Embolic compositions and methods

Abstract

The present disclosure pertains to crosslinkable compositions and methods for forming crosslinked compositions in situ as well as withdrawing the compositions with subsequent injections followed, including the use of the same for embolizing vasculature including the neurovasculature within a patient, among many other uses.

Description

Attorney Docket No. AMD-026WOEMBOLTC COMPOSITIONS AND METHODS CROSS-REFERENCE

[0001] This application claims priority to US Provisional Application Number 63 / 709,076 filed October 18, 2024, and US Provisional Application Number 63 / 751,571 filed January 30, 2025, each of which is incorporated herein by reference in its entirety.FIELD OF THE DISCLOSURE

[0002] The present disclosure pertains to biocompatible crosslinkable compositions and methods of using such crosslinkable compositions.BACKGROUND

[0003] Crosslinkable compositions that are capable of forming crosslinked compositions in situ have a number of biomedical advantages including, without limitation the ability to deliver in- situ-forming crosslinked compositions to closed cavities, for example intravascularly, the ability to deliver in-situ-forming crosslinked compositions to difficult-to-access body sites, the ability of in-situ-forming crosslinked compositions to fill empty space, potential space, or fill space filled with blood, the ability of in-situ-forming crosslinked compositions to support surrounding tissues, and so forth.

[0004] A general risk with embolization is the presence of unintended material in the proximal parent artery of targeted vasculature (e.g., due to vasospasm or unintended injection of too much material), which may lead to non-target embolization. Thus, there is a need to remove embolic material that is proximally present in the vasculature which would help mitigate potential for non-target embolization.SUMMARY

[0005] The present disclosure, in part pertains to methods for forming crosslinked compositions in situ and withdrawing the compositions with subsequent injections followed.

[0006] In one aspect of the disclosure, there is provided a method comprising (a) forming a crosslinkable composition for vascular embolization comprising (i) providing a first fluid1IPTS / 200152370.1Attorney Docket No. AMD-026WO composition that comprises a crosslinkable polymer and a first imaging agent, (ii) providing a second fluid composition that comprises a crosslinker and an optional second imaging agent, (iii) mixing the first fluid composition and the second fluid composition with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the crosslinkable composition for injection; (c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the first crosslinkable composition into the vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the vasculature before the first crosslinkable composition crosslinks and forms into a solid.

[0007] In another aspect of the disclosure, there is provided a method comprising (a) forming a crosslinkable composition for vascular embolization comprising (i) providing a first fluid composition that comprises a first crosslinkable polymer and a first imaging agent, (ii) providing a second fluid composition that comprises a first crosslinker and an optional second imaging agent that is the same or different from the third imaging agent, (iii) mixing the first fluid composition and the second fluid composition with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the first crosslinkable composition for injection; (c) injecting the first crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid; (e) forming a second crosslinkable2IPTS / 200152370.1Attorney Docket No. AMD-026WO composition for vascular embolization comprising: (i) providing a third composition that comprises a second crosslinkable polymer and a third imaging agent, (ii) providing a fourth fluid composition that comprises a second crosslinker and an optional fourth imaging agent that is the same or different from the third imaging agent; and (iii) mixing the first fluid composition and the second fluid composition with a second dry composition, wherein the second dry composition comprising a third silica filler and an optional fourth silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the third imaging agent, the optional fourth imaging agent, the third first silica filler, and the optional fourth silica filler are dispersed in the crosslinkable composition; (f) preparing the second crosslinkable composition for injection; (g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid.

[0008] In one aspect of the disclosure, there is provided a method comprising (a) forming a crosslinkable composition for vascular embolization comprising (i) providing a first suspension that comprises a crosslinkable polymer and a first imaging agent, (ii) providing a second suspension that comprises a crosslinker and an optional second imaging agent, (iii) mixing the first suspension and the second suspension with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the crosslinkable composition for injection; (c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the first crosslinkable composition into the vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the vasculature before the first crosslinkable composition crosslinks and forms into a solid.3IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0009] In another aspect of the disclosure, there is provided a method comprising (a) forming a first crosslinkable composition for vascular embolization comprising (i) providing a first suspension that comprises a first crosslinkable polymer and a first imaging agent, (ii) providing a second suspension that comprises a first crosslinker and an optional second imaging agent that is the same or different from the third imaging agent, (iii) mixing the first suspension and the second suspension with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the first crosslinkable composition for injection; (c) injecting the first crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid; forming a second crosslinkable composition for vascular embolization comprising: (i) providing a third suspension that comprises a second crosslinkable polymer and a third imaging agent; (ii) providing a fourth suspension that comprises a second crosslinker and an optional fourth imaging agent that is the same or different from the third imaging agent; and (iii) mixing the first suspension and the second suspension with a second dry composition, the second dry composition comprising a third silica filler and an optional fourth silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the third imaging agent, the optional fourth imaging agent, the third first silica filler, and the optional fourth silica filler are dispersed in the crosslinkable composition; (f) preparing the second crosslinkable composition for injection; (g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid.4IPTS / 200152370.1Attorney Docket No. AMD-026WOBRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIGS. 1 A-1D schematically illustrate the progressive embolization of a portion of the vasculature with a crosslinkable composition in accordance with the present disclosure.

[0011] FIG. 2A schematically illustrates the progressive behavior of a crosslinkable composition in accordance with the present disclosure during an embolization procedure.

[0012] FIG. 2B is a chemical equation representing curing of a crosslinkable composition in accordance with the present disclosure.

[0013] FIG. 3 shows phase angle recovery graphs of samples of an exemplary crosslinkable composition of the disclosure at 37°C and 25°C.

[0014] FIG. 4A displays a fluoroscopic image showing a vessel in a swine kidney embolized with the crosslinkable composition of Example 1 prior to cure. FIG. 4B displays a fluoroscopic image demonstrating aspiration of the crosslinkable material, showing the final position of the guide catheter tip with the crosslinkable composition no longer present proximal to the guide catheter tip. The proximal material was aspirated through the inner lumen of the guide catheter using negative pressure provided by a syringe.

[0015] FIG. 5 A shows an uncured crosslinkable composition of Example 1 present in the proximal portion in a human middle meningeal artery. FIG. 5B shows aspiration of the crosslinkable composition using an intermediate catheter and negative pressure provided by a syringe, where the material is no longer present in the proximal section of the vessel.DETAILED DESCRIPTION

[0016] As used herein, a material is described as a “fluid” if it is flowable, as is the case with, for example, liquid, semi-solid, paste, gels, suspensions, emulsions and viscoelastic materials.

[0017] For the purposes of this disclosure, the term “crosslinkable composition” generally refers to a polymer-based fluid that is capable of being delivered to a delivery site, after which crosslinking (i.e., curing) of the material continues to progress at the delivery site.

[0018] In various aspects, the present disclosure pertains to solvent-free crosslinkable compositions that comprise a first polysiloxane having two or more unsaturated groups, a first5IPTS / 200152370.1Attorney Docket No. AMD-026WO silica filler, a first imaging agent, a first hydride material having two or more hydride groups, a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, an optional second silica filler that is different from the first silica filler, an optional second imaging agent that is different from the first imaging agent, an optional second hydride material having two or more hydride groups that is different from first hydride material having two or more hydride groups, and an optional second polysiloxane having two or more unsaturated groups that is different from the first polysiloxane having two or more unsaturated groups. In various embodiments, the crosslinkable compositions comprise a total amount of at least 10 wt% of the first imaging agent and the optional second imaging agent.

[0019] In some aspects, the present disclosure provides methods in which these biocompatible, crosslinkable compositions are injected into a patient, such as into the vascular system or neurovascular system or a body cavity of a patient.

[0020] In various aspects, the present disclosure pertains to kits for forming biocompatible crosslinkable compositions that comprise (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 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, (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 a first imaging agent or a mixture of a second silica filler and a second imaging agent, and (e) one or more components for mixing and delivery of the first fluid composition, the first dry composition, the second fluid composition and the second dry composition, if present.

[0021] In this aspect, at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, wherein the first and second silica fillers may be the same or different and wherein the first and second imaging agents may be the same or different, and wherein the first fluid composition, the first dry composition, the second fluid composition, and the second dry composition (if present), when mixed, form a crosslinkable composition. In some embodiments, both the first and second fluids comprise the catalyst. In some embodiments, the first fluid composition comprises the catalyst and the second fluid composition does not comprise the catalyst, in which case the6IPTS / 200152370.1Attorney Docket No. AMD-026WO second fluid composition may comprise 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 comprises the catalyst and the first fluid composition does not comprise the catalyst, in which case the first fluid composition may comprise a second hydride material having two or more hydride groups that may be the same as or different from the first hydride material having two or more hydride groups. In the case where the first dry composition comprises only the first silica filler, the second dry composition is present and comprises a first imaging agent. The compositions of this aspect of the disclosure, as well as embodiments thereof, are referred to in the Examples as compositions that are “made at the time of injection.” In some embodiments, the silica filler is hydrophobic and in other embodiments, the silica filler is hydrophilic. In those embodiments in which a first and second silica filler are included in the composition, one or both silica fillers may be hydrophobic or hydrophilic. In some embodiments, the crosslinkable composition comprises a total amount of at least 10 wt% of the first and second imaging agent (if present).

[0022] In embodiments where the kits may include the second dry composition, the first fluid composition and the first dry composition or the second dry composition may be mixed to form a first mixture, and the second fluid composition and the remaining dry composition may form a second mixture, in which case the first mixture and the second mixture may be mixed to form the crosslinkable compositions. Typically, the ratio of the volume of the first mixture to the volume of the second mixture is approximately equal (—1:1), typically ranging, for example, from 4: 1 to 1 :4, more typically 2: 1 to 1 :2, among other possible proportions. To enhance mixing, the viscosities of the first and second mixtures may be similar, for example, the oscillatory viscosity of the first and second mixtures at a frequency of 0.1 Hz at 25°C (see below) may be within + / - 60 % of one another.

[0023] In another aspect, the present disclosure pertains to kits for forming crosslinkable compositions that comprise (a) a first fluid composition that comprises a first polysiloxane having two or more unsaturated groups, a first silica filler and / or a first imaging agent, (b) a second fluid composition that comprises 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 delivery of the first and second fluid compositions, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between the7IPTS / 200152370.1Attorney Docket No. AMD-026WO unsaturated groups and the hydride groups, wherein the first and second silica fillers may be the same or different, wherein the first and second imaging agents may be the same or different, wherein the first fluid composition and the second fluid composition, when mixed, form a crosslinkable composition. In some embodiments, the crosslinkable composition comprises a total amount of at least 10 wt% of the first and second imaging agents. In some embodiments, both the first and second fluid compositions comprise the catalyst. In some embodiments, the first fluid composition comprises the catalyst and the second fluid composition does not comprise the catalyst, in which case the second fluid composition may comprise 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 comprises the catalyst and the first fluid composition does not comprise the catalyst, in which case the first fluid composition may comprise a second hydride material having two or more hydride groups that 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 comprises a silica filler and the second fluid composition comprises an imaging agent, while in other embodiments, the first fluid composition comprises an imaging agent and the second fluid composition comprises a silica filler. In other embodiments, the first and second fluid compositions both comprise silica filler 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 filler 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 (—1:1), typically ranging, for example, from 4: 1 to 1 :4, more typically 2:1 to 1:2, among other possible proportions. To enhance mixing, the viscosities of the first and second fluid compositions may be similar, for example, the oscillatory viscosity of the first and second fluid compositions at a frequency of 0.1 Hz at 25°C (see below) may be within + / - 60 % of one another. Compositions of this aspect of the disclosure are referred to in the Examples as “preformulated compositions or “preformulated.”

