Embolization composition and method

Abstract

To provide embolic compositions and methods. [Solution] The disclosure relates to crosslinkable compositions and systems for embolizing vascular systems, including the neurovascular system, within a patient, among many other applications, and to methods for forming crosslinkable compositions in situ, including the use thereof. In one aspect of the disclosure, a kit is provided comprising (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent, (b) a second liquid composition comprising a first hydride material having two or more hydride groups, a second silica filler and / or a second imaging agent, and (c) one or more components for mixing and delivering the first and second fluid compositions.

Description

[Technical Field]

[0001] Areas of this disclosure This disclosure relates to a biocompatible crosslinkable composition, a system for forming a crosslinkable composition, and a method for using such a crosslinkable composition. [Background technology]

[0002] background Crosslinkable compositions that can form crosslinked compositions in situ have many biomedical advantages, including, but are not limited to, the ability to deliver in-situ formed crosslinked compositions to closed cavities, such as blood vessels; the ability to deliver in-situ formed crosslinked compositions to hard-to-reach body parts; the ability of in-situ formed crosslinked compositions to fill empty spaces, potential spaces, or blood-filled spaces; and the ability of in-situ formed crosslinked compositions to support surrounding tissues. [Overview of the project] [Means for solving the problem]

[0003] overview This disclosure relates to crosslinkable compositions and kits, as well as methods for forming crosslinked compositions in situ.

[0004] In one aspect of the present disclosure, a kit is provided comprising (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent; (b) a second liquid composition comprising a first hydride material having two or more hydride groups, a second silica filler and / or a second imaging agent; and (c) one or more components for mixing and delivering the first and second fluid compositions, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups, the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, and the first and second fluid compositions, when mixed, form a crosslinkable composition. In some embodiments of this model, the first fluid composition further comprises a second hydride material having two or more hydride groups, the second fluid composition comprising a catalyst, and the first and second hydride materials having two or more hydride groups may be the same or different; on the other hand, in other embodiments, the second fluid further comprises a second polysiloxane having two or more unsaturated groups, the first fluid composition comprising a catalyst, and the first and second polysiloxanes having two or more unsaturated groups may be the same or different. In yet another embodiment of this model, the first fluid composition comprises a first silica filler, and the second fluid composition comprises a second imaging agent; on the other hand, in yet another embodiment, the first fluid composition comprises a first imaging agent, and the second fluid composition comprises a second silica agent. In various embodiments, the composition further comprises a plasticizer. In certain embodiments, the crosslinkable composition comprises 10 to 50% by weight of the first and / or second imaging agent (if present). In some embodiments, one or both of the first and second fluid compositions are annealed.

[0005] In another aspect of the present disclosure, (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, (b) a first dry composition comprising a first silica filler or a mixture of the first silica filler and a first imaging agent, (c) a second fluid composition comprising a first hydride material having two or more hydride groups, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups, (d) an optional second dry composition comprising a first imaging agent or a mixture of the second silica filler and a second imaging agent, (e) the first fluid composition, the first dry composition, the second fluid composition and A kit is provided comprising one or more components for mixing and delivering an optional second dry composition, wherein the first silica filler and the second silica filler may be the same or different, the first imaging agent and the second imaging agent may be the same or different, if the first dry composition comprises the first silica filler, the second dry composition comprises the first imaging agent, if the first dry composition comprises a mixture of the first silica filler and the first imaging agent, the second dry composition is optional, and the first fluid composition, the first dry composition, the second fluid composition, and optionally the second dry composition form a crosslinkable composition when mixed.

[0006] In another aspect of the present disclosure, a kit comprising (i) (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first silica filler, (b) a second fluid composition comprising a first hydride material having two or more hydride groups and a second silica filler, (c) a dry composition comprising a first imaging agent and optionally a second imaging agent, and (d) one or more components for mixing and delivering the first fluid composition, the dry composition and the second fluid composition, wherein the first fluid composition, the dry composition and the second fluid composition form a crosslinkable composition when mixed; (ii)(a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first imaging agent; (b) a second fluid composition comprising a first hydride material having two or more hydride groups and a second imaging agent; (c) a dry composition comprising a first silica filler and optionally a second silica filler; and (d) one or more components for mixing and delivering the first fluid composition, the second fluid composition and the dry composition, wherein the first fluid composition, the dry composition and the second fluid composition form a crosslinkable composition when mixed; or (iii) (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, and a first silica filler and optionally a second silica filler or a first imaging agent and optionally a second imaging agent; (b) a second fluid composition comprising a first hydride material having two or more hydride groups, and a first silica filler and optionally a second silica filler or a first imaging agent and optionally a second imaging agent; and (c) the first fluid composition and the second fluid A kit comprising one or more components for mixing and delivering compositions, wherein if the first fluid composition comprises a first silica filler and optionally a second silica filler, the second fluid composition comprises a first imaging agent and optionally a second radiopaque agent, and if the first fluid composition comprises a first imaging agent and optionally a second imaging agent, the second fluid composition comprises a first silica filler and optionally a second silica filler, and the first and second fluid compositions, when mixed, form a crosslinkable composition. In each of (i), (ii), and (iii), the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, and at least one of the first and second fluid compositions contains a catalyst for catalyzing the reaction between an unsaturated group and a hydride group, or each of (i), (ii), and (iii) contains a third or fourth fluid composition containing a catalyst for catalyzing the reaction between an unsaturated group and a hydride group, and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups. A kit is provided in which, if the first fluid composition contains a catalyst and the second fluid composition does not contain a catalyst, the second fluid composition may contain an optional second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups, and if the second fluid composition contains a catalyst and the first fluid composition does not contain a catalyst, the first fluid composition may contain two or more optional second hydride materials, which may be the same as or different from the first hydride material having two or more hydride groups.

[0007] In another aspect of the present disclosure, the steps include: (a) annealing a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent to form a first annealed fluid composition; (b) annealing a second fluid composition comprising a first hydride material having two or more hydride groups, a second silica filler and / or a second imaging agent to form a second annealed fluid composition; and (c) annealing the first fluid composition. A method is provided comprising the steps of (d) mixing a first annealed fluid composition with a second annealed fluid composition to form a crosslinkable composition, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between an unsaturated group and a hydride group, the first and second silica fillers may be the same or different, and the first and second imaging agents may be the same or different; and (d) injecting the crosslinkable composition into the body of a patient, thereby allowing the crosslinkable composition to crosslink in the body.

[0008] In another aspect of the present disclosure, (a)(i) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, (ii) a mixture of a first silica filler and a first imaging agent or a first dry composition comprising a first silica filler, (iii) a second fluid composition comprising a first hydride material having two or more hydride groups, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups, and (iv) an optional second dry composition comprising a first radiopaque agent, or The step of forming a crosslinkable composition comprising a mixture of an optional second dry composition, wherein the second dry composition optionally comprises a mixture of a second silica filler and a second imaging agent, the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, if the first dry composition comprises a first silica filler, the second dry composition comprises a first imaging agent, and if the first dry composition comprises a mixture of a first silica filler and a first imaging agent, the second dry composition is optional, and (b) A step in which the crosslinkable composition is injected into the patient's body, and the crosslinkable composition is then crosslinked within the body. A method is provided that includes this.

[0009] In another aspect of this disclosure, a method, (a) A step of forming a crosslinkable composition, (i) forming a crosslinkable composition comprising a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first silica filler, a second fluid composition comprising a first hydride material having two or more hydride groups and a second silica filler which may be the same as or different from the first silica filler, and a dry composition comprising a first imaging agent and optionally a second imaging agent which may be the same as or different from the first imaging agent; and (b) injecting the crosslinkable composition into the body of a patient, thereby crosslinking the crosslinkable composition within the body; (ii) forming a crosslinkable composition comprising a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first imaging agent, a second fluid composition comprising a hydride material having two or more hydride groups and a second imaging agent which is the same as or different from the first imaging agent, and a dry composition comprising a first silica filler and optionally a second silica filler which is the same as or different from the first silica filler; (b) injecting the crosslinkable composition into the body of a patient, thereby allowing the crosslinkable composition to crosslink in the body; or (iii) A step to form a crosslinkable composition comprising a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, and a first silica filler and optionally a second silica filler which is the same as or different from the first silica filler, or a first imaging agent and optionally a second imaging agent which is the same as or different from the first imaging agent, a first hydride material having two or more hydride groups, and a second fluid composition comprising a first silica filler and optionally a second silica filler, or a first imaging agent and optionally a second imaging agent, wherein if the first fluid composition comprises a first silica filler and optionally a second silica filler, the second fluid composition comprises a first imaging agent and optionally a second radiopaque agent, and if the first fluid composition comprises a first imaging agent and optionally a second imaging agent, the second fluid composition comprises a first silica filler and optionally a second silica filler, In each of (i), (ii), and (iii), at least one of the first and second fluid compositions includes a catalyst for catalyzing the reaction between an unsaturated group and a hydride group, or each of (i), (ii), and (iii) further includes a third or fourth fluid composition including a catalyst for catalyzing the reaction between an unsaturated group and a hydride group, and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups, wherein the first fluid composition includes a catalyst and the second fluid composition does not include a catalyst. In addition, the second fluid composition may include an optional second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups, and if the second fluid composition includes a catalyst and the first fluid composition does not include a catalyst, the first fluid composition may include an optional second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups, step, and (b) A step in which the crosslinkable composition is injected into the patient's body, and the crosslinkable composition is then crosslinked within the body. A method is provided that includes and is a method for forming a vascular embolism.

[0010] In each of the above embodiments, the Disclosure provides embodiments in which the crosslinkable composition comprises a vinyl group to hydride group molar ratio of ≥0.9:1. In some embodiments of the various embodiments, the crosslinkable composition comprises a first imaging agent and a second imaging agent in a total amount of 10 to 50% by weight. In other embodiments of the various embodiments, the crosslinkable composition comprises at least one silanol compound in a total amount of 0.25 to 10% by weight.

