Beads and methods for making the same

Abstract

A method of manufacturing beads can include introducing, into a microfluidic pathway, a fluid flow of a fluid along a first direction; directing along a second direction a mixture of a plurality of particles and a polymer; and allowing the fluid flow to shear the mixture as the mixture enters the microfluidic pathway such that a plurality of beads are created each having a width of less than about 1000 μm.

Description

Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025BEADS AND METHODS FOR MAKING THE SAMETECHNICAL FIELD

[0001] The present disclosure is directed to beads for example, for the intravascular embolization of tumor cells, with or without the local delivery of radiation or therapeutics, and other applications, and methods of making the same.BACKGROUND

[0002] Malignant tumors of the liver include primary tumors like hepatocellular carcinoma(HCC) and intrahepatic cholangiocarcinoma, with HCC being the most common primary liver tumor. Additionally, metastatic tumors from sites such as the bowel, breast, lung, and esophagus can involve the liver. For some patients, curative treatment can be offered through surgical resection of a liver tumor. However, many patients with primary or metastatic liver cancers will have underlying medical comorbidities or impaired liver function that preclude radical liver surgery. Additionally, the anatomic location or extent of a liver tumor may render it technically unresectable.

[0003] Alternative treatment modalities for inoperable patients with liver tumors includes selective intraarterial embolization of the tumor with microsphere particles. Liver tumors possess an alternate blood supply from the normal liver parenchyma. Most primary and metastatic liver tumors will receive the majority of their blood supply from the systemic arterial circulation through branches of the celiac axis. However, the normal hepatocytes receive their blood supply through the portal venous circulation. By taking advantage of this difference in blood supply, intraarterial embolization selectively targets the tumor vasculature while preserving the majority of the blood supply for normal hepatocytes. Further, similar to the liver, the lungs are supplied with blood from two distinct supplies from the pulmonary artery and the bronchial artery. Most lung tumors derive their blood supply from the bronchial artery while the majority of the lung parenchyma derives its blood supply from the pulmonary artery. Therefore, much the same as the liver, branches of the bronchial artery can be embolized with a low risk of damage to the surrounding normal lung1ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 parenchyma. Further still, the instant disclosure includes applicability in treatment of gliomas in the brain or spinal cord and tumors of the prostate, among others.

[0004] Microspheres used for embolization of liver tumors can include drug eluting materials that are used to deliver chemotherapeutic agents. Alternatively, microspheres may contain radioactivity for a procedure commonly known as radioembolization. The most commonly used radioisotope is yttrium-90 (Y-90), which is a pure beta emitting isotope. Y-90 has a half-life of 64.1 hours and the beta particle emitted has an energy of 2.28 MeV. Y-90 is produced through the decay of strontium-90, a fission product of uranium in nuclear reactors, and it decays to zirconium-90. There are currently only two available Y-90 microspheres. Currently available glass spheres are microspheres composed of glass measuring 20 - 30 microns. Currently available resin spheres are resin spheres measuring 20 - 60 microns.

[0005] Low linear energy transfer forms of radiation, including the 2.28 MeV beta particles produced through the decay of Y-90, kill cancer cells through what is known as the indirect effect. The indirect effect causes strand breaks in the phospho-ribose backbone of DNA in chromosomes. Single strand breaks are easily repaired, but double strand DNA breaks will often lead to cell death at the time of mitosis. The indirect effect is mediated by the formation of hydroxyl and peroxide free radicals that are created when ionizing radiation passes through the body. The formation of these free radicals requires the presence of oxygen, and therefore the indirect effect is enhanced in well oxygenated tissues. This can be mathematically represented as the oxygen enhancement ratio (OER) and tissues with a robust vascular supply of well oxygenated blood have a higher OER. Through embolization of the small arteries feeding a tumor, the cancer cells are in a more hypoxic environment leading to a lower OER and thus a lower level of tumor cell kill.

[0006] Radiosensitizers are chemicals that enhance radiation related cell kill. Hypoxic cell radiosensitizers selectively enhance the killing of hypoxic cells, while having little effect on cells with normal oxygenation. Nitroimidazoles are a class of antibiotic medications (metronidazole being the most widely used as an antimicrobial) that also provide hypoxic cell radiosensitization. Misonidazole is a second generation 2-nitroimidazole that was shown to improve outcomes when used in conjunction with radiotherapy to treat head and neck cancer patients in a Dutch randomized study (DAHANCA 2). More recently, DAHANCA 5-85 showed an improvement in both local2ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 control and overall survival with the addition of nimorazole to radiotherapy for treatment of head and neck cancer. Unfortunately, the systemic use of medications like misonidazole and nimorazole is limited by their side effects including central nervous system toxicity, and the logistics of accurately timing the medication dose with radiotherapy.

[0007] Local delivery of a hypoxic cell radiosensitizer could increase the therapeutic ratio of radioembolization by enhancing tumor cell kill while also mitigating the systemic side effects of the radiosensitizing drug. In 1992, Wang, et al, published the results of an animal study that involved intrahepatic arterial infusion of misonidazole in rabbits with VX2 liver cancer cells. The hepatic artery infusion of misonidazole was then followed by 15 Gray external beam radiation therapy. When compared to rabbits who did not receive misonidazole, those who underwent hepatic arterial infusion demonstrated the greatest tumor response showing extensive fibrosis and necrosis.

[0008] In addition to hypoxic cell radiosensitization, many other chemicals and pharmaceuticals have been shown to have radiosensitizing properties. Chemotherapy medications are often delivered concurrently with external beam radiation therapy, taking advantage of synergistic cell killing effects due to radiosensitization. Alkylating agents and antimetabolite chemotherapy drugs inhibit DNA repair pathways that cells utilize to repair sublethal damage from ionizing radiation. The accumulation of sublethal damage that is not properly repaired leads to enhanced cell death. Taxane chemotherapy agents and other microtubule inhibitors arrest the cell cycle in the G2 - M phase interface, where cells are most sensitive to radiotherapy. Additionally, through radiation induced upregulation of antigen presenting cells (dendritic cells, etc.) and other proinflammatory effects, there is a well-documented synergy between ionizing radiation and immunotherapies used to upregulate immune targeting of cancer cells. These medications include anti-CTLA4 drugs, anti PD-1 and PDL-1 drugs / checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and other immunomodulating medications.

[0009] Here a novel method of manufacturing a bead is disclosed that can combine an embolic bead, radiation emitting or not, with a portion that is capable of containing, and delivering, drugs, including a radiosensitizer.3ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025SUMMARY

[0010] The present disclosure is directed to methods of making and using particles for use in treatment of tumor cells, and other conditions.

[0011] In an embodiment, a method of manufacturing beads is provided herein. The method includes introducing, into a microfluidic pathway, a fluid flow along a first direction; directing along a second direction a mixture of a plurality of particles and a polymer; and allowing the fluid flow to shear the mixture as the mixture enters the microfluidic pathway such that a plurality of beads are created each having a width of less than about 1000 pm.