[0024] In various aspects, the present disclosure pertains to kits for forming crosslinkable compositions that comprise:8IPTS / 200152370.1Attorney Docket No. AMD-026WO(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 that comprises 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 delivery of 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, when mixed, form a crosslinkable composition;(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 that comprises 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 delivery of the first fluid composition, the second fluid composition, and the dry composition; and wherein the first fluid composition, the dry composition, and the second fluid composition, when mixed, form a crosslinkable composition; or(iii) (a) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and either 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 that comprises a first hydride material having two or more hydride groups and either the first silica filler and optionally the second silica filler or the first imaging agent and optionally the second imaging agent, and (c) one or more components for mixing and delivery of the first fluid composition and the second fluid composition, wherein when 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 imaging filler, and in the case where 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 wherein 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, and at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups. Alternatively, each9IPTS / 200152370.1Attorney Docket No. AMD-026WO of (i), (ii), and (iii) further comprises a third and / or fourth fluid composition comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups. In the case where the first fluid composition comprises the catalyst and the second fluid composition does not comprise the catalyst, 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. When the second fluid composition comprises the catalyst and the first fluid composition does not comprise the catalyst, then the first fluid composition may comprise an optional second hydride material having two or more hydride groups that may be the same as or different from the first hydride material having two or more hydride groups.

[0025] In some embodiments of this aspect of the disclosure, the crosslinkable composition comprises a total amount of at least 10 wt% of the first and second imaging agent (if present). In some embodiments, both the first and second fluid compositions comprise the 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 the unsaturated groups and the hydride groups 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 filler (if present) are hydrophobic. In other embodiments, both the first and second silica filler (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 (—1:1), typically ranging, for example, from 4: 1 to 1 :4, more typically 2:1 to 1:2, among other possible proportions. To enhance mixing, the viscosities of the first and second fluid compositions may be similar, for example, the oscillatory viscosity of the first and second fluid compositions at a frequency of 0.1 Hz at 25°C (see below) may be within + / - 60 % of one another.

[0026] In some aspects, any of the above crosslinkable compositions formed by any of the above kits may be injected into a patient using a needle or a catheter.

[0027] In various aspects, the present disclosure pertains to methods of forming biocompatible crosslinkable compositions in which a mixture is formed that comprises the following:10IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0028] (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 a 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 second dry composition comprising mixture of a second silica filler and a second imaging agent. In those embodiments in which the first dry composition comprises the first silica filler and optionally the second silica filler, the second dry composition comprises the first imaging agent and optionally the second imaging agent. In those embodiments in which the first dry composition comprises a mixture of the first silica filler and the first imaging agent, the second dry composition is optional and when present comprises a mixture of the second silica filler and the second imaging agent.

[0029] In embodiments of this aspect, 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 comprise the catalyst. In some embodiments, the first fluid composition comprises the catalyst and the second fluid composition does not comprise the catalyst, in which case the second fluid composition may comprise 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 comprises the catalyst and the first fluid composition does not comprise the catalyst, in which case the first fluid composition may comprise a second hydride material having two or more hydride groups that may be the same as or different from the first hydride material having two or more hydride groups. In some embodiments, air bubbles are introduced in the mixture during mixing of the fluid and dry components. In other embodiments, gas may be added during the mixing process to create bubbles in the final mixture. In some embodiments, the bubbles act as the imaging agent.

[0030] In embodiments where the methods of forming the crosslinkable compositions comprise forming a mixture that includes the second dry composition, the methods may comprise (a) mixing the first fluid composition and the first dry composition to form a first mixture, (b)11IPTS / 200152370.1Attorney Docket No. AMD-026WO 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. Typically, the ratio of the volume of the first mixture to the volume of the second mixture is approximately equal (—1:1), typically ranging, for example, from 4: 1 to 1 :4, more typically 2:1 to 1 :2, among other possible proportions. To enhance mixing, the viscosities of the first and second mixtures may be similar, for example, the oscillatory viscosity of the first and second mixtures at a frequency of 0.1 Hz at 25°C may be within + / - 60 % of one another.

[0031] In any of the embodiments of this aspect, the crosslinking composition may be injected into a body of a patient using a needle or catheter whereupon the crosslinkable composition crosslinks in the body.

[0032] In various aspects, the present disclosure pertains to methods that comprise (a) forming a crosslinkable composition that comprises 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 the unsaturated groups and the hydride groups, an optional second silica filler that is different from the first silica filler, an optional second imaging agent that is different from the first imaging agent, an optional second hydride material having two or more hydride groups that is different from first hydride material having two or more hydride groups, and an optional second polysiloxane having two or more unsaturated groups that is different from the first poly siloxane having two or more unsaturated groups. In certain embodiments of this aspect, the method comprises (a) annealing a first fluid composition that comprises 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 that comprises 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.

[0033] In various embodiments of this aspect of the disclosure, only the first fluid composition or the second fluid composition is annealed prior to mixing of the two fluid compositions. In various embodiments, at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups. In some embodiments, the second fluid composition comprises the catalyst and the first fluid composition12IPTS / 200152370.1Attorney Docket No. AMD-026WO does not comprise the catalyst, in which case the first fluid composition may comprise a second hydride material having two or more hydride groups that may be the same as or different from the first hydride material having two or more hydride groups. In embodiments of this aspect, the first and second silica filler (if present) may be the same or different and the first and second imaging agent (if present) may be the same or different. In some embodiments, the first fluid composition comprises silica filler (the first and / or second silica filler) and the second fluid composition comprises imaging agent (the first and / or second imaging agent), while in other embodiments, the first fluid composition comprises the imaging agent (the first and / or second imaging agent) and the second fluid composition comprises the silica filler (the first and / or second silica filler). In other embodiments, the first and second fluid compositions comprise both silica filler(s) and imaging agent(s). In certain embodiments, the crosslinkable composition comprises a total amount of at least 10 wt% of the first imaging agent and second 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 filler 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 (~1 : 1), typically ranging, for example, from 4:1 to 1 :4, more typically 2: 1 to 1 :2, among other possible proportions. To enhance mixing, the viscosities of the first and second fluid compositions may be similar, for example, the oscillatory viscosity of the first and second fluid compositions at a frequency of 0.1 Hz at 25 °C (see below) may be within + / - 60 % of one another.

[0034] In those embodiments of this aspect in which the first fluid composition and second fluid composition are separately annealed, the annealing can be carried out in any manner that does not compromise the various components of the fluid compositions. For example, annealing may be carried out by allowing the fluid compositions to rest at room temperature for a sufficient period of time to allow the compositions to reach an equilibrium and / or improve ductility of the compositions. Alternatively, annealing of the compositions may involve heating the fluid compositions for a sufficient period of time such as 4 to 10 days to allow the compositions to reach an equilibrium and / or improve ductility of the compositions, e.g., 50°C to 80°C, such as 70°C for 7 days.13IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0035] In any of the embodiments of this aspect, the crosslinkable composition may be injected into a body of a patient using a needle or catheter whereupon the crosslinkable composition crosslinks in the body.

[0036] In various aspects, the present disclosure pertains to methods that comprise(a) forming a crosslinkable composition that comprises:(i) 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, that is the same or different from the first silica filler, a dry composition comprising a first imaging agent and optionally a second imaging agent that is the same or different from the first imaging agent;(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 that is the same or different from the first imaging agent, a dry composition comprising a first silica filler and optionally a second silica filler that is the same or different from the first silica filler; or(iii) a first fluid composition comprising a first polysiloxane having two or more unsaturated groups and either a first silica filler and optionally a second silica filler that is the same or different from the first silica filler or a first imaging agent and optionally a second imaging agent that is the same or different from the first imaging agent, a second fluid composition comprising a first hydride material having two or more hydride groups and either the first silica filler and optionally the second silica filler or the first imaging agent and optionally the second imaging agent, wherein when 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 imaging filler, and in the case where 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, wherein in each of (i), (ii), and (iii) at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups. Alternatively, each of (i), (ii), and (iii) further comprises a third or fourth fluid compositions comprising a catalyst for catalyzing a reaction between the unsaturated groups and14IPTS / 200152370.1Attorney Docket No. AMD-026WO the hydride groups and a first polysiloxane having two or more unsaturated groups or a first hydride material having two or more hydride groups. Upon forming the crosslinkable composition of (i), (ii), or (iii), the composition is injected into a body of a patient whereupon the crosslinkable composition crosslinks in the body. In the case where the first fluid composition comprises the catalyst and the second fluid composition does not comprise the catalyst, 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. When the second fluid composition comprises the catalyst and the first fluid composition does not comprise the catalyst, then the first fluid composition may comprise an optional second hydride material having two or more hydride groups that may be the same as or different from the first hydride material having two or more hydride groups.

[0037] In various embodiments, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may have a viscosity as measured by oscillatory rheology at 0.1 Hz and 1% strain at 25°C that ranges from 100 Pa*s or less to 10,000 Pa*s or more, for example, ranging anywhere from 100 Pa*s to 250 Pa*s to 500 Pa*s to 1000 Pa*s to 2500 Pa*s to 5000 Pa*s to 10000 Pa*s (in other words, ranging between any two of the preceding values) .

[0038] In various embodiments, the kits described herein, including the cured compositions formed by any of the above kits or methods, may be subjected to terminal sterilization, i.e., sterilization of the composition in its final container. For example, the kits may be exposed to electron-beam (e-beam) irradiation or ethylene oxide gas, dry heat, gamma irradiation, nitric oxide, x-ray irradiation, and the like. In some embodiments, components of the kits would be subjected to terminal sterilization. In other embodiments, components of the kits are sterilized using aseptic filtration rather than terminal sterilization.

[0039] In various embodiments, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may exhibit shear thinning fluid properties. For example, the crosslinkable compositions may have a viscosity as measured by oscillatory rheology at 0.1 Hz and 1% strain at 25°C that is at least ten-fold, beneficially at least one-hundred-fold, more beneficially at least five-hundred-fold, greater than a viscosity of the composition as measured by flow rheology at a frequency of 30 Hz at 25 °C.15IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0040] In various embodiments, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may have a gel time at temperatures of 25°C to 37°C ranging from 3 minutes or less to 60 minutes or more, for example, ranging anywhere from 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.

