indentation, ring, loop, or any other suitable device. In some embodiments, the forceps holder (230) is a ring. In some embodiments, the forceps holder (230) is a protruding thread design. In some embodiments, the ring is used in conjunction with a threaded rod (threaded pole). In some embodiments, the outer wall (215) is flush with the top of the protrusion (230) forming a small cavity. In some embodiments, the RBS has a diameter of about 10.5 mm. In some embodiments, the RBS has a height of about 4.25mm and the height of the tweezer gripper features is 1.75mm.

Referring to fig. 1A, in some embodiments, the active beta radioisotope material (220) is in a ring-like configuration. The present invention is not limited to this configuration. Referring to fig. 2, in some embodiments, the radioisotope material (220) is in an alternative configuration, such as a dome, disk, cube, circle, kidney, oval, layer (rounded), rectangle or cube, flattened dome, terrace (rounded), truncated pyramid (truncated pyramid), truncated cone (cone), trapezoid (trapezial), layer (e.g., wedding cake), or circular layer, bean, or any other suitable shape. In some embodiments, the material (220) is circular like a disk, but thicker at the edges than in the center. The present invention is not limited to those shapes and any shape that achieves the desired dose curve is encompassed herein. Fig. 3 shows the inner and outer diameters of the annular radioisotope material.

Interface and cap system

Referring to fig. 4A, 4B, 4C, 4D, 4E, 5A, 5B, 5D, 5E, 5F, 6A, 6B, 6C, 6D, 7A, 7B, 7C, 8A, 8B, and 9, the present invention also features a capping system and interface for use with the radionuclide brachytherapy sources described herein.

For example, the present invention provides a capping system (110) for housing a Radionuclide Brachytherapy Source (RBS) (210), the capping system (110) comprising an interior cavity (140) formed by a sidewall (115) and a bottom surface (112) sealed around its periphery to a bottom edge (115 c) of the sidewall (115), the interior cavity (140) for receiving the RBS (210). Although the drawing shows the bottom surface (122) as being flat, the invention is not limited to this configuration. In some embodiments, the bottom surface (112) has a curvature. For example, the bottom surface may be characterized as having a concave curvature. In some embodiments, the bottom surface has a convex curvature. In some embodiments, the bottom surface has a portion with curvature and a flat portion. In some embodiments, the shape of the bottom surface may be in the manner of shaping the radiation.

In some embodiments, the cap system is cylindrical, e.g., the sidewall is cylindrical and the bottom surface is circular. The capping system is not limited to a cylindrical configuration and may be shaped in any suitable manner to accommodate the RBS. For example, the cap system may be rounded, e.g., have a concave or convex curvature.

The capping system may be sized as desired for use with the RBS in combination with the capping system. In some embodiments, the sidewall or lumen has a diameter of 7 to 14mm. In some embodiments, the sidewall or lumen has a diameter of 12mm or 13 mm. In some embodiments, the sidewall has a height of 4 to 12mm from its bottom edge to its top edge. In some embodiments, the sidewall has a height of 8.2mm measured from its bottom edge to its top edge. In some embodiments, the bottom surface of the cap system is 12mm in diameter. In some embodiments, the bottom surface of the cap system is 8 to 10mm in diameter. In some embodiments, the bottom surface of the cap system is 10 to 12mm in diameter. In some embodiments, the bottom surface of the cap system is 7 to 14mm in diameter.

Referring to fig. 10A, radiation is emitted from the S-region, which is at least a portion of the bottom surface of the cap system. The T region refers to the diameter of the treatment volume. In certain embodiments, S is the same as T, e.g., the diameter of the radiation emitted from the cap system is equal to the diameter of the treatment volume. In some embodiments, S is greater than T, e.g., a portion of the emitted radiation is not considered to be a portion of the treatment volume. In some embodiments, the diameter of S is 9.8mm. In some embodiments, the diameter of S is 8mm. In some embodiments, S has a diameter of 6 to 12mm. In some embodiments, S is an area defined within a radius of 3mm from the center of the interface or bottom surface of the cap system. In some embodiments, S is an area defined within a radius of 4mm from the center or bottom surface of the cap system interface. In some embodiments, S is an area defined within a radius of 5mm from the center or bottom surface of the cap system interface. In some embodiments, T has a diameter of 9.8mm. In some embodiments, T has a diameter of 8mm. In some embodiments, T has a diameter of 6 to 12mm. In some embodiments, T is an area defined within a radius of 1mm from the center or bottom surface of the cap system interface. In some embodiments, T is an area defined within a radius of 3mm from the center or bottom surface of the cap system interface. In some embodiments, T is an area defined within a radius of 4mm from the center or bottom surface of the cap system interface. In some embodiments, T is an area defined within a radius of 5mm from the center or bottom surface of the cap system interface. In some embodiments, T is 60-80% of S. In some embodiments, T is 80-89% of S. In some embodiments, T is 90-99% of S. In some embodiments, t=s. The present invention is not limited to the above dimensions.

In some embodiments, radiation from the radioisotope is emitted from S or T, which is 20 to 75% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 20 to 80% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 20 to 90% of the surface area of the outer surface of the cap system. In some embodiments, the radiation from the radioisotope is emitted from S or T, which is 20 to 95% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 20 to 99% of the surface area of the outer surface of the cap system. In some embodiments, the radiation from the radioisotope is emitted from S or T, which is 55 to 75% of the surface area of the outer surface of the cap system. In some embodiments, the radiation from the radioisotope is emitted from S or T, which is 70 to 90% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 80 to 95% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 90 to 95% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 95 to 100% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 30 to 75% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 30 to 80% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 30 to 90% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 30 to 95% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 30 to 99% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 40 to 75% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 40 to 80% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 40 to 90% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 40 to 95% of the surface area of the outer surface of the cap system. In some embodiments, radiation from the radioisotope is emitted from S or T, which is 40 to 99% of the surface area of the outer surface of the cap system. The present invention is not limited to the above dimensions.

Referring to fig. 4E, in some embodiments, a ledge (148) is disposed in the interior cavity (140) at the intersection of the bottom surface (112) and the sidewall (115). The ledge (148) helps to distribute the weight of the RBS fixed thereto. In some embodiments, the ledge (148) is configured to be positioned 0.1mm above a top surface of the leveler (150). The present invention is not limited to this configuration.

Referring to fig. 5A, 5B, 5C, and 5D, in some embodiments, the lip (120) is disposed along a top edge of the sidewall (115) of the cap system (110). The lip (120) may extend outwardly from the top edge (111) of the outer wall (115) (e.g., oriented outwardly from the outer surface of the outer wall (115)).

In some embodiments, at least a portion of the cap system (110) is composed of a material comprising a polymer. In some embodiments, the polymer comprises High Impact Polystyrene (HIPS). In some embodiments, the polymer comprises polycarbonate. In some embodiments, at least a portion of the cap system (110) is composed of a material comprising stainless steel. In some embodiments, at least a portion of the cap system (110) is composed of a material comprising a titanium alloy, e.g., grade 5 titanium (Ti 6 ai 4V), grade 23 titanium, and the like.

In certain embodiments, the sidewall (115) includes an inner layer (160) and an outer layer (115), the outer layer being a sterile barrier. The sidewalls may be composed of a material comprising a metal, a metal alloy, a polymer, or a combination thereof. In certain embodiments, the polymer comprises a plastic material. In certain embodiments, the polymer comprises High Impact Polystyrene (HIPS). In certain embodiments, the inner layer (160) is composed of a shielding material of a particular electron density, including but not limited to tantalum. The outer layer may be composed of a polymeric material, such as a plastic material. In certain embodiments, the bottom surface, the leveler, or a combination thereof is constructed of stainless steel or titanium. In certain embodiments, the inner layer has a thickness of 0.35 mm. In certain embodiments, the outer layer has a thickness of 0.5 mm. The present invention is not limited to the above dimensions.

In some embodiments, the sidewall is configured such that only less than 5Sv may pass. In certain embodiments, the thickness of the sidewall is such that only 3% of the prescribed dose of RBS can pass. In certain embodiments, the thickness of the sidewall is such that less than 3Sv can pass through. In certain embodiments, the thickness of the sidewall is such that less than 5Sv can pass through.

In certain embodiments, the cap system (110) is reusable. In certain embodiments, the cap system (110) is sterilizable.

The cap system of the present invention may be used in conjunction with a brachytherapy applicator handle (610), for example, for housing an RBS therein. Referring to fig. 6A, 6B, 6C, and 6D, in some embodiments, the cap system includes threads (182) for threadably engaging complementary threads (184) on the distal end (612) of the brachytherapy applicator handle (610).

In certain embodiments, as described herein, the cap system (110) includes an equalizer (150) for reducing radiation emitted from an RBS in contact with or in proximity to the equalizer. An equalizer (150) may be disposed on the bottom surface (112) in the interior cavity (140). The leveler (150) may be integrated into the bottom surface (112) in the cavity (140). In some embodiments, the homogenizer is a separate component for placement on or near the bottom surface of the cap system (110). The homogenizer (150) reduces at least a portion of the beta radiation emitted from the RBS, thereby controlling the amount of beta radiation emitted from the bottom surface (112) of the capping system (110).

In some embodiments, the homogenizer is constructed of a material that is capable of being molded and has structural integrity. In some embodiments, the leveler is composed of a material comprising a polymer, a metal alloy, a ceramic, a glass, or a combination thereof. In some embodiments, the polymer is a plastic. In some embodiments, the polymer is High Impact Polystyrene (HIPS). In some embodiments, the metal or metal alloy comprises titanium. In some embodiments, the outer surface of the homogenizer is biocompatible. In some embodiments, the outer surface of the homogenizer is sterilizable.

In some embodiments, the homogenizer is ring, dome, disk, disc, rectangular or cube, flattened dome, terrace, truncated pyramid, truncated cone, or trapezoid, lamina (e.g., wedding cake), or round lamina, bean, kidney, or any other suitable shape. In certain embodiments, the homogenizer (150) is a combination of two or more components. In certain embodiments, the combination of two or more components includes components constructed of different materials. In certain embodiments, the combination of two or more components includes components constructed from different sizes. The present invention is not limited to the structure of the above-described leveler.

In some embodiments, the homogenizer is annular and has an inner diameter and an outer diameter and a thickness measured from the top surface of the homogenizer to the bottom surface of the homogenizer.

In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 0.01 to 1mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 0.01 to 1.5mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 0.05 to 0.1mm. In some embodiments, the thickness of the homogenizer (150) (or the thickness of the thickest portion) is 0.1 to 0.5mm. In some embodiments, the thickness of the homogenizer (150) (or the thickness of the thickest portion) is 0.1 to 1mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 1 to 2mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 1 to 3mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 1 to 4mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 1 to 5mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 1 to 6mm. In some embodiments, the thickness of the homogenizer (150) (or the thickness of the thickest portion) is 0.4mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 0.05 to 3mm. In some embodiments, the thickness of the homogenizer (or the thickness of the thickest portion) is 1 to 5mm. In some embodiments, the thickness of the homogenizer (150) (or the thickness of the thickest portion) is 0.5mm.

In some embodiments, the homogenizer (150) has an inner diameter of 1 to 6mm. In some embodiments, the homogenizer has an inner diameter of 1 mm. In some embodiments, the homogenizer has an inner diameter of 2 mm. In some embodiments, the homogenizer (150) has an inner diameter of 3 mm. In some embodiments, the homogenizer has an inner diameter of 4mm. In some embodiments, the homogenizer has an inner diameter of 5mm. In some embodiments, the homogenizer has an inner diameter of 6mm.

In some embodiments, the homogenizer (150) has a diameter, for example an outer diameter of 1 to 6mm. In some embodiments, the homogenizer (150) has a diameter, for example an outer diameter of 2 to 5mm. In some embodiments, the homogenizer (150) has an outer diameter of 2 to 6mm. In some embodiments, the homogenizer (150) has an outer diameter of 5 to 9 mm. In some embodiments, the homogenizer (150) has an outer diameter of 2 to 9 mm. In some embodiments, the homogenizer has an outer diameter of 3 mm. In some embodiments, the homogenizer has a diameter, for example, an outer diameter of 4mm. In some embodiments, the homogenizer has an outer diameter of 5mm. In some embodiments, the homogenizer (150) has an outer diameter of 6mm. The present invention is not limited to the above dimensions. In certain embodiments, the diameter of the homogenizer is 3mm and the thickness is 0.05mm. In certain embodiments, the homogenizer has an outer diameter of 3.5mm, an inner diameter of 2mm, and a thickness of 0.05mm.