[0012] In some embodiments, each bead can include a single particle. The plurality of particles can be covered, or coated, with the polymer. The fluid can be inert. The introduction of a fluid flow can include introducing a second flow of the fluid, flowing along a third direction, where the flow of fluid intersects the mixture. The directing step can include, directing a flow of the plurality of particles flowing into a flow of the polymer, upstream of where the fluid intersects the mixture. In some embodiments, the method can further include, directing at least two flows of polymer towards the flow of the plurality of particles. The polymer can be a hydrogel. The hydrogel can be one of sodium alginate, polyethylene glycol (PEG) copolymer hydrogel, poly (methacryloxyethyl) phosphory choline (PMPC), or Poly (N-isopropyl acrylamide) (PNIPAM).

[0013] In some embodiments, the allowing step can occur at one of a T junction or an X junction. The plurality of particles can be substantially spherical. The plurality of particles can be radiation emitting particles. The radiation emitting particles can have a width of about 5 - 100 pm. The radiation emitting particles can have a width of about 30 - 45 pm. The polymer can form a uniform coating around each of the respective particles. The plurality of beads can have a substantially same width. In the directing step, the mixture can include the polymer dissolved in a solvent.

[0014] In some embodiments, the method can further include, evaporating the solvent from the polymer in the plurality of beads. The method can further include, infusing a medication into the polymer. The plurality of beads can treat at least one of primary or metastatic tumors of a liver, lungs, the brain or spinal cord, prostate, breast, esophagus, upper aerodigestive tract including the4ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025 nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid, lungs, mediastinum, stomach, small bowel, large bowel, pancreas, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovary, lymph nodes, muscles, and bones. The plurality of beads can treat at least one of prostate artery embolization, genicular artery embolization, and embolization of an artery to treat musculoskeletal diseases including osteoarthritis, tennis elbow, plantar fasciitis. In the directing step, the mixture can include the polymer dissolved in a solvent. The method can further include, evaporating the solvent from the plurality of beads. The beads can have a width of approximately 30 - 60 pm after the evaporating step. The method can further include, infusing a medication into the polymer, the plurality of particles, the plurality of beads or a combination thereof. The polymer can be a combination of copolymers with natural polymers. A width of each of the plurality of beads can be a function of the relative flow rates of the fluid and the mixture.

[0015] In an embodiment, a plurality of beads produced by a process is provided herein. The process includes introducing a mixture of a plurality of particles and a polymer towards a junction; directing a flow of fluid to flow across the junction; and allowing the flow of fluid to shear at least one of the plurality of particles and polymer, from the mixture, with the flow of fluid such that the plurality of beads are created, where each of plurality of beads includes at least one particle and the polymer.

[0016] In an embodiment, a method of producing a plurality of beads is provided herein. The method includes, introducing a mixture of a plurality of particles and a polymer towards a junction; directing a flow of fluid to flow across the junction; and allowing the flow of fluid to shear at least one of the plurality of particles and polymer, from the mixture, with the flow of fluid such that the plurality of beads are created, where each of plurality of beads includes at least one particle and the polymer.BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1A is a perspective, partially broken away, view of a bead according to an embodiment of the present disclosure.5ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025

[0018] FIG. IB is a perspective, partially broken away, view of a bead having an inner particle with radioisotope particles surrounded by an external layer with radiosensitizing medication.

[0019] FIG. 1C is a top view of a bead, according to an embodiment of the present disclosure.

[0020] FIG. ID is a top view of multiple beads, according to an embodiments of the present disclosure.

[0021] FIG. 2A is a top view of a microfluidics chip according to an embodiment of the present disclosure.

[0022] FIG. 2B is a partial view of a microfluidics chip being used for droplet formation, according to an embodiment of the present disclosure.

[0023] FIG. 3A is a top view of a microfluidics chip according to an embodiment of the present disclosure.

[0024] FIG. 3B is a partial view of a microfluidics chip being used for droplet formation, according to an embodiment of the present disclosure.

[0025] FIG. 4 is a top view of a microfluidics chip according to an embodiment of the present disclosure.

[0026] FIGS. 5 A and 5B are illustrations of methods of infusion according to embodiments of the present disclosure.DETAILED DESCRIPTION

[0027] The present disclosure provides for particles, including coated particles in the form of beads, which can be used in a number of applications. For example, the instant beads can be used to treat liver tumors using, in one embodiment, radioembolization beads, i.e., radiationemitting particle, coated with a layer of polymer that has the properties to carry and deliver a drug payload. Currently, one challenge in being able to provide this treatment is properly coating the6ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025 radiation-emitting particle. Current industry-standard coating techniques - such as dip coating, spray coating, and vapor deposition - are not feasible due to the extremely small sizes of the radiation-emitting particle which can have a final diameter of about a about 30 to about 1,000 pm. The final, coated, particle, can be referred to as a bead, e.g., an embolic bead, that can be about <60 pm in diameter. In some embodiments, the bead can be about <1000 pm in diameter. The term diameter is not intended to denote geometry of the bead and can be simultaneously used with the term “width.” Moreover, with current industry-standard coating techniques, clumping of the newly coated particles at this scale becomes an almost-certainty using prior techniques.

[0028] The present disclosure provides for methods to create beads, including monodisperse beads, which can be substantially uniform in size, and approximating a spherical shape. Alternatively, the resulting beads may not be uniform in shape and size, or may have shapes other than a sphere. These beads, in an embodiment, can include a plurality of particles, and to the extent desired, one that can be encapsulated by a coating, in some cases a layer, of the polymer material, e.g., with a coating surrounding the respective individual particles. In some embodiments, the layer can be uniform, or substantially uniform, while in some embodiments the layer can be non-uniform. Additionally, or alternatively, the present disclosure provides for a coating process which can prevent clumping of the newly coated particles.

[0029] In an embodiment, the instant bead can initially allow for an increase in tumor cell death from irradiation of a tumor. The bead can combine a particle having a source of radiation with a drug-eluting component that contains a therapeutic, e.g., a radiosensitizer, in some embodiments, allowing for administration of the radiation therapy concurrently with, or followed by, the administration of the radiosensitizer. In some embodiments, the instant bead can allow for simultaneous administration of both therapeutics in the same location of the tumor microvasculature. The delivery of the drug from the outer layer can be dependent on the formulation of the outer layer to allow immediate release of the drug upon delivery (by dissolving of the outer layer), delayed / timed release of the drug (slower dissolving of the outer layer), or diffusing the medication into the environment or through transmittal of the drug through, or by the outer layer. In some embodiments, the instant beads can allow for a combined modality therapy for interventional oncology while minimizing the radioresistance of tumor cells due to hypoxia or other cellular and molecular processes. In some embodiments, the disclosed beads can provide for7ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025 optimized targeting of tumor cells by having favorable flow characteristics to reach the target destination. In some embodiments the particle can be radiation emitting, with or without a coating. Such devices can allow for curative treatments for various tumors, e.g., liver tumors, in an outpatient setting.

[0030] Said another way, the instant beads, in the various embodiments, can advantageously provide for at least a dual treatment of certain tumor cells. By providing a single bead type having a source of radiation for radiation treatment, for example of cancers of the liver, as well as a drug-eluting component containing a therapeutic, the instant beads can provide for a treatment that is more effective than one of the therapies alone. The instant beads can provide an important benefit that is not found in prior art treatments. For example, prior art treatments use only one of radiation or radiosensitizer, in contrast, the instant disclosure provides for a more comprehensive treatment than previously provided for.