[0011] Further aspects and embodiments of this disclosure are described in detail below with reference to the accompanying drawings. In embodiments of the present invention, for example, the following items are provided. (Item 1) A kit comprising (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent; (b) a second liquid composition comprising a first hydride material having two or more hydride groups, a second silica filler and / or a second imaging agent; and (c) one or more components for mixing and delivering the first and second fluid compositions, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups, the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, and the first and second fluid compositions, when mixed, form a crosslinkable composition. (Item 2) (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups; (b) a first dry composition comprising a first silica filler or a mixture of the first silica filler and a first imaging agent; (c) a second fluid composition comprising a first hydride material having two or more hydride groups, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups; (d) an optional second dry composition comprising a first imaging agent or a mixture of the second silica filler and a second imaging agent; (e) the first fluid composition, the first dry composition, the second fluid composition and the optional second dry mixture A kit comprising one or more components for mixing and delivering an object, wherein the first silica filler and the second silica filler may be the same or different, the first imaging agent and the second imaging agent may be the same or different, if the first dry composition comprises the first silica filler, the second dry composition comprises the first imaging agent, if the first dry composition comprises a mixture of the first silica filler and the first imaging agent, the second dry composition is optional, and the first fluid composition, the first dry composition, the second fluid composition, and optionally the second dry composition form a crosslinkable composition when mixed. (Item 3) (a) Annealing a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent to form a first annealed fluid composition; (b) Annealing a second fluid composition comprising a first hydride material having two or more hydride groups, a second silica filler and / or a second imaging agent to form a second annealed fluid composition; (c) Mixing the first annealed fluid composition and the second annealed fluid composition to form a crosslinkable composition, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated group and the hydride group, the first and second silica fillers may be the same or different, and the first and second imaging agents may be the same or different; and (d) Injecting the crosslinkable composition into a patient's body, and then allowing the crosslinkable composition to crosslink in the body. (Item 4) [[ID=ģ]] The method according to item 3, wherein the first fluid composition comprises the catalyst and the second fluid composition does not comprise the catalyst. (Item 5) The method according to item 4, wherein the second fluid composition comprises a second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups. (Item 6) The method according to item 3, wherein the second fluid composition comprises the catalyst and the first fluid composition does not comprise the catalyst. (Item 7) The method according to item 6, wherein the first fluid composition comprises a second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups. (Item 8) The method according to item 3, wherein the first fluid composition comprises the first silica filler and the second fluid composition comprises the second imaging agent. (Item 9) The method according to item 3, wherein the first fluid composition comprises the first imaging agent and the second fluid composition comprises the second silica agent. (Item 10) (a) a first fluid composition comprising (i) a first polysiloxane having two or more unsaturated groups, (ii) a mixture of a first silica filler and a first imaging agent or a first dry composition comprising a first silica filler, (iii) a second fluid composition comprising a first hydride material having two or more hydride groups, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups, and (iv) an optional second dry composition comprising a first radiopaque agent, or optionally the second dry The composition is a crosslinkable composition comprising a mixture of an optional second dry composition comprising a mixture of a second silica filler and a second imaging agent, wherein the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, if the first dry composition comprises the first silica filler, the second dry composition comprises the first imaging agent, and if the first dry composition comprises a mixture of the first silica filler and the first imaging agent, the second dry composition is optional, the step of forming a crosslinkable composition, and (b) The step of injecting the crosslinkable composition into the patient's body, and then allowing the crosslinkable composition to crosslink within the body. Methods that include... (Item 11) The method according to item 10, wherein the first dry composition comprises the first silica filler and the second dry composition comprises the first imaging agent. (Item 12) The method according to item 10, wherein the first dry composition comprises a mixture of the first silica filler and the first imaging agent, and the second dry composition comprises a mixture of the second silica filler and the second imaging agent. (Item 13) The method according to items 10 to 12, comprising the steps of (a) mixing the first fluid composition and the first dry composition to form a first mixture, (b) mixing the second fluid composition and the second dry composition to form a second mixture, and (c) mixing the first mixture and the second mixture to form the crosslinkable composition. (Item 14) The method according to any one of items 10 to 13, wherein the first fluid composition comprises the catalyst and the second fluid composition does not comprise the catalyst. (Item 15) The method according to item 14, wherein the second fluid composition comprises a second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups. (Item 16) The method according to any one of items 10 to 15, wherein the second fluid composition comprises the catalyst and the first fluid composition does not comprise the catalyst. (Item 17) The method according to item 16, wherein the first fluid composition comprises a second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups. (Item 18) The method according to any one of items 3 to 17, further comprising the steps of identifying a vessel that branches into a smaller distal vessel, and injecting the crosslinking composition into the vessel such that the crosslinking composition flows into the distal vessel and occludes the distal vessel. (Item 19) The method according to item 18, wherein the crosslinkable composition is introduced into a distal blood vessel having a diameter of less than 100 microns. (Item 20) A kit or method according to any one of items 1 to 19, wherein, once the crosslinkable composition is formed, the gelation time is in the range of 3 to 60 minutes. (Item 21) A kit or method according to any one of items 1 to 20, wherein the crosslinkable composition is injectable by hand once formed. (Item 22) The kit or method according to any one of items 1 to 21, wherein the crosslinkable composition comprises the first silica filler (and the second silica filler, if present) in a total amount of 0.25 to 10% by weight. (Item 23) The first silica filler (and the second silica filler, if present) is present in a quantity of 50-1000 m 2 A kit or method described in any of items 1 to 22, characterized by a surface area of ​​ / g. (Item 24) The kit or method according to any one of items 1 to 23, wherein the crosslinkable composition comprises the first imaging agent (and the second imaging agent, if present) in a total amount of 10 to 50% by weight. (Item 25) A kit or method according to any one of items 1 to 24, wherein the first imaging agent and the second radiopaque agent (if present) comprise a metal oxide. (Item 26) A kit or method according to any one of items 1 to 25, wherein the first imaging agent and the second imaging agent, if present, include bismuth trioxide. (Item 27) The kit or method according to any one of items 1 to 25, wherein the crosslinkable composition comprises a vinyl group to hydride group molar ratio of ≥0.9:1. (Item 28) The kit or method according to any one of items 1 to 27, wherein the first polysiloxane and the second polysiloxane, if present, are selected from one or more of vinyl-terminated polysiloxanes, acrylate-terminated polysiloxanes, methacrylate-terminated polysiloxanes, or alkyne-terminated polysiloxanes. (Item 29) A kit or method according to any one of items 1 to 28, wherein the first polysiloxane and the second polysiloxane are linear in their presence. (Item 30) A kit or method according to any one of items 1 to 29, wherein the first polysiloxane and the second polysiloxane, if present, have a weight-average molecular weight in the range of 200 to 10,000 Da. (Item 31) A kit or method according to any one of items 1 to 30, wherein the first hydride material and the second hydride material, if present, have 2 to 20 hydride groups. (Item 32) A kit or method according to any one of items 1 to 32, wherein the first hydride material and the second hydride material are, if present, polyfunctional polysiloxane hydrides. (Item 33) The kit or method according to item 32, wherein the polyfunctional polysiloxane hydride is a linear polysiloxane hydride. (Item 34) The kit or method described in item 33, wherein the linear polysiloxane hydride contains a hydride-terminated group. (Item 35) The kit or method according to any one of items 33 to 34, wherein the linear polysiloxane hydride comprises a hydride side group. (Item 36) The kit or method according to any one of items 32 to 35, wherein the polyfunctional polysiloxane hydride has a weight-average molecular weight in the range of 300 to 13,000 Da. (Item 37) A kit or method according to any one of items 1 to 36, wherein the catalyst is selected from platinum catalysts, rhodium catalysts, ruthenium catalysts, palladium catalysts, iridium catalysts, boron trihydride catalysts, and phosphine catalysts. (Item 38) The kit or method according to any one of items 1 to 37, wherein the crosslinkable composition contains a catalytic modifier. (Item 39) The kit or method according to any one of items 1 to 38, wherein the crosslinkable composition further comprises at least one physical crosslinking agent having a plurality of hydrogen bonding groups. (Item 40) The kit or method according to item 39, wherein the crosslinkable composition comprises at least one physical crosslinking agent in a total amount of 1 to 5% by weight. (Item 41) The kit or method according to any one of items 1 to 40, wherein the crosslinkable composition further comprises at least one silanol compound. (Item 42) The kit or method according to item 41, wherein the crosslinkable composition comprises at least one silanol compound in a total amount of 0.25 to 10% by weight. (Item 43) The kit or method according to any one of items 41 to 42, wherein the at least one silanol comprises a hydroxy-terminated polysiloxane. (Item 44) The kit or method according to any one of items 1 to 43, wherein the crosslinkable composition further comprises a plasticizer. (Item 45) The kit according to item 1, wherein the first fluid composition and / or the second fluid composition are each annealed. (Item 46) The kit according to item 1, wherein the first fluid composition comprises the first silica filler and the second fluid composition comprises the second imaging agent. (Item 47) The kit according to item 1, wherein the first fluid composition comprises the first imaging agent and the second fluid composition comprises the second silica agent. (Item 48) (i)(a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first silica filler; (b) a second fluid composition comprising a first hydride material having two or more hydride groups and a second silica filler; (c) a dry composition comprising a first imaging agent and optionally a second imaging agent; and (d) one or more components for mixing and delivering the first fluid composition, the dry composition and the second fluid composition, wherein the first fluid composition, the dry composition and the second fluid composition form a crosslinkable composition when mixed; (ii)(a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first imaging agent; (b) a second fluid composition comprising a first hydride material having two or more hydride groups and a second imaging agent; (c) a dry composition comprising a first silica filler and optionally a second silica filler; and (d) one or more components for mixing and delivering the first fluid composition, the second fluid composition and the dry composition, wherein the first fluid composition, the dry composition and the second fluid composition form a crosslinkable composition when mixed; or (iii) (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, and a first silica filler and optionally a second silica filler or a first imaging agent and optionally a second imaging agent; (b) a second fluid composition comprising a first hydride material having two or more hydride groups, and the first silica filler and optionally the second silica filler or the first imaging agent and optionally the second imaging agent; and (c) a mixture of the first fluid composition and the second fluid composition. A kit comprising one or more components for delivery, wherein the first fluid composition comprises a first silica filler and optionally the second silica filler, the second fluid composition comprises the first imaging agent and optionally the second radiopaque agent, and the first fluid composition comprises the first imaging agent and optionally the second imaging agent, the second fluid composition comprises the first silica filler and optionally the second silica filler, and the first fluid composition and the second fluid composition, when mixed, form a crosslinkable composition, In each of (i), (ii), and (iii), the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, at least one of the first and second fluid compositions includes a catalyst for catalyzing the reaction between the unsaturated group and the hydride group, or each of (i), (ii), and (iii) further includes a third or fourth fluid composition including a catalyst for catalyzing the reaction between the unsaturated group and the hydride group, and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups The kit includes, and if the first fluid composition includes the catalyst and the second fluid composition does not include the catalyst, the second fluid composition may include an optional second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups, and if the second fluid composition includes the catalyst and the first fluid composition does not include the catalyst, the first fluid composition may include two or more optional second hydride materials, which may be the same as or different from the first hydride material having two or more hydride groups. (Item 49) It is a method, (a) A step of forming a crosslinkable composition, (i) forming a crosslinkable composition comprising a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first silica filler, a second fluid composition comprising a first hydride material having two or more hydride groups and a second silica filler which may be the same as or different from the first silica filler, and a dry composition comprising the first imaging agent and optionally the second imaging agent which may be the same as or different from the first imaging agent; and (b) injecting the crosslinkable composition into the body of a patient, thereby crosslinking the crosslinkable composition within the body; (ii) forming a crosslinkable composition comprising a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first imaging agent, a second fluid composition comprising a hydride material having two or more hydride groups and a second imaging agent which is the same as or different from the first imaging agent, and a dry composition comprising a first silica filler and optionally a second silica filler which is the same as or different from the first silica filler; (b) injecting the crosslinkable composition into the body of a patient, thereby crosslinking the crosslinkable composition within the body; or (iii) A step to form a crosslinkable composition comprising a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, and a first silica filler and optionally a second silica filler which is the same as or different from the first silica filler, or a first imaging agent and optionally a second imaging agent which is the same as or different from the first imaging agent, a first hydride material having two or more hydride groups, and a second fluid composition comprising the first silica filler and optionally the second silica filler, or the first imaging agent and optionally the second imaging agent, wherein if the first fluid composition comprises the first silica filler and optionally the second silica filler, the second fluid composition comprises the first imaging agent and optionally the second radiopaque agent, and if the first fluid composition comprises the first imaging agent and optionally the second imaging agent, the second fluid composition comprises the first silica filler and optionally the second silica filler, In each of (i), (ii), and (iii), at least one of the first and second fluid compositions includes a catalyst for catalyzing the reaction between the unsaturated group and the hydride group, or each of (i), (ii), and (iii) further includes a third or fourth fluid composition including a catalyst for catalyzing the reaction between the unsaturated group and the hydride group, and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups, wherein the first fluid composition includes the catalyst and the second fluid composition does not include the catalyst. In this case, the second fluid composition may include an optional second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups, and if the second fluid composition includes the catalyst and the first fluid composition does not include the catalyst, the first fluid composition may include an optional second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups, step, and (b) The step of injecting the crosslinkable composition into the patient's body, and then allowing the crosslinkable composition to crosslink within the body. A method that includes a method for forming a vascular embolism. (Item 50) Use of the method or kit described in any one of items 1 to 50 for occlusion of the vascular system for the treatment of tumors including meningioma and peripheral tumors, for preoperative embolization of tumors, for the treatment of chronic subdural hematoma, cerebral aneurysm, arteriovenous malformation, arteriovenous fistula, gastrointestinal bleeding, traumatic bleeding, abdominal aortic aneurysm, intracranial artery aneurysm, pulmonary artery aneurysm, and bleeding, for prostatic artery embolization, uterine artery embolization, for the treatment of visceral artery aneurysm, spermatic varicocele, varicose veins, pelvic congestion, epistaxis, or endoleak. (Item 51) The use according to item 49 or 50, wherein the crosslinkable composition is injected into the patient's vascular or neurovascular system via an inflatable balloon catheter, the balloon inflates proximal to the injection site and remains in place for a period of time after the injection of the crosslinkable composition. [Brief explanation of the drawing]

[0012] [Figure 1] Figures 1A to 1D schematically illustrate the progressive embolus formation in a portion of the vascular system using the crosslinkable composition according to this disclosure.