In some embodiments, the homogenizer (150) is disk-shaped and has a concave surface. In some embodiments, the homogenizer (150) is disk-shaped and has a convex surface. In some embodiments, the leveler (150) is disk-shaped and has a different thickness. In some embodiments, the leveler (150) is disk-shaped and has a different density. In some embodiments, the homogenizer (150) is disk-shaped and is composed of a combination of two or more materials having different densities, different thicknesses, or a combination thereof.

The invention also includes an interface comprising a material layer (112), which may correspond to a bottom surface of the cap system, wherein the material layer (112) has a top surface and a bottom surface. The leveler (150) may be disposed on the material layer (112) or in the material layer (112). The leveler (150) reduces at least a portion of the beta radiation emitted from the RBS in contact with the material layer (112) or the RBS proximate to the material layer (112), thereby controlling the amount of beta radiation emitted from the RBS and the material layer (112).

The invention also includes a sidewall capping system (e.g., a sidewall of a capping system) comprising a sidewall (115), e.g., cylindrical or other shape suitable for use in an RBS, the sidewall being composed of a dense material, wherein the sidewall (115) blocks passage of at least a portion of radiation through the sidewall. In some embodiments, the dense material comprises a polymer, a metal, or a combination thereof. In some embodiments, the dense material comprises a powder or metal compounded in a polymer. In some embodiments, the system is biocompatible. In some embodiments, the outer surface of the system is biocompatible. In some embodiments, the system is sterilizable.

In some embodiments, the sidewall cap system has a sidewall (115) comprised of an inner layer and an outer layer, the outer layer being comprised of a material comprising a plastic material, the inner layer being comprised of a denser material than the outer layer, wherein the sidewall (115) blocks passage of at least a portion of radiation through the sidewall. In some embodiments, the inner layer comprises a polymer, a metal, or a combination thereof. In some embodiments, the inner layer comprises a powder or metal compounded in a polymer. In some embodiments, the inner layer is composed of a material comprising tantalum. In some embodiments, the outer layer is composed of a plastic material. In some embodiments, the outer layer of the system is biocompatible. In some embodiments, the system is sterilizable. In some embodiments, the inner layer has a thickness of 0.35 mm. In some embodiments, the outer layer has a thickness of 0.5 mm. In some embodiments, the system allows no more than 3% of the prescribed dose of the RBS. In some embodiments, the thickness of the sidewall is such that only 3% of the prescribed dose of RBS can pass. In some embodiments, the system allows no more than 3Sv to pass. In some embodiments, the thickness of the sidewall is such that less than 3Sv can pass. In some embodiments, the system allows no more than 5Sv to pass. In some embodiments, the thickness of the sidewall is such that less than 5Sv can pass.

In some embodiments, the sidewall blocks at least 85% of the radiation from passing through the sidewall. In some embodiments, the sidewalls block 90-98% of the radiation from passing through the sidewalls. In some embodiments, the sidewall blocks at least 95% of the radiation from passing through the sidewall. In some embodiments, the sidewall blocks at least 97% of the radiation from passing through the sidewall. In some embodiments, the sidewall blocks 95% to 98% of the radiation from passing through the sidewall.

The cap system and/or the homogenizer and/or the interface and/or the sidewall system, etc. of the present invention may be designed based on one method or a combination of methods, for example based on experimental results using in part the monte carlo method. J.e. gentle at International Encyclopedia of Education (Third Edition), 2010"Monte Carlo Methods in Statistics" indicates that the "monte carlo method is an experiment. The monte carlo experiment is some function of estimating the probability distribution using simulated random numbers. In the public lecture of the university of oslo in spring 2008 (norwegian oslo N-0316) physical and scientific computing group system k.nilsen doctor, "monte carlo simulation" can be regarded as a computer experiment. Results can be analyzed using the same statistical tools we used in analytical laboratory experiments. The los alamous monte carlo N particle transport code (MCNP) "may be used for neutron, photon, electron or coupled neutron/photon/electron transport. Specific fields of application include, but are not limited to, radiation protection and dosimetry, radiation shielding, radiography, medical physics, nuclear critical security, detector design and analysis, nuclear oil well logging (nuclear oil well logging), accelerator target design, fission and fusion reactor design, decontamination (decontamination), and shutdown (decommissioning). "these codes can be used to determine if the core system is critical, to determine the source dose, etc. "

The cap system and/or the homogenizer and/or the interface and/or the sidewall system, etc. may allow radiation to be delivered in a shape optimized for the diameter of the surgical wound and/or about the bleb. The cap system and/or the homogenizer and/or the interface and/or the sidewall system, etc. may comprise intermediate materials having various transmission characteristics that allow for the dose to be homogenized throughout the diameter or throughout the area. By the same way, attenuation of the radiation can also be achieved by varying the surface output of the beta source so that a portion of the surface has a lower output. By the same approach, a uniform dose across a diameter (or a substantially uniform dose across a diameter) may be obtained by varying the sum of the surface output of the beta source across the diameter (or area) and the contribution of masking.

Without wishing to limit the invention to any theory or mechanism, the cap system and/or homogenizer and/or interface and/or sidewall system, etc. and/or the output of the beta source may be designed to anticipate optimal and most adequate treatment of the target tissue (e.g., PTV) while limiting stray doses (stray dose) of the lens and other tissues. The capping system and/or the leveler and/or the interface and/or the sidewall system, etc. may selectively and variably attenuate the dose across the brachytherapy applicator surface. The relative attenuation may be achieved by a variety of methods including variations in density or distance, or variable use of materials and thicknesses that alter the mean free path of the radiated electrons.

The invention also features a system that includes two or a combination of the devices, systems, or components described herein. For example, the present invention provides a system comprising a Radionuclide Brachytherapy Source (RBS) as described herein (e.g., comprising a capsule (210) having a bottom surface (212), a proximal surface (211) opposite the bottom surface, and side walls (215), and an active beta-radioactive material (215) encapsulated in the capsule (210) in an annular configuration, optionally comprising a forceps holder); and a cap system as described herein. The present invention also provides a system comprising a Radionuclide Brachytherapy Source (RBS) as described herein (e.g., a cylindrical capsule (210) having a bottom surface (212), a proximal surface (211) opposite the bottom surface, and a sidewall (215), and an active beta-radioisotope material (220) encapsulated in the capsule (210) in an annular configuration, the active beta-radioisotope material (220) emitting beta radiation through at least a portion of the bottom surface (212) of the capsule (210), wherein the capsule diameter is 10.8mm, wherein the RBS has an activity of 110mCi, optionally comprising a forceps holder), and a capping system as described herein, e.g., wherein the system emits beta radiation through at least a portion of an interface or bottom surface of the capping system, the portion of the interface or bottom surface being the active surface area (S).

In some embodiments, the dose at all points at a depth within T is within an 80% isodose line (isodose contour), 90% isodose line, or 100% isodose line. In some embodiments, the dose at all points at a depth within T is within 70%, 80%, 90%, or 100% isodose lines. In some embodiments, the dose at all points at a depth within T is at least 80% of the prescribed dose of the RBS system. It should be noted that the depth of the plane or area of the treatment volume is measured from the bottom surface of the cap system of the RBS system. One of ordinary skill in the art will understand that a dose is defined as being in a medium such as water, tissue, or plastic water. In some embodiments, the depth is 0.15 to 0.25mm. In some embodiments, the depth is 0.2 to 0.3mm. In some embodiments, the depth is 0.2 to 0.4mm. In some embodiments, the depth is 0.2 to 0.5mm. In some embodiments, the depth is 0.2 to 0.6mm. In some embodiments, the depth is 0.2 to 0.7mm. In some embodiments, the depth is 0.2 to 0.8mm. In some embodiments, the depth is 0.2 to 0.9mm. In some embodiments, the depth is 0.2 to 1mm. In some embodiments, the depth is 0.2 to 1.2mm. In some embodiments, the depth is 0.2 to 1.3mm. In some embodiments, the depth is 0.2 to 1.4mm. In some embodiments, the depth is 0.2 to 1.5mm. In some embodiments, the depth is 0.2 to 1.8mm. In some embodiments, the depth is 0.2 to 2mm.

In some embodiments, T is 7mm in diameter and the dose at all points within T that are 0.1 to 2mm in depth is at least 70% or 80% of the prescribed dose of the RBS system. In some embodiments, T is 8mm in diameter and the dose at all points within T that are 0.1 to 2mm deep is at least 80% of the prescribed dose of the RBS system. In some embodiments, T is 9mm in diameter and the dose at all points within T that are 0.1 to 2mm deep is at least 80% of the prescribed dose of the RBS system. In some embodiments, T is 10mm in diameter and the dose at all points within T that are 0.1 to 2mm in depth is at least 80% of the prescribed dose of the RBS system. In some embodiments, T is 7mm in diameter and the dose at all points within T that are 0.1 to 1mm in depth is at least 80% of the prescribed dose of the RBS system. In some embodiments, T is 8mm in diameter and the dose at all points within T that are 0.1 to 1mm in depth is at least 80% of the prescribed dose of the RBS system. In some embodiments, T is 9mm in diameter and the dose at all points within T that are 0.1 to 1mm in depth is at least 80% of the prescribed dose of the RBS system. In some embodiments, T is 10mm in diameter and the dose at all points within T that are 0.1 to 1mm in depth is at least 80% of the prescribed dose of the RBS system.

In some embodiments, one or more components of the present invention (e.g., the applicator) are constructed of a material that can further shield the user from RBS injury. In some embodiments, materials with low atomic numbers (Z) may be used for shielding (e.g., polymethyl methacrylate). In some embodiments, one or more layers of material are used for shielding, wherein the inner layer comprises a material having a low atomic number (e.g., polymethyl methacrylate) and the outer layer comprises lead.

Brachytherapy applicator

The present invention also provides a brachytherapy applicator for engaging the RBS and/or cap system described herein. In certain embodiments, the applicator may be characterized by an RBS fixedly connected to the applicator. For example, the applicator may be manufactured such that the RBS is integrated into the applicator prior to dispensing or surgical use. In some embodiments, the applicator is manufactured to accept the RBS at a later time. For example, the applicator may be manufactured and dispensed, and the RBS may be connected to or inserted into the applicator before it is used in a surgical procedure. In certain embodiments, the applicator is manufactured to engage a cap system, e.g., for inclusion of an RBS therein.

In certain embodiments, the cap system (110) can be connected to a brachytherapy applicator handle. In some embodiments, the cap system (110) includes threads (182) for threadably engaging complementary threads (184) of a brachytherapy applicator handle. As shown in fig. 5E and 5F, in some embodiments, the cap system (110) includes tines (166) for engaging a snap feature on the brachytherapy applicator to connect to the brachytherapy applicator. The invention is not limited to any particular mechanism for connecting the cap to the brachytherapy applicator handle. Fig. 6A, 6B, 6C, and 6D illustrate non-limiting examples of systems in which a cap may be threadably connected to a brachytherapy applicator handle.

The brachytherapy applicator (e.g., components of the brachytherapy applicator) can be constructed of any suitable material (e.g., biocompatible material) or combination of materials. Non-limiting examples of biocompatible materials include, but are not limited to, metals (e.g., stainless steel, titanium, tantalum, titanium alloys, gold), ceramics, and polymers. In certain embodiments, the components of the system, or portions thereof, are composed of one or a combination of materials including stainless steel, titanium, copper, brass, tungsten copper, metal alloys, or polymers. In certain embodiments, the components of the system, or portions thereof, are composed of a material comprising a polymer. In certain embodiments, the polymer is one or a combination of the following materials: polycarbonate, PEEK, PEI, PET, PETG, ABS, epoxy, polyester, polystyrene, polyurethane, PVDF, polyimide, HIPS, or styrene-butadiene rubber. In certain embodiments, the components of the system, or portions thereof, are composed of materials comprising stainless steel, titanium, tantalum, titanium alloys, gold, ceramics, polymers, or combinations thereof. In certain embodiments, components of the system, or portions thereof, are constructed of materials comprising synthetic polymeric materials (e.g., plastics). In certain embodiments, the components of the system, or portions thereof, are composed of a material comprising a metal or metal alloy. The present invention is not limited to the specific materials described herein.

In general, applicators of the present invention may be characterized as having a handle and a distal portion at the tip (e.g., distal end) of the handle for engaging and/or retaining a Radionuclide Brachytherapy Source (RBS) (e.g., radioisotope) and/or a capping system. The distal portion may be integral to the distal end of the handle. In some embodiments, the distal portion is removably attached to the distal end of the handle.

