Hydrophobic embolic compositions

Abstract

Liquid embolic compositions, systems, and methods for occluding a treatment site are provided. In some embodiments, a system for occluding a treatment site includes a first precursor composition (Part A) including a first polymer (Polymer A) having a first reactive group (Reactive Group A), and a second precursor composition (Part B) including a second polymer (Part B) having a second reactive group (Reactive Group B). Mixing of Part A and B can cause a covalent crosslinking reaction between the Reactive Group A and Reactive Group B to form an embolic composition. The embolic composition is solvent free, hydrophobic, and immiscible with blood. The embolic composition has an initial viscosity that permits hand injection via a microcatheter to a treatment site and cures to an occlusive, soft solid.

Description

MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WOHYDROPHOBIC EMBOLIC COMPOSITIONSCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of priority to Greek Patent Application No. 20240100759, filed October 29, 2024, which is incorporated herein by reference in its entirety.TECHNICAL FIELD

[0002] The present technology generally relates to biocompatible materials, and in particular, to hydrophobic embolic compositions.BACKGROUND

[0003] The delivery of fluid compositions which solidify in vivo is useful for numerous vascular applications including the occlusion of aneurysms, arteriovenous malformations, arteriovenous fistulas, endoleaks, and highly vascularized tumors. However, conventional fluid compositions generally include organic solvents (e.g., dimethyl sulfoxide) that may cause undesirable side effects such as angionecrosis, vasospasms, and pain during injection (thus necessitating anesthesia). Moreover, conventional compositions are generally formulated from polymers having a glass transition temperature above physiological temperature, such that the resulting solid cast is stiff and brittle, which may lead to fragmentation, unintended embolization at non-target sites, and / or vascular trauma.BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Instead, emphasis is placed on illustrating clearly the principles of the present disclosure.

[0005] FIG. 1A is a partially schematic view of a treatment system configured in accordance with embodiments of the present technology.

[0006] FIG. IB is an exploded view of an embolic kit of the treatment system of FIG. 1A.

[0007] FIG. 1C is an enlarged cross-sectional view of a distal portion of the treatment system of FIG. 1 A with an optional occlusion device.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WODETAILED DESCRIPTION

[0008] The present technology relates to compositions configured for delivery to a treatment site in a patient’s body, such an arteriovenous malformation, an arteriovenous fistula, a middle meningeal artery, an aneurysm, or a tumor, and associated systems and methods. In some embodiments, for example, a system for occluding a treatment site includes a first precursor composition (Part A) including a first polymer (Polymer A) having a first reactive group (Reactive Group A), and a second precursor composition (Part B) including a second polymer (Part B) having a second reactive group (Reactive Group B). Mixing of Part A and B can cause a covalent crosslinking reaction between the Reactive Group A and Reactive Group B to form an embolic composition. The embolic composition is solvent free, hydrophobic, and immiscible with blood. The embolic composition has an initial viscosity that permits hand injection via a microcatheter to a treatment site and cures to an occlusive, soft solid.

[0009] The present technology can provide many advantages over conventional approaches for embolization. For example, conventional liquid embolic systems typically have some degree of hydrophilicity, which may result in inadequate displacement of blood from the treatment site and / or slow or incomplete occlusion. Moreover, conventional systems typically use organic solvents that may produce toxicity and / or other undesirable side effects (e.g., dimethyl sulfoxide can cause vasospasms, injection pain, and a garlic-like odor). Additionally, conventional systems are generally formulated with high glass transition temperature materials (e.g., greater than 37 °C), such that the resulting cast is stiff and brittle, and thus may fragment and / or cause trauma to the treatment site. In contrast, the embolic compositions disclosed herein are formulated from liquid hydrophobic polymers that are immiscible with the blood, thus leading to fast, complete, and permanent occlusion of the treatment site with low risk of leaching from the treatment site. Such compositions may be formulated without organic solvents (and, in some cases, without any solvent), thus avoiding the issue of solvent-induced toxicity. Moreover, the compositions herein can have a sufficiently low glass transition temperature to form an elastic, compliant cast within the treatment site.

[0010] Embodiments of the present disclosure will be described more fully hereinafter with reference to the accompanying drawings in which like numerals represent like elements throughout the several figures, and in which example embodiments are shown. Embodiments of the claims may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. The examples set forth herein are non-limiting examples and are merely examples among other possible examples.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0011] The headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed present technology. Embodiments under any one heading may be used in conjunction with embodiments under any other heading.I. Treatment Systems

[0012] FIG. 1 A shows a treatment system 100 (“system 100”) configured in accordance with embodiments of the present technology. The system 100 can be used in the treatment of many different types of diseases and conditions, such as arteriovenous malformations (e.g., brain arteriovenous malformations), arteriovenous fistulas, tumors (e.g., via occlusion of vessel(s) feeding a tumor), chronic subdural hematomas (e.g., via occlusion of the middle meningeal artery), perivascular leaks, varicose veins (e.g., via occlusion of one or more truncal veins such as the great saphenous vein), hemorrhoids, and sealing endoleaks adjacent to artificial heart valves, covered stents, and abdominal aortic aneurysm devices.

[0013] As shown in FIG. 1 A, the system 100 includes a delivery system 102 including a distal outlet 104 for delivering an embolic composition 152 to a treatment site, and an embolic kit 150 for preparing the embolic composition 152. The embolic composition 152 can be any material suitable for forming a solid or semi-solid viscoelastic structure (e.g., a cast) that partially or completely occludes the treatment site, as discussed further below.

[0014] The delivery system 102 has a proximal portion 106a configured to be extracorporeally positioned during treatment and a distal portion 106b including the distal outlet 104 that is configured to be intravascularly positioned at or within a treatment site (e.g., a vascular defect or other lesion). The delivery system 102 may include a handle 108 at the proximal portion 106a and a plurality of elongate shafts extending between the handle 108 and the distal portion 106b. In some embodiments, for example as shown in FIG. 1A, the delivery system 102 may include a first elongate shaft 110 (such as a guide catheter or balloon guide catheter), a second elongate shaft 112 (such as a microcatheter) configured to be slidably disposed within a lumen of the first elongate shaft 110, and a third elongate shaft 114 configured to be slidably disposed within a lumen of the second elongate shaft 112. In some embodiments, the delivery system 102 does not include the first elongate shaft 110.

[0015] The second elongate shaft 112 can be constructed to track over a conventional guidewire and into vasculature to access the treatment site. The second elongate shaft 112 may also be chosen according to several standard designs that are generally available. For example, the second elongate shaft 112 can have a length that is at least 125 cm long, and moreMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO particularly may be between about 125 cm and about 175 cm long. The second elongate shaft 112 can have an inner diameter less than or equal to 0.006 inches (0.015 cm), 0.011 inches (0.028 cm), 0.015 inches (0.038 cm), 0.017 inches (0.043 cm), 0.021 inches (0.053 cm), or 0.027 inches (0.069 cm).

[0016] The third elongate shaft 114 can be movable within the first and / or second elongate shafts 110, 112 to position the distal outlet 104 at a desired location. The third elongate shaft 114 can be sufficiently flexible to enable manipulation (e.g., advancement and / or retraction) through tortuous passages. Tortuous passages can include, for example, catheter lumens, microcatheter lumens, blood vessels, urinary tracts, biliary tracts, and airways. The third elongate shaft 114 can be formed of any material and in any dimensions suitable for the task(s) for which the system 100 is to be employed. In some embodiments, at least the distal portion of the third elongate shaft 114 can comprise a flexible metal hypotube. The hypotube, for example, can be laser cut along all or a portion of its length to impart increased flexibility. In some embodiments, the third elongate shaft 114 can be surrounded over some or all of its length by a lubricious coating, such as polytetrafluoroethylene (PTFE). The third elongate shaft 114 can have an inner diameter less than or equal to 0.006 inches (0.015 cm), 0.011 inches (0.028 cm), 0.015 inches (0.038 cm), 0.017 inches (0.043 cm), 0.021 inches (0.053 cm), or 0.027 inches (0.069 cm).