[0041] Rheological measurements may be made using a TA Instruments (Newcastle, DE, USA) Discovery HR-1 rheometer. For viscosity measurements the crosslinkable composition is placed into a 25mm parallel plate setup (using sandblasted plates to avoid slip), a Peltier system (TA Instruments) is used to control that temperature and maintain a gap of 1000 microns and (i) a first viscosity is measured using oscillatory rheology defined within the linear region, generally at 1% strain and 0.1Hz (lower shear) at 25°C and (ii) a second viscosity is measured using flow rheology at a frequency of 30 Hz at 25°C (higher shear). The higher shear value provides an indication of the properties of the composition under shear conditions similar to the conditions placed on the composition during delivery from a delivery device. The lower shear value provides an indication of the properties of the composition once implanted within the body where shear conditions are experienced having low strain and low frequency. The preceding measurements are made within three minutes after the crosslinkable composition is formed. For gel time measurements, the composition is loaded onto a rheometer with a 25 mm parallel plate setup (see above) and measurements are taken at constant frequency and strain (f=l 0 rad / s, Y=l%) over the course of 90 minutes at 37°C to observe the cure time and profile; gel time (time of cure) is defined as the time at which a peak of the phase angle (8) is observed. Curing time will change based on temperature and curing will take place in the within the body at 37°C at a faster rate than at room temperature (25 °C).

[0042] In various embodiments, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, can be injected by hand.

[0043] In various embodiments, the crosslinkable compositions described herein may have an injection force ranging from 1 to 30 Ibf.

[0044] Injection force is an important parameter that determines a formulation’s suitability for clinical use. In the present disclosure, injection force is determined by using an Instron setup similar to that described by Chen et al., Chen, M.H., et al., “Methods To Assess Shear-Thinning Hydrogels for Application As Injectable Biomaterials,” ACS biomaterials science & engineering,16IPTS / 200152370.1Attorney Docket No. AMD-026WO2017, 3(12): pp. 3146-3160. Samples are loaded into 1 mL Merit Medallion syringes and then affixed vertically with the plunger facing up. A 100 cm long catheter with a diameter appropriate for the target indication is then attached to the syringe and the test head of the Instron is advanced at a rate of 25 mm / min (equivalent to 0.5 mL / min injection rate). Injection force measurements are made within 3 minutes after the crosslinkable composition is initially mixed.

[0045] In various aspects, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may be employed in methods whereby the crosslinkable compositions are delivered to a body of a patient, for example, by injecting any of the crosslinkable compositions onto any tissue or into any body cavity or body lumen of a patient using any suitable device.

[0046] In certain embodiments, a composition of the disclosure is injected into the vasculature where it initially shear thins and flows downstream as a continuous stream; upon encountering higher shear, it breaks into discrete volumes that shear thins further to penetrate into distal branches (FIG. 1 A). As distal branches are occluded, flow decreases proximally; in response, the composition increases in viscosity. (FIG. IB). As the vasculature becomes more occluded, the composition exits the catheter as a viscous paste allowing controlled injection. (FIG. 1C). The result is complete casting and occlusion of the target vasculature without non-target embolization. (FIG. ID).

[0047] In certain embodiments, the methods comprise injecting the crosslinkable compositions into the vasculature and can be used, for example, for occlusion of the vasculature (e g., vascular embolization or neurovascular embolization) including portal vein embolization, embolization of tumors, including meningioma tumors, and peripheral tumors, pre-surgical embolization of tumors to minimize blood loss, chronic subdural hematoma, brain aneurysms, arteriovenous malformations, arteriovenous fistulas, cerebrospinal fluid (CSF) venous fistulas, gastrointestinal bleeds, bleeding due to trauma, prostate artery embolization, uterine artery embolization, visceral aneurysms, varicocele, varices, treatment for pelvic congestion, epistaxis, and treatment of endoleaks, among others.

[0048] In some embodiments, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may be introduced into the vasculature at a site proximal to the site to be treated through the use of an occlusion device or occlusion technique. In some embodiments, the injection catheter itself can be used to exclude17IPTS / 200152370.1Attorney Docket No. AMD-026WO blood flow. In other embodiments, the occlusion device is a balloon catheter. The shape, location and material of the inflatable balloon are selected such that when inflated, the balloon conforms to the shape of the vasculature, or at least a portion thereof, without appreciably deforming the vessel walls. In this manner the balloon is used to occlude a selected branch of the vasculature such that the composition may be injected deep into the vasculature without vessel construction or significant reflux of the composition beyond the site of injection, enabling deeper penetration of the composition into the vasculature. In general, the balloon is maintained in place after introduction of the composition into the vasculature until the composition cures. A balloon catheter is particularly useful for injecting compositions that are formed at the time of injection as described above, e.g., those compositions formed by mixing fluid and dry components immediately prior to injecting the crosslinkable composition into a patient.

[0049] In some embodiments, the method comprises injecting a composition described herein, including the crosslinkable compositions formed by any of the above kits or methods, into the vasculature of a patient for distal penetration treatment such as portal vein embolization, tumor embolization, and the like.

[0050] In some embodiments, the compositions of the disclosure may be injected into the vascular in conjunction with another device such as a coil, plug, or stent graft.

[0051] In some embodiments, the method comprises identifying a blood vessel that branches into smaller distal vessels (for example, distally branching into a capillary bed) and injecting the crosslinkable composition into the blood vessel such that the crosslinkable composition flows into the distal vessels and occludes the distal vessels. The crosslinkable composition flows into distal vessels having diameters less than 100 microns, such as from 100 microns to 30 microns in some cases.

[0052] For example, the crosslinkable compositions may be injected into the portal vein as part of a portal vein embolization (PVE) procedure. PVE is a technique used before hepatic resection to increase the size of liver segments that will remain after surgery. This therapy redirects portal blood to segments of the future liver remnant (FLR), resulting in hypertrophy. PVE is indicated when the FLR is either too small to support essential function or marginal in size and associated with a complicated postoperative course.

[0053] As another example, the crosslinkable compositions may be injected into the middle meningeal artery (MMA). Many diseases, including dural arteriovenous fistula (DAVF),18IPTS / 200152370.1Attorney Docket No. AMD-026WO pseudoaneuiysm, true aneurysm, traumatic arteriovenous fistula (AVF), moyamoya disease (MMD), recurrent chronic subdural hematoma (CSDH), migraine and meningioma, can involve the middle meningeal artery and can be treated by administration of a composition of the disclosure into the MMA.

[0054] Endovascular MMA embolization is an emerging treatment for CSDH, with preliminary data suggesting that this minimally invasive therapy may be more efficacious and equally as safe compared to conventional, more invasive surgery.

[0055] As another example, the crosslinkable compositions may be injected into a hypervascular brain tumor, for example a meningioma, prior to surgical resection. This therapy has been shown to reduce operative blood loss and reduce surgical procedure time.

[0056] As noted above, in various embodiments, the crosslinkable compositions have shear thinning properties. As seen from the Examples below, the present disclosure describes crosslinkable compositions that are flow-responsive materials that allow for the substantially complete fill and occlusion of targeted vasculature when injected into the targeted vasculature. Without wishing to be bound by theory, it is believed that, at the start of the procedure, flow velocity is high leading to a high shear rate within the blood vessel and its distal branches; thus, when the crosslinkable composition initially exits the catheter, it encounters high shear and becomes a low viscosity fluid that deeply penetrates into distal branches. As occlusion occurs in the distal branches, flow velocity is diminished proximally; in response, the shear decreases and the viscosity of the crosslinkable composition increases. Flow continues to diminish further as the vasculature becomes even more occluded proximally; consequently, the crosslinkable composition returns to a high viscosity resting state, behaving, for example, as a viscous paste. The end result is formation of an entire cast of the vasculature down to distal vessels that induces complete occlusion. This process is illustrated schematically in FIGs. 1A-1D.

[0057] In various aspects, the crosslinkable compositions described herein are delivered to a delivery site in a body of a patient through the use of a suitable delivery device or system. In various embodiments, the delivery system may comprise a catheter. As used herein, a “catheter” is any device that may be introduced into or adjacent to a patient's body or target location within a patient's body, and comprises at least one lumen of any appropriate size, shape or configuration for the movement of fluid therethrough. In certain embodiments, a catheter may be employed that ranges from 100-200 cm in length and has a diameter appropriate for the target indication19IPTS / 200152370.1Attorney Docket No. AMD-026WO(e.g., from 0.016” to 6 Fr), among many other possibilities. In certain embodiments, the catheter is a balloon catheter. As used herein, crosslinkable compositions described as being “injected,” “deposited,” “delivered” and the like include crosslinkable compositions that are placed via a delivery system at a delivery location on or within a patient's body using any suitable means, including syringe-based injection. In some embodiments, the crosslinkable compositions are delivered by hand. In other embodiments, depending on fluid viscosity, a hand-powered syringeassist, pneumatic or mechanical pressure pump, or other device may be used to control the flow rate and / or improve ease / force of injection. As previously noted, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, comprise a first silica filler (and a second silica filler, in some cases). Examples of silica fillers include fumed silica, precipitated silica, and hydrophobic silica, among others.

[0058] Silica fillers have been found to impart shear-thinning properties to the crosslinkable compositions of the present disclosure. Such properties allow, for example, for microcatheter injection and flow responsiveness for distal penetration and proximal control when flow is reduced. Such silica fillers have also been found to provide crosslinkable compositions in the form of a structured fluid or paste, which allows a radiopaque agent or other imaging agent to remain suspended, and allows for even radi opacity or imaging during injection.

[0059] Without wishing to be bound by theory, it is believed that the particles in the crosslinkable compositions of the present disclosure imparts shear-thinning behavior through the formation of a reversible hydrogen bonded network. For example, in the case where the crosslinkable composition comprises poly dimethyl siloxane (PDMS) having two or more unsaturated groups (and in some embodiments comprise PDMS having two or more hydride groups), and with reference to FIG. 2A, silica particles (shown with spheres) interact with each other and with PDMS (shown with lines) to form a high-viscosity structured fluid. When shear force is applied, the silica-silica interactions are disrupted, and the viscosity of the material drops temporarily and reversibly. As soon as the shear force is removed, immediate recovery of silicasilica interactions restores the paste-like structure of the crosslinkable composition. Thus, as a consequence of this property, the material acts as a low viscosity, flowable material when injected through a catheter and continues to be so upon entering a blood vessel, where the flow of blood continues to shear-thin the material and carry it distally to fill and cast distal branches. Over time, the material cures into a permanent elastic solid through hydrosilylation (shown in20IPTS / 200152370.1Attorney Docket No. AMD-026WOFIG. 2B); this point is known as the gel time. As vinyl and hydride groups react to form carboncarbon covalent bonds (shown with dots in FIG. 2A), the polymer network becomes chemically crosslinked.

[0060] In various embodiments, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, comprise a total amount of from 0.25 wt% or less to 10 wt% or more of silica filler, for example, ranging from 0.25 wt% to 0.5 wt% to 1 wt% to 2 wt% to 5 wt% to 7.5 wt% to 10 wt%.