Referring to fig. 8A, 8B, and 9, in certain embodiments, the applicator and/or cap system features a separation feature that allows the single use applicator and/or cap system, e.g., prevents or impedes the cap system (110) and/or applicator from being used more than once. Fig. 8A shows the cap system engaged with the handle. The cap system may engage the handle by various mechanisms, e.g., the cap may snap onto the handle, clip onto the handle, twist onto the handle, etc. Fig. 9 shows a separation feature that helps prevent cap reuse. For example, in some embodiments, the cap includes one or more tines (166) that function as part of a latch or snap or clamp mechanism through which the cap is engaged with the handle. The cap is characterized by further having ribs (168) which may break when the cap is disengaged from the handle.

Target plane

The system of the present invention delivers a dose of radiation to a target (e.g., a target plane of a treatment area). Fig. 10A, 10B, 10C, and 10D illustrate examples of target planes in a treatment region, where a target plane is a plane having a particular dimension (e.g., diameter) at a particular depth (e.g., distance from the outer surface of the applicator, distance from the surface of the eye, distance from the top of the bubble, distance from the RBS, etc.).

In certain embodiments, the target plane has a diameter of about 2 mm. In certain embodiments, the target plane has a diameter of about 3 mm. In certain embodiments, the target plane has a diameter of about 4 mm. In certain embodiments, the target plane has a diameter of about 5 mm. In certain embodiments, the target plane has a diameter of about 6 mm. In certain embodiments, the target plane has a diameter of about 7 mm. In certain embodiments, the target plane has a diameter of about 8 mm. In certain embodiments, the target plane has a diameter of about 9 mm. In certain embodiments, the target plane has a diameter of about 10 mm. In certain embodiments, the target plane has a diameter of about 11 mm. In certain embodiments, the target plane has a diameter of about 12 mm. In certain embodiments, the target plane has a diameter of 10 to 14 mm. In certain embodiments, the target plane has a diameter of 6 to 10 mm. In certain embodiments, the target plane has a diameter of 5 to 12 mm. In certain embodiments, the target plane has a diameter of 6 to 12 mm. In certain embodiments, the target plane has a diameter of 8 to 10 mm. In certain embodiments, the target plane has a diameter of 8 to 12 mm. In certain embodiments, the target plane has a diameter of 6 to 8 mm. In certain embodiments, the target plane has a diameter of 7 to 10 mm. In certain embodiments, the target plane has a diameter of 8 to 11 mm. In certain embodiments, the target plane has a diameter of 9 to 11 mm. In certain embodiments, the target plane has a diameter of 9 to 12 mm. The present invention is not limited to the above-described dimensions of the target surface.

Referring to fig. 10A, in some embodiments, T has a diameter of 9.8mm. In some embodiments, T has a diameter of 12mm. In some embodiments, T has a diameter of 11mm. In some embodiments, the diameter of T is 10mm. In some embodiments, T has a diameter of 9mm. In some embodiments, T has a diameter of 8mm. In some embodiments, the diameter of S is 10 to 11mm. In some embodiments, T has a diameter of 9 to 10mm. In some embodiments, T has a diameter of 8 to 9mm. In some embodiments, T has a diameter of 7 to 8mm. In some embodiments, T has a diameter of 7 to 8mm. In some embodiments, T has a diameter of 2 to 10mm. In some embodiments, T has a diameter of 4 to 11mm. In some embodiments, T is 5 to 10mm in diameter. In some embodiments, T has a diameter of 6 to 12mm. In some embodiments, T is an area defined within a radius of 1mm from the center or bottom surface of the cap system interface. In some embodiments, T is an area defined within a radius of 2mm from the center or bottom surface of the cap system interface. In some embodiments, T is an area defined within a radius of 3mm from the center or bottom surface of the cap system interface. In some embodiments, T is an area defined within a radius of 4mm from the center or bottom surface of the cap system interface. In some embodiments, T is an area defined within a radius of 5mm from the center or bottom surface of the cap system interface. In some embodiments, the dose across T is uniform, e.g., all points are within a specific percentage of the maximum dose in the region, or all points are within a specific percentage of the maximum dose in the treatment volume, etc.

In certain embodiments, the target plane is, for example, at a distance of 0 to 700 microns from the outer surface of the applicator (e.g., the portion of the applicator that contacts ocular tissue), from the surface of the eye, from the top of the bubble, from RBS, and the like. In certain embodiments, the target plane is, for example, at a distance of 0 to 100 microns from the outer surface of the applicator (e.g., the portion of the applicator that contacts ocular tissue), from the surface of the eye, from the top of the bubble, from RBS, and the like. In certain embodiments, the target plane is, for example, at a distance of 100 to 200 microns from the outer surface of the applicator (e.g., the portion of the applicator that contacts ocular tissue), from the surface of the eye, from the top of the bubble, from RBS, and the like. In certain embodiments, the target plane is, for example, at a distance of 200 to 400 microns from the outer surface of the applicator (e.g., the portion of the applicator that contacts ocular tissue), from the surface of the eye, from the top of the bubble, from RBS, and the like. In certain embodiments, the target plane is, for example, at a distance of 200 to 600 microns from the outer surface of the applicator (e.g., the portion of the applicator that contacts ocular tissue), from the surface of the eye, from the top of the bubble, from RBS, and the like. In certain embodiments, the target plane is, for example, at a distance of 400 to 600 microns from the outer surface of the applicator (e.g., the portion of the applicator that contacts ocular tissue), from the surface of the eye, from the top of the bubble, from RBS, and the like.

The dosages recited herein may refer to dosages at particular depths from the surface of the device, for example, depths of 0.05mm, 0.1mm, 0.15mm, 0.2mm, 0.25mm, 0.3mm, 0.35mm, 0.4mm, 0.45mm, 0.5mm, 0.55mm, 0.6mm, 0.65mm, 0.7mm, 0.75mm, 0.8mm, and the like.

Dosage of

RBS and/or RBS systems deliver a specific radiation dose to a target, e.g., to a plane within the target (e.g., a plane representing a specific dimension of a portion of a treatment area (e.g., a PTV)). In some embodiments, the system delivers a radiation dose of 1000cGy (10 Gy) to the target. In some embodiments, the system delivers a radiation dose of 900cGy to the target. In some embodiments, the system delivers a radiation dose of 800cGy to the target. In some embodiments, the system delivers a radiation dose of 750cGy to the target. In some embodiments, the system delivers a radiation dose of 600cGy to the target. In some embodiments, the system delivers a radiation dose of 500cGy to the target. In some embodiments, the system delivers a radiation dose of 400cGy to the target. In some embodiments, the system delivers a radiation dose of 300cGy to the target. In some embodiments, the system delivers a radiation dose of 200cGy to the target. In some embodiments, the system delivers a radiation dose of 100cGy to the target. In some embodiments, the system delivers a radiation dose of 50cGy to the target. In some embodiments, the system delivers a radiation dose of 1100cGy to the target. In some embodiments, the system delivers a radiation dose of 1200cGy to the target. In some embodiments, the system delivers a radiation dose of 1300cGy to the target. In some embodiments, the system delivers a radiation dose of 1500cGy to the target. In some embodiments, the system delivers radiation doses from 600cGy and 1500cGy to the target. In some embodiments, the system delivers a radiation dose from 50cGy to 100 cGy. In some embodiments, the system delivers a radiation dose from 100cGy to 150 cGy. In some embodiments, the system delivers a radiation dose from 150cGy to 200 cGy. In some embodiments, the system delivers a radiation dose from 200cGy to 250 cGy. In some embodiments, the system delivers a radiation dose from 250cGy to 300 cGy. In some embodiments, the system delivers a radiation dose from 300cGy to 350 cGy. In some embodiments, the system delivers a radiation dose from 350cGy to 400 cGy. In some embodiments, the system delivers a radiation dose from 400cGy to 450 cGy. In some embodiments, the system delivers a radiation dose from 450cGy to 500 cGy. In some embodiments, the system delivers a radiation dose from 500cGy to 550 cGy. In some embodiments, the system delivers a radiation dose from 550cGy to 600 cGy. In some embodiments, the system delivers a radiation dose from 600cGy to 650 cGy. In some embodiments, the system delivers radiation doses from 650cGy to 700 cGy. In some embodiments, the system delivers a radiation dose from 700cGy to 750 cGy. In some embodiments, the system delivers a radiation dose from 750cGy to 800 cGy. In some embodiments, the system delivers a radiation dose from 800cGy to 850 cGy. In some embodiments, the system delivers radiation doses from 850cGy to 900 cGy. In some embodiments, the system delivers radiation doses from 900cGy to 950 cGy. In some embodiments, the system delivers a radiation dose from 950cGy to 1000 cGy. In some embodiments, the system delivers radiation doses from 1000cGy to 1050 cGy. In some embodiments, the system delivers radiation doses from 1050cGy to 1100 cGy. In some embodiments, the system delivers radiation doses from 1100cGy to 1150 cGy. In some embodiments, the system delivers radiation doses from 1150cGy to 1200 cGy. In some embodiments, the system delivers a radiation dose from 1200cGy to 1250 cGy. In some embodiments, the system delivers a radiation dose from 1250cGy to 1300 cGy. In some embodiments, the system delivers radiation doses from 1300cGy to 1350 cGy. In some embodiments, the system delivers a radiation dose of from 1350cGy to 1400 cGy. In some embodiments, the system delivers a radiation dose from 1400cGy to 1450 cGy. In some embodiments, the system delivers a radiation dose from 1450cGy to 1500 cGy. In some embodiments, the system delivers a radiation dose from 1500cGy to 1550 cGy. In some embodiments, the system delivers radiation doses from 1550cGy to 1600 cGy. In some embodiments, the system delivers radiation doses from 1600cGy to 1800 cGy. In some embodiments, the system delivers radiation doses from 1800cGy to 2000 cGy. In some embodiments, the system delivers a radiation dose of 600cGy, 650cGy, 700cGy, 750cGy, 800cGy, 850cGy, 900cGy, 950cGy, 1000cGy, 1050cGy, 1100cGy, 1150cGy, 1200cGy, 1250cGy, 1300cGy, 1350cGy, 1400cGy, 1450cGy, or 1500cGy to the target. In some embodiments, the system delivers a radiation dose from 1500cGy to 3200 cGy. In some embodiments, the system delivers a radiation dose from 3200cGy to 8000 cGy. In some embodiments, the system delivers a radiation dose from 8000cGy to 10000 cGy. In some embodiments, the system delivers a radiation dose greater than 10000 cGy.

For example, in some embodiments, the dose rate (i.e., firing to the treatment volume) of the RBS system surface is from 90 to 100 cGy/sec. In some embodiments, the dosage rate (i.e., firing to the treatment volume) of the RBS system surface is 80 to 90 cGy/sec. In some embodiments, the dose rate (i.e., firing to the treatment volume) at the surface of the RBS system is 70 to 80 cGy/sec. In some embodiments, the dose rate at the surface of the RBS system (i.e., the firing to the treatment volume) is 60 to 70 cGy/sec. In some embodiments, the dose rate (i.e., firing to the treatment volume) at the surface of the RBS system is 50 to 60 cGy/sec. In some embodiments, the dose rate at the surface of the RBS system (i.e., the firing to the treatment volume) is 40 to 50 cGy/sec. In some embodiments, the dose rate (i.e., firing to the treatment volume) at the surface of the RBS system is 50 to 60 cGy/sec. In some embodiments, the dose rate at the surface of the RBS system (i.e., the firing to the treatment volume) is 30 to 40 cGy/sec. In some embodiments, the dose rate at the surface of the RBS system (i.e., the firing to the treatment volume) is 20 to 30 cGy/sec. In some embodiments, the dose rate at the surface of the RBS system (i.e., the firing to the treatment volume) is 50 to 100 cGy/sec. In some embodiments, the dose rate at the surface of the RBS system (i.e., the firing to the treatment volume) is 20 to 90 cGy/sec. The present invention is in no way limited to the above-mentioned dose rates at the surface (within the diameter of the treatment volume). These values are used as examples only.

In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 10 seconds to 20 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 20 seconds and 10 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 20 seconds to 60 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 30 seconds to 90 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose in a time of 60 seconds to 90 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 90 seconds to 2 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 2 minutes to 3 minutes.

In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 3 minutes to 4 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 3 minutes to 5 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 3 minutes to 6 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 4 minutes to 5 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 4 minutes to 6 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 5 minutes to 6 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 6 minutes to 7 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 7 minutes to 8 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 8 minutes to 9 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 9 minutes to 10 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 10 minutes to 12 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 12 minutes to 15 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a period of 15 minutes to 20 minutes.

In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 5 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 10 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 15 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 20 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 25 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 45 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 60 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 90 seconds. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 2 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 3 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 4 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 5 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 6 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 7 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 8 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 9 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 10 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 11 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 12 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 13 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 14 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 15 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 16 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 17 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 18 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 19 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose within 20 minutes. In some embodiments, the RBS and/or RBS system delivers the prescribed dose over a time frame of greater than 20 minutes.