[0031] In general, cancers of the liver can be treated with embolization. Embolization can be used with tumors that cannot be removed by traditional surgery. For example, embolization can be used in cases where tumors are too large to be treated with ablation, e.g., tumors larger than 5 cm across, and who also have adequate liver function. Embolization can reduce the blood supply to the normal liver tissue, so it may not be a good option for some patients whose liver has been damaged by diseases such as hepatitis or cirrhosis. However, because the liver has two blood supplies, the hepatic artery, which often provides a blood supply to the cancer in the liver, can be blocked, or otherwise limited, while allowing the portal vein to supply blood to the healthy liver cells. Further, similar to the liver, the lungs are supplied with blood from two distinct supplies from the pulmonary artery and the bronchial artery. Just like liver tumors which attach themselves to the hepatic artery, almost all lung tumors are attached to the bronchial artery. Therefore, much the same as the liver, one can embolize branches of the bronchial artery without damaging the remaining healthy tissue in the lungs. Other organs and anatomic sites in the human body are amenable to implantation of radioactive sources directly into the interstitial tissues or within a body cavity, a procedure known as interstitial or intracavitary brachytherapy. The instant beads can additionally be utilized for interstitial, or intracavitary brachytherapy, providing a means of anatomically localized concurrent delivery of therapeutic radiation and a therapeutic, e.g., a radiosensitizing agent, through a route other than transarterial embolization. As such, the instant8ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025 disclosure includes applicability in treatment of primary or metastatic tumors in the brain or spinal cord, prostate, breast, esophagus, upper aerodigestive tract including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid, lungs, mediastinum, stomach, small bowel, large bowel, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovary, lymph nodes, muscles, and bones, among others.

[0032] In an embodiment, a plurality of beads may not be radioactive but can treat a plurality of conditions and / or diseases. For example, the plurality of beads can treat at least one of prostate artery embolization, genicular artery embolization, and embolization of an artery to treat musculoskeletal diseases including osteoarthritis, tennis elbow, plantar fasciitis, or other musculoskeletal diseases.

[0033] The instant beads, in accordance with an embodiment of the present disclosure, can include a radioembolic or radiotherapy particle and a drug, or radiosensitizer, eluting portion. The radioembolic particle, in some embodiments, can be an inner portion of an embolic, and can be constructed from a substantially hard material, such as a polymer, glass, ceramic, or a glassceramic composite. To provide the inner portion with radiotherapy ability, the inner portion, in an embodiment, can be infused or embedded with Y-90 or a resin containing Y-90. Alternatively, any similar radioactive isotope could be utilized as the source of radiotherapy. As such, a substantially hard particulate material similar to glass or resin could also be used as a substrate for the radioisotope. In some embodiments, the radiation-emitting portion can be a uniform mixture of glass, polymeric or hydrogel, ceramic, a glass-ceramic composite, or any other material with the radiation-emitting radioisotope. Alternatively, the radiation-emitting portion can be a non- uniform mixture of glass, polymeric or hydrogel, ceramic, or glass-ceramic composite, or any other material with the radiation-emitting radioisotope.

[0034] In some embodiments, the beads of the present disclosure can be larger than about 15 micrometers in diameter, e.g., from about 30 to about 45 micrometers, to prevent passage though small arterial-venous shunts and non-target organ embolization, biliary ischemia, hepatobiliary infarction, or other untoward effects. While the term “diameter” is used to describe dimensions of the bead, it is understood that this term is not intended to imply that the bead has a spherical geometry and can describe one dimensional value of the bead, e.g., the width of the bead.9ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025In some embodiments, the beads can include an upper limit size threshold of about 1,000 micrometers, as larger sizes can cause occlusion of commonly used microcatheters. Alternatively, if the beads are for use in other fields, the instant methods can be applied to produce beads of larger diameters. Additionally, large beads create a more proximal arterial occlusion and promote hypoxia and may sub-select more resistant cancer cell populations. However, in practice the beads can be any size that fulfills the clinical requirement of reaching the desired anatomic distribution. In an embodiment, the bead can include a particle of glass, ceramic, glass-ceramic composite or resin containing Y-90 that can be coated with a drug-eluting layer. In some embodiments, the particle can be radiopaque due to the chosen precursor materials that form the particle. By being radiopaque, the particle can aid in visualizing the location of the bead while it is within a patient. In some embodiments, the particle can have a radiopacity such that the particle can prevent electromagnetic radiation to pass through the particle. In some embodiments, the radiopacity of the particle can be a result of the material of the particle. In some embodiments, the material of the particle can prevent some electromagnetic radiation from passing through the particle while allowing other electromagnetic radiation to pass through the particle, and can therefore be seen with external, or internal imagining equipment. For example, the precursor materials used to form the particle can block specific wavelengths. In an embodiment, the particle can be designed to be block X-rays. In some embodiments, the particle can be partially made of a radiopaque material.

[0035] In some embodiments, the bead can be infused, coated, encapsulated, or otherwise combined with, a drug-eluting compound that can carry a therapeutic, or medication, for slow release after, or during, the period of irradiation. For example, in some embodiments, the therapeutic can be released after the period of irradiation to ensure that any tumor cells not killed by the irradiation are eliminated. Drug-eluting embolics can include poly-vinyl-alcohol (PVA) polymers that are doped with sulfonyl groups allowing a static charge to bind with polarized molecules. Examples include DC / LC beads and QuadraSphere beads. Additional beads used for chemoembolization can include Lipiodol, gelatin sponge, polymethylmethacrylate (Oncozene), and degradable starch (Spherex). However, it should be understood that these beads do not share the same drug eluting properties as the PVA polymers. In some embodiments, the drug-eluting compound can be a radiopaque material. By being radiopaque, the drug-eluting compound can aid in visualizing the location of the bead while it is within a patient. In some embodiments, the10ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 drug-eluting compound can have a radiopacity such that the drug-eluting compound can prevent electromagnetic radiation to pass through the drug-eluting compound and can therefore be seen with external, or internal imagining equipment. In some embodiments, the radiopacity of the drugeluting compound can be a result of the material of the drug-eluting compound. In some embodiments, the material of the drug-eluting compound can prevent some electromagnetic radiation to pass through the drug-eluting compound while allowing other electromagnetic radiation to pass through the drug-eluting compound. For example, the material of the drug-eluting compound can block specific wavelengths. In an embodiment, the drug-eluting compound can be designed to be block X-rays. In some embodiments, the drug-eluting compound can be partially made of a radiopaque material. In some embodiments, the drug-eluding compound can form a layer about the particle and can have a thickness of about 5 to about 20 microns. In some embodiments, the drug-eluding compound layer can have a thickness of about 10 to 15 microns.

[0036] The present disclosure will now be described in detail hereinafter by reference to the accompanying drawings. The disclosure is not intended to be limited to the embodiments described; rather, this detailed description is provided to enable any person skilled in the art to make and practice the instant disclosure.