[0061] In various embodiments, the silica filler in the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, is characterized by a surface area of 50 m2 / g or less to 1000 m2 / g or more, for example ranging from 50 m2 / g to 100 m2 / g to 200 m2 / g to 500 m2 / g to 1000 m2 / g.

[0062] As noted above, in various embodiments, the silica filler in the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, is hydrophobic, e.g., has hydrophobic groups chemically bonded to the surface such as by treatment of silica with hexamethyldisilazane (HMDS). The hydrophobic groups may be alkyl or polydimethylsiloxane for example. In those embodiments in which the compositions comprise two different silica fillers, one or both silica fillers may be hydrophobic.

[0063] As previously noted, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, comprise a first imaging agent (and the second imaging agent in some embodiments). Such imaging agents impart visibility for imaging (e g. under fluoroscopy). For example, radiopaque agents impart radiopacity for radiographic imaging (e.g. under fluoroscopy). Radiopaque agents may be selected, for instance, from radiopaque metals, radiopaque metal alloys, radiopaque metal oxides and radiopaque polymers (e.g., iodinated polymers). In some embodiments, a radiopaque agent may 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, ultrasound contrast agents. Imaging agents for use in conjunction with magnetic resonance imaging (MRI), include agents that contain elements with relatively large magnetic moment such as gadolinium, manganese and iron (e.g., Gd(III), Mn(II), Fe(III), etc.) and compounds (including chelates) containing the same, such as gadolinium ion chelated with di ethylenetriaminepentaacetic acid. Nonlimiting examples of imaging agents for use in21IPTS / 200152370.1Attorney Docket No. AMD-026WO conjunction with ultrasound imaging include microbubbles filled with suitable gases such as air, carbon dioxide, hydrogen, oxygen, nitrogen, sulfur hexafluoride, perfluorobutane or octafluoropropane, among others.

[0064] In various embodiments, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, comprise a total amount of from 1 wt% to to 50 wt% or more of imaging agent, for example, ranging from 1 wt% to 5 wt % to 10 wt% to 15 wt% to 20 wt% to 25 wt% to 30 wt% to 35 wt% to 40 wt% to 45 wt% to 50 wt%.

[0065] In various embodiments, the imaging agent may be present in a size ranging from 10 nm to 20 pm. For example, the use of nanoparticle size imaging agent can minimize CT artifact, allowing for better imaging on follow-up.

[0066] In various embodiments, metal oxides are used as a radiopaque agent. Metal oxides such as bismuth oxide (typically bismuth trioxide) can provide shear-thinning advantages. In addition, bismuth oxide is not flammable (e.g., compared to commonly used tantalum), therefore risk of sparking and fire during surgical resection with electrocautery tools is minimized. Bismuth oxide also provides the crosslinked composition with a bright yellow color which clearly indicates which vessels have been embolized, which can lead, for example, to more accurate surgical resection and reduced complications.

[0067] As indicated above, metal oxides such as bismuth oxide can provide shear-thinning advantages. This is particularly apparent when provided in combination with silica. In some embodiments, mixing dry components (e.g., silica and radiopaque agent) with fluid components (e.g., the remaining components) at the time of injection (instead of storing with the components compounded) maximizes shear thinning of material (reduction in injection force for a given viscosity), with less silica required and little concern of long term stability.

[0068] In some embodiments of each of the aspects of the disclosure, particle dispersion may have a significant impact on the material properties of the various composition of the disclosure and can be controlled by various means including, for example, by ensuring sufficient wetting of the dry components of the compositions, high shear dispersion of the particles in the polymers, and other processing steps known to those in the art.

[0069] As previously noted, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, comprise a first22IPTS / 200152370.1Attorney Docket No. AMD-026WO polysiloxane having two or more unsaturated groups (and a second polysiloxane having two or more unsaturated groups, in some embodiments).

[0070] In some embodiments, the crosslinkable compositions described herein comprise a total amount of polysiloxane(s) having two or more unsaturated groups ranging from 20 wt% or less to 60 wt% more, for example ranging from 20 wt% to 25 wt% to 30 wt% to 35 wt% to 40 wt% to 45 wt% to 50 wt% to 55 wt% to 60 wt%.

[0071] As used herein, the terms “polysiloxane” and “polysiloxane-based polymer” refer to polymers having repeating -Si-O- bonds in the polymer backbone. Polysiloxanes for use in the present disclosure include those comprising homopolymer and / or copolymer regions consisting of, or containing, one or more organo-siloxane monomers, including dialkylsiloxane monomers, diarylsiloxane monomers and / or alkylarylsiloxane monomers, such as dimethylsiloxane, di ethyl siloxane, methylethylsiloxane, methylphenylsiloxane and / or diphenyl siloxane monomers, to name a few examples. In various beneficial embodiments described herein, polydialkylsiloxane-based polymers, including PDMS-based polymers, are employed as polysiloxanes. PDMS-based polymers are beneficial for use in the present disclosure for a variety of reasons, including low relative viscosity at higher molecular weights (MW), their well- established use in medical devices and implants, and their inherent biocompatibility.

[0072] For the purposes of this disclosure, “unsaturated groups” are groups with less than the maximum number of hydrogen atoms per carbon (not saturated with hydrogen atoms), including groups with carbon-carbon double or triple bonds such as alkene or alkyne groups. Specific examples of poly siloxanes having two or more unsaturated groups include unsaturated-group- terminated polysiloxanes such as vinyl-terminated PDMS, acrylate-terminated PDMS, or methacrylate-terminated PDMS).

[0073] In some embodiments, the unsaturated groups of the polysiloxane(s) are 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.

[0074] In some embodiments, the polysiloxane(s) is / are linear.

[0075] In some embodiments, the polysiloxane(s) has / have a weight average molecular weight ranging from 250 Da or less to 10000 Da or more, for example ranging from 250 Da to 500 Da to 1000 Da to 2500 Da to 5000 Da to 10000 Da. In some embodiments, polysiloxanes with lower23IPTS / 200152370.1Attorney Docket No. AMD-026WO molecular weight (500 Da to 10000 Da) might be blended with a smaller percentage of higher molecular weight polysiloxane (10000 Da to 100000 Da). In some embodiments, the compositions include a mixture of two poly siloxanes having different molecular weights, e.g., any combination of a lower molecular weight (500 to 5000 Da) and a higher molecular weight (5000 - 10000 Da) polysiloxane. In some embodiments the lower molecular weight polysiloxane is preferentially between 500 to 2100 Da. For example,. . 1+., where n is an integer may be used. As previously noted, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, comprise a first hydride material having two or more hydride groups (and a second hydride material having two or more hydride groups in some embodiments).

[0076] For purposes of the present disclosure a “hydride group” is a reactive group in which hydrogen is bonded to another atom and is typically a silicon hydride group in which hydrogen is bonded to a silicon atom. In certain embodiments, hydride materials are employed which contain from 2 to 20 hydride groups per molecule, for example ranging from 2 to 3 to 5 to 7 to 10 to 15 to 20 hydride groups per molecule.

[0077] In some embodiments, the crosslinkable compositions described herein comprises a total amount of hydride material(s) having two or more hydride groups ranging from 10 wt% or less to 40 wt % or more, for example, ranging from 10 wt% to 15 wt% to 20 wt% to 25 wt% to 30 wt% to 35 wt% to 40 wt%.

[0078] In some embodiments, the hydride material(s) having two or more hydride groups is / are multifunctional polysiloxane hydride(s).

[0079] In some embodiments, the multifunctional polysiloxane hydride(s) is / are linear poly siloxane hydride(s). In some of these embodiments, the linear poly siloxane hydride(s) comprise hydride end groups and / or hydride side groups.

[0080] In some embodiments, the multifunctional polysiloxane hydride(s) has / have a weight average molecular weight ranging from 250 Da or less to 10000 Da or more, for example ranging from 250 Da to 500 Da to 1000 Da to 2500 Da to 5000 Da to 10000 Da.24IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0081] Specific examples of hydride material(s) having two or more hydride groups include both small molecule hydrides and polymeric hydrides. Polymeric hydrides include multifunctional polysiloxane hydrides including multifunctional PDMS hydrides, for example,where n and m are integers. Such compounds are also referred to herein as “hydride crosslinker.” Examples of multifunctional PDMS hydrides further include hydride-terminated PDMS, for example,, where n is an integer. Such compounds are also referred to herein as “linear hydride”.

[0082] It is further noted that an excess amount of hydride groups (stoichiometrically) relative to vinyl groups can lead to the production of gas. In some embodiments, this gas is used as an imaging agent. In other embodiments, where gas is not desired, the crosslinkable compositions may have a >0.9: 1 vinyl-group-to-hydride-group molar ratio. In some embodiments, the crosslinkable compositions may have a vinyl-group-to-hydride-group molar ratio ranging from 1.1 : 1 to 1.5: 1, typically ranging from 1.2: 1 to 1.4: 1.

[0083] As seen from the above, polysiloxanes having two or more unsaturated groups for use in the present disclosure can be formed using PDMS elastomers. Similarly, hydride materials having two or more hydride groups for use in the present disclosure can be formed using PDMS elastomers. Such materials have several potential advantages including those to follow. First, PDMS is known to be biocompatible and non-cytotoxic (see also Example 7 below). Moreover, as seen from Example 6 below, being hydrophobic allows for complete casting of vessels, wherein blood is pushed from the blood vessels during embolization. In addition, PDMS cures into a soft elastic rubber, facilitating surgical resection, where necessary. Furthermore, as seen from Example 8 below, PDMS polymers having low molecular weight may be employed to reduce overall injection force. Finally, iodinated PDMS may be used in some embodiments, which could eliminate or decrease the level of imaging particles needed.

[0084] As previously noted, the crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, comprise a catalyst for catalyzing a reaction between unsaturated groups and hydride groups. Examples of such catalysts25IPTS / 200152370.1Attorney Docket No. AMD-026WO include for example, a platinum catalyst, a rhodium catalyst, a ruthenium catalyst, a palladium catalyst, an iridium catalyst, a boron trihydride catalyst, and a phosphine catalyst.

[0085] The crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may also optionally contain a catalyst modifier.

[0086] The crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may also optionally contain one or more physical crosslinking agent comprising a plurality of hydrogen bonding groups.

[0087] In various embodiments, physical crosslinking agents for use in the crosslinkable compositions of the present disclosure may comprise a plurality of hydroxy (-OH) groups as hydrogen bonding groups. Examples of physical crosslinking agents include, hydroxy-terminated polymers and dendrimers such as hydroxy-terminated polysiloxanes (e.g., carbinol (hydroxy) terminated polydimethylsiloxane), hydroxy-terminated poly(alkylene oxides) including hydroxyterminated polyethylene oxide and hydroxy-terminated polypropylene oxide, and hydroxyterminated polyvinyl alcohol. Such hydroxy -terminated polymers may be, for example, linear, or may be multiarmed or dendritic, for example, having three, four, five, six or more arms, one specific example of which is a three-arm polymer of the formula,where n is an integer. Other examples include sugars, such as sucrose, cellulose, glucose, and dextrose, and potassium phthalate, polyols (e.g., glycerol, diglycerol, triglycerol, tetraglycerol, pentaglycerol, hexaglycerol, ethylene glycol, propylene glycol, butylene glycol, 1,5-pentane diol, 1,6-hexane diol, trimethylolpropane, 1,2,6-hexane triol, pentaerythritol, sorbitol, mannitol, hydroxypropylmethylcellulose or hydroxypropylethylcellulose) and acrylates (e.g. poly (acrylic acid), 2-hydroxyethylmethacrylate, poly (methyl methacrylate-co-ethyl acrylate)).