In some embodiments, a dose (e.g., a prescribed dose) may be delivered in a single application. In other embodiments, the dose (e.g., a prescribed dose) may be administered in portions and in multiple applications. For example, in some embodiments, radiation (e.g., a prescribed dose) may be applied during 2 applications. In some embodiments, the radiation (e.g., prescribed dose) may be applied during the course of 3 applications. In some embodiments, the radiation (e.g., prescribed dose) may be applied during the course of 4 applications. In some embodiments, the radiation (e.g., prescribed dose) may be applied during 5 applications. In some embodiments, the radiation (e.g., prescribed dose) may be applied during more than 5 applications. In some embodiments, the radiation (e.g., prescribed dose) may be applied during 20 applications. In some embodiments, the radiation (e.g., prescribed dose) may be applied during more than 20 applications.

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

According to one embodiment, a dose of radiation may be applied prior to a treatment procedure, such as a procedure for implanting a device, such as a MIGS device, or other suitable glaucoma procedure, such as MIMS. For example, in some embodiments, a dose of radiation may be administered one or more days prior to surgery (e.g., insertion device, MIMS, etc.). In some embodiments, a dose of radiation may be applied within 24 hours prior to surgery (e.g., insertion of a device). In some embodiments, a dose of radiation may be applied prior to surgery (e.g., insertion device, MIMS, etc.), such as 1 hour prior to surgery, 30 minutes prior to surgery, 15 minutes prior to surgery, 5 minutes prior to surgery, 1 minute prior to surgery, etc. In some embodiments, a dose of radiation may be administered during, for example, a surgical procedure for implanting the device. In some embodiments, a dose of radiation may be applied immediately after surgery (e.g., implantation of a device (e.g., a MIGS device)) or within, for example, 1 minute, 2 minutes, 3 minutes, 5 minutes, 10 minutes, etc., after the formation of the hole. In some embodiments, a dose of radiation may be applied prior to making an incision in the conjunctiva. In some embodiments, a dose of radiation may be applied after an incision is made in the conjunctiva. In other embodiments, a dose of radiation may be administered after surgery (e.g., insertion of a device). In some embodiments, a dose of radiation may be applied within 24 hours after surgery (e.g., insertion of a device). In some embodiments, a dose of radiation may be applied within one to two days after surgery (e.g., insertion of a device). In some embodiments, a dose of radiation may be applied for two or more days after surgery (e.g., insertion of a device). In some embodiments, the dose may be administered at any time after glaucoma surgery. In some embodiments, the dose is administered months or years after glaucoma surgery. For example, a dose may be administered to a patient who did not receive the dose during surgery but had a scar or needle stick surgery in the future to destroy scar tissue.

Dose curve

Traditionally, the unique dose prescription convention for β ophthalmic applicator brachytherapy prescribes a maximum dose at the center point of the proximal surface. Thompson et al AAPM recommendations on medical physics practices for ocular plaque brachytherapy: report of task group 221 indicate that "the method of treatment planning differs from that of photon emission sources because the dosimetric form of planar beta sources is not compatible with the AAPM Tg-43 reporting form. .. TG-221 encourages 2D and/or 3D dose calculation. The unique 1D dose prescription convention used in "beta ophthalmic applicator brachytherapy" specifies the maximum dose at the proximal surface center point. The dose from the central dose to any point and/or any depth in the tissue is lower than the prescribed dose.

As a non-limiting example, in certain embodiments, the systems herein can provide an 80% isodose region comprising a diameter of about 6mm defining a Treatment Volume (TV), which is the volume of tissue enclosed within a particular isodose (e.g., 80% isodose) envelope. In some embodiments, the Outer Diameter (OD) (12 mm) of the applicators (e.g., systems) herein is greater than a closed disk of Sr-90 having an emitting surface diameter (e.g., about 8 mm). TV diameter is further shrunk by the edge effect and scattering of the active Sr-90 surface, characterized by the diameter of the penumbra invading the active surface.

In certain embodiments, the dose varies by no more than 10% of the maximum dose across a particular target plane on or within the target at a particular depth (e.g., a plane of a particular size/diameter within the depth of the treatment region). In certain embodiments, the dose varies by no more than 15% of the maximum dose across a particular target plane on or within the target at a particular depth (e.g., a plane of a particular size/diameter within the depth of the treatment region). In certain embodiments, the dose varies by no more than 20% of the maximum dose across a particular target plane on or within the target at a particular depth (e.g., a plane of a particular size/diameter within the depth of the treatment region). In certain embodiments, the dose varies by no more than 25% of the maximum dose across a particular target plane on or within the target at a particular depth (e.g., a plane of a particular size/diameter within the depth of the treatment region). In certain embodiments, the dose varies by no more than 30% of the maximum dose across a particular target plane on or within the target at a particular depth (e.g., a plane of a particular size/diameter within the depth of the treatment region). In certain embodiments, the dose varies by no more than 35% of the maximum dose across a particular target plane on or within the target at a particular depth (e.g., a plane of a particular size/diameter within the depth of the treatment region). In certain embodiments, the dose varies by no more than 40% of the maximum dose across a particular target plane on or within the target at a particular depth (e.g., a plane of a particular size/diameter within the depth of the treatment region).

In certain embodiments, the dose at any point on the target plane of the treatment region at a particular depth is within 10% of the dose at any other point on the target plane of the treatment region at that depth. In certain embodiments, the dose at any point on the target plane of the treatment region at a particular depth is within 15% of the dose at any other point on the target plane of the treatment region at that depth. In certain embodiments, the dose at any point on the target plane of the treatment region at a particular depth is within 20% of the dose at any other point on the target plane of the treatment region at that depth. In certain embodiments, the dose at any point on the target plane of the treatment region at a particular depth is within 25% of the dose at any other point on the target plane of the treatment region at that depth. In certain embodiments, the dose at any point on the target plane of the treatment region at a particular depth is within 30% of the dose at any other point on the target plane of the treatment region at that depth. In certain embodiments, the dose at any point on the target plane of the treatment region at a particular depth is within 35% of the dose at any other point on the target plane of the treatment region at that depth. In certain embodiments, the dose at any point on the target plane of the treatment area at a particular depth is within 40% of the dose at any other point on the target plane of the treatment area at that depth.

The calculation of the maximum dose or average maximum dose is understood by those of ordinary skill in the art. As an example, in some embodiments, the average maximum dose is an average of at least 100 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 4 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 9 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 16 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 25 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 36 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 49 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 64 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of at least 81 pixels surrounding the pixel with the maximum dose. As an example, in some embodiments, the average maximum dose is an average of greater than 100 pixels around the pixel with the maximum dose.

In some embodiments, uniformity is calculated based on, for example, a maximum dose of the target (within the diameter of the target volume) at a depth. In some embodiments, uniformity is calculated based on the maximum dose for the entire treatment volume. In some embodiments, uniformity is calculated based on, for example, an average maximum dose of the target (within the diameter of the target volume) at a depth. In some embodiments, uniformity is calculated based on the average maximum dose across the treatment volume. The invention is not limited to these means of defining or calculating uniformity.

Fig. 11A, 11B, 12A, 12B, 12C, 12D, 12E, 12F, 12G, 12H, 12I, 13A, 13B, 13C, 13D, 14, 15, 16A, 16B, 17, and 18 each illustrate theoretical or actual dosimetry results using a representative radionuclide brachytherapy source and system (e.g., characterized by having one of two representative cap systems).

Referring to fig. 11A and 12B, MCNP modeling of bare sources, the following table shows the dose (normalized to percentage of maximum dose) at 0.24mm and 0.56mm depths. The relative doses were at radii of 1mm, 2mm, 3mm, 4mm and 5mm from the centre. The following percentages are by way of example only. The invention is not limited to the numbers shown below. In some embodiments, the following percentage variation is 5%, 10%, 15%, 20%, etc.

r(mm)

0

1

2

3

4

5

z(mm)

0.24

60-64％

85-90％

98-100％

94-96％

90-92％

48-52％

0.56

60-64％

71-76％

78-82％

77-79％

67-71％

38-42％

Referring to fig. 11C and 11D, MCNP modeling of a system using caps (HIPS caps) the following table shows doses (normalized to percentage of maximum dose) at depths of 0.24mm and 0.56 mm. The relative doses were at radii of 1mm, 2mm, 3mm, 4mm and 5mm from the centre. The following percentages are by way of example only. The invention is not limited to the numbers shown below. In some embodiments, the following percentage variation is 5%, 10%, 15%, 20%, etc.

r(mm)

0

1

2

3

4

5

z(mm)

0.24

94-96％

96-97％

98-99％

99-100％

88-91％

57-60％

0.56

81-83％

80-81％

82-84％

80-82％

68-72％

44-46％

In certain embodiments, the dose at any point within 8mm diameter of the treatment volume at a depth of about 0.24mm is within 70 to 100% of the maximum dose of the treatment volume. In certain embodiments, the dose at any point within 8mm diameter of the treatment volume at a depth of about 0.24mm is within 75 to 100% of the maximum dose of the treatment volume. In certain embodiments, the dose at any point within 8mm diameter of the treatment volume at a depth of about 0.24mm is within 80 to 100% of the maximum dose of the treatment volume. In certain embodiments, the dose at any point of the 8mm diameter of the treatment volume at a depth of about 0.56mm is within 70-85% of the maximum dose of the treatment volume. In certain embodiments, the dose at any point of the 8mm diameter of the treatment volume at a depth of about 0.56mm is within 65-90% of the maximum dose of the treatment volume. In certain embodiments, the dose at any point of the 8mm diameter of the treatment volume at a depth of about 0.56mm is within 60-90% of the maximum dose of the treatment volume.

Referring to fig. 12A, 12B and 12C, dosimetry for a system without a cap, the following table shows the doses at 0.24mm and 0.56mm depths (normalized to percentage of maximum dose). The relative doses were at radii of 1mm, 2mm, 3mm, 4mm and 5mm from the centre.

The following percentages are by way of example only. The invention is not limited to the numbers shown below. In some embodiments, the following percentage variation is 5%, 10%, 15%, 20%, etc.

	r(mm)
								0	1	2	3	4	5
z(mm)
							0.19	67-69	90-100	85-92	80-84	72-76	42-45
0.46	60-61	67-70	63-67	60-64	56-59	31-44
							0.67	55-56	58-62	59-62	56-58	49-53	28-29
0.94	53-55	53-56	50-53	46-49	40-42	25-27
							1.51	38-40	27-29	35-38	33-35	29-31	19-22
1.99	28-30	27-30	25-29	23-35	18-20	12-14

Referring to fig. 12D, 12E and 12F, the following table shows the doses (normalized to percentage of maximum dose) at 0.24mm meters and 0.56mm depths for the system with HIPS caps. The relative doses were at radii of 1mm, 2mm, 3mm, 4mm and 5mm from the centre. The following percentages are by way of example only. The invention is not limited to the numbers shown below. In some embodiments, the following percentage variation is 5%, 10%, 15%, 20%, etc.

	r(mm)
								0	1	2	3	4	5
z(mm)
							0.19	94-96	99-100	90-94	85-87	76-82	50-68
0.67	68-72	69-71	65-66	61-63	55-56	38-42
							0.94	59-61	57-59	55-56	50-53	40-48	26-36
1.99	31-33	31-33	29-31	27-28	23-25	15-18

Referring to fig. 12G, 12H and 12I, the following table shows the doses (normalized to percentage of maximum dose) at 0.24mm and 0.56mm depths for the system with titanium caps. The relative doses were at radii of 1mm, 2mm, 3mm, 4mm and 5mm from the centre. The following percentages are by way of example only. The invention is not limited to the numbers shown below. In some embodiments, the following percentage variation is 5%, 10%, 15%, 20%, etc.

	r(mm)
								0	1	2	3	4	5
z(mm)
							0.19	86-88	92-98	77-79	78-80	80-85	50-68
0.67	66-68	64-66	56-60	55-59	56-59	40-45
							0.94	58-60	56-58	53-54	52-53	50-51	35-38
1.99	31-33	31-32	29-31	27-29	24-26	15-20

Fig. 13A, 13B, 13C, and 13C each show the data in fig. 12, where each data is a graph of depth and a comparison of the system.