[0037] Turning to FIGS. 1A and IB, the bead 1, in an embodiment, can be comprised of a particle 2 and outer layer 3. The bead 1 can be anywhere from about 5 microns to about 1000 microns in overall size. The term size, or dimension, as used herein, can mean an outer dimension including width, length, diameter, etc. The bead 1 can be any regular or irregular 3D shape including, but not limited to, spherical, half spherical, cubical, conical, cylindrical, octahedral, etc. The drawings presented in this disclosure are shown as spherical or circular. These are purely for illustrative purposes only and do not reflect the only embodiments that the particles can be. In some embodiments, the bead 1 can be constructed with any combination of layers such as, an inner particle 2 of radiation-emitting material 7 and an outer layer 3 of a drug-eluting material 6, as shown in FIGS. 1A and IB. In some embodiments, at least a portion of the bead 1 can have a radiopaque material embedded therein. For example, in some embodiments, the particle 2 can be a radiopaque material. In some embodiments, the radiation-emitting material 7 can be a radiopaque material. In some embodiments, the outer layer 3 can be a radiopaque material. In some embodiments, the drug-eluting material can be radiopaque. In some embodiments, the 11ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025 particle 2, the radiation- emitting material 7, the outer layer 3, and / or the drug-eluting material 6 can be made of a radiopaque material. The radiopaque material can, advantageously, allow for visualization of the delivery of one, or more, beads 1 within a patient to a site of interest, e.g., to the location of a tumor.

[0038] The particle 2, in some embodiments, can be made from a polymer, glass, ceramic, glass-ceramic composite, resin, or a combination thereof. In some embodiments, the particle 2 can be made from a radiopaque material to enhance visualization of the bead 1. Due to the radiopaque material, the particle 2 can be readily discernable from a capable viewing device. It is also within the scope of this disclosure to have the particle comprised of any other biocompatible material capable of housing, and delivering, a radioisotope. The particle 2 of bead 1, in some embodiments, can be provided with a volume within which can be disposed a radioisotope 7 capable of delivering local radiation therapy to the surrounding tumor when the bead 1 is deployed to the tumor site. In an embodiment, the particle 2 can include a number of interstitial pores, gaps, or cavities, within the particle 2 to accommodate the radioisotope or a medication, for example as shown in FIGS. 1C and ID. The density of the particle 2 can be a function of the density of the interstitial pores, which may or may not be interconnected. In an embodiment, the interstitial pores can extend into, or from, a hollow interior portion of the particle 2. In some embodiments the interstitial pores can extend from an outer surface of the particle 2 to another portion of the surface of the particle 2. The interstitial pores can, in an embodiment, fluidly connect the hollow interior of the particle 2 to the outer surface of the particle 2. In some embodiments, some of the interstitial pores can extend from the outer surface of the particle to the interior of the particle 2, but not all. In some embodiments, some of the interstitial pores can extend from the hollow portion of the particle 2, outward, to the surface of the particle 2, but not all. An example radioisotope used in such procedures can be yttrium-90 (Y-90) or Holmium 166, though it is within the scope of this disclosure to utilize any beta or gamma-emitting radioisotope known or unknown. In some embodiments, as shown in FIGS. 1A and IB, the particle 2 can be solid, e.g., a solid sphere. In some cases, the particle 2 can be a solid or hollow particle that is sintered to about 10 - about 75% porosity. While the interstitial pores can receive a radioisotope, the pores can additionally or alternatively contain a medication or other chemical agent, depending on the application. The12ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 particle 2 can, in some embodiments, be coated with at least one outer layer, such as the outer layer3 to form a bead 1.

[0039] The outer layer 3, in some embodiments, can include a drug eluting, or releasing, glass, ceramic, ceramic / glass, resin, polymer, metal, or other biocompatible material capable of being deposited, adhered, coated, or otherwise attached to the particle 2. In some embodiments, the outer layer 3 can be capable of drug delivery and elution when deployed in the body of a patient. In some embodiments the therapeutic can be a radiosensitizer which can be nitroimidazole hypoxic cell radiosensitizer. Alternatively, the drug eluting portion could contain any other therapeutic compound including but not limited to non-nitroimidazole hypoxic cell radiosensitizers, radiosensitizing chemotherapeutics like taxanes (e.g., paclitaxel) or platinum containing compounds (e.g., cisplatin), or other radiosensitizing compounds yet to be identified.

[0040] In some embodiments, the instant bead 1 can include the inner particle, or particle 2, and the outer layer 3, where the particle 2 may not contain radioactive material and the outer layer may not include a therapeutic. In such a case, the bead 1 can perform TAE, or bland embolization of the tumor to starve the tumor of an energy source by individually, or collectively, blocking an artery or vein such that no blood flow can reach the tumor site. Alternatively, in some cases, the instant bead 1 can be used in trans-arterial chemoembolization (TACE). TACE is often the initial type of embolization used for large liver cancers that cannot be treated with surgery or ablation and combines embolization with chemotherapy (chemo). For example, the drug-eluting portion 3 can include Doxorubicin, Cisplatin, Epirubicin, Miriplatin, Carboplatin, Mitomycin C, Gemcitabine, or 5 FU. In the case of treating metastasized tumors originating from hepatocellular carcinoma (HCC), the drug-eluting portion 3 can include certain systemic agents including Atezolizumab, Bevacizumab, Tremelimumab-actl, Darvalumab, Soreafenib, Lenvatinib, Pembrolizumab, Nivolumab, Ipilimumab, Regorafenib, Cabozantinib, Ramucirumab, Dostarlimab, or Selpercatinib. In some embodiments, in the case of treating metastasized tumors originating from colorectal cancer, the drug-eluting portion 3 can include 5 FU, Oxaliplatin, Leukovorin, Capecitabine, Irinotecan, Bevavcizumab, Panitumumab, Nivolumab, Ipilimumab, Pembrolizumab, Trastuzumab, Pertuzumab, Lapatinib, Tucatinib, Ramucirumab, Ziv-aflibercept, Cetuximab, Panitumumab, Encorafenib, Dostarlimab-gxly, Lapatinib, Fam-traztuzumab deruxtecan, Regorafenib, Trifluridine, or Tipiracil.13ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025

[0041] In some embodiments, when treating metastasized tumors originating from cholanigiocarcinoma, the drug-eluting portion 3 can include those medications commonly treated with TACE including Doxorubicin, Cisplatin, Epirubicin, Miriplatin, Carboplatin, Mitomycin C, Gemcitabine, or 5 FU. Alternatively, the drug-eluting portion 3 can include any of the following 5FU, Capecitabine, Oxaliplatin, Leukovorin, Gemcitabine, Cisplatin, Durvalumab, Paclitaxel & NAB-paclitaxel, Regorafenib, Irinotecan, Lenvatinib, Pembrolizumab, Entrectinib, Larotrectinib, Nivolumab, Ipilimumab, Pralsetinib, Selpercatinib, Dostarlimab-gxly, Dabrafenib, Trametinib, Futibatinib, Pemigatinib, Ivosidenib, Traztuzumab, or Pertuzumab.