[0088] 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 plasticizer may form rounded or beaded droplets when injected while a composition with plasticizer forms elongated droplets. In some embodiments, the plasticizer may be hydrophilic and in others it may be hydrophobic. In some embodiments, the plasticizer may be used to enhance the cohesion of the composition. Examples of plasticizers include trimethylolpropane ethoxylate (TMPEO),26IPTS / 200152370.1Attorney Docket No. AMD-026WO sucrose solution, dimethylsiloxane-(80% ethylene oxide) block copolymer, dimethylsiloxane- (30-35% ethylene oxide) block copolymer, polydimethylsiloxane, trimethylsiloxy terminated, and oils (including but not limited to coconut oil or sunflower oil).

[0089] The crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may also optionally contain one or more silanol compound.

[0090] As used herein, a “silanol” or “silanol compound” is a compound that comprises one or more silanol (Si-OH) groups and is commonly a polysiloxane-based polymer that comprises two or more silanol groups, for example a hydroxy-terminated PDMS, among other examples.

[0091] In various embodiments, silanol compounds for use in the crosslinkable compositions of the present disclosure include silanol-terminated polymers, such as hydroxy-terminatedpolysiloxanes, for example, , where n is an integer. In certain embodiments, hydroxy -terminated polysiloxanes may be selected which have a weight average molecular weight that is less than 4,000 Daltons.

[0092] The crosslinkable compositions described herein, including the crosslinkable compositions formed by any of the above kits or methods, may also optionally contain particles of any material having a diameter ranging from 5 pm or less to 300 pm or more, for example ranging from 5 pm to 10 pm to 25 pm to 50 pm to 100 pm to 300 pm. Such particles may be used to control the distal penetration of the crosslinkable compositions when used as embolics, with penetration distance being controlled based on size. Such particles can be the silica and / or the imaging agent, or may be in addition to them.

[0093] The following methods are applicable to any of the compositions of the disclosure and were applied, as indicated, in the Examples below.Methods of Use

[0094] In one aspect, the present disclosure provides a method in which these biocompatible, crosslinkable compositions are injected into a patient, such as into the vascular system or a body cavity of a patient, and substantially withdrawn from the vasculature of the patient.27IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0095] In an aspect, the present disclosure pertains to methods that comprise (a) forming a crosslinkable composition for vascular embolization as described herein: (b) preparing the crosslinkable composition for injection; (c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the first crosslinkable composition into the vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the vasculature before the first crosslinkable composition crosslinks and forms into a solid. In some embodiments, substantially withdrawing comprises substantially aspirating the crosslinkable composition from the vasculature with a catheter.

[0096] In some embodiments, the crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature.

[0097] In another aspect, the present disclosure pertains to methods that comprise (a) forming a crosslinkable composition for vascular embolization comprising (i) providing a first fluid composition that comprises a crosslinkable polymer and a first imaging agent, (ii) providing a second fluid composition that comprises a crosslinker and an optional second imaging agent, (iii) mixing the first fluid composition and the second fluid composition with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the crosslinkable composition for injection; (c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the first crosslinkable composition into the vasculature, the crosslinkable composition substantially flows into and occludes a target vessel in the vasculature, and wherein the crosslinkable composition is substantially withdrawn from the vasculature before the crosslinkable composition crosslinks and forms into a solid.

[0098] In some embodiments, the crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature.28IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0099] In some embodiments, substantially withdrawing comprises substantially aspirating the crosslinkable composition from the vasculature with a catheter.

[0100] In some embodiments, the method is a method for (1) occlusion of the vasculature for treatment of tumors, (2) pre-surgical embolization of tumors, (3) treatment of chronic subdural hematoma, brain aneurysms, arteriovenous malformations, arteriovenous fistulas, gastrointestinal bleeds, bleeding due to trauma, abdominal aortic aneurysm, intracranial aneurysm, pulmonary aneurysm, or hemorrhage, (4) prostate artery embolization or uterine artery embolization, (5) treatment of visceral aneurysms, varicoceles, or varices, (6) treatment for pelvic congestion, (7) treatment of epistaxis or (8) treatment of endoleaks.

[0101] In some embodiments, the vasculature is located within a hypervascular tumor in the patient. In other embodiments, the vasculature is in located within the middle meningeal artery (MMA) of the patient.

[0102] In some embodiments, the patient is suffering from chronic subdural hematoma.

[0103] In some embodiments, the first imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm.

[0104] In some embodiments, the first imaging agent is bismuth trioxide. In some embodiments, the optional second imaging agent is bismuth trioxide.

[0105] In some embodiments, the crosslinkable polymer is a polysiloxane. In some embodiments, the polysiloxane is a vinyl-terminated polysiloxane, an acrylate-terminated polysiloxane, or a methylacrylate-terminated polysiloxane. In some embodiments, the polysiloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.

[0106] In some embodiments, the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter. In some embodiments, a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

[0107] In some embodiments, the first silica filler and the second silica filler, if present, are fumed silica.

[0108] In some embodiments, the crosslinker is a hydride material having two or more hydride groups.29IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0109] In some embodiments, the crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first fluid composition and second fluid composition.

[0110] In some embodiments, the ratio of the volume of the first fluid composition to the volume of the second fluid composition is in the range of from 4:1 to 1 :4.[oni] In some embodiments, the crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9: 1.

[0112] In some embodiments, the crosslinkable composition contains a catalyst modifier.

[0113] In some embodiments, the crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature prior to substantial withdrawal of the crosslinkable composition, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

[0114] In some embodiments, at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a third and / or fourth fluid composition comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups.

[0115] In some embodiments, the present disclosure provides a method in which these biocompatible, crosslinkable compositions are injected into a patient, such as into the vascular system or a body cavity of a patient, and substantially withdrawn from the vasculature of the patient, followed by an injection of a second crosslinkable composition into a second injection site within a second vasculature of the patient.

[0116] In another aspect, the present disclosure pertains to methods that comprise (a) forming a first crosslinkable composition for vascular embolization as described herein: (b) preparing the first crosslinkable composition for injection; (c) injecting the first crosslinkable composition into a first injection site within a first vasculature of a patient; and (d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid; (e) forming a second crosslinkable composition for vascular embolization comprising: (i) providing a third composition that comprises a second crosslinkable polymer and a third imaging agent, (ii) providing a fourth fluid30IPTS / 200152370.1Attorney Docket No. AMD-026WO composition that comprises a second crosslinker and an optional fourth imaging agent that is the same or different from the third imaging agent; and (iii) mixing the first fluid composition and the second fluid composition with a second dry composition, wherein the second dry composition comprising a third silica filler and an optional fourth silica filler that is the same or different from the first silica filler; thereby forming the second crosslinkable composition, wherein the third imaging agent, the optional fourth imaging agent, the third first silica filler, and the optional fourth silica filler are dispersed in the second crosslinkable composition; (f) preparing the second crosslinkable composition for injection; (g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid. In some embodiments, substantially withdrawing comprises substantially aspirating the first crosslinkable composition from the vasculature with a catheter.

[0117] In some embodiments, the crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature.

[0118] In another aspect, the present disclosure pertains to methods that comprise (a) forming a first crosslinkable composition for vascular embolization comprising (i) providing a first fluid composition that comprises a first crosslinkable polymer and a first imaging agent, (ii) providing a second fluid composition that comprises a first crosslinker and an optional second imaging agent that is the same or different from the third imaging agent, (iii) mixing the first fluid composition and the second fluid composition with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the first crosslinkable composition for injection; (c) injecting the first crosslinkable composition into a first injection site within a first vasculature of a patient; and (d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition31IPTS / 200152370.1Attorney Docket No. AMD-026WO substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid; (e) forming a second crosslinkable composition for vascular embolization comprising: (i) providing a third composition that comprises a second crosslinkable polymer and a third imaging agent, (ii) providing a fourth fluid composition that comprises a second crosslinker and an optional fourth imaging agent that is the same or different from the third imaging agent; and (iii) mixing the first fluid composition and the second fluid composition with a second dry composition, wherein the second dry composition comprising a third silica filler and an optional fourth silica filler that is the same or different from the first silica filler; thereby forming the second crosslinkable composition, wherein the third imaging agent, the optional fourth imaging agent, the third first silica filler, and the optional fourth silica filler are dispersed in the second crosslinkable composition; (f) preparing the second crosslinkable composition for injection; (g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid.

[0119] In some embodiments, the crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature.

[0120] In some embodiments, substantially withdrawing comprises substantially aspirating the first crosslinkable composition from the first vasculature with a catheter.

[0121] In some embodiments, the method is a method for (1) occlusion of the vasculature for treatment of tumors, (2) pre-surgical embolization of tumors, (3) treatment of chronic subdural hematoma, brain aneurysms, arteriovenous malformations, arteriovenous fistulas, cerebrospinal fluid (CSF) venous fistulas, gastrointestinal bleeds, bleeding due to trauma, abdominal aortic aneurysm, intracranial aneurysm, pulmonary aneurysm, or hemorrhage, (4) prostate artery embolization or uterine artery embolization, (5) treatment of visceral aneurysms, varicoceles, or varices, (6) treatment for pelvic congestion, (7) treatment of epistaxis or (8) treatment of endoleaks.32IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0122] In some embodiments, each of the first vasculature and second vasculature is located within a hypervascular tumor in the patient. In other embodiments, each of the first vasculature and second vasculature is located within the middle meningeal artery (MMA) of the patient.

[0123] In some embodiments, the patient is suffering from chronic subdural hematoma.

[0124] In some embodiments, the first imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the third imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the optional fourth imaging agent has an average primary particle size from about 80 nm to about 200 nm.

[0125] In some embodiments, the first imaging agent is bismuth trioxide. In some embodiments, the optional second imaging agent is bismuth trioxide. In some embodiments, the third imaging agent is bismuth trioxide. In some embodiments, the optional fourth imaging agent is bismuth trioxide.

[0126] In some embodiments, each of the first crosslinkable polymer and second crosslinkable polymer is a polysiloxane. In some embodiments, the polysiloxane is a vinyl-terminated polysiloxane, an acrylate-terminated polysiloxane, or a methylaciylate-terminated polysiloxane. In some embodiments, the polysiloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.

[0127] In some embodiments, the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter. In some embodiments, a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

[0128] In some embodiments, the first silica filler and the second silica filler, if present, are fumed silica. In some embodiments, the third silica filler and the fourth silica filler, if present, are fumed silica.