[0013] [Figure 2A] Figure 2A schematically shows the progressive behavior of the crosslinkable composition according to this disclosure during embolization treatment.

[0014] [Figure 2B] Figure 2B is a chemical formula representing the curing of the crosslinkable composition according to this disclosure.

[0015] [Figure 3ABC] Figures 3A-3C are angiographic images taken at different times during renal vascular embolus formation, showing renal vascular occlusion with the crosslinkable composition according to this disclosure. The upward arrows in Figures 3A-3C indicate the catheter tip. The downward arrow in Figure 3A indicates the continuous flow of the crosslinkable composition. The lower right arrow in Figure 3B indicates individual volumes of the crosslinkable composition, and the lower left arrow in Figure 3B indicates a volume of the crosslinkable composition showing distal infiltration.

[0016] [Figure 3D] Figure 3D shows a macroscopic image of the kidney 90 days after embolus formation, with arrows indicating the embolus formation area.

[0017] [Figure 3EF] Figures 3E-3F show X-ray and 3D micro-CT reconstructed images of the renal vascular system filled with a crosslinkable composition, respectively.

[0018] [Figure 4]Figures 4A and 4B show the histopathological results 30 days (Figure 4A) and 90 days (Figure 4B) after renal embolism formation using the crosslinkable composition according to this disclosure.

[0019] [Figure 5] Figure 5 shows viscosity-to-injection force data for various crosslinkable compositions described herein.

[0020] [Figure 6] Figure 6 shows the effect of the preparation methods of the two compositions of this disclosure on the fusion of the compositions.

[0021] [Figure 7] Figure 7 shows the effect of pre-wetting with silica or bismuth on the fusion of the compositions of this disclosure, compared to compositions that have not been pre-wetted with either silica or bismuth.

[0022] [Figure 8] Figure 8 shows the effect of pre-wetting with either silica or bismuth on fusion in compositions where both bismuth and silica are pre-wetted, and in compositions where neither silica nor bismuth is pre-wetted.

[0023] [Figure 9] Figure 9 shows the effects of pre-wetting with either silica or bismuth on the plastic viscosity (slope of the hysteresis curve) (Figure 9A), shear recovery of the composition (Figure 9B), storage modulus (Figure 9C), and ductile elongation curve (Figure 9D) for compositions in which both bismuth and silica are pre-wetted and compositions in which neither silica nor bismuth is pre-wetted.

[0024] [Figure 10AB] Figure 10A shows the effect of imaging agent (bismuth trioxide) dispersions in various compositions on injection force. Figure 10B shows the effect of imaging agent particle dispersion on vascular stenosis and casting of compositions to the distal branches of a pig kidney during injection. Figure 10C shows the effect of imaging agent dispersion on injection force. [Figure 10C]Figure 10A shows the effect of imaging agent (bismuth trioxide) dispersions in various compositions on injection force. Figure 10B shows the effect of imaging agent particle dispersion on vascular stenosis and casting of compositions to the distal branches of a pig kidney during injection. Figure 10C shows the effect of imaging agent dispersion on injection force.

[0025] [Figure 11] Figure 11 shows injection force data collected from an injection test method using low-frequency vibration rheology to measure viscosity, comparing a formulation in which the powder was mixed into the polymer phase (pre-wet) with a formulation in which the powder was mixed in a dry state immediately before injection.

[0026] [Figure 12] Figure 12 shows the effect of silica type (hydrophobic vs. hydrophilic) on the stability of the preliminary formulation composition of this disclosure.

[0027] [Figure 13] Figure 13A shows the effect of including a hydrophilic plasticizer on the fusion of the compositions of this disclosure. Figure 13B shows the effect of a hydrophilic plasticizer on the ductility and elasticity of the compositions.

[0028] [Figure 14] Figure 14 shows the effect of silica content on the fusion and ductility of the composition.

[0029] [Figure 15] Figure 15 shows the effect of the molecular weight of the silicone component in the composition on the ability to perform final sterilization of the crosslinked composition by electron beam sterilization.

[0030] [Figure 16] Figures 16A to 16D show progressive embolus formation in a portion of a porcine vascular system during embolus formation treatment using the crosslinkable composition according to this disclosure. [Modes for carrying out the invention]

[0031] Detailed explanation As used herein, a material is described as a “fluid” if it is fluid, such as in the case of liquids, semi-solids, pastes, gels, suspensions, emulsions, and viscoelastic materials.

[0032] For the purposes of this disclosure, the term “crosslinkable composition” generally refers to a polymer-based fluid that can be delivered to a delivery site, after which crosslinking (i.e., curing) of the material continues to proceed at the delivery site.

[0033] In various embodiments, the disclosure relates to a solvent-free crosslinkable composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler, a first imaging agent, a first hydride material having two or more hydride groups, a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups, an optional second silica filler different from the first silica filler, an optional second imaging agent different from the first imaging agent, an optional second hydride material having two or more hydride groups different from the first hydride material having two or more hydride groups, and an optional second polysiloxane having two or more unsaturated groups different from the first polysiloxane having two or more unsaturated groups. In various embodiments, the crosslinkable composition comprises a total amount of at least 10% by weight of the first imaging agent and the optional second imaging agent.

[0034] In some embodiments, the present invention provides a method for injecting these biocompatible crosslinkable compositions into a patient's vascular system, neurovascular system, or body cavity.

[0035] In various embodiments, the Disclosure relates to a kit for forming a biocompatible crosslinkable composition comprising (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and optionally a second hydride material having two or more hydride groups; (b) a mixture of the first silica filler and a first imaging agent or a first dry composition comprising the first silica filler and optionally the second silica filler; (c) a second fluid composition comprising a first hydride material having two or more hydride groups and optionally a second polysiloxane having two or more unsaturated groups; (d) an optional second dry composition comprising the first imaging agent or a mixture of the second silica filler and a second imaging agent; and (e) one or more components for mixing and delivering the first fluid composition, the first dry composition, the second fluid composition and, if present, the second dry composition.

[0036] In this embodiment, at least one of the first and second fluid compositions includes a catalyst for catalyzing the reaction between unsaturated groups and hydride groups, the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, and the first fluid composition, the first dry composition, the second fluid composition, and the second dry composition (if present) form a crosslinkable composition when mixed. In some embodiments, both the first and second fluids include a catalyst. In some embodiments, the first fluid composition includes a catalyst and the second fluid composition does not include a catalyst, in which case the second fluid composition may include a second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups. In some embodiments, the second fluid composition includes a catalyst, and the first fluid composition does not include a catalyst, in which case the first fluid composition includes a second hydride material having two or more hydride groups, which may be the same as or different from a first hydride material having two or more hydride groups. If the first dry composition contains only the first silica filler, then a second dry composition exists and contains the first imaging agent. Compositions and embodiments of this aspect of the present disclosure are referred to as “compositions made at the time of injection” in examples. In some embodiments, the silica filler is hydrophobic, and in other embodiments, the silica filler is hydrophilic. In embodiments in which the composition contains first and second silica fillers, one or both of the silica fillers may be hydrophobic or hydrophilic. In some embodiments, the crosslinkable composition contains first and second imaging agents (if present) in a total amount of at least 10% by weight.

[0037] In embodiments in which the kit may include a second dry composition, the first fluid composition may be mixed with the first or second dry composition to form a first mixture, or the second fluid composition may be mixed with the remaining dry composition to form a second mixture, in which case the first mixture and the second mixture may be mixed to form a crosslinkable composition. Typically, the ratio of the volume of the first mixture to the volume of the second mixture is approximately equal (about 1:1), and typically in the range of, for example, 4:1 to 1:4, and more typically 2:1 to 1:2, among other possible ratios. To improve mixing, the viscosities of the first and second mixtures may be similar, for example, the vibrational viscosities of the first and second mixtures at 25°C and a frequency of 0.1 Hz (see below) may be within + / - 60% of each other.

[0038] In another embodiment, the Disclosure relates to a kit for forming a crosslinkable composition comprising (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent, (b) a second fluid composition comprising a first hydride material having two or more hydride groups, a second silica filler and / or a second imaging agent, and (c) one or more components for mixing and delivering the first and second fluid compositions, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups, the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, and the first and second fluid compositions, when mixed, form a crosslinkable composition. In some embodiments, the crosslinkable composition comprises the first and second imaging agents in a total amount of at least 10% by weight. In some embodiments, both the first and second fluid compositions contain a catalyst. In some embodiments, the first fluid composition includes a catalyst, and the second fluid composition does not include a catalyst, in which case the second fluid composition may include a second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups. In some embodiments, the second fluid composition includes a catalyst, and the first fluid composition does not include a catalyst, in which case the first fluid composition may include a second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups. In some embodiments, the first fluid composition includes a silica filler, and the second fluid composition includes an imaging agent, and in other embodiments, the first fluid composition includes an imaging agent, and the second fluid composition includes a silica filler. In other embodiments, both the first and second fluid compositions include a silica filler and an imaging agent. In some embodiments, at least the first or second silica filler is hydrophobic, and in certain embodiments, both the first and second silica fillers are hydrophobic.In other embodiments, both the first and second silica fillers are hydrophilic, and in other embodiments, at least the first or second silica filler is hydrophilic. Typically, the ratio of the volume of the first fluid composition to the volume of the second fluid composition is approximately equal (about 1:1), typically in the range of, for example, 4:1 to 1:4, and more typically 2:1 to 1:2, among other possible ratios. To improve mixing, the viscosities of the first and second fluids may be similar, for example, the vibrational viscosities of the first and second fluid compositions at a frequency of 0.1 Hz at 25°C (see below) may be within + / - 60% of each other. Compositions of this embodiment of the present disclosure are referred to as “preformulated compositions” or “preformulated compositions” in embodiments.