Kit of parts

The invention also features kits that include one or more components of the brachytherapy systems of the invention. For example, in certain embodiments, the kit includes a cap system. For example, in some embodiments, the kit includes a brachytherapy applicator, such as an applicator without an RBS. In some embodiments, the kit may include an applicator (e.g., a handle) and a capping system for engaging the handle once the RBS is inside the capping system. In some embodiments, the kit includes a beta radiation source (e.g., RBS) and a brachytherapy applicator. In some embodiments, the kit includes a portion of a component of a brachytherapy applicator. In some embodiments, the kit further comprises a radiation attenuating shield. In certain embodiments, the radiation attenuating shield is integrated into the cap system.

In certain embodiments, the kit includes a brachytherapy applicator (e.g., a handle portion and cap system) and an implant for transscleral insertion (e.g., an implant for transscleral insertion that forms a bleb in the subconjunctival space of the eyeball (or a bleb in the space between the conjunctiva and the tenon's capsule)). In some embodiments, the kit includes a brachytherapy applicator (e.g., a handle portion and cap system), a radionuclide brachytherapy source, and an implant for transscleral insertion (e.g., an implant for transscleral insertion that forms a bleb in the subconjunctival space of the eyeball (or a bleb in the space between the conjunctiva and the tenon's capsule)). For example, in certain embodiments, the handle and cap are provided in a kit packaged with the MIGS drainage device.

In some embodiments, the kit is disposable. The kit may be provided in a sterile package.

Method

The system and apparatus of the present invention can be used in a variety of ways. Non-limiting examples of methods of using the systems and devices herein include methods of applying beta radiation to an ocular target, such as the site of a bleb formed by a MIGS implant or surgery. Other methods include methods of inhibiting or fibrosis or inhibiting or reducing inflammation in the alveoli or pores associated with MIGS implants or procedures, trabeculectomy, MIMS procedures, and the like.

By way of example, the systems and devices of the present invention provide methods of treating glaucoma drainage surgical conjunctival blebs with substantially uniform doses of beta therapy (e.g., substantially uniform doses of beta therapy spanning diameters of about 10mm, 9mm, 8mm, 7mm, 6mm, 5mm, etc.).

Other methods include methods of maintaining bleb function, methods of enhancing MIGS implant function (e.g., by maintaining a functional bleb), methods of increasing MIMS success rate, methods of repairing failed trabeculectomy, methods of repairing failed MIMS, methods of lowering intraocular pressure (IOP), methods of maintaining healthy IOP, methods of treating glaucoma, and the like.

The methods herein include applying beta radiation to a target region of an eye. In some embodiments, the target region is a site of a bubble or an intended site of a bubble. (note that the target is not limited to a bubble or a portion of a bubble.) in some embodiments, the target region surrounds an end of the implant. In some embodiments, the target is 2 to 5mm in diameter. In some embodiments, the target is 5 to 12mm in diameter. In some embodiments, the thickness of the target is 0.3mm to 0.5mm. In some embodiments, the thickness of the target is 0.01mm to 0.7mm. In some embodiments, the thickness of the target is 0.1mm to 0.6mm. The present invention is not limited to the size of the target described above.

In some embodiments, the method includes applying beta radiation prior to a particular surgical procedure, e.g., prior to insertion of the MIGS implant, prior to dissection of the conjunctiva, prior to creation of the MIMS-related aperture, etc. In some embodiments, the method includes applying beta radiation after a particular surgical procedure.

The invention features methods of inhibiting or reducing fibrosis and inflammation in the blebs of an eye being treated for glaucoma. The invention also provides methods of maintaining functional drainage blisters in the eye of a patient receiving glaucoma treatment. The invention also features a method of treating glaucoma. The invention also features a method of lowering intraocular pressure (IOP). The invention also features a method of reducing inflammation of an eye containing a foreign body (e.g., 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 the ternon's sac), wherein the implant results in the formation of a bleb for draining aqueous humor.

The method features applying a therapeutic amount of beta radiation from a radioisotope to a target region of an eye using an applicator system as described herein.

Beta radiation may be effective in lowering intraocular pressure (IOP) of the eye, beta radiation may be effective in treating glaucoma, beta radiation may cause cell cycle arrest in fibroblasts on tennong's vesicles to inhibit or reduce fibrotic processes and inflammation leading to failure of the vesicles, beta radiation may reduce or inhibit fibrotic processes and inflammation leading to failure of the vesicles, beta radiation may help to effectively maintain drainage function of the vesicles.

In some embodiments, the method comprises implanting a Minimally Invasive Glaucoma Surgery (MIGS) implant into the eye, wherein the implant causes (e.g., in the subconjunctival space of the eye, in the space between the conjunctiva and the ternon's sac) a bleb; the function of the bubble is to drain the aqueous humor. In certain embodiments, the implant is inserted transsclerally 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 the ternon's sac, or the like.

In some embodiments, the methods herein include introducing a drug to a site, e.g., a site of a MIGS implant, a site of a bleb, a different portion of an eye.

As previously mentioned, ionizing radiation has an effect on cells, which can lead to cell cycle arrest. In some embodiments, the beta radiation of the present invention results in cell cycle arrest in fibroblasts on or associated with the tennong's sac or conjunctiva, thereby inhibiting or reducing fibrotic processes and inflammation that lead to failure of the bleb.

As previously described, the beta radiation may be applied by a Radionuclide Brachytherapy Source (RBS). RBS can be applied to the target by an applicator. As previously discussed, in some embodiments, the RBS provides a dose of about 750cGy to the target. In some embodiments, the RBS provides a dose of 500 to 1000cGy to the target.

The invention also features a method of making an applicator for emitting beta radiation. In some embodiments, the method includes inserting a Radionuclide Brachytherapy Source (RBS) into the applicator, for example, into a suitable location or cavity in the applicator. In some embodiments, the method includes connecting the RBS to an applicator.

In some embodiments, the systems and devices of the present invention may be used in methods associated with needlepunching procedures, such as, for example, the release of blebs or the removal of scar tissue and/or cystic structures within and/or around blebs and/or the manipulation of surgical wound healing or scarring or sites where inflammatory reactions may occur following glaucoma surgery. The needling procedure may affect the morphology of the surgical site, restore surgical function, and/or lower IOP.

Without wishing to limit the invention to any theory or mechanism, it is believed that treating scar tissue formed on the blebs formed by trabeculectomy is different from treating the blebs that are newly created (and without scar tissue) by trabeculectomy. In some embodiments, the methods herein comprise applying β therapy to the blebs formed by the trabeculectomy procedure concurrently with the needling procedure. In some embodiments, the methods herein comprise applying β -therapy to the trabeculectomy blebs of scar tissue that has formed. In some embodiments, the methods herein comprise administering β therapy to bubbles in the eye of a trabeculectomy patient that increases intraocular pressure (IOP). In some embodiments, the methods herein comprise administering β -therapy to a bleb that failed or has failed a trabeculectomy. In some embodiments, the methods herein comprise administering β therapy to a bleb in a second trabeculectomy in which the first trabeculectomy has failed.

In some embodiments, the methods herein comprise administering β therapy to a bleb that fails or has failed. In some embodiments, the methods herein comprise administering β therapy to a failed or failed MIGS device bulb. In some embodiments, the methods herein comprise administering β -therapy to a MIGS device bleb that has scar tissue formed. In some embodiments, the methods herein comprise administering β therapy to bubbles in the eye of an MIGS device patient with increased intraocular pressure (IOP).

In some embodiments, the methods herein comprise applying another drug to the eye (e.g., target, region near target, etc.) in addition to beta radiation. As a non-limiting example, the method may further comprise administering a pharmaceutical eye drop or an antimetabolite (e.g., a liquid antimetabolite). In various embodiments, the drug may be administered before, during, or after the surgical implantation procedure. In some embodiments, the methods herein comprise the administration of another antimetabolite (e.g., mitomycin-c or 5-fluorouracil) in addition to beta radiation. In some embodiments, the method comprises administering a pharmaceutical eye drop or a liquid antimetabolite or other liquid drug. In some embodiments, the medicament is administered before, during, and/or after the surgical procedure.

The systems and devices (and methods) of the present invention may also be used for wound healing, such as ocular wounds due to foreign body insertion, trauma, ocular surface wounds, and the like. A wound healing model divides this process into hemostasis, inflammation, proliferation and remodeling. The first stage of hemostasis begins immediately after injury, with vasoconstriction and fibrin clot formation. The clot and surrounding wound tissue release pro-inflammatory cytokines and growth factors such as Transforming Growth Factor (TGF) -beta, 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 sequential infiltration of neutrophils, macrophages and lymphocytes. In early wounds, macrophages release cytokines, which promote the inflammatory response by recruiting and activating additional leukocytes. When macrophages clear these apoptotic cells, they undergo a phenotypic transition to a repair state, stimulating keratinocytes, fibroblasts and angiogenesis to promote tissue regeneration. T-lymphocytes migrate into the wound after inflammatory cells and macrophages and peak during the late proliferation/early remodeling stages. T-cells regulate many aspects of wound healing, including maintaining tissue integrity, protecting against pathogens, and regulating inflammation. The proliferative phase generally follows and overlaps with the inflammatory phase and is characterized by epithelial proliferation and migration (epidermal cell regeneration) on the temporary matrix within the wound. Among the reparative dermis, fibroblasts and endothelial cells are the most prominent cell types, which support capillary growth, collagen formation and granulation tissue formation at the site of injury. Within the wound bed, fibroblasts produce collagen as well as glycosaminoglycans and proteoglycans, which are the major components of the extracellular matrix (ECM). After vigorous proliferation and ECM synthesis, wound healing enters the final remodelling stage, which can last for years.

The radiation attenuating mask of the present invention reduces the use of beta radiation as a competitive first choice therapy in trabeculectomy to acceptable medical practice. This can be achieved by: (1) The beta radiation source output is optimized for the specific planned treatment volume of the trabeculectomy surgical wound and bleb, and (2) the stray dose of the lens is minimized, thereby reducing the side effects of inducing cataracts, otherwise limiting the choice of such treatment modality.

Notably, by convention, dose variation is described as assuming a change in center point maximum dose spanning diameter. However, it has in practice been shown that the maximum dose may be off-centre. Thus, the description of the dose across the diameter may also include the variation of the dose over this area.

As previously described, the present invention provides therapeutic doses of beta radiation, e.g., optimized doses of beta radiation, modified therapeutic doses of beta radiation, and the like. For example, the systems and devices of the present invention as described herein provide a relatively uniform dose over at least a portion of the target area.

For example, the invention also features the use of a Radionuclide Brachytherapy Source (RBS) system that emits beta radiation in a method of treating glaucoma. In some embodiments, the method comprises performing a glaucoma drainage procedure on the patient's eye to form a bleb in the subconjunctival space or between the conjunctiva and the ternon's sac, and allowing aqueous humor to drain into the bleb; and applying a therapeutic dose of beta radiation from the RBS system to the target region associated with the blebs, drainage channels, drainage implants, or a combination thereof.

The invention also features the use of a Radionuclide Brachytherapy Source (RBS) system that emits beta radiation in a method of treating glaucoma (e.g., for helping to lower IOP). In some embodiments, the method comprises performing a glaucoma drainage procedure on the patient's eye to form a bleb in the subconjunctival space or between the conjunctiva and the ternon's sac, and allowing aqueous humor to drain into the bleb; and applying a therapeutic dose of beta radiation from the RBS system to the target region associated with the blebs, drainage channels, drainage implants, or a combination thereof.

The invention also features a method of lowering intraocular pressure (IOP) undergoing or having undergone glaucoma treatment to form a bleb in the subconjunctival space or between the conjunctiva and the ternon's sac and to allow aqueous humor to be introduced into the drainage bleb. In some embodiments, the method includes applying a therapeutic amount of beta radiation from a Radionuclide Brachytherapy (RBS) system to a target region associated with a bubble, a drainage channel, a drainage implant, or a combination thereof.

The invention also features a method of treating glaucoma (e.g., helping to effectively lower IOP, etc.), wherein the method includes performing glaucoma drainage surgery (e.g., MIGS, MIMS, trabeculectomy) in the eye to form a bleb in the subconjunctival space or between the conjunctiva and the ternon's sac and allowing aqueous humor to drain into the drainage bleb; and applying a therapeutic amount of beta radiation from a Radionuclide Brachytherapy (RBS) system to a target region associated with a bubble, a drainage channel, a drainage implant, or a combination thereof.

In some embodiments, the methods herein are effective to reduce intraocular pressure (IOP). In some embodiments, the therapeutic amount of beta radiation helps maintain a functional drainage bubble. In some embodiments, the therapeutic amount of beta radiation helps reduce conjunctivitis.