[0129] In some embodiments, each of the first crosslinker and second crosslinker is a hydride material having two or more hydride groups.

[0130] In some embodiments, the first crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first fluid composition and second fluid composition. In some embodiments, the second crosslinkable composition comprises a total33IPTS / 200152370.1Attorney Docket No. AMD-026WO amount of at least 10 wt% of the imaging agent in each of the third fluid composition and fourth fluid composition.

[0131] In some embodiments, the ratio of the volume of the first fluid composition to the volume of the second fluid composition is in the range of from 4:1 to 1 :4.

[0132] In some embodiments, each of the first crosslinkable composition and the second crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9: 1.

[0133] In some embodiments, the crosslinkable composition contains a catalyst modifier.

[0134] In some embodiments, at least one of the first, second, third, and fourth fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a fifth and / or sixth fluid composition comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the first crosslinkable composition, and / or providing a seventh and / or eighth fluid composition comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the second crosslinkable composition.

[0135] In some embodiments, the first crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature prior to substantial withdrawal of the crosslinkable composition, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

[0136] In some embodiments, the second crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns, and whereafter the crosslinkable composition substantially flows into and occludes the plurality of distal vessels in the vasculature, the crosslinkable composition crosslinks and forms into a solid.

[0137] In some aspects, the present disclosure provides a method in which these biocompatible, crosslinkable compositions are injected into a patient, such as into the vascular system or a body cavity of a patient, and substantially withdrawn from the vasculature of the patient.

[0138] In such aspects, the present disclosure pertains to methods that comprise (a) forming a crosslinkable composition for vascular embolization as described herein: (b) preparing the crosslinkable composition for injection; (c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the first34IPTS / 200152370.1Attorney Docket No. AMD-026WO crosslinkable composition into the vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the vasculature before the first crosslinkable composition crosslinks and forms into a solid.

[0139] In another aspect, the present disclosure pertains to methods that comprise (a) forming a crosslinkable composition for vascular embolization comprising (i) providing a first suspension that comprises a crosslinkable polymer and a first imaging agent; (ii) providing a second suspension that comprises a crosslinker and an optional second imaging agent that is the same or different from the first imaging agent; and (iii) mixing the first suspension and the second suspension with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, and the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the crosslinkable composition for injection; (c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the crosslinkable composition into the vasculature, the crosslinkable composition substantially flows into and occludes a target vessel in the vasculature, and wherein the crosslinkable composition is substantially withdrawn from the vasculature before the crosslinkable composition crosslinks and forms into a solid.

[0140] In some embodiments, the crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature. In some embodiments, substantially withdrawing comprises substantially aspirating the crosslinkable composition from the vasculature with a catheter.

[0141] In some embodiments, the method is a method for (1) occlusion of the vasculature for treatment of tumors, (2) pre-surgical embolization of tumors, (3) treatment of chronic subdural hematoma, brain aneurysms, arteriovenous malformations, arteriovenous fistulas, cerebrospinal fluid (CSF) venous fistulas, gastrointestinal bleeds, bleeding due to trauma, abdominal aortic aneurysm, intracranial aneurysm, pulmonary aneurysm, or hemorrhage, (4) prostate artery embolization or uterine artery embolization, (5) treatment of visceral aneurysms, varicoceles, or varices, (6) treatment for pelvic congestion, (7) treatment of epistaxis or (8) treatment of endoleaks.35IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0142] In some embodiments, the vasculature is located within a hypervascular tumor in the patient. In other embodiments, the vasculature is in located within the middle meningeal artery (MMA) of the patient.

[0143] In some embodiments, the patient is suffering from chronic subdural hematoma.

[0144] In some embodiments, the first imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm.

[0145] In some embodiments, the first imaging agent is bismuth trioxide. In some embodiments, the optional second imaging agent is bismuth trioxide.

[0146] In some embodiments, the crosslinkable polymer is a poly siloxane. In some embodiments, the polysiloxane is a vinyl-terminated polysiloxane, an acrylate-terminated polysiloxane, or a methylacrylate-terminated polysiloxane. In some embodiments, the polysiloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.

[0147] In some embodiments, the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter. In some embodiments, a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

[0148] In some embodiments, the first silica filler and the second silica filler, if present, are fumed silica.

[0149] In some embodiments, the crosslinker is a hydride material having two or more hydride groups.

[0150] In some embodiments, the crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first suspension and second suspension.

[0151] In some embodiments The method of any one of claims 51-67, wherein the ratio of the volume of the first suspension to the volume of the second suspension is in the range of from 4: 1 to 1 :4.

[0152] In some embodiments, the crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9: 1.

[0153] In some embodiments, the crosslinkable composition contains a catalyst modifier.

[0154] In some embodiments, the crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature prior to substantial withdrawal of the36IPTS / 200152370.1Attorney Docket No. AMD-026WO crosslinkable composition, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

[0155] In some embodiments, at least one of the first and second suspensions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a third and / or fourth suspension comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups.

[0156] In some embodiments, the present disclosure provides a method in which these biocompatible, crosslinkable compositions are injected into a patient, such as into the vascular system or a body cavity of a patient, and substantially withdrawn from the vasculature of the patient, followed by an injection of a second crosslinkable composition into a second injection site within a second vasculature of the patient.

[0157] In another aspect, the present disclosure pertains to methods that comprise (a) forming a crosslinkable composition for vascular embolization as described herein: (b) preparing the first crosslinkable composition for injection; (c) injecting the first crosslinkable composition into a first injection site within a first vasculature of a patient; and (d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid; (e) forming a second crosslinkable composition for vascular embolization described herein: (f) preparing the second crosslinkable composition for injection; (g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid. In some embodiments, substantially withdrawing comprises substantially aspirating the first crosslinkable composition from the vasculature with a catheter. In some embodiments, the crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature.37IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0158] In such aspects, the present disclosure pertains to methods that comprise (a) forming a first crosslinkable composition for vascular embolization comprising (i) providing a first suspension that comprises a first crosslinkable polymer and a first imaging agent, (ii) providing a second suspension that comprises a first crosslinker and an optional second imaging agent that is the same or different from the third imaging agent, (iii) mixing the first suspension and the second suspension with a dry composition, wherein the dry composition comprising a first silica filler and an optional second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optional second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition; (b) preparing the first crosslinkable composition for injection; (c) injecting the first crosslinkable composition into an injection site within a vasculature of a patient; and (d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid; forming a second crosslinkable composition for vascular embolization comprising: (i) providing a third suspension that comprises a second crosslinkable polymer and a third imaging agent; (ii) providing a fourth suspension that comprises a second crosslinker and an optional fourth imaging agent that is the same or different from the third imaging agent; and (iii) mixing the first suspension and the second suspension with a second dry composition, the second dry composition comprising a third silica filler and an optional fourth silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the third imaging agent, the optional fourth imaging agent, the third first silica filler, and the optional fourth silica filler are dispersed in the crosslinkable composition; (f) preparing the second crosslinkable composition for injection; (g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid.38IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0159] In some embodiments, the crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature.

[0160] In some embodiments, substantially withdrawing comprises substantially aspirating the first crosslinkable composition from the vasculature with a catheter.

[0161] In some embodiments, the method is a method for (1) occlusion of the vasculature for treatment of tumors, (2) pre-surgical embolization of tumors, (3) treatment of chronic subdural hematoma, brain aneurysms, arteriovenous malformations, arteriovenous fistulas, cerebrospinal fluid (CSF) venous fistulas, gastrointestinal bleeds, bleeding due to trauma, abdominal aortic aneurysm, intracranial aneurysm, pulmonary aneurysm, or hemorrhage, (4) prostate artery embolization or uterine artery embolization, (5) treatment of visceral aneurysms, varicoceles, or varices, (6) treatment for pelvic congestion, (7) treatment of epistaxis or (8) treatment of endoleaks.

[0162] In some embodiments, each of the first vasculature and second vasculature is located within a hypervascular tumor in the patient. In other embodiments, each of the first vasculature and second vasculature is located within the middle meningeal artery (MMA) of the patient.

[0163] In some embodiments, the patient is suffering from chronic subdural hematoma.

[0164] In some embodiments, the first imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the third imaging agent has an average primary particle size from about 80 nm to about 200 nm. In some embodiments, the optional fourth imaging agent has an average primary particle size from about 80 nm to about 200 nm.

[0165] In some embodiments, the first imaging agent is bismuth trioxide. In some embodiments, the optional second imaging agent is bismuth trioxide. In some embodiments, the third imaging agent is bismuth trioxide. In some embodiments, the optional fourth imaging agent is bismuth trioxide.

[0166] In some embodiments, each of the first crosslinkable polymer and second crosslinkable polymer is a polysiloxane. In some embodiments, the polysiloxane is a vinyl-terminated polysiloxane, an acrylate-terminated polysiloxane, or a methylacrylate-terminated polysiloxane. In some embodiments, the polysiloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.39IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0167] In some embodiments, the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter. In some embodiments, a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

[0168] In some embodiments, the first silica filler and the second silica filler, if present, are fumed silica. In some embodiments, the third silica filler and the fourth silica filler, if present, are fumed silica.

[0169] In some embodiments, each of the first crosslinker and second crosslinker is a hydride material having two or more hydride groups.

[0170] In some embodiments, the first crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first suspension and second suspension. In some embodiments, the second crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the third suspension and fourth suspension.

[0171] In some embodiments, the ratio of the volume of the first suspension to the volume of the second suspension is in the range of from 4: 1 to 1 :4.

[0172] In some embodiments, each of the first crosslinkable composition and the second crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9:1.

[0173] In some embodiments, the crosslinkable composition contains a catalyst modifier.

[0174] In some embodiments, at least one of the first, second, third, and fourth suspensions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a fifth and / or sixth suspension comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the first crosslinkable composition, and / or providing a seventh and / or eighth suspension comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the second crosslinkable composition.

[0175] In some embodiments, the first crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature prior to substantial withdrawal of the crosslinkable composition, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

[0176] In some embodiments, the second crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the40IPTS / 200152370.1Attorney Docket No. AMD-026WO plurality of distal vessels has a diameter of less than 100 microns, and whereafter the crosslinkable composition substantially flows into and occludes the plurality of distal vessels in the vasculature, the crosslinkable composition crosslinks and forms into a solid.

[0177] Exemplary crosslinkable compositions that may be used in the present methods as disclosed herein (e.g., a crosslinkable composition, a first crosslinkable composition, or a second crosslinkable composition as provided in the present methods) are provided in Table A below.41IPTS / 200152370.1Attorney Docket No. AMD-026WOEXAMPLESExample 1. Structural Properties of an Embolic Composition

[0178] The structural properties of a crosslinkable composition formulated from two wet phases and a dry phase was studied. The first wet phase contained (i) 32 weight percent vinyl poly dimethylsiloxane (PDMS) with a catalyst and vinyl catalyst modifier, and (ii) 17.5 weight percent bismuth trioxide; the second wet phase contained (i) 32 weight percent hydride PDMS and crosslinker, and (ii) 17.5 weight percent bismuth tri oxide; and the dry phase contained 1 weight percent silica. Weight percentages are indicated relative to the total weight of the composition.