[0042] In some embodiments, when treating metastasized tumors originating from breast cancer, the drug-eluting portion 3 can include Adriamycin, Cyclophosphamide, Paclitaxel, Docetaxel, Olaparib, Pebrolizumab, Carboplatin, Epirubicin, Methotrexate, 5FU, Capecitabine, Trastuzumab, Pertuzumab, Neratinib, TDM-1, Tamoxifen, Anastrozole, Letrozole, Riboci clib, Abemaciclib, Palbociclib, Fulvestrant, Exemestane, or Everolimus. In some embodiments, when treating metastasized tumors originating from non-small cell lung cancer, the drug-eluting portion 3 can include Carboplatin, Paclitaxel, Cisplatin, Pemetrexed, Gemcitabine, Docetaxel, Vinorelbine, Etoposide, Nivolumab, Osimertinib, Atezolizumab, Pembrolizumab, or Darvalumab. In some embodiments, when treating metastasized tumors originating from prostate cancer, the drug-eluting portion 3 can include Nilutamide, Flutamide, Bicalutamide, Abiraterone, Enzalutamide, Apalutamide, Darolutamide, Docetaxel, Ketoconazole, Cabazitaxel, Carboplatin, Mitoxantrone, Pembrolizumab. In some embodiments, when treating metastasized tumors originating from pancreatic cancer, the drug-eluting portion 3 can include 5FU, Oxaliplatin, Irinotecan, Leucovorin, Gemcitabine, Paclitaxel, Nab-paclitaxel, Cisplatin, Erlotinib, Dabrasfenib, Trametinib, Pembrolizumab, Larotrectinib, Entrectinib, Dabrafenib, Olaparib, Rucaparib.

[0043] By combining the radioisotope and a drug-eluting layer infused with a therapeutic on the same bead 1 , or particle, the tumor cell kill can be enhanced while maintaining a simplified procedure requiring only a single hepatic artery cannulation and a single injection of therapeutic material. Additionally, the range of the Y-90 emitted beta particles can be on the order of only 1 mm in tissue, however other ranges are considered to be within the scope of this disclosure. It can therefore be important to ensure co-location of the radiation source and the radiosensitizer elution. Such co-location can be accomplished through coadministration on the same bead 1, as combining 14ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 a bead with separate drug-eluting particles would not guarantee that both therapeutics would be delivered to the same anatomic location. In some embodiments, the instant beads can be used for TAE (or bland embolization), TACE (or chemoembolization), and TARE (or radioembolization), in addition to bio-radioembolization which involves concurrent delivery of therapeutics. In the case of TARE, the instant bead can have the capability to deliver drugs if the physician so choses to do. In some embodiments in the case of TARE, the instant bead 1 can have the radioactive material that is embedded within the inner particle 2 activated, without a therapeutic embedded within the outer layer 3. In such an embodiment, the bead 1 can be infused into the patient to allow the bead 1 to treat a tumor at a site of interest by emitting radiation alone. In some embodiments, the therapeutic material can be infused into the outer layer 3 after the time of delivery to a hospital, or healthcare facility, but before infusion to the patient. In some embodiments, the instant bead can provide for the specific combination of a particular drug with the radiation-emitting beads. In some cases, the instant beads may not have activated radioisotopes, which would result in a particle with a core and a polymeric coating on the outside, which would also serve the TAE and TACE markets. Therefore, the instant beads can allow for beads that can have radiation emission, drug delivery and embolization capability while some beads can only have the drug delivery and embolization (no radiation).

[0044] In some embodiments, the radiosensitizer can be used to treat a number of metastasized tumors effecting the liver. For example, the radiosensitizer can be nitroimidazole hypoxic cell radiosensitizer. Alternatively, the drug-eluting layer 3 could contain any other radiosensitizing compound including but not limited to non-nitroimidazole hypoxic cell radiosensitizers, radiosensitizing chemotherapeutics like taxanes (e.g., paclitaxel) or platinum containing compounds (e.g., cisplatin), or other radiosensitizing compounds yet to be identified. For example, in some embodiments, in the case of treating metastasized tumors in the liver originating from colorectal cancer, the drug-eluting portion, or outer layer 3, can be infused with 5 FU, Oxaliplatin, Leukovorin, Capecitabine, Irinotecan, Bevavcizumab, Panitumumab, Nivolumab, Ipilimumab, Pembrolizumab, Trastuzumab, Pertuzumab, Lapatinib, Tucatinib, Ramucirumab, Ziv-aflibercept, Cetuximab, Panitumumab, Encorafenib, Dostarlimab-gxly, Lapatinib, Fam-traztuzumab deruxtecan, Regorafenib, Trifluridine, or Tipiracil.15ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025

[0045] In some embodiments, the particle 2, can have a first material density and the outer layer 3 can have a second material density. The first material density can be, in some embodiments, denser than the second material density. However, advantageously, the bead 1 can be formed of the particle 2 and the outer layer 3, therefore the bead 1 can have a lower overall, or combined, density than the particle 2 alone such that the bead 1 can be buoyant, or neutrally buoyant, within a fluid therefore the bead 1 can have a favorable flow characteristic within the fluid, e.g., human blood. A favorable flow characteristic can be understood to mean that the bead 1 can flow within the fluid without sinking and becoming lodged within a lumen, e.g., a human artery or vein. The lower density of the bead 1 can be a function of the ratio of volumes of the particle 2 to the outer layer 3. In some embodiments, the lower density can also be a function of the physical characteristics of the particle 2. For example, a particle 2 with pores or a hollow cavity may be more buoyant than a solid inner core of the same dimensions.

[0046] In an embodiment, the outer layer 3 can be deposited, or coated, onto the particle 2 such that the resulting bead 1 does not have any rough or jagged edges to prevent the bead 1 from damaging any healthy tissue it comes into contact with during the administration. In some embodiments, the outer layer 3 of bead 1 can have a thickness, and therefore a resulting volume, which can accommodate a therapeutic, e.g., a radiosensitizing compound, hypoxic cell cytotoxins, immunotherapy, CAR-T therapies, etc., that can be diffused, or emitted, from the bead into the surrounding tumor and body tissues at the same time, or a different time, as the radioisotope compound(s) are treating the tumor. In an embodiment, this compound can be a hypoxic cell radiosensitizer such as a nitroimidazole. However, it is within the scope of this disclosure to use any therapeutic compound, known or unknown. In some embodiments, the outer layer 3 can remain intact after delivery to a site of interest within a patient, or alternatively, the outer layer 3 can be absorbed into the body after delivery. Additionally, although it is shown in the figures to have the radioisotope in the particle 2 and the drug-eluting portion in the outer layer 3, the position of the two layers could be reversed to have the drug-eluting portion in the core and the radioisotope in the outer layer.

[0047] The outer layer 3 can be formed from any number of different materials. In an embodiment, the outer layer 3 can be formed from a polymer, e.g., where the polymer coating either does or does not carry drugs, but the polymer can have that capability. In an embodiment 16ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 the polymer can be ethylene vinyl acetate (EVA). Coating the beads with this polymer can be achieved using microfluidics. For example, the EVA can be dissolved in an appropriate solvent, such as dichloromethane, cyclohexane, or ethyl acetate, in order to be applied to the beads. In an embodiment, hydrogels can be a category of materials well suited to coat the particles 2 to allow for the uptake and release of drugs. In some embodiments, by adding iodinated monomers in the polymer networks the bead 1 can be provided with radiopacity, or enhanced radiopacity. The hydrogel material can be selected from the group of sodium alginate, polyethylene glycol, poly phosphoryl choline, N-isopropyl acrylamide, or equivalents thereof.

[0048] In an embodiment, the coating can be sodium alginate. Sodium alginate is an anionic polysaccharide that can coat the particles 2 which can be beads having approximately final outer diameter of about 5- 100 pm. In some embodiments, the final outer diameter can be about 30 - 45 pm. The resulting bead 1 can have a final outer diameter of approximately less than 60 pm, regardless of the specific coating 3 used, after a drying process. The coating 3 can be formed from sodium alginate can be crosslinked by exposure to calcium chloride solution. The density and drug release kinetics of the coating 3 can be tuned using dual crosslinking with both calcium and photocrosslinking.