[0017] Although FIG. 1 A illustrates the delivery system 102 with three elongate shafts 110, 112, and 114, in other embodiments, some of the elongate shafts may be omitted or the delivery system 102 may include additional elongate shafts.

[0018] The embolic kit 150 includes an embolic composition 152 (e.g., a hydrophobic embolic composition as described in Section II below) and an injector 154 configured to be fluidly coupled to a proximal portion of the delivery system 102 for injection of the embolic composition 152 into a treatment site. For example, a distal end portion of the injector 154 can be fluidly coupled to a proximal end portion of the third elongate shaft 114 via a port 118. The port 118 can be located at the proximal portion 106a of the delivery system 102, such as on or proximal to the handle 108.

[0019] Referring next to FIG. IB, in some embodiments, the embolic kit 150 includes one or more precursor compositions for formulating the embolic composition 152. For example, the embolic kit 150 may include a first precursor composition 156a and a second precursor composition 156b that can be mixed together to form the embolic composition 152.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WOThe first precursor composition 156a can include a first reactive polymer, and the second precursor composition 156b can include a second reactive polymer. Mixing of the first precursor composition 156a and second precursor composition 156b can initiate a chemical crosslinking reaction between the first and second reactive polymers, thereby forming a cohesive solid suitable for occluding the treatment site. Additional details of materials that may be used in the first precursor composition 156a and the second precursor composition 156b, as well as details of the crosslinking process, are described in Section II below.

[0020] In some embodiments, the embolic kit 150 is configured for mixing the first precursor composition 156a and the second precursor composition 156b. For example, in the illustrated embodiment, the injector 154 is configured as a dual-barrel syringe include a first barrel 158a containing the first precursor composition 156a, and a second barrel 158b containing the second precursor composition 156b, and a pair of plungers 160 configured to be slidably received within the first and second barrels 158a, 158b. The injector 154 can be configured to couple to a static mixer 162 (e.g., via a Luer lock or other connector), and the static mixer 162 can be configured to couple to the delivery system 102 (e.g., via a Luer lock or other connector). To mix the first and second precursor compositions 156a, 156b, the plungers 160 can be inserted into the respective first and second barrels 158a, 158b, thereby pushing the first and second precursor compositions 156a, 156b into the static mixer 162. The static mixer 162 can include mixing elements (e.g, baffles, channels) that cause the first and second precursor compositions 156a, 156b to be mixed with each other as they flow through the static mixer 162, thereby initiating a chemical crosslinking reaction to form the embolic composition 152. Continued application of pressure to the plungers 160 can cause the embolic composition 152 to flow out of the static mixer 162 and into the delivery system 102.

[0021] Although FIG. IB illustrates an example configuration for the embolic kit 150, it will be appreciated that other configurations are possible. For example, in other embodiments, the embolic kit 150 can include two separate syringes containing the first precursor composition 156a and the second precursor composition 156b, respectively, and mixing can be performed by coupling the syringes to each other and pushing the precursor compositions 156a, 156b back and forth between the two syringes. One of the two syringes may be used as the injector 154, or the injector 154 may be a third syringe that is coupled to the two syringes to collect the combined compositions after mixing is complete.

[0022] Referring again to FIG. 1 A, the injector 154 can be configured to pressurize the embolic composition 152 to a pressure that is sufficiently high to push the embolic compositionMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO152 through the components of the delivery system 102 (e.g., through the lumen of the third elongate shaft 114) and into the treatment site to fill and occlude the treatment site. As described further in Section II below, the embolic composition 152 can be liquid before the crosslinking reaction is complete so that relatively low pressures are needed to inject the embolic composition 152 through the delivery system 102, e.g., the embolic composition 152 can be injectable by hand through a standard disposable syringe. In some embodiments, the maximum pressure needed to inject the embolic composition 152 is less than or equal to 5000 psi, 4000 psi, 3000 psi, 2000 psi, 1000 psi, 500 psi, 200 psi, or 100 psi.

[0023] Referring next to FIG. 1C, the system 100 can optionally include an occlusive device 120 (also referred to herein as an “occlusive member,” “neck cover,” or a “neck protection device” — shown schematically) at the distal portion 106b. The occlusive device 120 may be used, for example, to prevent the embolic composition 152 from leaking out of the treatment site. For example, in embodiments where the system 100 is used to treat an aneurysm, the embolic composition 152 can be delivered to a space between the occlusive device 120 and the dome of the aneurysm to fill and occlude the aneurysm cavity. The occlusive device 120 prevents migration of the embolic composition 152 into the parent vessel, and together the occlusive device 120 and embolic composition 152 prevent blood from flowing into the aneurysm. As described in greater detail below, bioabsorption of the embolic composition 152 (in embodiments where the embolic composition 152 is biodegradable) and / or endothelialization of the occlusive device 120 may cause the aneurysm wall to fully degrade, leaving behind a successfully remodeled (aneurysm free) region of the blood vessel.

[0024] In some embodiments, the occlusive device 120 is configured to be detachably coupled to the delivery system 102, and the delivery system 102 is configured to intravascularly position the occlusive device 120 within the treatment site. Representative examples of occlusive devices suitable for use with the system 100 are described in U.S. Patent No. 8,142,456, U.S. Patent No. 9,855,051, U.S. Patent No. 10,327,781, U.S. Patent Application Publication No. 2020 / 0187953, U.S. Patent Application Publication No. 2021 / 0128169, and U.S. Patent Application Publication No. 2021 / 0153872, the disclosures of which are incorporated by reference herein in their entirety.

[0025] The occlusive device 120 may comprise an expandable element having a low- profile or constrained state while positioned within a catheter (such as the second elongate shaft 112) for delivery to the treatment site and an expanded, deployed state for positioning within the treatment site. In some embodiments, the occlusive device 120 includes a mesh and aMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO connector 122 coupled to the mesh. The connector 122 is configured to be coupled to one or more components of the delivery system 102, such as the third elongate shaft 114 and / or an extension 116. The mesh can be formed of a resilient material and shape set such that upon exiting the second elongate shaft 112, the mesh self-expands to a predetermined shape. The mesh can have any shape or size in the expanded state that enables the mesh to cover the treatment site (e.g., an aneurysm neck). The mesh can have a porosity sufficient to prevent leakage of the embolic composition 152 out of the treatment site (e.g., a parent vessel of an aneurysm).

[0026] In some embodiments, the mesh is formed of a plurality of braided filaments that have been heat-set to assume a predetermined shape when released from the constraints of the delivery catheter. The mesh may be formed of metal wires, polymer wires, or both, and the wires may have shape memory and / or superelastic properties. The mesh may be formed of 24, 32, 36, 48, 64, 72, 96, 128, or 144 filaments. The mesh may be formed of a range of filament or wire sizes, such as wires having a diameter of from about 0.0004 inches to about 0.0020 inches, or of from about 0.0009 inches to about 0.0012 inches. In some embodiments, each of the wires or filaments have a diameter of about 0.0004 inches, about 0.0005 inches, about 0.0006 inches, about 0.0007 inches, about 0.0008 inches, about 0.0009 inches, about 0.001 inches, about 0.0011 inches, about 0.0012 inches, about 0.0013 inches, about 0.0014 inches, about 0.0015 inches, about 0.0016 inches, about 0.0017 inches, about 0.0018 inches, about 0.0019 inches, or about 0.0020 inches. In some embodiments, all of the filaments of the braided mesh may have the same diameter. For example, in some embodiments, all of the filaments have a diameter of no more than 0.001 inches. In some embodiments, some of the filaments may have different cross-sectional diameters. For example, some of the filaments may have a slightly thicker diameter to impart additional strength to the braid. In some embodiments, some of the filaments can have a diameter of no more than 0.001 inches, and some of the filaments can have a diameter of greater than 0.001 inches. The thicker filaments may impart greater strength to the braid without significantly increasing the device delivery profile, with the thinner wires offering some strength while filling out the braid matrix density. In some embodiments, the mesh can be a non-braided structure, such as a laser-cut stent.