[0179] Even prior to cure, which takes 9.0 ± 0.7 min at 37°C to complete, the crosslinkable composition exhibited sufficient structure to maintain occlusion as evidenced by lack of material movement under fluoroscopy after injections were completed; during this period, the crosslinkable composition maintained the ability to behave as a fluid and could therefore be aspirated if desired by an interventionalist.

[0180] FIG. 3 shows phase angle recovery graphs of samples of the crosslinkable composition at 37°C and 25°C that supports the above findings. “Cure time” is defined as the time at which the phase angle exhibits a local maximum (indicated by the arrows) following application of high shear. The cure time at 37°C was 9.0 ± 0.7 minutes. The cure time at 25°C was 30.1 ± 2.9 minutes.Example 2. Aspiration Study of an Embolic Material in a Swine Kidney

[0181] The feasibility of the aspiration of the crosslinkable composition of Example 1 was demonstrated in an animal study. Briefly, uncured crosslinkable material in the proximal section of an artery of a swine kidney was successfully aspirated using a 5Fr guide catheter.

[0182] FIG. 4A provides a fluoroscopic image showing vessel embolized with the crosslinkable composition prior to cure. A guide catheter is positioned at the proximal end of the cast. The guide catheter is advanced forward as material is aspirated (by application of a vacuum through the guide catheter provided by a syringe). FIG. 4B provides a fluoroscopic image showing the final position of the guide catheter tip with the crosslinkable composition no longer present proximal to the guide catheter tip.47IPTS / 200152370.1Attorney Docket No. AMD-026WO

[0183] Removal of embolic agent that is present proximally within the parent artery is feasible with the crosslinkable composition of Example 1 because the material solidifies via a time-based curing mechanism. At the completion of embolization, the crosslinkable composition of Example 1 remains in a structured but uncured state, enabling material to be removed from the vasculature via aspiration.Example 3. Aspiration Study of an Embolic Material

[0184] This Example describes aspiration of the crosslinkable composition of Example 1 in a human clinical study. FIG. 5A shows the presence of the composition in the proximal portion of the vessel. An intermediate catheter (Penumbra Midway 043 DAC) was advanced into the patient’s middle meningeal artery, and suction was applied via a syringe. The crosslinkable composition was successfully aspirated from the proximal portion of the vessel (FIG. 5B).48IPTS / 200152370.1

Claims

Attorney Docket No. AMD-026WOCLAIMSWhat Is Claimed Is:

1. A method, comprising:(a) forming a crosslinkable composition for vascular embolization comprising:(i) providing a first fluid composition comprising (A) a crosslinkable polymer and (B) a first imaging agent;(ii) providing a second fluid composition comprising (A) a crosslinker and, optionally, (B) a second imaging agent that is the same or different from the first imaging agent; and(iii) mixing the first fluid composition and the second fluid composition with a dry composition, the dry composition comprising a first silica filler and, optionally, a second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optionally second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition;(b) preparing the crosslinkable composition for injection;(c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and(d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the crosslinkable composition into the vasculature, the crosslinkable composition substantially flows into and occludes a target vessel in the vasculature, and wherein the crosslinkable composition is substantially withdrawn from the vasculature before the crosslinkable composition crosslinks and forms into a solid.

2. The method of claim 1, wherein substantially withdrawing comprises substantially aspirating the crosslinkable composition from the vasculature with a catheter.49IPTS / 200152370.1Attorney Docket No. AMD-026WO3. The method of claim 1 or 2, wherein the method is a method for (1) occlusion of the vasculature for treatment of tumors, (2) pre-surgical embolization of tumors, (3) treatment of chronic subdural hematoma, brain aneurysms, arteriovenous malformations, arteriovenous fistulas, cerebrospinal fluid (CSF) venous fistulas, gastrointestinal bleeds, bleeding due to trauma, abdominal aortic aneurysm, intracranial aneurysm, pulmonary aneurysm, or hemorrhage, (4) prostate artery embolization or uterine artery embolization, (5) treatment of visceral aneurysms, varicoceles, or varices, (6) treatment for pelvic congestion, (7) treatment of epistaxis or (8) treatment of endoleaks.

4. The method of any one of claims 1-3, wherein the vasculature is located within a hypervascular tumor in the patient.

5. The method of any one of claims 1-3, wherein the vasculature is in located within the middle meningeal artery (MMA) of the patient.

6. The method of any one of claims 1-5, wherein the patient is suffering from chronic subdural hematoma.

7. The method of any one of claims 1-6, wherein the first imaging agent has an average primary particle size from about 80 nm to about 200 nm.

8. The method of any one of claims 1-7, wherein the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm.

9. The method of any one of claims 1-8, wherein the first imaging agent is bismuth trioxide.

10. The method of any one of claims 1-9, wherein the optional second imaging agent is bismuth trioxide.

11. The method of any one of claims 1-10, wherein the crosslinkable polymer is a polysiloxane.

12. The method of claim 11, wherein the polysiloxane is a vinyl -terminated polysiloxane , an acrylate-terminated polysiloxane, or a methylacrylate-terminated polysiloxane.

13. The method of claim 11 or 12, wherein the poly siloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.50IPTS / 200152370.1Attorney Docket No. AMD-026WO14. The method of any one of claims 1-13, wherein the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter.

15. The method of any one of claims 1-14, wherein a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

16. The method of any one of claims 1-15, wherein the first silica filler and the second silica filler, if present, are fumed silica.

17. The method of any one of claims 1-16, wherein the crosslinker is a hydride material having two or more hydride groups.

18. The method of any one of claims 1-17, wherein the crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first fluid composition and second fluid composition.

19. The method of any one of claims 1-18, wherein the ratio of the volume of the first fluid composition to the volume of the second fluid composition is in the range of from 4: 1 to 1 :4.

20. The method of any one of claims 1-19, wherein the crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9: 1.21 . The method of any one of claims 1-20, wherein the crosslinkable composition contains a catalyst modifier.

22. The method of any one of claims 1-21, wherein, prior to substantially withdrawing the crosslinkable composition, the crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

23. The method of any one of claims 1-22, wherein at least one of the first and second fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a third and / or fourth fluid51IPTS / 200152370.1Attorney Docket No. AMD-026WO composition comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups.

24. A method, comprising:(a) forming a first crosslinkable composition for vascular embolization comprising:(i) providing a first fluid composition comprising (A) a first crosslinkable polymer and (B) a first imaging agent;(ii) providing a second fluid composition comprising (A) a first crosslinker and, optionally, (B) a second imaging agent that is the same or different from the first imaging agent; and(iii) mixing the first fluid composition and the second fluid composition with a first dry composition, the first dry composition comprising a first silica filler and, optionally, a second silica filler that is the same or different from the first silica filler; thereby forming the first crosslinkable composition, wherein the first imaging agent, the optionally second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition;(b) preparing the first crosslinkable composition for injection;(c) injecting the first crosslinkable composition into a first injection site within a first vasculature of a patient; and(d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid;(e) forming a second crosslinkable composition for vascular embolization comprising:52IPTS / 200152370.1Attorney Docket No. AMD-026WO(i) providing a third fluid composition comprising (A) a second crosslinkable polymer and (B) a third imaging agent;(ii) providing a fourth fluid composition comprising (A) a second crosslinker and, optionally, (B) a fourth imaging agent that is the same or different from the third imaging agent; and(iii) mixing the third fluid composition and the fourth fluid composition with a second dry composition, the second dry composition comprising a third silica fdler and, optionally, a fourth silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the third imaging agent, the optional fourth imaging agent, the third first silica filler, and the optional fourth silica filler are dispersed in the crosslinkable composition;(f) preparing the second crosslinkable composition for injection;(g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid.

25. The method of claim 23, wherein substantially withdrawing comprises substantially aspirating the first crosslinkable composition from the first vasculature with a catheter.

26. The method of claim 23 or 24, wherein each of the first vasculature and second vasculature is located within a hypervascular tumor in the patient.

27. The method of claim 23, wherein each of the first vasculature and second vasculature is located within the middle meningeal artery (MMA) of the patient.

28. The method of any one of claims 24-27, wherein the patient is suffering from chronic subdural hematoma.

29. The method of any one of claims 24-28, wherein the first imaging agent has an average primary particle size from about 80 nm to about 200 nm.53IPTS / 200152370.1Attorney Docket No. AMD-026WO30. The method of any one of claims 24-29, wherein the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm.

31. The method of any one of claims 24-30, wherein the third imaging agent has an average primary particle size from about 80 nm to about 200 nm.

32. The method of any one of claims 24-31, wherein the optional fourth imaging agent has an average primary particle size from about 80 nm to about 200 nm.

33. The method of any one of claims 24-32, wherein the first imaging agent is bismuth trioxide.

34. The method of any one of claims 24-33, wherein the optional second imaging agent is bismuth trioxide.

35. The method of any one of claims 24-34, wherein the third imaging agent is bismuth trioxide.

36. The method of any one of claims 24-35, wherein the optional fourth imaging agent is bismuth trioxide.

37. The method of any one of claims 24-36, wherein each of the first crosslinkable polymer and second crosslinkable polymer is a polysiloxane.

38. The method of claim 37, wherein the polysiloxane is a vinyl -terminated polysiloxane , an acrylate-terminated polysiloxane, or a methylacrylate-terminated polysiloxane.

39. The kit of claim 37 or 38, wherein the polysiloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.

40. The method of any one of claims 24-39, wherein the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter.

41. The method of any one of claims 24-40, wherein a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

42. The method of any one of claims 24-41, wherein the first silica filler and the second silica filler, if present, are fumed silica.54IPTS / 200152370.1Attorney Docket No. AMD-026WO43. The method of any one of claims 24-42, wherein the third silica fdler and the fourth silica filler, if present, are fumed silica.

44. The method of any one of claims 24-43, wherein each of the first crosslinker and second crosslinker is a hydride material having two or more hydride groups.

45. The method of any one of claims 24-44, wherein the first crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first fluid composition and second fluid composition.

46. The method of any one of claims 24-45, wherein the second crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the third fluid composition and fourth fluid composition.

47. The method of any one of claims 24-46, wherein the ratio of the volume of the first fluid composition to the volume of the second fluid composition is in the range of from 4:1 to 1 :4.

48. The method of any one of claims 24-47, wherein each of the first crosslinkable composition and the second crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9: 1.

49. The method of any one of claims 24-48, wherein the crosslinkable composition contains a catalyst modifier.

50. The method of any one of claims 24-49, wherein at least one of the first, second, third, and fourth fluid compositions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a fifth and / or sixth fluid composition comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the first crosslinkable composition, and / or providing a seventh and / or eighth fluid composition comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the second crosslinkable composition.