[0049] In an embodiment, the coating 3 can be formed from polyethylene glycol (PEG) copolymer hydrogels. PEG copolymer hydrogels can coat the microspheres via a two-step process, first modifying the surface of the bead with PEG acrylate, PEG-thiol, or similar, and then photopolymerizing PEG-diacrylate (PEGDA) or multi-arm PEG-norbornene and a photo initiator (polymerizing via UV light).

[0050] In an embodiment, the coating 3 can be a poly (methacryloxyethyl) phosphoryl choline (PMPC) coating. The PMPC coating can be otherwise described as a zwitterionic polymer and can be copolymerized with, for example, n-butyl methacrylate to tune the crosslink density and drug release kinetics. The PMPC coating can be applied via microfluidics after polymerization or grafted up from a suitably functionalized surface by surface-initiated polymerization.

[0051] In an embodiment, the coating 3 can be a poly (N-isopropyl acrylamide) (PNIPAM) coating. The PNIPAM coating can be a thermosensitive polymer which can convert from solution to a gel state at a critical solution temperature and can attach to the bead surface using surface17ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 coupling agents containing polymerizing groups. Copolymers with natural polymers can be used in combination with the PNIPAM to tailor the temperature response and drug release kinetics of the coating.

[0052] In an embodiment, the coating 3 can be poly lactic-co-glycolic acid (PLGA). The PLGA coating can be a biodegradable polymer that has characteristics that enhance the stability and functionality during the manufacturing process. For example, in an embodiment, the PLGA coating can yield a higher quality of coating 3, with a high rate of manufacturing consistency.

[0053] The present disclosure additionally provides for microfluidic techniques for application of the aforementioned coating 3 onto the surface of the particle 2 to form the bead 1. While reference is made to spherical particles 2, it is understood that the present disclosure has applicability for application of a coating 3 onto any shaped particle 2, including irregular shapes. In an embodiment, microfluidic techniques can be a suitable coating method, for example when taking into account the scale of the particle. For example, inertial and turbulence effects are negligible at this scale. In some embodiments, where the coating 3 will be a polymer such as EVA, the choice of solvent and the concentration of the polymer dissolved in the solvent can be control variables, as the resulting density of the fluid interacts differently with the buoyancy of the beads. In an embodiment, the microfluidic techniques can include the use of a microfluidic chip for coating the particle 2. For example, an appropriate microfluidics chip design can be chosen, such as a standard T-junction, 3D flow focusing, droplet junction, 2 Reagent droplet, 2 Reagent 3D flow focusing, or other such chip designs. Microfluidics chip channel size and the hydrophilic / hydrophobic properties of the chip materials can also be important control variables.

[0054] In an embodiment, droplets of the solvent-dissolved polymer, with the particles 2 suspended within, can be generated in the microfluidics chip 100, for example as shown in FIG. 2A. In an embodiment, the particles 2 can be radioactive before introduction into the chip 100. Upon exiting the chip, the solvent can evaporate out of the polymer coating material, resulting in the desired monodispersed beads. Monodispersed beads can be understood to mean beads 1, e.g., embolic beads, having a uniform polymer coating in which all of the beads can have substantially the same relative size or relative molecular mass, within production tolerances. Further, the surface tension of the solvent-dissolved polymer can effectively encapsulate the particle 2 within18ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 the coating 3. With the particle 2 encapsulated within the coating 3, a known thickness of coating 3 can be determined to ensure that the total volume of medication being delivered to a site of interest is precise.

[0055] In an embodiment, as shown in FIGS. 2A and 2B, the microfluidics chip 100 can be a T-junction microfluidics chip 100. In a T-junction microfluidics chip 100, there can be two inlet flows combining to one outlet flow at a T shaped junction 108. Particles 2 can be dispersed in a solvent-dissolved polymer material, mixture, or solution, 110. The solution 110 can enter through one inlet 102 to form a mixture, or solution, of a plurality of particles 2 and the polymer dissolved in solvent. In an embodiment, an inert fluid such as water 112 can be run through the second inlet 104 towards the junction 108. In an embodiment, in place of water 112, other inert or non-reactive fluids can be used in combination with water, or in place of water. At the T- junction 108, the water flow 112 can shear off droplets 114 from the flow containing particles 2 in dissolved polymer, as seen in FIG. 2B. For example, in an embodiment, the flow of water 112 can flow along a first direction towards and past the junction 108, and the flow of the solution of particles 2 and polymer dissolved in solvent 110 can flow in a second direction, such that the droplets 114, or embolic particles 1, can be individually formed. In an embodiment, at the junction 108, the water flow 112 can flow perpendicular to the flow of the solution 110. The resulting coated particles, or beads 1 , can then exit the microfluidics chip 100 via the outlet 106. The relative flow rates of the two inlet streams can be altered to effect droplet 114 size. For example, the relative flow rates can be a function of pressure ratio between the solution 110 and the water 112. In some embodiments, the pressure of the solution 110 can be about 20 mbar to about 1000 mbar, or about 200 mbar to about 700 mbar, or about 250 to about 500 mbar. In some embodiments, the pressure of the water 112 can be about 200 mbar to about 1500 mbar, or about 400 to about 1000 mbar, or about 500 to about 800 mbar. The concentration of particles 2 in the solvent-dissolved polymer inflow 110 can determine whether all resulting droplets 114 contain a bead or are just the polymer.

[0056] In some embodiments, as shown in FIGS. 3 A and 3B, the microfluidics chip 100 can be a flow focusing chip, or 3D flow focusing chip. Similar to the T-junction chip, the flow focusing design has one inlet 102 for introduction of the particles 2 dispersed in the solvent- dissolved polymer 110 and there can be two inlets 104a, 104b where water 112 can be introduced.19ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025The specific geometry of the junction 108 where these three flows combine can generate the monodisperse droplets 114 by the water flow 112 pinching off the droplets from the bead / polymer solution flow 110 which can exit through an outlet 106. For example, in some embodiments, the water flow 112 can be at an angle, or perpendicular, to the flow of the solution 110, at the junction 108. The relative flow rates and the concentration of beads in the solution can be adjusted to optimize droplet size. For example, the relative flow rates can be a function of pressure ratio between the solution 110 and the water 112. In some embodiments, the pressure of the solution 110 can be about 20 mbar to about 1000 mbar, or about 200 mbar to about 700 mbar, or about 250 to about 500 mbar. In some embodiments, the pressure of the water 112 can be about 200 mbar to about 1500 mbar, or about 400 to about 1000 mbar, or about 500 to about 800 mbar.