[0027] In other embodiments, however, the occlusive device 120 may be replaced with a different type of device (e.g., a flow diverter) or the embolic composition 152 can be used without any occlusive device (e.g., if physiological fluid flow at the treatment site is expectedMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO to be sufficiently low such that leakage of the embolic composition 152 is not a significant concern).II. Embolic Compositions

[0028] The present technology provides an injectable liquid embolic system that forms a soft solid suitable for partially or fully occluding a treatment site. The treatment site is one that would benefit from embolization, such as an aneurysm, an arteriovenous malformation, an arteriovenous fistula, a tumor, a chronic subdural hematoma, a perivascular leak, varicose veins, hemorrhoids, or an endoleak.

[0029] The liquid embolic system comprises compositions suitable for injection via microcatheter and the ability to conform to the anatomy of the treatment site, solidifying to an elastic, soft solid to provide long-term occlusion. Advantages of the liquid embolic system disclosed herein include compositions that are solvent-free, easy to inject, and immiscible with blood. Unlike some liquid embolic systems such as precipitating hydrophobic injectable liquid (PHIL), which require the polymer to be dissolved in dimethyl sulfoxide (DMSO), the disclosed compositions are solvent-free. The compositions of the present disclosure comprise polymers (e.g., Polymers A and B) that are in a liquid state and do not require a solvent to solubilize the polymer. As used herein, “solvent-free” compositions refer to the absence of a solvent used to solubilize the polymers. Compositions may be considered solvent-free even if they have residual solvent (e.g., from manufacturing or processing steps, or from solubilizing an additive). In some embodiments, the solvent-free compositions described herein have an amount of residual solvent of less than 1 wt%, less than 0.5 wt%, less than 0.25 wt%, less than 0.1 wt%, or less than 0.05 wt%.

[0030] The solvent-free compositions eliminate the possibility of solvent (e.g., DMSO) leaching into the body and adverse effects related to the solvent. The initial low viscosity of the system (e.g., Parts A and B) disclosed herein provides good distal penetration of the composition, e.g., via injection through a microcatheter. The components of the compositions are selected to provide a formulation that thickens to a solid composition only after exiting the microcatheter and placed in the target location. The resulting formed embolic cast is elastic, soft, and hydrophobic. The term “cast” refers to the embolic composition in the context of occupying a vessel. These characteristics permit the embolic cast to flex and retain its form while ensuring immediate occlusion and good stability (long term, permanent occlusion). TheMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO present disclosure also provides for embolic compositions having additional agents such as fillers, contrast agents, and crosslinkers.

[0031] Effective occlusion with a liquid embolic system may benefit from adequate blood displacement, which is facilitated by low miscibility between the embolic material and blood. A highly hydrophobic liquid embolic system may lead to faster and more complete occlusion, minimizing the risk of material leaching due to its reduced interaction with aqueous environments. Despite claims of hydrophobicity in certain commercially available liquid embolic systems (e.g., Precipitating Hydrophobic Injectable Liquid (PHIL)), they exhibit some level of water solubility. Components in commercially available LESs like ethylene vinyl- alcohol (EVOH) and polyvinyl alcohol (PVA) are partially hydrophilic. Partially hydrophilic components increase miscibility with blood, which is greater than 90% water.

[0032] The compositions (e.g., Parts A and B) described herein are hydrophobic and provide for hydrophobic embolic casts. In some embodiments, the disclosed compositions are completely immiscible with blood. In some embodiments, the disclosed compositions are more hydrophobic compared to compositions comprising EVOH or PVA.

[0033] In some embodiments, the liquid embolic system comprises a composition Part A comprising a Polymer A having at least one Reactive Group A; and a composition Part B comprising a Polymer B having at least one Reactive Group B; wherein combining Part A and Part B results in the formation of an embolic composition. The compositions Part A and composition Part B may be referred to herein as “Part A” and “Part B,” respectively, for the purpose of brevity. Combining Part A and B results in Polymer A covalently crosslinked with a Polymer B and a solvent-free, hydrophobic, cohesive solid composition. The covalent crosslinks between Polymers A and B are formed via a chemical crosslinking reaction between Reactive Groups A and B that is initiated immediately before delivery of the embolic composition into the treatment site (e.g., via mixing of Part A and Part B). Reactive Group A of Polymer A forms a covalent bond with Reactive Group B of Polymer B, thereby producing an embolic composition. The chemical crosslinking reaction between Reactive Groups A and B can continue during and after delivery of the embolic composition into the treatment site, thereby resulting in formation of a solid mass within the treatment site to occlude the treatment site cavity.

[0034] Considerations in the selection of the polymer for Parts A and B include the desired glass transition temperature (Tg) and viscosity of the polymer. A Tg above bodyMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO temperature results in an embolic composition that is stiff and brittle when implanted in an individual. This could cause undesirable fragmentation of the embolic cast and unintended embolization and / or trauma in the vessel wall. Parts A and B comprise polymers with a Tg that provides for a soft, flexible embolic cast, similar to the physical properties of the vessel occupied by the embolic cast. In some embodiments, the Tg for Parts A and B are each independently less than 0 °C, less than -50 °C, less than -100 °C, less than -110 °C, less than -120 °C, or less than -130 °C.

[0035] The polymers as disclosed herein have a sufficiently low molecular weight and / or viscosity that permits the ability to hand-inject Parts A and B through a microcatheter. In some embodiments, the viscosity at 22 °C of Parts A and B are each independently less than 100 cP, less than 90 cP, less than 80 cP, less than 70 cP, less than 60 cP, or less than 50 cP.A. Polymers

[0036] The embolic composition described herein is composed of one or more polymers that are covalently crosslinked with each other to form soft, solid mass. The polymer is biocompatible (e.g., produces little or no toxicity, inflammatory response, or other undesirable side effects in vivo). The polymer can be branched polymers, linear polymers, or combinations thereof. The embolic composition is composed of any suitable number of polymers, such as one, two, three, four, five, or more polymers. Polymers as disclosed herein refer to homo- or co-polymers. Homopolymers are formed from one type of monomer. Copolymers comprise as least two different types of monomers. Depending on the arrangement of the monomers, copolymers can take on different forms, for example, random copolymers, alternating copolymers, block copolymers, and graft copolymers.

[0037] In some embodiments, the Tg for Polymers A and B are each independently less than 0 °C, less than -50 °C, less than -100 °C, less than -110 °C, less than -120 °C, or less than -130 °C.

[0038] The Tg for Polymers A and B are each independently less than 0 °C, less than -50 °C, less than -100 °C, less than -110 °C, less than -120 °C, or less than -130 °C.

[0039] In some embodiments, Polymer A and Polymer B are the same. In some embodiments, Polymer A and Polymer B are different. In some embodiments, Polymers A and B are siloxane-based polymers. In some embodiments, Polymers A and B are olefin-based polymers. The siloxane-based polymers and olefin-based polymers as disclosed herein are hydrophobic polymers.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO1. Siloxane-Based Polymers[00401 Siloxane-based polymers, also known as polysiloxane or silicones, are a class of synthetic polymer composed of repeating units of siloxane linkages. Siloxane linkages are characterized by Si-O-Si linkages. Siloxane-based homopolymers are comprised of the same monomer repeat unit. Siloxane-based copolymers are comprised of more than one monomer repeat unit. An example of a chemical formula of the monomer repeat unit is represented by: - (OR2Si)n-, wherein each R is independently selected from the group consisting of H and an organic group (e.g., C1-C4 alkyl, C1-C4 alkenyl, efc.), and n is the number of repeating units. Examples of polysiloxanes include polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof. Exemplary structures of homo- and co- poly siloxanes are shown below:

[0041] In some embodiments, Polymer A is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof. In some embodiments, Polymer A is selected from the group consisting of polydimethylsiloxane, methylhydrosiloxanedimethylsiloxane copolymer, diethylsiloxane-dimethylsiloxane copolymer, and vinylmethylsiloxane-dimethylsiloxane copolymer.[0042[ In some embodiments, Polymer B is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof. In some embodiments, Polymer A isMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO selected from the group consisting of polydimethylsiloxane, methylhydrosiloxanedimethylsiloxane copolymer, diethylsiloxane-dimethylsiloxane copolymer, and vinylmethylsiloxane-dimethylsiloxane copolymer.