[0039] In various embodiments, the Disclosure provides a kit comprising (i) (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first silica filler; (b) a second fluid composition comprising a first hydride material having two or more hydride groups and a second silica filler; (c) a dry composition comprising a first imaging agent and optionally a second imaging agent; and (d) one or more components for mixing and delivering the first fluid composition, the dry composition and the second fluid composition, wherein the first fluid composition, the dry composition and the second fluid composition form a crosslinkable composition when mixed; (ii)(a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first imaging agent; (b) a second fluid composition comprising a first hydride material having two or more hydride groups and a second imaging agent; (c) a dry composition comprising a first silica filler and optionally a second silica filler; and (d) one or more components for mixing and delivering the first fluid composition, the second fluid composition and the dry composition, wherein the first fluid composition, the dry composition and the second fluid composition form a crosslinkable composition when mixed; or (iii) (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, and a first silica filler and optionally a second silica filler or a first imaging agent and optionally a second imaging agent; (b) a second fluid composition comprising a first hydride material having two or more hydride groups, and a first silica filler and optionally a second silica filler or a first imaging agent and optionally a second imaging agent; and (c) a mixture of the first fluid composition and the second fluid composition and The present invention relates to a kit for forming a crosslinkable composition comprising one or more components for delivery, wherein the first fluid composition comprises a first silica filler and optionally a second silica filler, the second fluid composition comprises a first imaging agent and optionally a second imaging filler, and the first fluid composition comprises a first imaging agent and optionally a second imaging agent, the second fluid composition comprises a first silica filler and optionally a second silica filler, and the first and second fluid compositions, when mixed, form a crosslinkable composition. In each of (i), (ii), and (iii), the first and second silica fillers may be the same or different, the first and second imaging agents may be the same or different, and at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between an unsaturated group and a hydride group. Alternatively, each of (i), (ii), and (iii) further comprises a third and / or fourth fluid composition comprising a catalyst for catalyzing a reaction between an unsaturated group and a hydride group, and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups. If the first fluid composition comprises a catalyst and the second fluid composition does not, the second fluid composition may comprise an optional second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups.If the second fluid composition contains a catalyst and the first fluid composition does not contain a catalyst, the first fluid composition may contain an optional second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups.

[0040] In some embodiments of this aspect of the present disclosure, the crosslinkable composition comprises a total amount of at least 10% by weight of first and second imaging agents (if present). In some embodiments, both the first and second fluid compositions comprise a catalyst. In some embodiments, each of (i), (ii), and (iii) further comprises a third and / or fourth fluid composition comprising a catalyst for catalyzing a reaction between an unsaturated group and a hydride group, and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups. In some embodiments, at least the first or second silica filler (if present) is hydrophobic, and in certain embodiments, both the first and second silica fillers (if present) are hydrophobic. In other embodiments, both the first and second silica fillers (if present) are hydrophilic, and in other embodiments, at least the first or second silica filler (if present) is hydrophilic. Typically, the ratio of the volume of the first fluid composition to the volume of the second fluid composition is approximately equal (about 1:1), and typically ranges from 4:1 to 1:4, and more typically from 2:1 to 1:2, among other possible ratios. To improve mixing, the viscosities of the first and second fluids may be similar; for example, the vibrational viscosities of the first and second fluid compositions at 25°C and a frequency of 0.1 Hz (see below) may be within + / - 60% of each other.

[0041] In some embodiments, any of the crosslinkable compositions formed by any of the above kits can be injected into a patient using a needle or catheter.

[0042] In various embodiments, this disclosure relates to a method for forming a biocompatible crosslinkable composition in which a mixture comprising the following is formed.

[0043] (i) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups; (ii) a first dry composition comprising a mixture of a first silica filler and a first imaging agent or a first silica filler and optionally a second silica filler; (iii) a second fluid composition comprising a first hydride material having two or more hydride groups, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing the reaction between the unsaturated groups and the hydride groups; and (iv) a second dry composition comprising a first imaging agent and optionally a second imaging agent, or optionally a mixture of a second silica filler and a second imaging agent. In those embodiments, where the first dry composition comprises a first silica filler and optionally a second silica filler, the second dry composition comprises a first imaging agent and optionally a second imaging agent. In those embodiments, the first dry composition comprises a mixture of a first silica filler and a first imaging agent, and the second dry composition is optional and, if present, comprises a mixture of a second silica filler and a second imaging agent.

[0044] In this embodiment, the first and second silica fillers may be the same or different, and the first and second imaging agents may be the same or different. In some embodiments, both the first and second fluids contain a catalyst. In some embodiments, the first fluid composition contains a catalyst, and the second fluid composition does not contain a catalyst, in which case the second fluid composition may contain a second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups. In some embodiments, the second fluid composition contains a catalyst, and the first fluid composition does not contain a catalyst, in which case the first fluid composition may contain a second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups. In some embodiments, bubbles are introduced into the mixture during mixing of the fluid and the dry components. In other embodiments, gas can be added during the mixing process to generate bubbles in the final mixture. In some embodiments, the bubbles act as imaging agents.

[0045] In embodiments in which the method for forming a crosslinkable composition comprises forming a mixture containing a second dry composition, the method may include the steps of (a) mixing a first fluid composition with a first dry composition to form a first mixture, (b) mixing a second fluid composition with a second dry composition to form a second mixture, and (c) mixing the first mixture with the second mixture to form a crosslinkable composition. Typically, the ratio of the volume of the first mixture to the volume of the second mixture is approximately equal (about 1:1), and typically in the range of, for example, 4:1 to 1:4, and more typically 2:1 to 1:2, among other possible ratios. To improve mixing, the viscosities of the first and second mixtures may be similar, for example, the vibrational viscosities of the first and second mixtures at 25°C and a frequency of 0.1 Hz may be within + / - 60% of each other.

[0046] In any embodiment of this aspect, the crosslinkable composition may be injected into the patient's body using a needle or catheter, in which case the crosslinkable composition crosslinks within the body.

[0047] In various embodiments, the Disclosure relates to a method comprising the step of forming a crosslinkable composition comprising (a) a first polysiloxane having two or more unsaturated groups, a first silica filler, a first imaging agent, a first hydride material having two or more hydride groups, a catalyst for catalyzing a reaction between unsaturated groups and hydride groups, an optional second silica filler different from the first silica filler, an optional second imaging agent different from the first imaging agent, an optional second hydride material having two or more hydride groups different from the first hydride material having two or more hydride groups, and an optional second polysiloxane having two or more unsaturated groups different from the first polysiloxane having two or more unsaturated groups. In a particular embodiment of this aspect, the method includes the steps of (a) annealing a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent to form a first annealed fluid composition; (b) annealing a second fluid composition comprising a first hydride material having two or more hydride groups, a second silica filler and / or a second imaging agent to form a second annealed fluid composition; and (c) mixing the first annealed fluid composition and the second annealed fluid composition to form a crosslinkable composition.

[0048] In various embodiments of this aspect of the present disclosure, only the first or second fluid composition is annealed before the mixing of the two fluid compositions. In various embodiments, at least one of the first and second fluid compositions contains a catalyst for catalyzing the reaction between unsaturated groups and hydride groups. In some embodiments, the second fluid composition contains a catalyst and the first fluid composition does not contain a catalyst, in which case the first fluid composition may contain a second hydride material having two or more hydride groups, which may be the same as or different from a first hydride material having two or more hydride groups. In embodiments of this aspect, the first and second silica fillers (if present) may be the same or different, and the first and second imaging agents (if present) may be the same or different. In some embodiments, the first fluid composition comprises a silica filler (first and / or second silica filler) and the second fluid composition comprises an imaging agent (first and / or second imaging agent). In other embodiments, the first fluid composition comprises an imaging agent (first and / or second imaging agent) and the second fluid composition comprises a silica filler (first and / or second silica filler). In other embodiments, the first and second fluid compositions comprise both silica fillers and imaging agents. In certain embodiments, the crosslinkable composition comprises a total amount of at least 10% by weight of the first and second imaging agents. In some embodiments, at least the first or second silica filler is hydrophobic, and in certain embodiments, both the first and second silica fillers are hydrophobic. In other embodiments, both the first and second silica fillers are hydrophilic, and in other embodiments, at least the first or second silica filler is hydrophilic. Typically, the ratio of the volume of the first fluid composition to the volume of the second fluid composition is approximately equal (about 1:1), and typically ranges from 4:1 to 1:4, and more typically from 2:1 to 1:2, among other possible ratios.To improve mixing, the viscosities of the first and second fluids may be similar; for example, the vibrational viscosities (see below) of the first and second fluid compositions at 25°C and a frequency of 0.1 Hz may be within + / - 60% of each other.

[0049] In those embodiments of this model, where the first fluid composition and the second fluid composition are annealed separately, the annealing can be carried out in any manner that does not impair the various components of the fluid composition. For example, annealing may be carried out by leaving the fluid composition at room temperature for a time sufficient to allow the composition to reach equilibrium and / or improve the ductility of the composition. Alternatively, the annealing of the composition may involve heating the fluid composition for a period sufficient to allow the composition to reach equilibrium and / or improve the ductility of the composition, for example, 4 to 10 days, for example, heating at 50°C to 80°C, for example, 70°C for 7 days.

[0050] In any embodiment of this aspect, the crosslinkable composition may be injected into the patient's body using a needle or catheter, and the crosslinkable composition then crosslinks within the body.

[0051] In various forms, this disclosure is, (a) A step of forming a crosslinkable composition, (i) A step of forming a crosslinkable composition comprising: a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first silica filler; a second fluid composition comprising a first hydride material having two or more hydride groups and a second silica filler which may be the same as or different from the first silica filler; and a dry composition comprising a first imaging agent and optionally a second imaging agent which may be the same as or different from the first imaging agent; (ii) A step to form a crosslinkable composition comprising: (ii) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and a first imaging agent; a second fluid composition comprising a hydride material having two or more hydride groups and a second imaging agent which is the same as or different from the first imaging agent; and a dry composition comprising a first silica filler and optionally a second silica filler which is the same as or different from the first silica filler; or (iii) A step to form a crosslinkable composition comprising a first fluid composition comprising a first polysiloxane having two or more unsaturated groups, and a first silica filler and optionally a second silica filler which is the same as or different from the first silica filler, or a first imaging agent and optionally a second imaging agent which is the same as or different from the first imaging agent, a first hydride material having two or more hydride groups, and a second fluid composition comprising a first silica filler and optionally a second silica filler, or a first imaging agent and optionally a second imaging agent, wherein if the first fluid composition comprises a first silica filler and optionally a second silica filler, the second fluid composition comprises a first imaging agent and optionally a second imaging filler, (i), (ii) and (iii) each relate to a method in which at least one of the first and second fluid compositions contains a catalyst for catalyzing the reaction between an unsaturated group and a hydride group. Alternatively, each of (i), (ii) and (iii) comprises a third or fourth fluid composition containing a catalyst for catalyzing the reaction between an unsaturated group and a hydride group, and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups. When forming the crosslinkable composition of (i), (ii) and (iii), the composition is injected into the patient's body, whereupon the crosslinkable composition crosslinks in vivo. When the first fluid composition contains a catalyst and the second fluid composition does not contain a catalyst, the second fluid composition may contain an optional second polysiloxane having two or more unsaturated groups, which may be the same as or different from the first polysiloxane having two or more unsaturated groups. When the second fluid composition contains a catalyst and the first fluid composition does not contain a catalyst, the first fluid composition may contain an optional second hydride material having two or more hydride groups, which may be the same as or different from the first hydride material having two or more hydride groups.

[0052] In various embodiments, the crosslinkable compositions described herein that include crosslinkable compositions formed by any of the above kits or methods have a viscosity, when measured by oscillatory rheology at 0.1 Hz and 1% strain at 25 °C, in the range of * 100 Pa * s or less to 10,000 Pa * s or more, for example, from 100 Pa * s to 250 Pa * s to 5, * 00 Pa * s to 1000 Pa * s to 2500 Pa[[ID=…]] * s to 10000 Pa (i.e., in the range between any two of the preceding values), and may have a viscosity in any of these ranges.

[0053] <0000In various embodiments, the kits described herein, which include a cured composition formed by any of the above kits or methods, may be subjected to final sterilization, i.e., sterilization of the composition in its final container. For example, the kit may be exposed to electron beam (e-beam) irradiation or ethylene oxide gas, dry heat, gamma ray irradiation, nitric oxide, X-ray irradiation, etc. In some embodiments, the components of the kit will be subjected to final sterilization. In other embodiments, the components of the kit will be sterilized using sterile filtration rather than final sterilization.