In some embodiments, the method comprises implanting a Minimally Invasive Glaucoma Surgery (MIGS) implant into the eye, wherein the implant causes (e.g., in the subconjunctival space of the eye, or the space between the conjunctiva and the ternon's sac) a bleb; the function of the bubble is to drain the aqueous humor. In certain embodiments, the implant is inserted transsclerally between the anterior chamber of the eye and the subconjunctival space of the eye, between the anterior chamber of the eye and the space between the conjunctiva and the ternon's capsule, and the like.

In certain embodiments, the RBS and system herein are used to provide dose grading, wherein the RBS or system rotates a certain number of times during application. This may help to provide a more uniform radiation distribution.

In some embodiments, the applicator system is placed and pressed against a target area in contact with the eye, the distance from the outer surface of the distal end of the applicator system and the bottom surface of the bubble being substantially uniform across the target area.

In some embodiments, at least 50% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed. In some embodiments, at least 60% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed. In some embodiments, at least 70% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed. In some embodiments, at least 80% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed. In some embodiments, at least 90% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed. In some embodiments, at least 90% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed. In some embodiments, at least 95% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed. In some embodiments, at least 99% of the surface area of the outer surface of the distal end is in contact with the eye when the applicator system is in contact with the eye at the target area and pressed.

Example 1: process steps for beta radiation application

The present invention provides an example of a process for 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.

Preparation and Assembly

The device assembly process may be completed behind a plexiglass beta shield (e.g., a large double angle beta radiation shield from general medical company (Universal Medical inc.). A medical technician or medical physicist or other user opens a Radioisotope Brachytherapy Source (RBS) storage container. The RBS is removed from its container using a suitable handling technique (e.g., long tweezers). The RBS was placed on a clean field.

The brachytherapy applicator can be a disposable sterile packaging device. The packaging may be inspected by inspecting the sterile barrier for damage (damage) or breakage (break). If not, the brachytherapy applicator package is opened and the applicator assembly is placed in the sterile field.

The brachytherapy applicator includes a handle and an RBS cap. Using aseptic and remote processing techniques, the RBS is loaded into the brachytherapy applicator, e.g. the RBS can be inserted into the cap, and then the handle connected to the cap, thereby securing the RBS. Care was taken to avoid contamination.

The radiation output can confirm the quality of the radiation treatmentThe amount assurance standard (see, e.g., palmer, antonny l., andrew Nisbet, and David bradley, "Verification of high dose rate brachytherapy dose distributions with EBT3 Gafchromic film quality control technologies," Physics in medicine and biology 58.3.3 (2013): 497). In one quality assurance method, an applicator is applied to a radiographic film in a sterile overwrap, and left for a specified period of time (e.g., ashland Inc.)Film). The overwrap is removed. The medical physicist examined the evidence of film exposure in the area of application.

The device may be placed in a sterile plexiglas Beta shipping box (e.g., a large IBI Beta-Gard acrylic storage container from general medical company (Universal Medical inc.)) and the box placed on an operational international for the medical treatment (Mayo) display.

Previously, the attenuation activity of the RBS has been calculated to determine the current dose per unit time (e.g., cGy/sec). Decay calculation methods are known to those skilled in the medical arts and are also described in NRC Information Notice, 96-66:United States Nuclear Regulatory Commission,Office of Nuclear Material Safety and Safeguards,Washington D.C.20555,December 13,1996. The residence time of the total prescribed dose is then calculated. For example, the prescribed dose is 1,000cGy from a center point of a depth of 0.19mm from the conjunctival surface. For example, the decay activity of RBS was 30 cGy/sec at a water equivalent depth of 0.19 mm. In this example, the dwell time is calculated to be about 33 seconds, providing a 990cGy dose.

Surgical applications

Beta therapy may be applied after glaucoma surgery is completed. (note that the invention is not limited to the application of beta radiation after glaucoma surgery.) the eye is rotated to a downward gaze position by providing traction using a probe placed against the sclera (e.g., the distal end of Vera Hook placed against the eye.) this allows better visual and surgical access to the superior conjunctiva.

The ophthalmologist obtains the brachytherapy applicator device (e.g., from a shipping box). The tip (e.g., distal, active) of the applicator is placed on the conjunctiva just above the limbus. The diameter of the applicator includes the appropriate surface area of the target (e.g., bubble). The brachytherapy applicator is pressed against the surface of the eye. In some embodiments, pressing the brachytherapy applicator to the surface of the eye causes all or substantially all of the edema fluid to be pushed aside. The applicator remains in place for a specified dwell time. In some embodiments, the dwell time has been programmed as a countdown clock. After a specified dwell time, the brachytherapy applicator is removed from the surgical field.

At the end of the procedure, antibiotic ointment is applied to the eye and covers the eye.

In certain embodiments, the brachytherapy applicator is disassembled behind the acrylic beta shield after surgery. The radioisotope brachytherapy source is returned to its storage container. The disposable portion of the device is discarded in a manner consistent with proper disposal of biological waste (e.g., "red bag" waste).

Example 2: application of beta radiation

The present invention provides an example of the application of beta radiation to the eye. The present invention is in no way limited to the specific steps, methods, devices, systems, and compositions described herein.

Assembling and disassembling

Using aseptic techniques, the beta radiation source (which may be connected to the applicator) is inserted into the cavity of the cap system, taking care not to cross-contaminate the outer surface of the cap system with the beta radiation source and/or the connected applicator.

Force vertically downward until the cap system is fully secured and a click can be heard.

The cap system was verified as firmly connected by visual inspection. The inspection source is fully secured in the cap system.

To disassemble the cap system and the beta radiation source after the procedure is completed, forceps are used to place tines on either side of the applicator handle attached to the periphery of the cap system ledge.

Using forceps, a downward force is applied to the cap system, pulling the applicator with the beta radiation source upward until the cap system and the beta radiation source are separated. Once the separation occurs, the pulling is stopped. The top of the source will hit the bottom of the forceps-ensuring that the applied force is not excessive.

The beta radiation source is removed from the cap system.

Use of the same

After the cap system is fixed, the beta radiation source dose rate is reduced. The time (residence time) required to deliver a particular dose will be increased compared to the residence time of the beta radiation source of the unfixed cap system.

The medical physicist or responsible person verifies the relative dose distribution and absolute dose rate of the beta radiation source modified by the capping system according to established protocols.

The operator may find a dwell time of about 2.5 times, 3 times, 3.5 times, etc. the previous dwell time of the beta radiation source alone. This safety check time factor is not used for patient treatment planning.

In certain embodiments, the application β radiation source is separate from the cap system. For example, in some embodiments, the applications are divided into a series of applications of 4 x 1/4 dwell time, each application having an incremental rotation of 90 degrees. The operator may advance the rotation without lifting the applicator off the application site. Clinical experience has demonstrated that some Original Equipment Manufacturers (OEMs) provide sources of beta radiation where the maximum dose rate is not necessarily centered on the device axis. For such a beta radiation source, the maximum interaction of the off-axis dose rate with the center attenuation feature of the cap system may result in a maximum dose rate of the off-axis region. The rotation application distributes the off-axis maximum dose rate over the middle circumference, providing a more uniform dose delivery.

The cap system is placed over the treatment application site for a predetermined length of time and in a predetermined manner (e.g., graded) according to physician practices, internal institutional steps, and surgical instructions.

Example 3: cap system

The present invention provides one example of the cap system of the present invention. The present invention is in no way limited to the specific steps, methods, devices, systems, and compositions described herein.

In certain embodiments, the cap system comprises grade 5 titanium (Ti 6 ai 4V). In certain embodiments, the cap system has a radius of 16.5mm, including a lip/flange (120). In certain embodiments, the cap system has a radius of 14.4mm, excluding the lip/flange (120). In certain embodiments, the cap system has a height of 8.2 mm. The cap system is biocompatible. The cap system may be sterilized using an autoclave process or other suitable sterilization technique.

The cap system is characterized by a dampening feature on the distal face of the cap. This helps to modify the natural radiation output of the radiation source.

In certain embodiments, the cap system has an internal circumferential channel that allows the source to be placed, e.g., snapped into place.

In certain embodiments, the cap system reduces the center dose by about 60-70% (relative to the natural output of the radiation source). In some embodiments, the cap system widens the clinically useful dose region (relative to the natural output of the radiation source).

Various modifications of the application in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by reference in its entirety.

As used herein, the term "about" may refer to a number that is plus or minus 10% of the reference number, or within its range, which would be recognized by one of ordinary skill in the art as equivalent to the recited value.

Examples

The following examples are intended to be illustrative only and are not to be limiting in any way.

Example group A

Any of the embodiments may be freely connected with each of the other or a combination of each of the other, unless mutually exclusive.

Example A1: a Radionuclide Brachytherapy Source (RBS), comprising: a capsule (210) having a distal surface (212), a proximal surface (211) opposite the distal surface (212), and a sidewall (215); an active beta radioisotope material (220) encapsulated in a capsule (210) in an annular configuration, the active beta radioisotope material (220) emitting beta radiation through at least a portion of a distal surface (212) of the capsule (210). Example A2: wherein the capsule is cylindrical. Example A3: wherein the capsule is kidney-shaped.

Example A4: wherein the sidewall (215) extends upwardly through the proximal surface (211) of the capsule. Example A5: wherein the active beta radioisotope material (220) is any beta radiation source. Example A6: wherein the active beta radioisotope material (220) comprises strontium 90 (Sr-90), phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90), an isotope of strontium 90, cesium, I-125, or a combination thereof in long-term equilibrium with yttrium 90. Example A7: wherein the active beta radioisotope material comprises strontium 90 in long-term equilibrium with yttrium 90. Example A8: wherein the active beta radioisotope material (220) is gamma rays or X-rays or any source of bremsstrahlung, which provides radiation attenuated by substances having a linear energy transfer similar to beta radiation. Example A9: wherein the capsule is comprised of a material comprising stainless steel, gold, platinum, titanium, tantalum, titanium alloy, silver, tin, zinc, copper, nickel, aluminum, ceramic, glass, metal alloy, zirconium, or a combination thereof. Example a10: wherein the capsule has a diameter of 2 to 12mm. Example a11: wherein the capsule has a diameter of 10.8mm. Example a12: wherein the RBS has an activity of 100 to 120mCi, or 3.7 to 4.4 GBq. Example a13: wherein the RBS has an activity of up to 300 mCi. Example 14: wherein RBS has an activity of 11.1GBq or less. Example a15: wherein the RBS has an activity of 116mCi or 4.292 GBq. Example a16: wherein the RBS has an activity of 50mCi or 4.292 GBq. Example a17: wherein the RBS has an activity of 58mCi or 4.292 GBq.

Example a18: also included is a forceps holder (230) disposed in or on the proximal surface (211) of the capsule, which forceps holder can be engaged with the pairs of tines or forceps to allow collection of RBS. Example a19: wherein the forceps holder (230) may serve as an indicator for the user to indicate that the RBS is preferably only collected by the proximal surface (211). Example a20: wherein the tweezers gripper (230) prevents the RBS from being inserted into the cap system in an unintended direction. Example a21: wherein the RBS is a sealed radiation source or radiation source. Example a22: wherein RBS emits beta radiation from the treatment surface towards a treatment volume, the treatment volume having a diameter of 8 mm; the RBS system has a dosimetry curve such that: all points across the treatment volume at the treatment surface have a dose rate of 55-85 cGy/sec, all points across the treatment volume at a depth of 0.6mm have a dose rate of 45-55 cGy/sec, all points across the treatment volume at a depth of 1mm have a dose rate of 35-48 cGy/sec, and all points across the treatment volume at a depth of 2mm have a dose rate of 17-25 cGy/sec.

Example a23: a Radionuclide Brachytherapy Source (RBS), comprising: a capsule (210) having a distal surface (212), a proximal surface (211) opposite the distal surface (212), and a sidewall (215); an active beta radioisotope material (220) encapsulated in a capsule (210) in an annular configuration, the active beta radioisotope material (220) emitting beta radiation through at least a portion of a distal surface (212) of the capsule (210); and a forceps holder (230) disposed in or on the proximal surface (211) of the capsule, the forceps holder being engageable with the pair of tines or forceps to allow collection of RBS. Example a24: wherein the tweezers gripper (230) prevents the RBS from being inserted into the cap system in an unintended direction. Example a25: wherein the sidewall (215) and the forceps holder (230) extend through the proximal surface (211) of the capsule. Example a26: wherein the forceps holder (230) extends through the proximal surface (211) of the capsule. Example a27: wherein the forceps holder (230) has at least a first side and a second side opposite the first side, wherein only the first side and the second side can be gripped by the forceps. Example a28: wherein the forceps holder (230) has at least a first side, a second side opposite the first side, and a third side, wherein the third side is not gripped by the forceps. Example a29: wherein the forceps holder (230) is recessed into the proximal surface (211) of the capsule. Example a30: wherein the forceps holder (230) protrudes from the proximal surface (211) of the capsule.