[0043] In some embodiments Polymer A is methylhydrosiloxane-dimethylsiloxane copolymer and Polymer B is polydimethylsiloxane. In some embodiments Polymer A is selected from the group consisting of methylhydrosiloxane-dimethylsiloxane copolymer and polydimethylsiloxane; and Polymer B is selected from the group consisting of polydimethylsiloxane, diethylsiloxane-dimethylsiloxane copolymer, and vinylmethylsiloxane- dimethylsiloxane copolymer.

[0044] In some embodiments, the concentration of Polymer A in Part A (% w / w), is greater than or equal to 60%, 70%, 80%, 90% or 95%. In some embodiments, the concentration of Polymer B in Part B (% w / w), is greater than or equal to 60%, 70%, 80%, 90%, or 95%.

[0045] In some embodiments, the embolic composition is formulated by mixing a first precursor composition Part A including Polymer A with a second precursor composition Part B including Polymer B. In some embodiments, the concentration of Polymer A in the embolic composition (% w / w) is greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiments, the concentration of Polymer B in the embolic composition (% w / w) is greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.

[0046] In some embodiments, the concentration of Polymer A in the embolic composition (% w / w) is within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%, 30% to 50%, 50% to 75% or 75% to 95%. In some embodiments, the concentration of Polymer B in the embolic composition (% w / w) is within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%, 30% to 50%, 50% to 75% or 75% to 95%.2. Olefin-Based Polymers

[0047] Olefin-based polymers, also known as polyolefins, are a class of synthetic polymers derived from hydrocarbons containing a carbon-carbon double bond. Olefins are alsoMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO known as alkenes. In some embodiments, olefin-based polymers are substituted with C1-C8 alkyl or C2-C8 alkenyl. In some embodiments, olefin-based polymers contain unsaturated groups in the polymer backbone or as a pendant group (side chain). In some embodiments, the formula for the olefin-based polymer is -(CH2CHR)n, where R is selected from the group consisting of C1-C8 alkyl and C2-C8 alkenyl. The number of monomeric repeat units is denoted by “n” and can be determined in large part by the molecular weight of the polymer chain. Non-limiting examples of olefin-based polymers and their corresponding Tg are shown below:

[0048] In some embodiments, the olefin-based polymer is a selected from the group consisting of 1,2-polybutadiene, 1,4-polybutadiene, polyisoprene, polyisobutylene, poly(l- octene), poly(l -hexene), and copolymers thereof.

[0049] In some embodiments, the olefin-based polymer is substituted with a phenyl ring. In some embodiments, the formula for the olefin-based polymer is -(CH2CHR)n, wherein R is a phenyl ring.

[0050] In some embodiments, the olefin-based polymer is selected from the group consisting of polystyrene, polybutadiene, polyethylene, polybutylene, and copolymers thereof. In some embodiments, the olefin-based copolymer is selected from the group consisting of poly(styrene-butadiene-styrene), and poly(styrene-ethylene-butylene-styrene).MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO3. Polymer Molecular Weight

[0051] The molecular weight of the polymers herein can be selected to provide desired properties in the embolic composition, e.g., higher molecular weight polymers can produce stiffer, more cohesive, solid masses, while lower molecular weight polymers can produce softer solid masses. In some embodiments, the molecular weight of the polymer is sufficiently low so that the polymers are liquid at room temperature (e.g., 20-25 °C) and / or before crosslinking and delivery into the body. In some embodiments, the molecular weight of the polymer (weight average, number average, or viscosity average molecular weight) is greater than or equal to 900 Da, 1 kDa, 2 kDa, 5 kDa, 10 kDa, or 15 kDa; and / or is less than or equal to 50 kDa, 25 kDa, 10 kDa, 5 kDa, 2 kDa, 1 kDa, or 900 Da. In some embodiments, the molecular weight of the polymer is within a range from 900 Da to 15 kDa, 900 Da to 10 kDa, 900 Da to 7.5 kDa, 900 Da to 5 kDa, 900 Da to 2 kDa, 1.5 kDa to 15 kDa, 1.5 k Da to 10 kDa, 1.5 kDa to 7.5 kDa, 1.5 kDa to 5 kDa, 1.5 kDa to 2 kDa, 2 kDa to 15 kDa, 2 k Da to 10 kDa, 2 kDa to 7.5 kDa, 2 kDa to 5 kDa, 3 kDa to 15 kDa, 3 kDa to 10 kDa, 3 kDa to 7.5 kDa, 3 kDa to 5 kDa, 4 kDa to 15 kDa, 4 kDa to 10 kDa, 4 kDa to 7.5 kDa, or 4 kDa to 5 kDa. In some embodiments, the molecular weight is the number average Mn. In some embodiments, the dispersity (D, “D- stroke”) of the polymer is less than 3, less than 2.75, or less than 2.0. In some embodiments, the D of the polymer is 1.2 to 3.0, 1.2 to 2.75, 1.2 to 2.5, 1.2 to 2.3, 1.2 to 2.1, 1.2 to 2, 1.2 to 1.75, 1.2 to 1.5, 1.5 to 3.0, 1.5 to 2.75, 1.5 to 2.5, 1.5 to 2.3, 1.5 to 2.1, 1.5 to 2, or 1.5 to 1.75. D is calculated by dividing the weight average molecular weight by the number average molecular weight. D indicates the breadth of the molecular weight distribution. The larger the D, the broader the molecular weight. For monodisperse polymers (all chains of same length), the D is 1.

[0052] In some embodiments, the molecular weight (Mn) of the polymer is 1.2 kDa to 8 kDa with a D of 1.4 to 2.7. In some embodiments, the molecular weight (Mn) of the polymer is 3 kDa to 7 kDa with a D of 1.4 to 2.5. In some embodiments, the molecular weight (Mn) of the polymer is 1.5 kDa to 7 kDa with a D of 1.4 to 2.7.

[0053] In some embodiments, Polymer A is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa. In some embodiments, Polymer B is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0054] In some embodiments, Polymer A is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 1.2 kDa to 8 kDa with a D of 1.4 to 2.7. In some embodiments, Polymer A is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 3 kDa to 7 kDa with a D of 1.4 to 2.5. In some embodiments, Polymer A is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 1.5 kDa to 7 kDa with a D of 1.4 to 2.7.

[0055] In some embodiments, Polymer B is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 1.2 kDa to 8 kDa with a D of 1.4 to 2.7. In some embodiments, Polymer B is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 3 kDa to 7 kDa with a D of 1.4 to 2.5. In some embodiments, Polymer B is a polysiloxane, wherein the polysiloxane has a molecular weight (Mn) of 1.5 kDa to 7 kDa with a D of 1.4 to 2.7.B. Reactive Groups and Crosslinking Reactions

[0056] The polymers described herein can include or be modified to include a reactive group that is capable of forming covalent bonds with a reactive group of another polymer. The reactive group can be located at the polymer chain end or can be part of a repeating unit. Thus, crosslinking may occur at the chain ends or at the non-chain end of the polymers, depending on the location of the reactive groups.

[0057] Examples of reactive groups include acyl groups, acrylate groups, acrylamide groups, alcohol groups, aldehyde groups, alkene groups, (e.g., substituted alkene groups), alkyne groups, amine groups (e.g., primary amine groups, secondary amine groups), anhydride groups, azide groups, carboxylic acid groups, diene groups, epoxy groups, furan groups, isocyanate groups, a,P-unsaturated ketone groups (e.g., a,P-unsaturated ketone aldehyde groups, a,P-unsaturated ketone ester groups, a,P-unsaturated ketone amide groups, a,P- unsaturated ketone nitro groups), mercapto groups, malonate groups, nitroalkane groups, oxalate groups, succinimide groups (e.g, N-hydroxy succinimide groups), and thiol groups.