[0054] In various embodiments, the crosslinkable compositions described herein, including those formed by any of the above kits or methods, may exhibit shear-reducing fluid properties. For example, the crosslinkable composition may have a viscosity at least 10 times, beneficially at least 100 times, and more beneficially at least 500 times greater than the viscosity of the composition when measured by fluid rheology at a frequency of 30 Hz at 25°C, compared to the viscosity of the composition when measured by vibrational rheology at 0.1 Hz and 1% strain at 25°C.

[0055] In various embodiments, the crosslinkable compositions described herein, including a crosslinkable composition formed by any of the above kits or methods, may have a gelation time at a temperature of 25°C to 37°C in the range of 3 minutes or less to 60 minutes or more, for example, in the range of 3 minutes to 5 minutes to 10 minutes to 15 minutes to 20 minutes to 25 minutes to 30 minutes to 45 minutes to 60 minutes.

[0056] Rheological measurements can be performed using a Discovery HR-1 rheometer from TA Instruments (Newcastle, Delaware, USA). For viscosity measurements, the crosslinkable composition is placed in a 25 mm parallel plate setup (using sandblasted plates to avoid slippage), and its temperature is controlled using a Peltier system (TA Instruments) to maintain a 1000 micron gap. (i) The first viscosity is measured using vibrational rheology defined within the linear region, generally at 25°C, 1% strain, and 0.1 Hz (lower shear), and (ii) the second viscosity is measured using fluid rheology, at 25°C, 30 Hz (higher shear). Higher shear values ​​provide an indicator of the composition's properties under shear conditions similar to those imposed on the composition during delivery from the delivery device. Lower shear values ​​provide an indicator of the composition's properties after implantation in the body, where shear conditions with lower strain and lower frequency are experienced. The above measurements are performed within 3 minutes after the crosslinkable composition is formed. To measure gelation time, the composition is loaded into a rheometer with a 25 mm parallel plate apparatus (see above), and measurements are performed at 37°C for 90 minutes at a constant frequency and strain (f=10 rad / s, γ=1%), observing the curing time and profile. Gelation time (curing time) is defined as the time at which a peak in the phase angle (δ) is observed. Curing time varies with temperature, and curing occurs in the body at a faster rate at 37°C than at room temperature (25°C).

[0057] In various embodiments, the crosslinkable compositions described herein, including those formed by any of the above kits or methods, can be injected by hand.

[0058] In various embodiments, the crosslinkable compositions described herein may have an injection force ranging from 1 to 30 pounds by weight.

[0059] Injection force is a critical parameter for determining the suitability of a formulation for clinical use. In this disclosure, the injection force is determined by using an Instron setup similar to that described in Chen et al., Chen, MH et al., "Methods To Assess Shear-Thinning Hydrogels for Application As Injectable Biomaterials," ACS Biomaterials Science & Engineering, 2017, 3(12): pp. 3146-3160. The sample is loaded into a 1 mL Merit Medallion syringe, and then the plunger is fixed vertically with the plunger facing upwards. A 100 cm long catheter with a diameter suitable for targeting is then attached to the syringe, and the Instron test head is advanced at a speed of 25 mm / min (corresponding to an injection rate of 0.5 mL / min). The injection force is measured within 3 minutes after the initial mixing of the crosslinkable composition.

[0060] In various embodiments, the crosslinkable compositions described herein, including those formed by any of the above kits or methods, may be used in a manner in which the crosslinkable compositions are delivered to the patient's body, for example, by injecting any of the crosslinkable compositions onto any tissue of the patient or into any body cavities or tubules using any suitable device.

[0061] In certain embodiments, the composition of the present disclosure is injected into the vascular system, where it is initially sheared into shear thins and flows downstream as a continuous flow. Upon encountering higher shear, it breaks into individual volumes, which are further sheared into thins and penetrate into the distal branches (Figure 1A). As the distal branches are occluded, the flow decreases proximal; in response, the viscosity of the composition increases (Figure 1B). As the vascular system becomes more occluded, the composition exits the catheter as a viscous paste, allowing for controlled injection (Figure 1C). This results in complete casting and occlusion of the target vascular system without non-target embolus formation (Figure 1D).

[0062] In certain embodiments, the method includes the step of injecting a crosslinkable composition into the vascular system and can be used, among other things, for occlusion of the vascular system including portal vein embolization (e.g., vascular embolization or neurovascular embolization), embolization of tumors including meningioma and peripheral tumors, hemorrhage, chronic subdural hematoma, cerebral aneurysm, arteriovenous malformation, arteriovenous fistula, gastrointestinal bleeding, traumatic bleeding, prostatic artery embolization, uterine artery embolization, visceral artery aneurysm, spermatic varicocele, preoperative embolization of tumors to minimize varicose veins, pelvic congestion, epistaxis, and endoleak treatment.

[0063] In some embodiments, the crosslinkable compositions described herein, including those formed by any of the kits or methods described above, can be introduced into the vascular system at a proximal site to the site treated by the use of an occlusion device or technique. In some embodiments, the injection catheter itself can be used to eliminate blood flow. In other embodiments, the occlusion device is a balloon catheter. The shape, position, and material of the inflatable balloon are selected so that, when inflated, the balloon conforms to the shape of the vascular system or at least a part of it without significantly deforming the vessel wall. In this way, the balloon is used to occlude a selected branch of the vascular system, thereby allowing the composition to be injected deep into the vascular system without vasoconstriction or significant backflow of the composition beyond the injection site, enabling deeper penetration of the composition into the vascular system. Generally, the balloon is maintained in place after the composition has been introduced into the vascular system until the composition hardens. Balloon catheters are particularly useful for injecting compositions formed at the time of injection as described above, for example, compositions formed by mixing fluid and dry components immediately before injecting the crosslinkable composition into the patient.

[0064] In some embodiments, the method includes the step of injecting a composition described herein, which comprises a crosslinkable composition formed by any of the above kits or methods, into the patient's vascular system for a distal penetration procedure such as portal vein embolization or tumor embolization.

[0065] In some embodiments, the compositions of the present disclosure may be injected into a blood vessel in conjunction with another device, such as a coil, plug, or stent graft.

[0066] In some embodiments, the method includes the steps of identifying vessels that branch into smaller distal vessels (e.g., those branching distally into the capillary bed) and injecting the crosslinking composition into the vessels so that the crosslinking composition flows into the distal vessels and occludes them. The crosslinking composition may, in some cases, flow into distal vessels having a diameter of less than 100 microns, for example, 100 to 30 microns.

[0067] For example, cross-linking compositions can be injected into the portal vein as part of a portal vein embolization (PVE) procedure. PVE is a technique used before hepatectomy to increase the size of the remaining liver segment after surgery. This treatment redirects portal blood to the segment of the future liver remnant (FLR), resulting in hypertrophy. PVE is indicated when the FLR is too small or its size is limiting to support various vital functions and is associated with a complex postoperative course.

[0068] As another example, the crosslinking composition may be injected into the middle meningeal artery (MMA). Many conditions, including dural arteriovenous fistula (DAVF), pseudoaneurysm, true aneurysm, traumatic arteriovenous fistula (AVF), moyamoya disease (MMD), recurrent chronic subdural hematoma (CSDH), migraine, and meningioma, may involve the middle meningeal artery and can be treated by administering the compositions of this disclosure to the MMA.

[0069] Intravascular MMA embolization is a novel treatment method for chronic subdural hematoma (cSDH), and preliminary data suggest that this minimally invasive therapy may be more effective and equally safe compared to conventional highly invasive surgery.

[0070] As another example, cross-linking compositions can be injected into hypervascular brain tumors, such as meningiomas, before surgical resection. This treatment has been shown to reduce surgical blood loss and shorten surgical procedure time.

[0071] As described above, in various embodiments, crosslinkable compositions have shear-thinning properties. As can be seen from the following examples, this disclosure describes a crosslinkable composition that is a flow-responsive material that enables substantially complete filling and occlusion of a target vascular system when injected into the target vascular system. While we do not wish to be bound by theory, it is assumed that at the start of the procedure, the flow velocity is high, resulting in a high shear rate within the vessel and its distal branches. Thus, as the crosslinkable composition first exits the catheter, it encounters high shear and becomes a low-viscosity fluid that penetrates deeply into the distal branches. As occlusion occurs in the distal branches, the flow velocity decreases proximally. In response, the shear decreases and the viscosity of the crosslinkable composition increases. As the vascular system is further occluded proximally, the flow continues to decrease further. As a result, the crosslinkable composition returns to a high-viscosity static state, behaving, for example, as a viscous paste. The final result is the formation of an entire cast of the vascular system to the distal vessel, inducing complete occlusion. This process is schematically shown in Figures 1A–1D.

[0072] In various embodiments, the crosslinkable compositions described herein are delivered to a delivery site within the patient's body by the use of a suitable delivery device or system. In various embodiments, the delivery system may include a catheter. As used herein, “catheter” is any device that can be introduced into or adjacent to the patient’s body or a target location within the patient’s body and includes at least one lumen of any suitable size, shape or configuration for the movement of fluid through it. In certain embodiments, among many other possibilities, a catheter may be used that is in the range of 100 to 200 cm in length and has a diameter suitable for target indication (e.g., 0.016 inches to 6 Fr). In certain embodiments, the catheter is a balloon catheter. As used herein, the crosslinkable compositions described as “injected,” “deposited,” “delivered,” etc., include crosslinkable compositions that are placed on or within the patient’s body via a delivery system using any suitable means, including syringe-based injection. In some embodiments, the crosslinkable compositions are delivered by hand. In other embodiments, depending on the viscosity of the fluid, a manual syringe assist, a pneumatic or mechanical pressure pump, or other device may be used to control the flow rate and / or improve the ease / force of injection. As described above, the crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, include a first silica filler (and optionally a second silica filler). Examples of silica fillers include, among others, fumed silica, precipitated silica, and hydrophobic silica.

[0073] Silica fillers have been found to impart shear-thinning properties to the crosslinkable compositions of this disclosure. Such properties enable flow responsiveness for distal penetration and proximal control when microcatheter injection and flow are reduced. Such silica fillers have also been found to provide crosslinkable compositions in the form of structured fluids or pastes that allow radiopaque agents or other imaging agents to remain suspended, enabling radiopaqueness or even imaging during injection.

[0074] While we do not wish to be bound by theory, it is believed that the particles in the crosslinkable compositions of this disclosure impart shear-thinning behavior through the formation of a reversible hydrogen bond network. For example, if the crosslinkable composition contains polydimethylsiloxane (PDMS) having two or more unsaturated groups (and in some embodiments, PDMS having two or more hydride groups), referring to Figure 2A, the silica particles (shown as spheres) interact with each other and with the PDMS (shown as lines) to form a high-viscosity structured fluid. When a shear force is applied, the silica-silica interactions are broken, and the viscosity of the material temporarily and reversibly decreases. As soon as the shear force is removed, the immediate recovery of the silica-silica interactions restores the paste-like structure of the crosslinkable composition. Thus, as a result of this property, the material acts as a low-viscosity, flowable material when injected through a catheter, and this state continues once it enters the bloodstream, where the blood flow continues to shear-thin the material, transporting it distally to fill and cast distal branches. Over time, the material hardens into a permanent elastic solid through hydrosilylation (shown in Figure 2B). This point is known as the gelation time. When vinyl groups and hydride groups react to form carbon-carbon covalent bonds (shown as dots in Figure 2A), the polymer network is chemically crosslinked.

[0075] In various embodiments, the crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, contain silica filler in a total amount ranging from less than 0.25% by weight to 10% by weight or more, for example, in the range of 0.25% by weight to 0.5% by weight to 1% by weight to 2% by weight to 5% by weight to 7.5% by weight to 10% by weight.