Example a31: the forceps holder has a first side (231 a) and a second side (231 b) opposite the first side (231 a), wherein a first indentation (232) is provided at the intersection of the first side (231 a) and the proximal surface (211) of the capsule (210), and a second indentation (232) is provided at the intersection of the second side (231 b) and the proximal surface (211) of the capsule (210). Example a32: wherein the forceps holder (230) is a ring. Example a33: wherein the forceps holder (230) is a protruding thread design. Example a34: wherein the ring is adapted to engage the threaded rod. Example a35: wherein the capsule is cylindrical. Example a36: wherein the capsule is kidney-shaped. Example a37: wherein the sidewall (215) extends upwardly through the proximal surface (211) of the capsule. Example a38: wherein the active beta radioisotope material (220) is any beta radiation source. Example a39: wherein the active beta radioisotope material (220) comprises strontium 90 (Sr-90), phosphorus 32 (P-32), ruthenium 106 (Ru-106), yttrium 90 (Y-90), an isotope of strontium 90, cesium, I-125, or a combination thereof in long-term equilibrium with yttrium 90. Example a40: wherein the active beta radioisotope material comprises strontium 90 in long-term equilibrium with yttrium 90. Example a41: wherein the active beta radioisotope material (220) is gamma rays or X-rays or any source of bremsstrahlung, which provides radiation attenuated by substances having a linear energy transfer similar to beta radiation. Example a42: wherein an active beta radioisotope material is any source of radiation that provides radiation attenuated by a substance having a linear energy transfer similar to beta radiation. Example a43: wherein the capsule is comprised of a material comprising stainless steel, gold, platinum, titanium, tantalum, titanium alloy, silver, tin, zinc, copper, nickel, aluminum, ceramic, glass, metal alloy, zirconium, or a combination thereof. Example a44: wherein the capsule has a diameter of 2 to 12mm. Example a45: wherein the capsule has a diameter of 10.8mm. Example a46: wherein the RBS has an activity of 100 to 120mCi, or 3.7 to 4.4 GBq. Example a47: wherein the RBS has an activity of 116mCi or 4.292 GBq. Example a48: wherein the RBS is a sealed radiation source or radiation source.

Example group B

Example B1: an interface for a Radionuclide Brachytherapy Source (RBS) (210), the interface comprising a material layer (112) having a top surface and a bottom surface, wherein an homogenizer (150) is provided on or in the material layer (112), the homogenizer being annular and having an inner diameter, an outer diameter and a thickness measured from the homogenizer top surface to the homogenizer bottom surface, the homogenizer (150) reducing at least a portion of beta radiation emitted from the RBS in contact with the material layer (112) or from the RBS proximate to the material layer (112), thereby controlling the amount of beta radiation emitted from the RBS and the material layer (112).

Example B1: wherein the thickness of the leveler (150) is 0.1 to 1mm. Example B2: wherein the thickness of the equalizer (150) is 0.4mm. Example B3: wherein the thickness of the equalizer (150) is 0.5mm. Example B4: wherein the homogenizer (150) has an inner diameter of 1 to 6 mm. Example B5: wherein the homogenizer (150) has an inner diameter of 3 mm. Example B6: wherein the homogenizer (150) has an outer diameter of 2 to 6 mm. Example B7: wherein the homogenizer (150) has an outer diameter of 6 mm.

Example B8: an interface for a Radionuclide Brachytherapy Source (RBS) (210), the interface comprising a material layer (112) having a top surface and a bottom surface, wherein an homogenizer (150) is provided on or in the material layer (112), the homogenizer being annular, dome-shaped, disk-shaped, flat dome, truncated pyramid-shaped, truncated cone-shaped or trapezoid-shaped, the homogenizer (150) reducing at least a portion of beta radiation emitted from the RBS in contact with the material layer (112) or from an RBS proximate to the material layer (112), thereby controlling the amount of beta radiation emitted from the RBS and the material layer (112). Example B9: wherein the homogenizer (150) is disk-shaped and has a concave surface. Example B10: wherein the homogenizer (150) is disk-shaped and has a convex surface. Example B11: wherein the homogenizers (150) are disk-shaped and have different thicknesses. Example B12: wherein the homogenizers (150) are disk-shaped and have different densities. Example B13: wherein the homogenizer (150) is disk-shaped and is composed of a combination of two or more materials having different densities, different thicknesses, or a combination thereof.

Example group C

Example C1: a homogenizer for reducing radiation emitted from an RBS in contact with or near the homogenizer, said homogenizer being annular and having a thickness measured from the top surface of the homogenizer to the bottom surface of the homogenizer of 0.5mm, an inner diameter of 3mm and an outer diameter of 6mm. Example C2: wherein it is composed of a material capable of being formed and having structural integrity. Example C3: wherein the homogenizer is composed of a material comprising a polymer, a metal alloy, a ceramic, a glass, or a combination thereof. Example C4: wherein the polymer is a plastic. Example C5: wherein the polymer is High Impact Polystyrene (HIPS). Example C6: wherein the metal or metal alloy comprises titanium. Example C7: wherein the outer surface of the homogenizer is biocompatible. Example C8: wherein the outer surface of the homogenizer is capable of sterilization.

Example C9: an homogenizer for reducing radiation emitted from an RBS in contact with or close to the homogenizer, said homogenizer being annular, dome-shaped, disk-shaped, flattened dome, truncated pyramid-shaped, truncated cone-shaped or trapezoidal. Example C10: wherein the homogenizer (150) is disk-shaped and has a concave surface. Example C11: wherein the homogenizer (150) is disk-shaped and has a convex surface. Example C12: wherein the homogenizers (150) are disk-shaped and have different thicknesses. Example C13: wherein the homogenizers (150) are disk-shaped and have different densities. Example C14: wherein the homogenizer (150) is disk-shaped and is composed of a combination of two or more materials having different densities, different thicknesses, or a combination thereof.

Example group D

Example D1: a capping system (110) for housing a Radionuclide Brachytherapy Source (RBS) (210), the capping system (110) comprising an inner cavity (140) formed by a side wall (115) and a bottom surface (112) sealed around its periphery to a bottom edge (115 c) of the side wall (115), the inner cavity (140) for receiving the RBS (210), wherein an homogenizer (150) is provided on the bottom surface (112) of the inner cavity (140), the homogenizer (150) reducing at least a portion of beta radiation emitted from the RBS, thereby controlling the amount of beta radiation emitted from the bottom surface (112) of the capping system (110).

Example D2: wherein the homogenizer (150) is according to any of the disclosure herein. Example D3: wherein the homogenizer (150) is integrated into the bottom surface (112) of the cap system (110). Example D4: wherein the homogenizer (150) is a separate component for placement on the bottom surface (112) of the cap system (110) or proximate to the bottom surface (112) of the cap system (110). Example D5: wherein the sidewall (115) is cylindrical. Example D6: wherein the sidewall or lumen has a diameter of 7 to 14 mm. Example D7: wherein the sidewall or lumen has a diameter of 12mm or 13 mm. Example D8: wherein the side wall has a height of 4 to 12mm from its bottom edge to its top edge. Example D9: wherein the side wall has a height of 8.2mm measured from its bottom edge to its top edge. Example D10: also included is a ledge (148) disposed in the interior cavity (140) at an intersection of the bottom surface (112) and the sidewall (115), the ledge (148) facilitating distribution of weight of the RBS secured thereto. Example D11: wherein the ledge (148) is configured to be positioned 0.1mm above a top surface of the leveler (150). Example D12: wherein the lip (120) is disposed along a top edge of a sidewall (115) of the cap system (110).

Example D13: wherein at least a portion of the cap system (110) is comprised of a material comprising a titanium alloy. Example D14: wherein the material comprises grade 5 titanium (Ti 6 ai 4V). Example D15: wherein the material comprises grade 23 titanium. Example D16: wherein at least a portion of the cap system (110) is comprised of a material comprising a polymer. Example D17: wherein the polymer comprises High Impact Polystyrene (HIPS). Example D18: the polymer comprises polycarbonate. Example D19: wherein at least a portion of the cap system (110) is constructed of a material comprising stainless steel. Example D20: wherein the cap system (110) is connectable to a brachytherapy applicator handle.

Example D21: wherein the cap system (110) includes threads (182) for threadably engaging complementary threads (184) of a brachytherapy applicator handle embodiment D22 wherein the cap system (110) includes tines (166) for engaging snap features on a brachytherapy applicator for connection to the brachytherapy applicator embodiment D23 wherein the cap system (110) includes one or more separation features to prevent or hinder the cap system (110) from being used more than once embodiment D24 wherein the sidewall (115) includes an inner layer and an outer layer, the outer layer being a sterile barrier embodiment D25 wherein the sidewall (115) is comprised of a material comprising a metal, metal alloy, polymer, or a combination thereof embodiment D26 wherein the polymer comprises a plastic material embodiment D27 wherein the polymer comprises a High Impact Polystyrene (HIPS) embodiment D28 wherein the inner layer is comprised of a shielding material of a specific electron density embodiment D29 wherein the shielding material comprises tantalum embodiment D30 wherein the outer layer is comprised of a high polymer material embodiment D31 wherein the polymer comprises a material comprising an inner layer, a thickness of 0.35mm embodiment D32.0.35 mm wherein the outer layer has a thickness of 0.35mm The leveler or combination thereof is composed of stainless steel or titanium. Example D35: wherein the cap system (110) is reusable. Example D36: wherein the cap system (110) is sterilizable. Example D37: wherein the side walls are configured such that only less than 5Sv may pass. Example D38: wherein the thickness of the sidewall is such that only 3% of the prescribed dose of RBS can pass. Example D39: wherein the sidewall thickness is such that less than 3Sv can pass. Example D40: wherein the sidewall thickness is such that less than 5Sv can pass.

Example D41: a capping system (110) for housing a Radionuclide Brachytherapy Source (RBS) (210), the capping system (110) comprising an inner cavity (140) formed by a sidewall (115) and a bottom surface (112) sealed around its periphery to a bottom edge (115 c) of the sidewall (115), the inner cavity (140) for receiving the RBS (210), wherein an homogenizer (150) is provided on the bottom surface (112) of the inner cavity, the homogenizer (150) reducing at least a portion of beta radiation emitted from the RBS, thereby controlling the amount of beta radiation emitted from the bottom surface (112) of the capping system (110). Example D42: also included is a brachytherapy applicator handle for engaging the cap system and receiving the RBS therebetween. Example D43: wherein the homogenizer is composed of titanium. Example D44: wherein the height of the homogenizer is 0.36mm relative to wherein the bottom surface of the cap system is within the interior cavity. Example D45: wherein the cap system includes threads (182) for threadably engaging complementary threads (184) on the distal end of the brachytherapy applicator handle.

Example D46: a capping system (110) for housing a Radionuclide Brachytherapy Source (RBS) (210), the capping system (110) comprising a cavity (140) formed by a sidewall (115) and a bottom surface (112) sealed around its periphery to a bottom edge (115 c) of the sidewall (115), the cavity (140) for receiving the RBS (210), the cavity having a diameter of 11 mm; wherein a homogenizer (150) is provided on the bottom surface (112) of the inner cavity (140), the homogenizer (150) reducing at least a portion of the beta radiation emitted from the RBS, thereby controlling the amount of beta radiation emitted from the bottom surface (112) of the cap system (110), the homogenizer being annular and having a thickness of 0.5mm, an inner diameter of 3mm and an outer diameter of 6mm.

Example group E

Example E1: a sidewall cap system comprising a cylindrical sidewall (115) constructed of a dense material, wherein the sidewall (115) prevents at least a portion of radiation from passing therethrough. Example E2: wherein the dense material comprises a polymer, a metal, or a combination thereof. Example E3: wherein the dense material comprises a powder or metal compounded in a polymer. Example E4: wherein the system is biocompatible. Example E5: wherein the outer surface of the system is biocompatible. Example E6: wherein the system is sterilizable.

Example E7: a sidewall cap system comprising a cylindrical sidewall (115) comprised of an inner layer and an outer layer, the outer layer being comprised of a material comprising a plastic material, the inner layer being comprised of a tighter material than the outer layer, wherein the sidewall (115) inhibits at least a portion of radiation from passing therethrough. Example E8: wherein the inner layer comprises a polymer, a metal, or a combination thereof. Example E9: wherein the inner layer comprises a powder or metal compounded in a polymer. Example E10: wherein the inner layer is comprised of a material comprising tantalum. Example E11: wherein the outer layer is composed of a plastic material. Example E12: wherein the outer layer of the system is biocompatible. Example E13: wherein the system is sterilizable. Example E14: wherein the inner layer has a thickness of 0.35 mm. Example E15: wherein the outer layer has a thickness of 0.5 mm.