[0058] A polymer may include any suitable number of reactive groups, such as single reactive group, two reactive groups (e.g, at both ends of a linear polymer chain), three reactive groups, four reactive groups, five reactive groups, six reactive groups, seven reactive groups, eight reactive groups, or more.

[0059] Reactive groups A and B are selected based on their ability to react with each other to form covalent crosslinks between Polymer A and Polymer B. For instance, Polymer A (e.g., PDMS, or methylhydrosiloxane-dimethylsiloxane copolymer) has two or more Reactive groups A selected from the group silicone hydride, acrylate, epoxy, maleic anhydride, alcohol,MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO isocyanate, mercapto, and oxalate; Polymer B (e.g., PDMS) has two or more Reactive Groups B selected from the group consisting of vinyl, primary amine, secondary amine, acetoxy, enoxy, oxime, and alkyoxy; wherein Reactive Groups A and B are selected based on their ability to react with each other to form covalent crosslinks. Reactive pairs include 1) silicone hydride and vinyl, 2) acrylate or methacrylate and a primary or secondary amine, 3) epoxy and a primary or secondary amine, 4) maleic anhydride and a primary or secondary amine, 5) alcohol and acetoxy, enoxy, oxime, alkyoxy, or amine, 6) isocyanate and a primary or secondary amine, 7) mercapto group and a primary or secondary amine, and 8) oxalate and primary or secondary amine.

[0060] Reaction conditions for the reactive pairs are known in the art. For instance, covalent linkages form from reacting silicone hydride and vinyl groups in the presence of a platinum catalyst. Other examples include reacting diacrylate PDMS with a polyamine PDMS in the presence of a triethylamine (TEA), tetramethylethylenediamine (TMEDA), or N, N, N, N, N -pentamethyldiethylenetriamine (PMDETA); difunctional epoxy PDMS and a polyamine PDMS in the presence of TEA or TMEDA; a difunctional maleic anhydride PDMS and a polyamine PDMS; a silanol terminated PDMS and a multifunctional silicone component which consists of one of the groups selected from acetoxy, enoxy, oxime, alkoxy, and amine in the presence of di-n-butyldiacetoxytin (> 50 ppm); PDMS diisocyanate and a polyamine in the presence of TEA, PMDETA, TMEDA, bismuth, zinc, or dibutyltin dilaurate; dimercapto PDMS and multiamine PDMS; and PDMS capped with oxalate groups (alkyl, aryl, or trifluoro esters) and a multiamine PDMS.

[0061] In some embodiments, the reactive groups of the polymers are capable of forming covalent bonds with each other upon mixing of the polymers, without requiring a separate catalyst, crosslinking agent, or other additional component to initiate the covalent crosslinking reaction. The covalent crosslinking reaction can occur under mild conditions, such as at room temperature (e.g., 20-25 °C) and / or physiological temperature (e.g., 37 °C), and / or without requiring organic solvents. In such cases, simple mixing of the polymers results in curing within seconds or minutes depending on different considerations including the density of the functional groups, the molecular weight of the individual components (e.g., Polymers A and B), and the type of reactive group pairs (e.g. isocyanate and amine is expected to proceed within a few seconds).

[0062] Polymers A and B, which form the bulk of Parts A and B, respectively, are liquid. Because of the liquid nature of Polymers A and B, no solvent is needed to solubilize theMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO polymers. In some embodiments, the systems provided herein are substantially solvent-free. In some embodiments, the systems provided herein are completely solvent-free.

[0063] In some embodiments, Reactive Groups A or B are located at each chain end of Polymers A and B, respectively. In some embodiments, Reactive Groups A or B are located at non-chain ends (monomer units) of Polymers A and B, respectively. In some embodiments at least one Reactive Group A is located at non-chain ends (monomer units) of Polymer A, and at least one Reactive Group B is located at the chain ends of Polymer B. In some embodiments at least one Reactive Group A is located at the chain ends of Polymer A, and at least one Reactive Group B is located at the non-chain ends (monomer units) of Polymer B.

[0064] In addition to covalent crosslinks forming between Polymer A and Polymer B, in some embodiments, crosslinks between other kinds of groups occur. In some embodiments, Polymer A or Polymer B may form intrachain crosslinks, where a polymer chain reacts with itself to form one or more internal crosslinks. In some embodiments, Polymer A or Polymer B may form one or more interchain crosslinks between polymers of the same type, e.g., crosslinking between two Polymer A chains or two Polymer B chains.

[0065] In some embodiments, Reactive Group A is silicone hydride and Reactive Group B is vinyl. In some embodiments, at least one Reactive Group A is located at non-chain ends of Polymer A and is silicone hydride; and at least one Reactive Group B is located at the chain ends of Polymer B. In some embodiments, at least one Reactive Group A is located the chain ends of Polymer A and is silicone hydride; and at least one Reactive Group B is located at the chain ends of Polymer B. In some embodiments, at least one Reactive Group A is located the chain ends of Polymer A and is silicone hydride; and at least one Reactive Group B is located at non-chain ends of Polymer B.

[0066] In some embodiments, Part A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, and hydride- terminated polydimethylsiloxane. In some embodiments, Polymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, and hydride-terminated polydimethylsiloxane.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0067] In some embodiments, Part B is selected from the group consisting of vinyl- terminated polydimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer. In some embodiments, Polymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer.

[0068] In some embodiments, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer has an m:n ratio of about 7:3 to about 9: 1. In some embodiments, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer has an m:n ratio of about 8:2, about 9: 1, about 7:3. In some embodiments, the percentage of dimethyl siloxane monomer units is about 80% and the percentage of diethylsiloxane monomer units is about 20%. In some embodiments, the percentage of dimethyl siloxane monomer units is 70%-90% and the percentage of di ethyl siloxane monomer units is 10%-30%.

[0069] In some embodiments, trimethylsiloxy-terminated vinylmethylsiloxane- dimethylsiloxane copolymer has a m:n ratio of about 99: 1 to about 50:50. In some embodiments, the percentage of vinyl-containing monomer units is 1% to 50%.

[0070] In some embodiments, Polymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, and hydride- terminated polydimethylsiloxane, wherein Polymer A has a molecular weight (Mn) of 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa. In some embodiments, Polymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminatedMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, wherein Polymer B has a molecular weight (Mn) of 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa.

[0071] In some embodiments, Polymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, and hydride- terminated polydimethylsiloxane, wherein Polymer A has a molecular weight (Mn) of 1.2 kDa to 8 kDa with a D of 1.4 to 2.7. In some embodiments, Polymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, and hydride-terminated polydimethylsiloxane, wherein Polymer A has a molecular weight (Mn) of 3 kDa to 7 kDa with a D of 1.4 to 2.5. In some embodiments, Polymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxanedimethylsiloxane copolymer, and hydride-terminated polydimethylsiloxane, wherein Polymer A has a molecular weight (Mn) of 1.5 kDa to 7 kDa with a D of 1.4 to 2.7.

[0072] In some embodiments, Polymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, wherein Polymer B has a molecular weight (Mn) of 1.2 kDa to 8 kDa with a D of 1.4 to 2.7. In some embodiments, Polymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, wherein Polymer B has a molecular weight (Mn) of 3 kDa to 7 kDa with a D of 1.4 to 2.5. In some embodiments, Polymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer, wherein Polymer B has a molecular weight (Mn) of 1.5 kDa to 7 kDa with a D of 1.4 to 2.7.

[0073] In some embodiments, Polymer A is trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, wherein Polymer A has a molecular weight (Mn) of 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa. In some embodiments, Polymer A is trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer, wherein Polymer A has a molecular weight (Mn) of 1.2 kDa to 8 kDa with a D of 1.4 to 2.7. In some embodiments, Polymer A is trimethylsiloxy-terminated methylhydrosiloxanedimethylsiloxane copolymer, wherein Polymer A has a molecular weight (Mn) of 3 kDa to 7 kDa with a D of 1.4 to 2.5. In some embodiments, Polymer A is hydride-terminatedMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO polydimethylsiloxane, wherein Polymer A has a molecular weight (Mn) of 1.5 kDa to 7 kDa with a D of 1.4 to 2.7.