[0076] In various embodiments, the silica filler in the crosslinkable composition described herein, which includes a crosslinkable composition formed by any of the above kits or methods, is 50m 2 / g or less ~ 1000m 2 / g or more, for example, 50m 2 / g~100m2 / g~200m 2 / g~500m 2 / g~1000m 2 It is characterized by a surface area in the range of / g.

[0077] As described above, in various embodiments, the silica filler in the crosslinkable composition described herein, which includes a crosslinkable composition formed by any of the above kits or methods, is hydrophobic and has hydrophobic groups chemically bonded to its surface, for example, by treatment of silica with hexamethyldisilazane (HMDS). The hydrophobic groups may be, for example, alkyl or polydimethylsiloxane. In embodiments in which the composition includes two different silica fillers, one or both of the silica fillers may be hydrophobic.

[0078] As described above, the crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, include a first imaging agent (and in some embodiments, a second imaging agent). Such imaging agents impart visibility for imaging (e.g., under fluoroscopy). For example, radiopaque agents impart radiopaqueness for radiographic imaging (e.g., under fluoroscopy). Radiopaque agents can be selected from, for example, radiopaque metals, radiopaque metal alloys, radiopaque metal oxides, and radiopaque polymers (e.g., iodized polymers). In some embodiments, radiopaque agents can be selected from tantalum, tungsten, bismuth(III) oxide, zinc oxide, titanium dioxide, and zinc titanate. In some embodiments, imaging agents may include MRI (magnetic resonance imaging) contrast agents and ultrasound contrast agents. Imaging agents for use in conjunction with magnetic resonance imaging (MRI) include agents containing elements with relatively large magnetic moments, such as gadolinium, manganese, and iron (e.g., Gd(III), Mn(II), Fe(III), etc.), as well as compounds containing these elements (including chelates), such as gadolinium ions chelated with diethylenetriaminepentaacetic acid. Non-limiting examples of imaging agents for use in conjunction with ultrasound imaging include, in particular, microbubbles filled with suitable gases such as air, carbon dioxide, hydrogen, oxygen, nitrogen, sulfur hexafluoride, perfluorobutane, or octafluoropropane.

[0079] In various embodiments, the crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, contain an imaging agent in a total amount of 1% to 50% by weight or more, for example, in the range of 1% to 5% to 10% to 15% to 20% to 25% to 30% to 35% to 40% to 45% to 50% by weight.

[0080] In various embodiments, the imaging agent may be present in a size range of 10 nm to 20 μm. For example, using nanoparticle-sized imaging agents can minimize CT artifacts and enable better imaging in follow-up.

[0081] In various embodiments, metal oxides are used as radiopaque agents. Metal oxides such as bismuth oxide (typically bismuth trioxide) can offer the advantage of shear reduction. Furthermore, since bismuth oxide is non-flammable (compared to, for example, commonly used tantalum), the risk of sparks and ignition during surgical excision with electrocautery tools is minimized. Bismuth oxide also provides a crosslinking composition with a bright yellow color that clearly indicates which vessels have been embolused, which can result in, for example, more accurate surgical excision and a reduction in complications.

[0082] As described above, metal oxides such as bismuth oxide can offer the advantage of shear viscosity reduction. This is particularly evident when provided in combination with silica. In this regard, as can be seen from Example 8 and Figure 5 below, by mixing the dry components (e.g., silica and radiopaque agents) with the fluid components (e.g., residual components) at the time of injection (rather than compounding and storing the components), the shear viscosity reduction of the material is maximized (reduction of injection force relative to a given viscosity), the amount of silica required is small, and there are few concerns about long-term stability.

[0083] In some embodiments of each aspect of the present disclosure, particle dispersion may have a significant effect on the material properties of the various compositions of the present disclosure and can be controlled by various means, including, for example, ensuring sufficient wetting of the dry components of the composition, high shear dispersion of particles in the polymer, and other processing steps known to those skilled in the art.

[0084] As described above, the crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, include a first polysiloxane having two or more unsaturated groups (and, in some embodiments, a second polysiloxane having two or more unsaturated groups).

[0085] In some embodiments, the crosslinkable compositions described herein include polysiloxanes (or polysiloxanes) having two or more unsaturated groups in a total amount of less than 20% by weight to more than 60% by weight, for example, in the range of 20% by weight to 25% by weight to 30% by weight to 35% by weight to 40% by weight to 45% by weight to 50% by weight to 55% by weight to 60% by weight.

[0086] As used herein, the terms “polysiloxane” and “polysiloxane polymer” refer to polymers having repeating -Si-O- bonds in their polymer backbone. Examples of polysiloxanes for use in this disclosure include those comprising one or more organosiloxane monomers, such as dialkylsiloxane monomers, diarylsiloxane monomers, and / or alkylarylsiloxane monomers, including dimethylsiloxane, diethylsiloxane, methylethylsiloxane, methylphenylsiloxane, and / or diphenylsiloxane monomers, or those comprising homopolymers and / or copolymer regions containing them. In various beneficial embodiments described herein, polydialkylsiloxane polymers, including polydimethylsiloxane (PDMS) polymers, are used as polysiloxanes. PDMS polymers are beneficial for use in this disclosure for a variety of reasons, including their low relative viscosity at high molecular weights (MW), well-established use in medical devices and implants, and their inherent biocompatibility.

[0087] For the purposes of this disclosure, “unsaturated group” refers to a group having fewer than the maximum number of hydrogen atoms per carbon (a group not saturated with hydrogen atoms), including groups having carbon-carbon double or triple bonds such as alkene or alkyne groups. Specific examples of polysiloxanes having two or more unsaturated groups include unsaturated group-terminated polysiloxanes such as vinyl-terminated PDMS, acrylate-terminated PDMS, and methacrylate-terminated PDMS.

[0088] In some embodiments, the unsaturated group of the polysiloxane(s) is selected from -CH=CH2 and -C≡CH groups, with specific examples including vinyl-terminated polysiloxanes, acrylate-terminated polysiloxanes, methacrylate-terminated polysiloxanes, and alkyne-terminated polysiloxanes.

[0089] In some embodiments, the polysiloxane(s) are linear.

[0090] In some embodiments, the polysiloxane(s) have a weight-average molecular weight in the range of less than 250 Da to more than 10000 Da, for example, in the range of 250 Da to 500 Da to 1000 Da to 2500 Da to 5000 Da to 10000 Da. In some embodiments, a low molecular weight (500 Da to 10000 Da) polysiloxane may be blended with a lower proportion of a high molecular weight polysiloxane (10000 Da to 100000 Da). In some embodiments, the composition includes a mixture of two polysiloxanes having different molecular weights, for example, any combination of a low molecular weight (500 to 5000 Da) and a high molecular weight (5000 to 10000 Da) polysiloxane. In some embodiments, the low molecular weight polysiloxane is preferably between 500 and 2100 Da. For example, [ka] [wherein n is an integer] can be used. As described above, the crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, include a first hydride material having two or more hydride groups (and in some embodiments a second hydride material having two or more hydride groups).

[0091] For the purposes of this disclosure, a “hydride group” is a reactive group in which hydrogen is bonded to another atom, typically a silicon hydride group in which hydrogen is bonded to a silicon atom. In certain embodiments, a hydride material is used that contains 2 to 20 hydride groups per molecule, for example, in the range of 2 to 3 to 5 to 7 to 10 to 15 to 20 hydride groups per molecule.

[0092] In some embodiments, the crosslinkable compositions described herein include a hydride material (or more) having two or more hydride groups in a total amount ranging from less than 10% by weight to more than 40% by weight, for example, in the range of 10% by weight to 15% by weight to 20% by weight to 25% by weight to 30% by weight to 35% by weight to 40% by weight.

[0093] In some embodiments, the hydride material(s) having two or more hydride groups is a polyfunctional polysiloxane hydride(s).

[0094] In some embodiments, the polyfunctional polysiloxane hydride(s) is a linear polysiloxane hydride(s). In some of these embodiments, the linear polysiloxane hydride(s) includes hydride terminal groups and / or hydride side groups.

[0095] In some embodiments, the polyfunctional polysiloxane hydride(s) have a weight-average molecular weight in the range of 250 Da or less to 10000 Da or more, for example, in the range of 250 Da to 500 Da to 1000 Da to 2500 Da to 5000 Da to 10000 Da.

[0096] Specific examples of hydride materials having two or more hydride groups include both small molecule hydrides and polymer hydrides. Polymer hydrides include polyfunctional polysiloxane hydrides, such as polyfunctional PDMS hydrides, for example, [ka] Examples include [wherein n and m are integers]. Such compounds are also referred to herein as “hydride crosslinkers.” Examples of polyfunctional PDMS hydrides include, for example, hydride-terminated PDMS. [ka] Further examples include [wherein n is an integer]. Such compounds are also referred to herein as “linear hydrides”.

[0097] It should be further noted that an excess of hydride groups relative to vinyl groups (stoichiometrically) can lead to gas generation. In some embodiments, this gas is used as an imaging agent. In other embodiments where the gas is undesirable, the crosslinkable composition may have a vinyl-to-hydride molar ratio of ≥0.9:1. In some embodiments, the crosslinkable composition may have a vinyl-to-hydride molar ratio in the range of 1.1:1 to 1.5:1, typically in the range of 1.2:1 to 1.4:1.

[0098] As is evident from the above, polysiloxanes having two or more unsaturated groups for use in this disclosure can be formed using polydimethylsiloxane (PDMS) elastomers. Similarly, hydride materials having two or more hydride groups for use in this disclosure can be formed using PDMS elastomers. Such materials have several potential advantages, including the following: Firstly, PDMS is known to be biocompatible and non-cytotoxic (see also Example 7 below). Furthermore, as can be seen from Example 6 below, its hydrophobicity allows for complete casting of blood vessels and the expulsion of blood from the vessels during embolization. In addition, PDMS can harden into a soft elastic rubber if necessary, facilitating surgical excision. Furthermore, as can be seen from Example 8 below, PDMS polymers having low molecular weights can be used to reduce the overall injection force. Finally, iodized PDMS can be used in some embodiments, which allows for the elimination or reduction of the required level of imaging particles.

[0099] As described above, the crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, include a catalyst for catalyzing the reaction between an unsaturated group and a hydride group. Examples of such catalysts include platinum catalysts, rhodium catalysts, ruthenium catalysts, palladium catalysts, iridium catalysts, boron trihydrogen catalysts, and phosphine catalysts.

[0100] As can be seen in Example 7 below, catalyzed bulk cure allows for more distal penetration and complete casting (unlike commercially available liquid embolizers that react with the environment, it remains fluid until cured).

[0101] The crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, may also optionally contain a catalytic modifier.

[0102] The crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, may also optionally contain one or more physical crosslinking agents comprising multiple hydrogen bonding groups.

[0103] In various embodiments, the physical crosslinking agents for use in the crosslinkable compositions of this disclosure may contain multiple hydroxy(-OH) groups as hydrogen bonding groups. Examples of physical crosslinking agents include hydroxy-terminated polysiloxanes (e.g., carbinol(hydroxy)-terminated polydimethylsiloxanes), hydroxy-terminated poly(alkylene oxides) including hydroxy-terminated polyethylene oxides and hydroxy-terminated polypropylene oxides, and hydroxy-terminated polymers and dendrimers such as hydroxy-terminated polyvinyl alcohols. Such hydroxy-terminated polymers may be linear, for example, or multi-armed or dendritic, having, for example, 3, 4, 5, 6 or more arms, one specific example being formula [ka] It is a three-arm polymer of [wherein n is an integer]. Other examples include sugars such as sucrose, cellulose, glucose and dextrose, as well as potassium phthalate, polyols (e.g., glycerol, diglycerol, triglycerol, tetraglycerol, pentaglycerol, hexaglycerol, ethylene glycol, propylene glycol, butylene glycol, 1,5-pentanediol, 1,6-hexanediol, trimethylolpropane, 1,2,6-hexanetriol, pentaerythritol, sorbitol, mannitol, hydroxypropyl methylcellulose or hydroxypropyl ethylcellulose) and acrylates (e.g., poly(acrylic acid), 2-hydroxyethyl methacrylate, poly(methyl methacrylate-co-ethyl acrylate)).