Example E16: a sidewall cap system comprising a cylindrical sidewall (115) comprised of an inner layer comprised of a material comprising tantalum and an outer layer comprised of a material comprising a plastic material, wherein the sidewall (115) blocks at least a portion of radiation from passing therethrough. Example E17: wherein the outer layer of the system is biocompatible. Example E18: wherein the system is sterilizable. Example E19: wherein the inner layer has a thickness of 0.35 mm. Example E20: wherein the outer layer has a thickness of 0.5 mm. Example E21: wherein the system allows not to exceed 3% of the prescribed dose of the RBS. Example E22: wherein the thickness of the sidewall is such that only 3% of the prescribed dose of RBS can pass. Example E23: wherein the system allows no more than 3Sv to pass. Example E24: wherein the sidewall thickness is such that less than 3Sv can pass. Example E25: wherein the system allows no more than 5Sv to pass. Example E26: wherein the sidewall thickness is such that less than 5Sv can pass.

Example group F

Example F1: a system, the system comprising: a Radionuclide Brachytherapy Source (RBS) comprising: a capsule (210) having a bottom surface (212), a proximal surface (211) opposite the bottom surface (212), and a sidewall (215); an active beta radioisotope material (220) encapsulated in a capsule (210) in an annular configuration, the active beta radioisotope material (220) emitting beta radiation through at least a portion of a bottom surface (212) of the capsule (210); and a cap system according to the invention, which accommodates an RBS, is shaped and fitted to conform to the conjunctival area of the general population, provides a sterile barrier for the patient, provides attenuation features to achieve a more uniform dose delivery, provides a sidewall radiation shield for the patient, and is fully assembled with the handle to minimize the occupied dose by operating room staff and authorized users, wherein the system emits beta radiation through at least a portion of the interface or bottom surface of the cap system, which is the active surface area (S). Example F2: also included is a forceps holder (230) disposed in or on the capsule proximal surface (211), the forceps holder (230) being engageable with tines of a pair of forceps to allow collection of RBS.

Example F3: a system, the system comprising: a Radionuclide Brachytherapy Source (RBS) comprising: a cylindrical capsule (210) having a bottom surface (212), a proximal surface (211) opposite the bottom surface (212), and a sidewall (215); an active beta radioisotope material (220) encapsulated in a capsule (210) in an annular configuration, the active beta radioisotope material (220) emitting beta radiation through at least a portion of a bottom surface (212) of the capsule (210); wherein the capsule diameter is 10.8mm, wherein the RBS has an activity of 110 mCi; and a cap system according to the invention comprising a 11.0mm sidewall cylindrical body connected to a bottom portion of minimum thickness of 0.25mm in certain areas, and a thicker portion having a thickness (constant or gradient thickness) ranging within 0.75mm defining a geometric shape (annular, trapezoidal, disk-like, tie column shape of different radii in single or multiple versions of the pattern, etc.), wherein the system emits β radiation through at least a portion of the interface or bottom surface of the cap system, the interface or bottom surface of said portion of the cap system being the active surface area (S).

Example F4: wherein the diameter of S is 9.8mm. Example F5: wherein the diameter of S is 8mm. Example F6: wherein the diameter of S is 6 to 12mm. Example F7: where S is an area defined within a radius of 4mm from the interface center or bottom surface of the cap system. Example F8: where S is an area defined within a radius of 5mm from the interface center or bottom surface of the cap system. Example F9: wherein T has a diameter of 9.8mm. Example F10: wherein T has a diameter of 8mm. Example F11: wherein T has a diameter of 6 to 12mm. Example F12: where T is an area defined within a radius of 4mm from the center or bottom surface of the cap system interface. Example F13: where T is an area defined within a radius of 5mm from the center or bottom surface of the cap system interface. Example F14: wherein T is 70-100% of S. Example G1: where t=s. Example F15: wherein the RBS system emits a radiation zone, wherein at least a portion of the radiation zone is a homogeneous zone. Example F16: wherein the uniform region has a diameter of 6 to 8mm. Example F16: wherein the dose at all points within T at a depth is within 80%, 90% or 100% isodose lines. Example F17: wherein the dose at all points at a depth within T is within 70%, 80%, 90% or 100% isodose lines. Example F18: wherein the dose at all points within T at a depth is at least 80% of the prescribed dose of the RBS system.

Example F19: wherein the depth is measured from a bottom surface of a capping system of the RBS system. Example F20: wherein the depth is 0.15 to 0.25mm. Example F20: wherein the depth is 0.2 to 2mm. Example G22: wherein T has a diameter of 7mm and the dose at all points within T having a depth of 0.1 to 2mm is at least 80% of the prescribed dose of the RBS system. Example F23: wherein T has a diameter of 8mm and the dose at all points within T having a depth of 0.1 to 2mm is at least 80% of the prescribed dose of the RBS system. Example F24: wherein T has a diameter of 9mm and the dose at all points within T having a depth of 0.1 to 2mm is at least 80% of the prescribed dose of the RBS system. Example F25: wherein T has a diameter of 10mm and the dose at all points within T having a depth of 0.1 to 2mm is at least 80% of the prescribed dose of the RBS system. Example F26: wherein T has a diameter of 7mm and the dose at all points within T having a depth of 0.1 to 1mm is at least 80% of the prescribed dose of the RBS system. Example F27: wherein T has a diameter of 8mm and the dose at all points within T having a depth of 0.1 to 1mm is at least 80% of the prescribed dose of the RBS system. Example F28: wherein T has a diameter of 9mm and the dose at all points within T having a depth of 0.1 to 1mm is at least 80% of the prescribed dose of the RBS system. Example F29: wherein T has a diameter of 10mm and the dose at all points within T having a depth of 0.1 to 1mm is at least 80% of the prescribed dose of the RBS system.

Example group G

Example G1: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm have a dose rate of 60-75% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

Example G2: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm have a dose rate of 60-75% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

Example G3: RBS system, which emits a radiation field from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein a point within the volume has a dose rate relative to a maximum dose rate of 100% at the surface; wherein all points across the volumetric plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% maximum dose; wherein all points across the volume plane at a depth of 0.67mm have a dose rate of 60-75% relative to 100% maximum dose, wherein all points across the volume plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose, wherein all points across the volume plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

Example G4: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 20% at 1.6 mm. Example G5: wherein the gamma function analyses the difference between the measured value and its reference value, which is compressed into a number that combines the dose error in the usual intra-field region and the position error in the half-shadow region on the basis of a normalized vector.

Example G6: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 10% at 1 mm.

Example G7: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 0.94mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 1.99mm do not vary by more than 20% of the average dose across said plane.

Example G8: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 10mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% of the maximum dose; all points across the volumetric plane at a depth of 0.67mm have a dose rate of 60-75% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

Example G9: RBS system, which emits a radiation field from a surface into a volume having a diameter of 10mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 80% -100% relative to 100% of the maximum dose; wherein all points across the volume plane at a depth of 0.67mm have a dose rate of 60-75% relative to 100% maximum dose, wherein all points across the volume plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose, wherein all points across the volume plane at a depth of 1.99mm have a dose rate of 25-35% relative to 100% maximum dose.

Example G10: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 20% at 1.6 mm.

Example G11: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 10% at 1 mm.

Example G12: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 70% -100% relative to 100% of the maximum dose; all points across the volumetric plane at a depth of 0.67mm have a dose rate of 55-70% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 45-65% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-40% relative to 100% maximum dose.

Example G13: RBS system, which emits a radiation field from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 70% -100% relative to 100% of the maximum dose, wherein all points across the volume plane at a depth of 0.67mm have a dose rate of 55-70% relative to 100% of the maximum dose, wherein all points across the volume plane at a depth of 0.94mm have a dose rate of 45-65% relative to 100% of the maximum dose, wherein all points across the volume plane at a depth of 1.99mm have a dose rate of 20-40% relative to 100% of the maximum dose.

Example G14: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 20% at 1.6 mm. Example G15: RBS systems having a dosimetry curve having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the implementations herein, wherein the gamma function value constraint is 10% at 1 mm.

Example G16: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to a 100% maximum dose rate at the surface, wherein for a 100% maximum dose, all points across the volume plane at a depth of 0.19mm have a dose rate of 70% -100%; wherein all points across the volumetric plane at a depth of 0.67mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 0.94mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 1.99mm do not vary by more than 20% of the average dose across said plane.

Example G17: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

Example G18: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

Example G19: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 19mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

Example G20: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 10mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 70% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm have a dose rate of 55-70% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 45-65% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-40% relative to 100% maximum dose.

Example G21: RBS system, which emits a radiation field from a surface into a volume having a diameter of 10mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 70% -100% relative to 100% of the maximum dose, wherein all points across the volume plane at a depth of 0.67mm have a dose rate of 55-70% relative to 100% of the maximum dose, wherein all points across the volume plane at a depth of 0.94mm have a dose rate of 45-65% relative to 100% of the maximum dose, wherein all points across the volume plane at a depth of 1.99mm have a dose rate of 20-40% relative to 100% of the maximum dose.

Example G22: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 20% at 1.6 mm. Example G23: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 10% at 1 mm. Example G24: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 65% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm have a dose rate of 50-65% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-30% relative to 100% maximum dose.

Example G25: RBS system, which emits a radiation field from a surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 65% -100% relative to 100% of the maximum dose; wherein all points of the volume plane at a depth of 0.67mm crossing have a dose rate of 50-65% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-30% relative to 100% maximum dose.

Example G26: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 20% at 1.6 mm.

Example G27: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 10% at 1 mm.

Example G28: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 65% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 0.94mm do not vary by more than 20% of the average dose across said plane; wherein all points across the volumetric plane at a depth of 1.99mm do not vary by more than 20% of the average dose across said plane.

Example G29: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

Example G30: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 8mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

Example G31: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 19mm and a depth of 2 mm; wherein the variation across all points of each plane within the volume is no more than 20% of the average dose across the planes.

Example G32: a radiation field emitted from the RBS system from the surface into a volume having a diameter of 10mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 65% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm have a dose rate of 50-65% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-30% relative to 100% maximum dose.

Example G33: RBS system, which emits a radiation field from a surface into a volume having a diameter of 10mm and a depth of 2 mm; wherein points within the volume have a dose rate relative to 100% of the maximum dose rate at the surface, wherein all points across the volume plane at a depth of 0.19mm have a dose rate of 65% -100% relative to 100% of the maximum dose; wherein all points across the volumetric plane at a depth of 0.67mm have a dose rate of 50-65% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 0.94mm have a dose rate of 40-60% relative to 100% maximum dose; wherein all points across the volumetric plane at a depth of 1.99mm have a dose rate of 20-30% relative to 100% maximum dose.

Example G34: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 20% at 1.6 mm.

Example G35: RBS systems having dosimetry curves having a gamma function value of 1.0 or less when compared to the dosimetry curve of any of the embodiments herein, wherein the gamma function value constraint is 10% at 1 mm.

Example G36: wherein the relative dose rate varies by up to 5%. Example G37: wherein the relative dose rate varies by up to 10%. Example G38: wherein the relative dose rate varies by up to 15%. Example G39: wherein the relative dose rate varies by up to 20%. Example G40: wherein the relative dose rate varies based on the gamma function.

While the preferred embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that modifications thereto may be made without departing from the scope of the appended claims. Accordingly, the scope of the invention is limited only by the following claims. The numerals referred to in the claims are exemplary and are only for ease of patent office examination and are not limiting in any way. In some embodiments, the drawings presented in this patent application are drawn to scale, including angles, dimensional proportions, and the like. In some embodiments, the drawings are merely representative, and the claims are not limited by the dimensions of the drawings. In some embodiments, the specification of the invention described herein using the phrase "comprising" includes embodiments that may be described as "consisting of" and, therefore, conform to the requirements of a written description of one or more embodiments of the invention as claimed using the phrase "consisting of.

The reference signs in the appended claims are only for facilitating the examination of the present patent application and are exemplary and are not intended to limit the scope of the claims in any way to the specific features having corresponding reference signs in the figures.

Claims

1. A Radionuclide Brachytherapy Source (RBS) comprising a beta radioisotope assembly encapsulated in a capsule, wherein at least a portion of the bottom surface of the RBS is an active region from which beta rays are emitted, wherein a region 3 to 4mm from the center of the active region of the bottom surface of the RBS emits a dose of at least 80% of the dose emitted at the center of the active region.