[0074] In some embodiments, Polymer B is vinyl-terminated polydimethylsiloxane, wherein Polymer B has a molecular weight (Mn) of 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa. In some embodiments, Polymer B is vinyl-terminated polydimethylsiloxane, wherein Polymer B has a molecular weight (Mn) of 1.2 kDa to 8 kDa with a D of 1.4 to 2.7. In some embodiments, Polymer B is vinyl-terminated polydimethylsiloxane, wherein Polymer B has a molecular weight (Mn) of 3 kDa to 7 kDa with a D of 1.4 to 2.5. In some embodiments, Polymer B is vinyl-terminated polydimethylsiloxane, wherein Polymer B has a molecular weight (Mn) of 1.5 kDa to 7 kDa with a D of 1.4 to 2.7.

[0075] The disclosure provides for a reaction between Reactive Groups A and B resulting in the formation of a covalent crosslink between Polymers A and B. The pairs of Reactive Groups described above have functional groups that react together in well-known reactions such as hydrosilylation, as discussed above, Aza-Michael addition, anhydride / amine reaction, silanol condensation or epoxy-amine reactions. These reactions result in the formation of new covalent bonds in the form of, for example, amide bonds, Si-O-Si bonds, and C-N bonds.1. Aza-Michael Addition Reaction

[0076] The aza-Michael addition reaction can involve a reaction between an amine group (Michael donor) on Polymer B and an electrophilic group (Michael acceptor) on Polymer A. Nucleophilic primary and secondary amines of Polymer B can function as a Michael donor and react with the Michael acceptor of Polymer A. The electrophilic group can be a a,P- unsaturated compound conjugated to an electron withdrawing group such as carbonyl (e.g., enone, enal), nitro, CF3, ester, amide, and nitrile groups. In some embodiments, the covalent crosslinking reaction is an aza-Michael addition reaction. In some embodiments, Polymer A includes an a,P-unsaturated carbonyl group. In some embodiments, Reactive Group A is an a,P-unsaturated carbonyl group. In some embodiments, Reactive Group A is selected from the group consisting of acrylate and methacrylate.2. Anhydride-Amine Reaction

[0077] In an anhydride-amine reaction, an amide bond is formed from the reaction between an anhydride (e.g., maleic anhydride and succinic anhydride) and amine. In some embodiments, the covalent crosslinking reaction involves a reaction between an anhydride andMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO amine to form an amide bond. In some embodiments, Reactive Group A is selected from the group consisting of maleic anhydride and succinic anhydride; and Reactive Group B is an amine (e.g., a primary or a secondary amine) or a thiol. In some embodiments, the Reactive Group A is an anhydride (e.g., maleic anhydride, succinic anhydride); and Reactive Group B is an amine (e.g., a primary or a secondary amine).3. Silanol Condensation[00781 Silanol condensation involves a reaction between two silanol groups to form a siloxane bond (Si-O-Si) and water. In some embodiments, the covalent crosslinking reaction involves a silanol condensation reaction. In some embodiments, Reactive Groups A and B are hydroxyl groups. In some embodiments the Polymers A and B are PDMS functionalized with hydroxyl groups on the chain ends or on non-chain ends (monomers).4. Epoxy-Amine Reaction

[0079] An epoxy-amine reaction involves a nucleophilic attack of the amine on a carbon of the epoxide ring and leads to an opened ring, a hydroxyl group, and a covalent bond formed between the nitrogen and carbon. In some embodiments, the covalent crosslinking reaction involves an epoxide and amine and the formation of a covalent C-N bond. In some embodiments, the covalent crosslinking reaction involves a reaction between an epoxy group and a primary amine, wherein the nucleophilic attack of the amine results in the ring-opening of the epoxy group and the formation of a secondary amine and hydroxyl group. In some embodiments, the covalent crosslinking reaction involves a reaction between an epoxy group and a secondary amine, wherein the nucleophilic attack of the amine results in the ring-opening of the epoxy group and the formation of a tertiary amine and hydroxyl group.5. Catalyst

[0080] In some embodiments, a catalyst is needed for Reactive Groups A and B to react to form a covalent crosslinking bond. The type of reaction and the type of reactive groups play a role in the selection of the catalyst. Non-limiting examples of catalysts include platinum, triethylamine, tetramethylethylenediamine (TMEDA), and N,N,N,N,N- pentamethyldiethylenetriamine (PMDETA), Di-n-butyldiacetoxytin, bismuth, zinc, or dibutyltin dilaurate. In some embodiments, the system further comprises a catalyst. In some embodiments, Part A further comprises a catalyst. In some embodiments, Part B further comprises a catalyst. In some embodiments, Part A and Part B further comprise a catalyst.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WOC. Additives[00811 In some embodiments, the compositions described herein further comprise one or more additives. Examples of additives in includes fillers, contrast agents, and crosslinkers. Another example of an additive is non-functional silicone oil, which refers to inert silicone oil that does not chemically react with the other components of the composition.

[0082] In some embodiments, the Part A includes a first additive, and Part B includes a second additive. The first additive may be the same as the second additive, or the first additive may be different than the second additive. The concentration of the first additive in Part A may be the same as the concentration of the second additive in Part B, or the concentration of the first additive in the Part A may be different than the concentration of the second additive in Part B. In some embodiments, Part A includes an additive and Part B does not include any additives. In some embodiments, Part B includes an additive and Part A does not include any additives.1. Fillers

[0083] The disclosure provides for compositions further comprising additives to modify the rheology of the compositions. In some embodiments, the embolic compositions described herein comprises a shear-thinning filler. In the presence of a shear-thinning filler, the viscosity of the embolic composition decreases when shear stress is applied to the composition and increases when the shear stress is removed. While maintaining injectability of the embolic composition, shear-thinning properties can prevent the embolic composition from leaking out of the treatment site and / or moving further distally in a vessel or lesion and causing unintended embolization before the chemical crosslinking reaction between Polymers A and B is complete,

[0084] Non-limiting examples of a shear-thinning filler include silica (e.g., fumed silica, and precipitated silica), and MQ resin. In some embodiments, silica is treated with dimethyldichlorosilane to impart hydrophobic characteristics to the material. In some embodiments, silica is partially treated or untreated with dimethyldichlorosilane to retain hydrophilic characteristics of the material. In some embodiments, the surface area of the filler is 50-400 m2 / g, 60-350 m2 / g, or 40-450 m2 / g.

[0085] Part A, Part B, or both Part A and B can include a plurality of nanoparticles. The nanoparticles can interact non-covalently with each other such that the mixture of Part A and Part B has shear-thinning properties before the covalent crosslinking reaction is complete.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0086] In some embodiments, shear-thinning fillers are nanoparticles. The nanoparticles can be made out of any suitable biocompatible material (e.g., the material produces little or no toxicity, inflammatory response, or other undesirable side effects in vivo), which may or may not be biodegradable. In some embodiments, the nanoparticles are inorganic nanoparticles including one or more inorganic materials, such as silicates, oxides, halides, carbonates, phosphates, sulfide, sulfates, etc. For instance, the nanoparticles can be silicate nanoparticles that are composed of a silicate material, such as a layered silicate (also known as a phyllosilicate or nanoclay). Examples of layered silicates include smectites (e.g., laponite, montmorillonite, saponite, hectorite, bentonite), kaolinite, chlorite, and illite. In some embodiments, the embolic composition comprises a single type of nanoparticle. In some embodiments, the embolic composition comprises multiple different types of nanoparticles.

[0087] The concentration of the filler(s) in the embolic composition (% w / w), individually or collectively, can be greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiments, the concentration of the filler(s) in the embolic composition, individually or collectively, is within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%, 30% to 50%, 50% to 75% or 75% to 95%.