51. The method of any one of claims 24-50, wherein, prior to substantially withdrawing the first crosslinkable composition, the first crosslinkable composition substantially flows into and55IPTS / 200152370.1Attorney Docket No. AMD-026WO occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

52. The method of any one of claims 24-51, wherein the second crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns, and whereafter the crosslinkable composition substantially flows into and occludes the plurality of distal vessels in the vasculature, the crosslinkable composition crosslinks and forms into a solid.

53. A method, comprising:(a) forming a crosslinkable composition for vascular embolization comprising:(i) providing a first suspension comprising (A) a crosslinkable polymer and (B) a first imaging agent;(ii) providing a second suspension comprising (A) a crosslinker and, optionally, (B) a second imaging agent that is the same or different from the first imaging agent; and(iii) mixing the first suspension and the second suspension with a dry composition, the dry composition comprising a first silica filler and, optionally, a second silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the first imaging agent, the optionally second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition;(b) preparing the crosslinkable composition for injection;(c) injecting the crosslinkable composition into an injection site within a vasculature of a patient; and(d) substantially withdrawing the crosslinkable composition from the vasculature of the patient; whereupon injection of the crosslinkable composition into the vasculature, the crosslinkable composition substantially flows into and occludes a target vessel in the vasculature,56IPTS / 200152370.1Attorney Docket No. AMD-026WO and wherein the crosslinkable composition is substantially withdrawn from the vasculature before the crosslinkable composition crosslinks and forms into a solid.

54. The method of claim 53, wherein substantially withdrawing comprises substantially aspirating the crosslinkable composition from the vasculature with a catheter.

55. The method of claim 53 or 54, wherein the method is a method for (1) occlusion of the vasculature for treatment of tumors, (2) pre-surgical embolization of tumors, (3) treatment of chronic subdural hematoma, brain aneurysms, arteriovenous malformations, arteriovenous fistulas, cerebrospinal fluid (CSF) venous fistulas, gastrointestinal bleeds, bleeding due to trauma, abdominal aortic aneurysm, intracranial aneurysm, pulmonary aneurysm, or hemorrhage, (4) prostate artery embolization or uterine artery embolization, (5) treatment of visceral aneurysms, varicoceles, or varices, (6) treatment for pelvic congestion, (7) treatment of epistaxis or (8) treatment of endoleaks.

56. The method of any one of claims 53-55, wherein the vasculature is located within a hypervascular tumor in the patient.

57. The method of any one of claims 53-55, wherein the vasculature is in located within the middle meningeal artery (MMA) of the patient.

58. The method of any one of claims 53-57, wherein the patient is suffering from chronic subdural hematoma.

59. The method of any one of claims 53-58, wherein the first imaging agent has an average primary particle size from about 80 nm to about 200 nm.

60. The method of any one of claims 53-59, wherein the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm.

61. The method of any one of claims 53-60, wherein the first imaging agent is bismuth trioxide.

62. The method of any one of claims 53-61, wherein the optional second imaging agent is bismuth tri oxide.57IPTS / 200152370.1Attorney Docket No. AMD-026WO63. The method of any one of claims 53-62, wherein the crosslinkable polymer is a polysiloxane.

64. The method of claim 63, wherein the polysiloxane is a vinyl-terminated polysiloxane , an acrylate-terminated polysiloxane, or a methylacrylate-terminated polysiloxane.

65. The method of claim 63 or 64, wherein the poly siloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.

66. The method of any one of claims 53-65, wherein the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter.

67. The method of any one of claims 53-66, wherein a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

68. The method of any one of claims 53-67, wherein the first silica filler and the second silica filler, if present, are fumed silica.

69. The method of any one of claims 53-68, wherein the crosslinker is a hydride material having two or more hydride groups.

70. The method of any one of claims 53-69, wherein the crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first suspension and second suspension.

71. The method of any one of claims 53-70, wherein the ratio of the volume of the first suspension to the volume of the second suspension is in the range of from 4: 1 to 1 :4.

72. The method of any one of claims 53-71, wherein the crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9: 1.

73. The method of any one of claims 53-72, wherein the crosslinkable composition contains a catalyst modifier.58IPTS / 200152370.1Attorney Docket No. AMD-026WO74. The method of any one of claims 53-73, wherein, prior to substantially withdrawing the crosslinkable composition, the crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

75. The method of any one of claims 53-74, wherein at least one of the first and second suspensions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a third and / or fourth suspension comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups.

76. A method, comprising:(a) forming a first crosslinkable composition for vascular embolization comprising:(i) providing a first suspension comprising (A) a first crosslinkable polymer and (B) a first imaging agent;(ii) providing a second suspension comprising (A) a first crosslinker and, optionally, (B) a second imaging agent that is the same or different from the first imaging agent; and(iii) mixing the first suspension and the second suspension with a first dry composition, the first dry composition comprising a first silica filler and, optionally, a second silica filler that is the same or different from the first silica filler; thereby forming the first crosslinkable composition, wherein the first imaging agent, the optionally second imaging agent, the first silica filler, and the optional second silica filler are dispersed in the crosslinkable composition;(b) preparing the first crosslinkable composition for injection;(c) injecting the first crosslinkable composition into a first injection site within a first vasculature of a patient; and59IPTS / 200152370.1Attorney Docket No. AMD-026WO(d) substantially withdrawing the first crosslinkable composition from the first vasculature of the patient; whereupon injection of the first crosslinkable composition into the first vasculature, the first crosslinkable composition substantially flows into and occludes a target vessel in the first vasculature, and wherein the first crosslinkable composition is substantially withdrawn from the first vasculature before the first crosslinkable composition crosslinks and forms into a solid;(e) forming a second crosslinkable composition for vascular embolization comprising:(i) providing a third suspension comprising (A) a second crosslinkable polymer and (B) a third imaging agent;(ii) providing a fourth suspension comprising (A) a second crosslinker and, optionally, (B) a fourth imaging agent that is the same or different from the third imaging agent; and(iii) mixing the first suspension and the second suspension with a second dry composition, the second dry composition comprising a third silica filler and, optionally, a fourth silica filler that is the same or different from the first silica filler; thereby forming the crosslinkable composition, wherein the third imaging agent, the optional fourth imaging agent, the third first silica filler, and the optional fourth silica filler are dispersed in the crosslinkable composition;(f) preparing the second crosslinkable composition for injection;(g) injecting the second crosslinkable composition into a second injection site within a second vasculature of the patient, wherein the second vasculature is the same as or different than the first vasculature and the second injection site is the same as or different than the first injection site, whereupon the second crosslinkable composition substantially flows into and occludes a target vessel in the second vasculature, and whereafter the second crosslinkable composition crosslinks and forms into a solid.

77. The method of claim 76, wherein substantially withdrawing comprises substantially aspirating the first crosslinkable composition from the first vasculature with a catheter.60IPTS / 200152370.1Attorney Docket No. AMD-026WO78. The method of claim 76 or 77, wherein each of the first vasculature and second vasculature is located within a hypervascular tumor in the patient.

79. The method of claim 76 or 77, wherein each of the first vasculature and second vasculature is located within the middle meningeal artery (MMA) of the patient.

80. The method of any one of claims 76-79, wherein the patient is suffering from chronic subdural hematoma.

81. The method of any one of claims 76-80, wherein the first imaging agent has an average primary particle size from about 80 nm to about 200 nm.

82. The method of any one of claims 76-81, wherein the optional second imaging agent has an average primary particle size from about 80 nm to about 200 nm.

83. The method of any one of claims 76-82, wherein the third imaging agent has an average primary particle size from about 80 nm to about 200 nm.

84. The method of any one of claims 76-83, wherein the optional fourth imaging agent has an average primary particle size from about 80 nm to about 200 nm.

85. The method of any one of claims 76-84, wherein the first imaging agent is bismuth trioxide.

86. The method of any one of claims 76-85, wherein the optional second imaging agent is bismuth trioxide.

87. The method of any one of claims 76-86, wherein the third imaging agent is bismuth trioxide.

88. The method of any one of claims 76-87, wherein the optional fourth imaging agent is bismuth tri oxide.

89. The method of any one of claims 76-88, wherein each of the first crosslinkable polymer and second crosslinkable polymer is a polysiloxane.

90. The method of claim 89, wherein the polysiloxane is a vinyl -terminated polysiloxane , an acrylate-terminated polysiloxane, or a methylacrylate-terminated polysiloxane.61IPTS / 200152370.1Attorney Docket No. AMD-026WO91 . The method of claim 89 or 90, wherein the polysiloxane has a weight average molecular weight ranging from 250 Da to 10,000 Da.

92. The method of any one of claims 76-91, wherein the crosslinkable composition is injected into the vasculature via an inflatable balloon catheter.

93. The method of any one of claims 76-92, wherein a balloon of the balloon catheter is inflated at a site proximal to the injection site and maintained in place for a period of time following injection of the crosslinkable composition.

94. The method of any one of claims 76-93, wherein the first silica filler and the second silica filler, if present, are fumed silica.

95. The method of any one of claims 76-94, wherein the third silica filler and the fourth silica filler, if present, are fumed silica.

96. The method of any one of claims 76-95, wherein each of the first crosslinker and second crosslinker is a hydride material having two or more hydride groups.

97. The method of any one of claims 76-96, wherein the first crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the first suspension and second suspension.

98. The method of any one of claims 76-97, wherein the second crosslinkable composition comprises a total amount of at least 10 wt% of the imaging agent in each of the third suspension and fourth suspension.

99. The method of any one of claims 76-98, wherein the ratio of the volume of the first suspension to the volume of the second suspension is in the range of from 4: 1 to 1 :4.

100. The method of any one of claims 76-99, wherein each of the first crosslinkable composition and the second crosslinkable composition comprises a molar ratio of vinyl groups to hydride groups of >0.9: 1.

101. The method of any one of claims 76-100, wherein the crosslinkable composition contains a catalyst modifier.62IPTS / 200152370.1Attorney Docket No. AMD-026WO102. The method of any one of claims 76-101, wherein at least one of the first, second, third, and fourth suspensions comprises a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups, or the method further comprises providing a fifth and / or sixth suspension comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the first crosslinkable composition, and / or providing a seventh and / or eighth suspension comprising a catalyst for catalyzing a reaction between the unsaturated groups and the hydride groups to form the second crosslinkable composition.

103. The method of any one of claims 76-102, wherein, prior to substantially withdrawing the first crosslinkable composition, the first crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns.

104. The method of any one of claims 76-103, wherein the second crosslinkable composition substantially flows into and occludes a plurality of distal vessels in the vasculature, wherein at least one distal vessel in the plurality of distal vessels has a diameter of less than 100 microns, and whereafter the crosslinkable composition substantially flows into and occludes the plurality of distal vessels in the vasculature, the crosslinkable composition crosslinks and forms into a solid.

105. The method of any one of claims 1-104, wherein the first crosslinkable composition is substantially withdrawn from the proximal portion of the vasculature.63IPTS / 200152370.1

Images