[0057] In an embodiment, as illustrated in FIG. 4, a custom microfluidics chip 100 can be used. The custom microfluidics chip can include five inlets 102, 103a, 103b, 104a, 104b, and one outlet 106. The particles 2 dispersed in the solvent-dissolved polymer 110 can be introduced through a first inlet 102. In an embodiment, the particles 2 can be introduced directly into the inlet 102 without any additional fluid. Alternatively, the particles 2 can be introduced into inlet 102 being dispersed in any inert fluid to enhance the flow rate through the inlet 102. The solvent- dissolved polymer 110 can be introduced through the two inlets 103a, 103b leading to the first X- junction 108a to create a solution of particles 2 suspended in the solvent-dissolved polymer. The solvent-dissolved polymer can be introduced at the same time as the particles 2, or before the particles 2 are introduced into the inlet 102. Water can be introduced through the remaining two inlets 104a, 104b, meeting the combined stream at a second X-junction 108b. The water flow can pinch off separate particles of the particles 2 suspended in the solvent-dissolved polymer. Again, the relative flow rates of the two inlet streams can be adjusted to determine droplet size.

[0058] With any of the above noted microfluidics chips 100, a plurality of variables can be taken into account for to ensure reliability in production at a desired output with a desired consistency at scale. For example, to create a bead 1, for example a desired monodisperse beads, meaning radiation-emitting beads coated with a polymeric shell, microfluidics droplet formation techniques provide the process controls necessary. Those variables can include 1) bead size; 2) bead density; 3) polymer coating material selection; 4) solvent selection for dissolving the polymer; 5) polymer concentration within the solvent solution; 6) microfluidic chip geometry / 20ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 design; 7) hydrophilic / hydrophobic behavior of chosen chip materials; 8) bead concentration in the solvent solution; or 9) relative flowrates of various fluid inlets. Optimizing these factors can reliably produce the desired output with consistency at scale.

[0059] In an embodiment, with the PEG and PMPC hydrogels and PNIPAM materials, the coating could be achieved by grafting the appropriate combinations of polymers and polymerization agents from the surface of the beads using thermal or photo crosslinking mechanisms. As noted above, radiopacity and the drug release kinetics can be fine-tuned by the selection of additives and processing techniques.

[0060] In some embodiments, the solvent within the solution 110 can be extracted to encase or encapsulate the particle 2 with the polymer coating. After the particles 2 are suspended in the solvent-dissolved polymer, the solvent can then be extracted, leaving the particle 2 therein encapsulated by the remaining polymer once the solvent has been removed to form a bead 1. The extraction of solvent can result in a particle 2 initially having a diameter of less than about 1000 pm reducing in size to a diameter ranging between about 100 pm - about 5 pm, or less. In some embodiments, this process can create substantially spherical beads 1 by encapsulating the particle 2 with an outer coating. In some embodiments, the solvent and solution can be varied to reduce or increase the thickness of the polymer coating encapsulating the particles 2. In some embodiments, the extraction can create a coating with a thickness of about 5 to about 20 microns surrounding the particle 2. In some embodiments, the extraction occurs through evaporation of the solvent. The evaporation can be accelerated by adding various combinations of solvents or by adding accelerants that rapidly evaporate. In some embodiments, the extraction process can occur in a vacuum or under a presure other than atmospheric conditions to reduce the time required during the extraction process. In some embodiments, the extraction can occur when the pressure is atmospheric conditions.

[0061] In some embodiments, a method for delivering a radiation emitting, micron-sized, bead 1 that can be mixed into a fluid 40, is provided. For example, the bead 1 and the fluid 40 can be infused into the patient simultaneously, as shown in FIGS. 5A-5B. In some embodiments the fluid 40 can be a chemotherapeutic drug, a hypoxic radiosensitizer drug, or any other agent used to treat tumor cells. The term radiosensitizer used herein can refer to hypoxic cell radiosensitizers,21ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 bioreductive drugs, radiosensitizing chemotherapy agents, immunotherapies, or any other radiosensitizing chemical, protein, medication, or compound known today or in the future. The beads 1 and fluid 40 can be contained in a single vial 1000 and delivered as such to a clinician for use. For example, the bead 1 can be shipped where the drug eluting layer 3 does not include any therapeutic agents. In such a case, the hospital can mix the bead 1 with a therapeutic agent, via fluid 40, before administering the beads 1 to a patient. In some embodiments, the therapeutic agent can be infused into the bead 1 before coating, during the coating process, into the coating ahead of the coating process, or infused into the bead 1 after the coating process, or combinations thereof.

[0062] In some embodiments, the bead 1 may need the fluid 40 to “activate” the drugeluting layer 3, which can be a polymeric layer. In the case of a polymeric layer, or coating, the fluid 40 can be approximately 100% NaCl 0.9% aqueous solution, non-ionic contrast medium, or approximately a 50 / 50 mix of NaCl 0.9% aqueous solution and contrast. Alternatively, the fluid 40 can be any of the therapeutic agents disclosed herein. As the polymeric layer, e.g., the drug eluting layer 3, is exposed to the fluid 40, the beads 1 can swell such that they expand in diameter. Alternatively, the exposure of the fluid 40 to the beads may activate the drug eluting layer 3 without causing the beads 1 to swell. In some embodiments, the introduction of the beads 1 to the fluid 40 can occur before, or after, the beads 1 are shipped to the hospital. In an alternative embodiment, the radiation-emitting, micron-sized, beads 1 can be delivered in a separate vial 1000 from the fluid 40 with the two mixed and infused via a delivery mechanism, as shown in FIG. 5B.

[0063] In a method of delivery of the instant beads, according to an embodiment, the method can encompass the non-concurrent delivery of a radiation emitting, embolic, bead 1 and the fluid 40 (e.g., chemotherapeutic drugs, hypoxic radiosensitizer drugs, or any other agent used to treat tumor cells). In some embodiments, the fluid 40 can first be delivered to an arterial branch of the patient that feeds the tumor by a microcatheter. Either immediately, or later, the method can include the delivery of the beads 1 into the same arterial branch. The idea is that the fluid 40, or drugs, are delivered to the tumor and the beads 1 can occlude the lumen to capture the drugs in place and prevent systemic migration of the drugs. In addition, and advantageously, the bead 1 can deliver the necessary radiation to treat the tumor. Alternatively, the method can include delivering the drug directly into the tumor using an ultrasound-guided, percutaneous method22ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025 followed by delivery of the embolic using a standard technique of a microcatheter placed in the appropriate vessel.

[0064] In some embodiments, in addition to the drugs that are added to the bead 1, there can be the addition of a CAR-T therapy, or other cellular therapies, as an additional element. Cellular therapies, including CAR-T, typically require extraction of a patient’s native cells, genetic modification of those cells, and reintroduction of the modified cells into the patient. In the case of CAR-T, a patient’s T cells (both CD4 and CD8) can be harvested from a patient. The T cells are then genetically engineered to recognize and target tumor specific antigens through a gene editing technology such as CRISPR / Cas9. The modified T cells can then be reintroduced into the patient through infusion, stimulating an immune response targeting cancer cells. CAR-T can not only include targeting specific antigen and proteins but can also be tailored to target hypoxic cancer cells. This is different from hypoxic cell radiosensitization, in that CAR-T can be more like bioreductive drugs, which are directly toxic to hypoxic cells. Therefore, the CAR-T therapy could be introduced in addition to the hypoxic cell radiosensitizer drug, not necessarily replace it. Systemic administration of CAR-T therapy frequently leads to Cytokine Release Syndrome (CRS), a potentially life-threatening inflammatory reaction to treatment. It is possible that localized delivery of CAR-T cells directly to a tumor, for example with the instant beads, can mitigate the severity of CRS.