[0088] In some embodiments, the embolic composition is formulated by mixing a first precursor composition Part A including Polymer A with a second precursor composition Part B including Polymer B, where at least one of Parts A and B further includes a filler. The concentration of the filler in Part A (% w / w) can be greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. The concentration of the filler in Part A can be within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%, 30% to 50%, 50% to 75% or 75% to 95%. The concentration of the filler in Part B (% w / w) can be greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. The concentration of the filler in Part B can be within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%,MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO2. Contrast Agents[00891 In some embodiments, the embolic compositions described herein include at least one contrast agent that allows for visualization of the composition during and / or after injection into the treatment site. For example, the contrast agent can be configured for radiographic imaging. Examples of contrast agents that may be used include tantalum, bismuth trioxide, bismuth oxychloride, tungsten, tungsten carbide, barium sulfate, gadolinium, iodized oil (e.g., LIPIODOL®), iohexol (e.g., OMNIP AQUE™ from GE Healthcare), iopamidol (e.g., ISOVUE™ from Bracco Diagnostics, Inc.), ioxilan, iopromide (e.g., Ultravist™), iodixanol (e.g., VISIPAQUE™ from GE Healthcare), iobitridol, ioversol, diatrizoate (e.g., HYP AQUE™ from GE Healthcare), metrizoate, iothalamate (e.g., CONRAY™ from Covidien), ioxaglate, iopromide, iothalamate / meglumine, ioxaglate / meglumine, diatrizoate / meglumine, iodamide sodium, metrizamide, or combinations thereof. The embolic composition can include a single type of contrast agent or can include a plurality of different types of contrast agents (e.g., two, three, four, five, or more different types of contrast agents).

[0090] The concentration of the contrast agent(s) in the embolic composition (% w / w), individually or collectively, can be greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiments, the concentration of the contrast agent(s) in the embolic composition, individually or collectively, is within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%, 30% to 50%, 50% to 75% or 75% to 95%.

[0091] In some embodiments, the embolic composition is formulated by mixing a first precursor composition Part A including Polymer A with a second precursor composition Part B including Polymer B, where at least one of Parts A and B further includes a contrast agent. The concentration of the contrast agent in Part A (% w / w) can be greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%. The concentration of the contrast agent in Part A can be within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%, 30% to 50%, 50% to 75% or 75% to 95%. The concentration of the contrast agent in Part B (% w / w) can be greater than or equal to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, and / or no more than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO or 10%. The concentration of the contrast agent in Part B can be within a range from 10% to 90%, 10% to 80%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 20% to 90% 20% to 80%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 75%, 25% to 50%, 30% to 80%, 30% to 50%, 50% to 75% or 75% to 95%.

[0092] In some embodiments, the Part A includes a first contrast agent, and Part B includes a second contrast agent. The first contrast agent may be the same as the second contrast agent, or the first contrast agent may be different than the second contrast agent. The concentration of the first contrast agent in the first precursor composition may be the same as the concentration of the second contrast agent in the second precursor composition, or the concentration of the first contrast agent in the first precursor composition may be different than the concentration of the second contrast agent in the second precursor composition. In some embodiments, the first precursor composition includes a contrast agent and the second precursor composition does not include any contrast agent. In some embodiments, the second precursor composition includes a contrast agent and the first precursor composition does not include any contrast agent.

[0093] In some embodiments, neither Part A nor Part B include any contrast agent. In such embodiments, the contrast agent may be provided as part of a third precursor composition that is separate from the first and second precursor compositions, Parts A and B. The third precursor composition may be mixed with Part A before Part A is mixed with Part B, or the third precursor composition may be mixed with Part B composition before Part B is mixed with Part A, or the third precursor composition may be mixed with Parts A and B after Parts A and B are mixed with each other.

[0094] In other embodiments, the contrast agent is optional and may be omitted from the embolic composition. In such embodiments, the degree of occlusion of the treatment site by the embolic composition may be assessed using other techniques, such as based on extent of inversion of occlusive device by the embolic composition (e.g., as discussed above with respect to FIGS. 3 A-3D).3. Crosslinker

[0095] In some embodiments, covalent crosslinking involves a crosslinker additive, wherein the crosslinker additive has multiple reactive groups and forms part of the covalent link between Reactive Groups A and B.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0096] In some embodiments, a crosslinker is included in the system to link Polymers A and B. An example of a crosslinker is a multifunctional vinyl siloxane, which has multiple vinyl groups capable of reacting with a reactive partner (e.g., silicone hydride.) Non-limiting examples of a multifunctional vinyl siloxane include bis(divinyl)-terminated polydimethylsiloxane, polyvinylmethylsiloxane, tetravinylsilane, tetraallylsilane, and 1, 3,5,7- tetravinyl-l,3,5,7-tetramethylcyclotetrasiloxane. The crosslinking additive forms part of the covalent linkage between the two Reactive Groups (e.g, Reactive Groups A- A, A-B, or B- B )D. Properties of Embolic Compositions

[0097] The embolic compositions described herein can be configured for intravascular delivery into a treatment site (e.g, an aneurysm or other vascular defect) via injection through an elongate shaft (e.g., a microcatheter or other delivery catheter). Typical liquid embolic system compositions such as N-butyl cyanoacrylate (NBCA) or precipitating hydrophobic injectable liquid (PHIL), have a stiffness similar to glass. As opposed to being brittle and stiff, the embolic compositions disclosed herein are soft and flexible similar to the vessels they occupy.

[0098] In some embodiments, the embolic composition has a Shore hardness of less than 50A, less than 45A, less than 40A, less than 35A, or less than 30A.

[0099] Upon completion of the chemical crosslinking reaction, the embolic composition is a soft solid. In some embodiments, the embolic composition has a storage modulus within the linear viscoelastic region that is within a range from 1 kPa to 10 MPa, 1 kPa to 1 MPa, 1 kPa to 500 kPa, 1 kPa to 200 kPa, 1 kPa to 100 kPa, 1 kPa to 50 kPa, 1 kPa to 10 kPa, 10 kPa to 10 MPa, 10 kPa to 1 MPa, 10 kPa to 500 kPa, 10 kPa to 200 kPa, 10 kPa to 100 kPa, 10 kPa to 50 kPa, 50 kPa to 10 MPa, 50 kPa to 1 MPa, 50 kPa to 500 kPa, 50 kPa to 200 kPa, 50 kPa to 100 kPa, 100 kPa to 10 MPa, 100 kPa to 1 MPa, 100 kPa to 500 kPa, 100 kPa to 200 kPa, 200 kPa to 10 MPa, 200 kPa to 1 MPa, 200 kPa to 500 kPa, 500 kPa to 10 MPa, 500 kPa to 1 MPa, or 1 MPa to 10 MPa. In some embodiments, the embolic composition has a storage modulus within the linear viscoelastic region that is within a range from 5 kPa to 225 kPa, 10 kPa to 1 MPa, 10 kPa to 500 kPa, 10 kPa to 180 kPa, or 15 kPa to 175 kPa.

[0100] In some embodiments, the storage modulus of the embolic composition reaches at least 80%, 85%, 90%, 95%, or 99% of its final value at least 15 seconds, 30 seconds, 45MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO seconds, 60 seconds, 90 seconds, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes after mixing of the precursor compositions.

[0101] Alternatively, or in combination, the storage modulus of the embolic composition may reach at least 80%, 85%, 90%, 95%, or 99% of its final value no more than 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 90 seconds, 60 seconds, 45 seconds, 30 seconds, or 15 seconds after mixing of the precursor compositions Part A and B.

[0102] In some embodiments, the embolic composition has a loss modulus within the linear viscoelastic region that is within a range from 100 Pa to 10 kPa, 100 Pa to 5 kPa, 100 Pa to 1 kPa, 100 Pa to 500 Pa, 500 Pa to 10 kPa, 500 Pa to 5 kPa, 500 Pa to 1 kPa, 1 kPa to 10 kPa, 1 kPa to 5 kPa, or 5 kPa to 10 kPa. In some embodiments, the embolic composition has a loss modulus within the linear viscoelastic region that is within a range from 500 Pa to 3000 Pa, 500 Pa to 2000 Pa, 1 kPa to 5 kPa, 1 kPa to 3 kPa, or 1 kPa to 2 kPa.