[0104] In various embodiments, plasticizers may be added to the composition. Plasticizers can be used to improve the ductility of the material. For example, a composition without plasticizers may form rounded or bead-like droplets when injected while a composition containing plasticizers is forming elongated droplets. In some embodiments, the plasticizer may be hydrophilic, and in other embodiments, it may be hydrophobic. In some embodiments, the plasticizer can be used to increase the tackiness of the composition. Examples of plasticizers include trimethylolpropane ethoxylate (TMPEO), sucrose solutions, dimethylsiloxane-(80% ethylene oxide) block copolymer, dimethylsiloxane-(30-35% ethylene oxide) block copolymer, polydimethylsiloxane, trimethylsiloxy terminators, and oils (including, but not limited to, coconut oil or sunflower oil).

[0105] The crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the above kits or methods, may also optionally contain one or more silanol compounds.

[0106] As used herein, “silanol” or “silanol compound” is a compound containing one or more silanol (Si-OH) groups, and is generally a polysiloxane polymer containing two or more silanol groups, such as hydroxy-terminated PDMS, among other examples.

[0107] In various embodiments, the silanol compounds used in the crosslinkable compositions of this disclosure are silanol-terminated polymers such as hydroxy-terminated polysiloxanes, for example, [ka] The formula includes [wherein n is an integer]. In certain embodiments, a hydroxy-terminated polysiloxane having a weight-average molecular weight of less than 4,000 daltons may be selected.

[0108] The crosslinkable compositions described herein, which include a crosslinkable composition formed by any of the kits or methods described above, may also optionally contain particles of any material having a diameter in the range of less than 5 μm to more than 300 μm, for example, in the range of 5 μm to 10 μm to 25 μm to 50 μm to 100 μm to 300 μm. When used as an embolizer, such particles can be used to control the distal penetration of the crosslinkable composition, the penetration distance being controlled based on size. Such particles may be silica and / or imaging agents, or may be added to them.

[0109] The following methods are applicable to any of the compositions of this disclosure and were applied as shown in the following examples. method. Rheology:

[0110] The formulations were characterized using rheological measurements recorded with a TA Instruments DHR-1 rheometer using a 25 mm sandblasted parallel plate with a Peltier temperature control system. Tests were performed at 37°C with the material loaded at a gap height of 1000 μm. For each characterization, the rheometer was set to flow mode at 100 / sec (s). -1 The material was first "pre-sheared" by running it for 75 seconds at a shear rate of ). Following the pre-shearing step, three different characterizations were performed: Hysteresis (flow) loop:

[0111] The flow gradient is the shear rate from 1 to 100 s in 30 seconds. -1 Increase the amount and process the material for 15 seconds (100s). -1 Hold it in place, then increase the shear rate from 100 to 1s over 30 seconds. -1 It was reduced to 10s. Then the material was 10s -1 After conditioning for 15 seconds at the shear rate, 10s -1 The material viscosity was measured for 15 seconds. Finally, the material was then subjected to 50 seconds. -1 After conditioning for 15 seconds at the shear rate, 50s -1The material viscosity was measured over a 15-second period. Yield distortion:

[0112] The material was allowed to recover under low stress (controlled to 0.01 Pa) for 150 seconds. Subsequently, amplitude sweeping was performed at a constant frequency (1 Hz) to increase the stress from 0.01 Pa to 20.0 Pa. Shear recovery:

[0113] The material was probed over time under low strain (2.0%) and low frequency (1 Hz) conditions. Injection test:

[0114] The material injection characteristics were characterized using an Instron 3343 single-column test frame. The final mixed formulation was loaded into a 1 ml syringe and mounted on a custom fixture on the test frame. A clinically appropriate catheter was attached to the syringe, and the distal catheter tip was immersed in a container of 1 × PBS warmed to 37°C. The Instron was set to a constant displacement rate (25 mm / min), and the force was recorded over time using a load cell. A camera was positioned to record the injection of the material into the PBS. This test allows for direct measurement of the injection force, as well as evaluation of material properties, including the morphology and fusion of material droplets. Droplet morphology can be measured quantitatively using frames from video and image analysis software, while fusion is evaluated qualitatively on a scale of 1 to 4 (referred to as the "QS" score), where 1 is no fusion (clear depiction of boundaries between individual volumes of material) and 4 is complete fusion (no visually discernible boundaries between individual volumes of material). Compositions. The compositions listed in Table A below were used in some of the examples shown therein. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] Example 1. Two-phase formulation containing components with MW 5,000 to 10,000 Da and hydrophilic silica.

[0115] Two-phase formulations (phases A and B, both liquid phases) were prepared according to the formulations shown in Table 1. [Table 1]

[0116] A crosslinkable compound was formed by combining phases A and B, and its properties were measured and are shown in Table 2. The methods for measuring viscosity (measured by vibrational rheology at 0.1 Hz and 1% strain at 25°C), gelation time, and injection force are described above. [Table 2] Example 2. Two-phase formulation containing components with MW 5,000 to 11,000 Da and hydrophobic silica (silica treated with hexamethyldisilazane)

[0117] Two-phase formulations (phases A and B, both liquid phases) were prepared according to the formulations shown in Table 3. [Table 3]

[0118] A crosslinkable compound was formed by combining phases A and B, and its properties were measured and are shown in Table 4. [Table 4] Example 3. Simple two-phase formulation containing components with MW 5,000 to 10,000 Da and hydrophilic silica.

[0119] Two-phase formulations (phase A and phase B, both fluid phases) were prepared according to the formulations shown in Table 5. [Table 5]

[0120] A crosslinkable compound was formed by combining phases A and B, and its properties were measured and are shown in Table 6. [Table 6] Example 4: A formulation comprising components with a MW of 5,000 to 10,000 Da, wherein the dry component and the fluid component are mixed at the time of administration.

[0121] The formulations were prepared as shown in Table 7. Phase A and Phase B were prepared separately. Then, the formulations were prepared by mixing Phase A and Phase B with dry components (i.e., fumed silica and bismuth oxide). [Table 7]

[0122] A crosslinkable compound was formed by combining phase A, phase B, and the dry components, and its properties were measured and are shown in Table 8. [Table 8] Example 5. A simple formulation composed of a low MW polymer (less than 2100 Da), wherein the dry component and the fluid component are mixed at the time of administration.

[0123] The formulations were prepared as shown in Table 9. Phase A and Phase B were prepared separately. Then, the formulations were prepared by mixing Phase A and Phase B with dry components (i.e., fumed silica and bismuth oxide). [Table 9]

[0124] A crosslinkable compound was formed by combining phase A, phase B, and the dry components, and its properties were measured and are shown in Table 10. [Table 10] Example 6. In vivo long-term study

[0125] Using the crosslinkable composition of Example 1, a single pole of each kidney of three pigs was embolized, and the animals were kept alive for 30 or 90 days to evaluate vascular penetration, occlusive performance, and histopathology in a pilot long-term study. Figures 3A–3C show the shear-thinning properties and behavior of the crosslinkable composition during embolization. The crosslinkable composition initially exits the catheter as a continuous flow (the catheter is indicated by the upward arrow in each of Figures 3A–3C), as indicated by the downward arrow in Figure 3A. As the crosslinkable composition flows more distally and encounters higher shear, the crosslinkable composition adapts in response by separating into separate volumes that show deeper penetration within the branches (see Figure 3B, left downward arrow). As injection continues, the crosslinkable composition fuses to form a complete cast in solid form that fills the entire volume of the vessel, providing complete occlusion (see Figure 3C). Macroscopic images of the kidneys at 90 days showed significant tissue shrinkage as a result of embolization (Figure 3D). As determined by angiography, there was no evidence of recanalization at either 30 or 90 days. Radiographic imaging of the crosslinking composition showed good distal penetration (see Figure 3E). Micro-CT scans showed minimal image artifacts and confirmed that the crosslinking composition penetrated and occluded vessels less than 100 microns in diameter (see Figure 3F). Furthermore, the material was sufficiently radiopaque, which allowed for real-time visualization during the embolization procedure. Example 7. Biocompatibility of crosslinkable compositions

[0126] To assess inflammation, vascular damage, necrosis, and hemorrhage, embolusted kidneys from the above pilot study were prepared for histopathological analysis using hematoxylin and eosin staining. Scoring was based on Sabareesh Kumar, N et al., Histopathological changes in brain arteriovenous malformations after embolization using Onyx or N-butyl cyanoacrylate, Journal of Neurosurgery JNS,2009.111(1):p.105-113 and Siskin, GP et al., Pathologic Evaluation of a Spherical Polyvinyl Alcohol Embolic Agent in a Porcine Renal Model.Journal of Vascular The assessment was performed using a graded scale from 0 to 3 (none, minimal, mild / moderate, and severe) as described in and Interventional Radiology, 2003.14(1):p.89-98. The results showed no vascular damage, no necrosis, and only minimal to mild inflammation, and a good biocompatibility profile at both time points. See Table 11, Figure 4A (showing histopathological results at 30 days), and Figure 4B (showing histopathological results at 90 days). [Table 11] Example 8. Further observations

[0127] Viscosity (measured by vibrational rheology at 0.1 Hz and 1% strain at 25°C) and injection force were measured for the following polymer formulations: (a) a polymer formulation similar to Example 4 but without catalyst and catalyst modifier; (b) the polymer formulation of (a) with 1% silica added; (c) the polymer formulation of (a) with 1.5% silica added; (d) the polymer formulation of (a) with 35% bismuth oxide added; and (e) the polymer formulation of (a) with 35% bismuth oxide and 1% silica added. The results are shown in Figure 5. As can be seen from Figure 5, the viscosity increased by approximately 10 times with either silica (1%) or bismuth oxide (35%) alone, and when silica and bismuth oxide were combined, the viscosity increased by approximately 2800 times, with a relatively small increase in injection force. Example 9. Effect of preparation and addition order on material properties

[0128] Two compositions, AMP-10 and AMP-11 (Table A), having the same formulation at the same concentrations for most components, were prepared using different methods of this disclosure. As shown in Figure 6, the different preparation methods resulted in significantly different behavior in the PBS injection test (described later). AMP-10 exited the catheter as droplets and exhibited material fusion, while AMP-11 exited the catheter as non-fused extruded droplets. These different behaviors ultimately affect in vivo performance (e.g., degree of distal penetration, integrity of casting, proximal reflux, vasospasm, or vascular stenosis) and highlight the effect of the same component preparations on material properties. The differences in preparation are as follows: AMP-10 was prepared by equally distributing and compounding silica and bismuth in phases A and B. For AMP-11, 100% silica was compounded in phase B and 100% bismuth trioxide in phase A.