[0065] The introduction of CAR-T into bead 1, can create a radioembolic with the following modalities. The bead 1, in an embodiment, can provide for 1) vascular embolization to stop the flow of blood to the tumor cells; 2) radiation emission to expose the tumor cells to ionizing radiation, killing tumor cells and upregulating tumor related antigen presentation; 3) radiosensitization to enhance radiation induced cell death in the tumor; and 4) CAR-T to target the tumor cells over a prolonged period of time after the radiation emission and hypoxic cell radiosensitizer have subsided.

[0066] In some embodiments, the beads formed via methods disclosed herein can additionally aggregate within a solution. For example, the beads 1 can be introduced into a patient and aggregate at a desired location within the patient.23ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 2025

[0067] As utilized herein, the terms “comprises” and “comprising” are intended to be construed as being inclusive, not exclusive. As utilized herein, the terms “exemplary”, “example”, and “illustrative”, are intended to mean “serving as an example, instance, or illustration” and should not be construed as indicating, or not indicating, a preferred or advantageous configuration relative to other configurations. As utilized herein, the terms “about”, “generally”, and “approximately” are intended to cover variations that may existing in the upper and lower limits of the ranges of subjective or objective values, such as variations in properties, parameters, sizes, and dimensions. In one non-limiting example, the terms “about”, “generally”, and “approximately” mean at, or plus 10 percent or less, or minus 10 percent or less. In one nonlimiting example, the terms “about”, “generally”, and “approximately” mean sufficiently close to be deemed by one of skill in the art in the relevant field to be included. As utilized herein, the term “substantially” refers to the complete or nearly complete extend or degree of an action, characteristic, property, state, structure, item, or result, as would be appreciated by one of skill in the art. For example, an object that is “substantially” circular would mean that the object is either completely a circle to mathematically determinable limits, or nearly a circle as would be recognized or understood by one of skill in the art. The exact allowable degree of deviation from absolute completeness may in some instances depend on the specific context. However, in general, the nearness of completion will be so as to have the same overall result as if absolute and total completion were achieved or obtained. The use of “substantially” is equally applicable when utilized in a negative connotation to refer to the complete or near complete lack of an action, characteristic, property, state, structure, item, or result, as would be appreciated by one of skill in the art.

[0068] Numerous modifications and alternative embodiments of the present disclosure will be apparent to those skilled in the art in view of the foregoing description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the best mode for carrying out the present disclosure. Details of the structure may vary substantially without departing from the spirit of the present disclosure, and exclusive use of all modifications that come within the scope of the appended claims is reserved. Within this specification embodiments have been described in a way which enables a clear and concise specification to be written, but it is intended and will be appreciated that embodiments may be24ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025 variously combined or separated without parting from the invention. It is intended that the present disclosure be limited only to the extent required by the appended claims and the applicable rules of law.25ACTIVE 713435304v1

Claims

Attorney Docket No. 215532-010401 / PCTDate of Deposit: August 7, 2025CLAIMSWhat is claimed is:

1. A method of manufacturing beads, the method comprising: introducing, into a microfluidic pathway, a fluid flow of a fluid along a first direction; directing along a second direction a mixture of a plurality of particles and a polymer; and allowing the fluid flow to shear the mixture as the mixture enters the microfluidic pathway such that a plurality of beads are created each having a width of less than about 1000 pm.

2. The method of claim 1, wherein each bead includes a single particle.

3. The method of claim 1, wherein the plurality of particles are covered, or coated, with the polymer.

4. The method of claim 1 , wherein the fluid is inert.

5. The method of claim 1, wherein the introduction of a fluid flow includes introducing a second flow of the fluid, flowing along a third direction, where the flow of fluid intersects the mixture.

6. The method of claim 5, wherein the directing step includes, directing a flow of the plurality of particles flowing into a flow of the polymer, upstream of where the fluid intersects the mixture.

7. The method of claim 6 further comprising, directing at least two flows of polymer towards the flow of the plurality of particles.

8. The method of claim 1, wherein the polymer is a hydrogel.

9. The method of claim 8, wherein the hydrogel is one of sodium alginate, polyethylene glycol (PEG) copolymer hydrogel, poly (methacryloxyethyl) phosphory choline (PMPC), or Poly (N-isopropyl acrylamide) (PNIPAM).

10. The method of claim 1, wherein the allowing step occurs at one of a T junction or an X junction.

11. The method of claim 1, wherein the plurality of particles are substantially spherical.26ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 202512. The method of claim 1, wherein the plurality of particles are radiation emitting particles.

13. The method of claim 12, wherein the radiation emitting particles have a width of about 5 - 100 pm.

14. The method of claim 12, wherein the radiation emitting particles have a width of about 30 - 45 pm.

15. The method of claim 12, wherein the polymer forms a uniform coating around each of the respective particles.

16. The method of claim 15, wherein the plurality of beads have a substantially same width.

17. The method of claim 12, wherein in the directing step, the mixture includes the polymer dissolved in a solvent.

18. The method of claim 17 further comprising, evaporating the solvent from the polymer in the plurality of beads.

19. The method of claim 12 further comprising, infusing a medication into the polymer.

20. The method of claim 12, wherein the plurality of beads treat at least one of primary or metastatic tumors of a liver, lungs, the brain or spinal cord, prostate, breast, esophagus, upper aerodigestive tract including the nasopharynx, nasal cavity, oral cavity, oropharynx, hypopharynx, larynx, neck, thyroid, lungs, mediastinum, stomach, small bowel, large bowel, pancreas, spine, kidneys, ureters, bladder, urethra, vagina, uterus, cervix, ovary, lymph nodes, muscles, and bones.

21. The method of claim 1, wherein the plurality of beads treats at least one of prostate artery embolization, genicular artery embolization, and embolization of an artery to treat musculoskeletal diseases including osteoarthritis, tennis elbow, plantar fasciitis.

22. The method of claim 1, wherein in the directing step, the mixture includes the polymer dissolved in a solvent.

23. The method of claim 22 further comprising, evaporating the solvent from the plurality of beads.27ACTIVE 713435304v1Attorney Docket No. 215532-010401 / PCT Date of Deposit: August 7, 202524. The method of claim 23, wherein the beads have a width of approximately 30 - 60 pm after the evaporating step.

25. The method of claim 1 further comprising, infusing a medication into the polymer, the plurality of particles, the plurality of beads or a combination thereof.

26. The method of claim 1 , wherein the polymer can be a combination of copolymers with natural polymers.

27. The method of claim 1 , wherein a width of each of the plurality of beads is a function of relative flow rates of the fluid and the mixture.

28. A plurality of beads produced by a process, the process comprising: introducing a mixture of a plurality of particles and a polymer towards a junction; directing a flow of fluid to flow across the junction; and allowing the flow of fluid to shear at least one of the plurality of particles and polymer, from the mixture, with the flow of fluid such that the plurality of beads are created, where each of plurality of beads includes at least one particle and the polymer.

29. A method of producing a plurality of beads, the method comprising: introducing a mixture of a plurality of particles and a polymer towards a junction; directing a flow of fluid to flow across the junction; and allowing the flow of fluid to shear at least one of the plurality of particles and polymer, from the mixture, with the flow of fluid such that the plurality of beads are created, where each of plurality of beads includes at least one particle and the polymer.28ACTIVE 713435304v1

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