[0129] The material injection characteristics were characterized using an Instron 3343 single-column test frame. The final mixed formulation was loaded into a 1 ml syringe and mounted on a custom fixture on the test frame. A clinically relevant catheter (0.021-inch catheter) was attached to the syringe, and the distal catheter tip was immersed in a container of 1 × PBS warmed to 37°C. The Instron was set to a constant displacement rate (25 mm / min), and the force was recorded over time using a load cell. A camera was positioned to record the injection of the material into the PBS. This test allows for direct measurement of the injection force, as well as evaluation of material properties, including the morphology and fusion of material droplets. Droplet morphology is measured quantitatively using frames from video and image analysis software, while fusion is evaluated qualitatively on a scale of 1 to 4 (referred to as the "QS" score), where 1 is no fusion (clear depiction of boundaries between individual volumes of material) and 4 is complete fusion (no visually discernible boundaries between individual volumes of material). Example 10. Effect of preparation and addition order on material properties: Composition prepared at the time of injection vs. pre-moistened silica vs. pre-moistened bismuth

[0130] Three compositions were prepared to investigate the effect of pre-wetting either silica (AMP-9) or bismuth (AMP-5) on a composition (AMP-13) that had not been pre-wetted with either bismuth or silica. See Table A for the compositions. All formulations were subjected to the PBS injection assay described in Example 9.

[0131] As can be seen in Figure 7, different preparation methods resulted in significantly different behavior in the PBS injection assay test. The formulation with neither silica nor bismuth pre-moistened (AMP-13) exited the catheter as a slightly elongated droplet with poor fusion (QS of 1). When the silica in this system was pre-moistened at 70°C for 3 days (AMP-9), the material exited the catheter as a well-fused, rounded droplet (QS of 4). In the formulation with only bismuth pre-moistened (AMP-5), the material exited the catheter as an elongated droplet with a QS of 3. These data demonstrate that different extrusion and fusion behaviors can be obtained by moistening the silica or bismuth component. These different behaviors affect in vivo performance, including the presence of proximal backflow, distal infiltration, and casting integrity, highlighting the effect of preparation of the same components on material properties. Example 11. Effect of preparation and addition order on material properties

[0132] The effect of pre-wetting with either silica (AMP-9) or bismuth (AMP-5) on the rheological properties of compositions pre-wetted with both bismuth and silica (AMP-1) and compositions not pre-wetted with either silica or bismuth (AMP-13) was investigated. The results are shown in Figure 8, which illustrates the range of properties achievable with respect to extrusion behavior in a PBS injection assay, rheologically shown via hysteresis curves, yield strain-yield stress curves, yield strain-ductility curves, and shear recovery phase angle curves. A brief explanation highlighting these properties is given below:

[0133] In a pre-compounded system where both silica and bismuth are wetted and annealed (AMP-1), the material exhibits viscoelastic fluid behavior with a QS of 4 (or good fusion) in injection tests (Figure 8). Rheologically, this material has high plastic viscosity (slope of hysteresis curve), a storage modulus of approximately 900 Pa at a stress of <1 Pa, a ductile elongation curve, and a phase angle of >45 degrees immediately after shear (Figure 9).

[0134] In the system where only bismuth trioxide is pre-wetted and annealed (AMP-5), the material behaves as an elastoplastic solid. Rheologically, this is observed through its elongation curve, which has little ability to plastically deform and a low phase angle of about 10 degrees immediately after shearing. AMP-9 shows the effect of pre-wet silica instead of bismuth trioxide on material behavior. In this case, the material behaves as a droplet when exiting the catheter in an injection test. Rheologically, the material has a much lower storage modulus than AMP-5 (160 vs. 740 Pa, respectively), exhibits ductility, and has a phase angle of >30 degrees.

[0135] Finally, in systems where neither silica nor imaging agent is wetted or annealed (AMP-13), the material exits the catheter as droplets with poor fusion (QS:1), as evidenced by a phase angle of <10 degrees, making it a rheologically more solid-like material. Example 12: Effect of imaging agent dispersion on injectability and vasospasm

[0136] The effect of particle dispersion of the radiopaque agent in the composition of this disclosure on injection force and in vivo performance was investigated.

[0137] Formulations representing different preparation methods of this disclosure were prepared (AMP-5, AMPp-6, and AMP-7, Table A). Each composition was injected into a 1 mm inner diameter silicone tube via a catheter and then imaged using uCT. Radiopaque agent dispersion was qualitatively evaluated using uCT reconstruction with a voxel resolution of 15 μm (Figure 10A). Clearly, mixing of dry powder at the time of injection (AMP-7) resulted in larger and less dispersed radiopaque agent particles compared to formulations in which the radiopaque agent was incorporated into a polymer (AMP-5 and AMP-6). While not bound by any theory, the particles appeared to be more completely wetted in AMP-5 and AMP-6 compared to the composition mixed at the time of injection (AMP-7), resulting in better dispersion of particles, as evidenced by the reduced number of aggregates observed. The importance of radiopaque agent dispersion is shown in Figure 10B, where AMP-6 and AMP-7 were injected into the same kidney of a pig. AMP-7 was found to have fewer dispersed radiopaque particles, resulting in both vascular stenosis and a lack of casting at very distal bifurcations compared to AMP-6. Larger particles are thought to stimulate the endothelium and cause contraction. Furthermore, dispersion of the imaging agent has been shown to increase the injection force when using the injection test method (above) (Figure 10C), and particularly in smaller catheter lumens such as 0.016 inches, larger, less dispersed particles present when the powder is introduced in a dry state (AMP-13; upper curve) may promote agglomeration and clogging of the catheter lumen compared to pre-moistened particles (AMP-5; lower curve).

[0138] Injection test method: Using a 1 ml syringe, the solution was injected at a constant rate of 0.5 ml / min through a 100 cm long, 0.016 inch catheter. Example 13: Effect of silica mixing at the time of injection

[0139] The injection of materials via small lumen catheters is important for many clinical applications. Injecting materials requiring only the force generated by one hand (estimated to be approximately 10 lbs ± 5 lbs) would enable widespread use, as it would allow for tactile feedback based on current medical practices. The injection force of the formulations of this disclosure can be adjusted by composition in some embodiments and by preparation method in other embodiments. Figure 11 shows injection force data collected from an injection test method (above) for viscosity measured using low-frequency vibration rheology, comparing formulations in which the powder was incorporated into the polymer phase (AMP-1 and AMP-2) with formulations in which the powder was mixed in a dry state immediately before injection (AMP-15, AMP-16, AMP-17, AMP-18, AMP-19, AMP-20). Figure 11 demonstrates that mixing dry powder with the polymer at the time of injection yields materials with less silica and approximately half the injection force (AMP-18 vs. AMP-1) while maintaining similar viscosity. While not bound by any particular theory, it is thought that polymer adsorption to the silica surface in AMP-1 reduces the silica's ability to form interparticle interactions and network structures (requiring more silica to reach a similar viscosity), whereas when particles are mixed at the time of injection, the time for particle wetting and polymer adsorption is shorter, resulting in a network structure with fewer particles. Furthermore, the reduction in polymer molecular weight further reduces the required injection force, as demonstrated by comparing AMP-19 and AMP-15, where AMP-15, with the same proportion of silica and similar viscosity, can be well below the target injection force through a 0.021-inch lumen catheter, as the injection force is reduced to about a quarter.

[0140] Injection test method: Using a 1 ml syringe, the solution was injected at a constant rate of 0.5 ml / min through a 100 cm long, 0.021 inch catheter. Example 14: Effect of silica hydrophobicity on the stability of the preliminary formulation composition

[0141] The effect of silica type (hydrophobic vs. hydrophilic) on the stability of the preliminary formulation composition of this disclosure was analyzed.

[0142] It is known that viscosity decreases when hydroxyl groups present on the silica surface interact with siloxane groups present on the silicone polymer backbone. Compounds prepared using either hydrophilic (AMP-1) silica or hydrophobic (AMP-2) silica were prepared by blending each phase and storing them at 70°C. Rheological properties were measured under vibration (as described above) at individual point in time when the phases were mixed. Compounds prepared using hydrophilic silica showed a decrease in viscosity measured over time, while compoundes prepared using hydrophobic silica showed a stable viscosity over time after the initial annealing period (Figure 12). Compounds in which hydrophilic silica was mixed immediately before testing (fluid silicone and silica powder stored separately (AMP-18)) also showed a stable viscosity over time. This demonstrates that stable compound can be prepared by using hydrophobic silica or by combining hydrophilic silica with the compound at the time of use, thus minimizing the interaction between the silica surface and the polymer backbone. Example 15: Effect of hydrophilic plasticizer on fusion and ductility

[0143] The use of hydrophilic plasticizers has been shown to affect both the ductility and elasticity of the formulation, as well as its fusion properties. Formulations were prepared by combining bismuth trioxide with the liquid phase and fumed silica separately in a dry state, with the liquid phase being combined immediately before testing. In one example, trimethylolpropane ethoxylate (TMPEO) was included as the hydrophilic plasticizer (AMP-8), while in another formulation, this component was absent (AMP-5). The formulations were rheologically evaluated as described above and characterized using injection tests. The results are shown in Figure 13A. AMP-5 exhibited elongated droplets with good fusion (QS score of 3), while AMP-8 showed increased structure, with the material being extruded from the catheter as a continuous flow and then constructed as a coil at the bottom of the cup as separate volumes (QS score of 2). When measured rheologically, AMP-5 exhibits brittle behavior on the stress / strain curve, but the addition of TMPEO to AMP-8 improves the ductility / elasticity of the compound (Figure 13B). Example 16. Effect of silica level on fusion and ductility

[0144] The level of silica used in the compositions of this disclosure has been found to affect the physical properties of the material when injected through a catheter and characterized using injection tests. As shown in Figure 14, the amount of silica in the system, when stored in a dry state and mixed with the polymer before injection, affects the ability of the formulation to build structure. Increasing silica leads to increased material structure due to percolation (the percolation threshold is a mathematical concept in percolation theory that explains the formation of long-range connectivity in random systems). Injection behavior can be changed from short droplets (AMP-12) to elongated droplets (AMP-13) and continuous coils (AMP-14) by even a slight increase in silica content. Each of these different properties may be particularly suitable for a wide range of potential clinical applications depending on the desired performance. Example 17. Effect of MW of silicone component on the ability of composition to final sterilize via electron beam sterilization

[0145] The molecular weight of the silicone (polydimethylsiloxane, PDMS) component used in the compositions of this disclosure was found to affect the ability to use final sterilization (electron beam, e-beam) as a modality. Two formulations were prepared using dry powder and mixed immediately before injection using PDMS components in two different molecular weight (MW) ranges. AMP-4 contained PDMS components of 5000-10000 Da, and AMP-3 contained 17 DMS components of 500-2000 Da. The formulations were subjected to e-beam sterilization, irradiated with 15 kGy three times for a total dose of 45 kGy. A bench control that had not undergone e-beam sterilization was prepared for comparison. The rheological properties of the materials were evaluated. AMP-4 showed a decrease in gelation time after e-beam treatment compared to the non-sterilized control sample. AMP-3 showed no difference in gelation time after e-beam treatment compared to the non-sterilized control sample (Figure 15). These results demonstrate that the use of PDMS components with lower MW may enable the use of radiation-based final sterilization modalities. Example 18. Progressive vascular embolus formation by the composition of the present disclosure.

[0146] A 4Fr balloon catheter (9mm diameter balloon) was used to occlude a bifurcation of the porcine portal vein. AMP-13 was prepared by mixing dry and fluid components immediately before injection. Figure 16(A-D) shows the progress of the injection obtained by fluoroscopy, with (A) being the initial injection and (D) being after material hardening when the occluding balloon deflated. AMP-13 flowed from proximal to distal, allowing it to be injected into a very distal bifurcation of the vessel, resulting in a complete cast of the portal vein bifurcation. While not theoretically bound, the shear-thinning and flow-responsive properties of AMP-13 enabled this deep penetration without overpressuring the vessel or causing the balloon to kick back proximal. Figure 16D shows that once hardened, the balloon could be easily deflated and removed without adhering to the material.

Claims

[Claim 1] The invention described in the present specification.

Images