[0103] The ratio of the loss modulus to the storage modulus (tan(delta) of the embolic composition can be within a range from 0.005 to 0.1, 0.005 to 0.05, 0.01 to 0.05, 0.05 to 0.1, or 0.1 to 0.5, or 0.5 to 1.

[0104] Storage and loss moduli of a material can be measured via any suitable technique, such as using an oscillatory parallel plate rheometer (e.g, 8 mm plate diameter) operating in shear mode at a suitable temperature (e.g, 37 °C). The storage and loss moduli can be measured within the linear viscoelastic region of the material, where the linear viscoelastic region of the material corresponds to a critical strain value that is less than or equal to 5%, 4%, 3%, 2%, or 1%. The storage and loss moduli can be measured at a suitable angular frequency, such as an angular frequency of 0.1 rad / s, 1 rad / s, 10 rad / s, or 100 rad / s.F. Methods

[0105] In some embodiments, the present technology provides a method for preparing an embolic composition for occluding a treatment site. A treatment site is at or near an area of dysfunction, for instance, arteriovenous malformations (e.g., brain arteriovenous malformations), arteriovenous fistulas, tumors (e.g., via occlusion of vessel(s) feeding a tumor), chronic subdural hematomas (e.g., via occlusion of the middle meningeal artery), perivascular leaks, varicose veins (e.g., via occlusion of one or more truncal veins such as the great saphenous vein), hemorrhoids, and endoleaks adjacent to artificial heart valves, covered stents, and abdominal aortic aneurysm devices. An arteriovenous fistula (AVF) is an abnormal,MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO direct and simple connection between an artery and a vein. On the other hand, a typical arteriovenous malformation (AVM) has multiple connections that are complex, net-like structures.[0106J The method comprises mixing a first precursor composition (Part A) with a second precursor composition (Part B). Part A comprises a first polymer (Polymer A) having a first reactive group (Reactive Group A), and Part B comprises a second polymer (Polymer B) having a second reactive group (Reactive Group B). The mixing of Part A and Part B results in a covalent crosslinking reaction between the Reactive Group A of Polymer A and the Reactive Group B of the Polymer B, thereby forming an embolic composition. In some embodiments, Part A and Part B do not comprise a catalyst to initiate the covalent crosslinking reaction.

[0107] In some embodiments, Parts A and B each independently comprise additives (e.g., fillers, contrast agents, crosslinkers) or catalysts. In some embodiments, Parts A and B do not require solvent to solubilize Polymers A and B, which are liquid. The types and concentrations of filler, contrast agent, crosslinker, and catalyst are described herein e.g., Sections C above.

[0108] In some embodiments, the present technology provides a method for treating an individual using an embolic composition as described herein. The method can include preparing an embolic composition by mixing Part A and Part B as described herein and delivering the embolic composition to a treatment site. For example, the embolic composition can be delivered into a treatment site to partially or fully occlude the treatment site. The embolic composition can be delivered via injection, e.g., via a catheter or other elongate shaft that is introduced to the treatment site via the vasculature. As discussed herein, the embolic composition can be liquid before the covalent crosslinking reaction is complete and can form a solid or semi-solid mass after the covalent crosslinking reaction is complete. The method can further include forming an embolic cast that occludes the treatment site, where the embolic cast is composed of the covalently crosslinked Part A and Part B.

[0109] In some embodiments, the embolic composition is prepared by mixing two or more precursor compositions with each other to initiate a chemical crosslinking reaction. The reaction time (also referred to herein as the “curing time”) can be sufficiently long so that the embolic composition can be delivered to the treatment site via injection, but sufficiently short so that the embolic composition solidifies into a cohesive embolic cast within a reasonable timeMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO period after delivery into the treatment site. The curing time can also be described as the amount of time from mixing Parts A and B to the formation of an embolic cast that is sufficiently solid and able to occlude the target vessel. Curing time is a function of the formation of crosslinks between Polymers A and B, which in turn is dependent on the degree of Reactive Group functionalization of the Polymers, and reactivity of the Reactive Groups A and B. In some embodiments, the curing time is 1-3 minutes, 1-5 minutes, 1-10 minutes, 1-15 minutes, 1-20 minutes, 0.5-3 minutes, 0.5-5 minutes, 0.5-10 minutes, 0.5-15 minutes, 0.5-20 minutes. 0.2- 3 minutes, 0.2-5 minutes, 0.2-10 minutes, 0.2-15 minutes, or 0.2-20 minutes,. In some embodiments, the curing time is the amount of time for the embolic composition to reach at least 80%, 85%, 90%, 95%, or 99% of its final crosslinking conversion value after at least 15 seconds, at least 30 seconds, at least 45 seconds, at least 60 seconds, at least 90 seconds, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, or at least 10 minutes from mixing of the precursor compositions (Parts A and B). The final crosslinking conversion value refers to the final amount of crosslinking in the reaction mixture, where no further crosslinking occurs.

[0110] In some embodiments, at least 80%, 85%, 90%, 95%, or 99% of the final total crosslinking value are formed 0.5-20 minutes, 1-20 minutes, 2-20 minutes, 3-20 minutes, 4- 20 minutes, 5-20 minutes, 7-20 minutes, 10-20 minutes, or 15-20 minutes after Parts A and B are combined. In some embodiments, at least 80% of the final total crosslinking value are formed 1-10 minutes after Parts A and B are combined. In some embodiments, at least 90% of the final total crosslinking value are formed 1-10 minutes after Parts A and B are combined. In some embodiments, at least 90% of the final total crosslinking value are formed 1-5 minutes after Parts A and B are combined.

[0111] In some embodiments, curing time is the time elapsed between when the precursor compositions (Parts A and B) are mixed to when the embolic composition reaches its final state, e.g., the properties of the embolic composition (e.g., storage modulus, viscosity, degree of crosslinking) are at least 80%, 85%, 90%, 95%, or 99% of their final values. The curing time can be controlled based on the ratio between the two precursor compositions Parts A and B, the molecular weight of the polymers, the degree of functionalization of the polymers with reactive groups, and the type of reactive groups present on the polymers. Optionally, either or both of Part A and B includes a catalyst to accelerate the chemical crosslinking reaction.

[0112] In some embodiments, the reaction time is at least 12 seconds, at least 15 seconds, 30 seconds, 45 seconds, 60 seconds, 90 seconds, 2 minutes, 3 minutes, 4 minutes, 5MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes; and / or is no more than 10 minutes, 9 minutes, 8 minutes, 7 minutes, 6 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 90 seconds, 60 seconds, 45 seconds, 30 seconds, or 15 seconds. In some embodiments, the reaction time is within a range from 15 seconds to 60 seconds, 10 seconds to 90 seconds, 30 second to 60 seconds, 1 minute to 3 minutes, 2 minutes to 5 minutes, or 5 minutes to 10 minutes.|0113] Before the embolic composition reaches its final state, the embolic composition can optionally exhibit shear-thinning properties suitable for injection into the treatment site via an elongate shaft having a relatively small inner diameter, such as a microcatheter having an inner diameter less than or equal to 0.02 inches, 0.015 inches, 0.014 inches, 0.013 inches, 0.012 inches, 0.011 inches, or 0.01 inches. The viscosity of the embolic composition can decrease when subjected to shear stress (e.g., during injection through the delivery catheter) to allow the embolic composition to be delivered into the treatment site with relatively low injection forces. When the shear stress is removed (e.g., after the embolic composition has exited the delivery catheter), the viscosity of the embolic composition can increase so that the embolic composition forms a cohesive solid or semi-solid mass that does not dissolve, disperse, fragment, or otherwise flow out of the treatment site. This approach can reduce the risk of the embolic composition leaking out of the treatment site before the chemical crosslinking reaction is complete.

[0114] A precursor composition (Part A or Part B) used to form the embolic compositions herein can optionally have shear-thinning properties before mixing with another precursor composition to initiate the chemical crosslinking reaction. In some embodiments, the precursor composition has a first, higher viscosity at a first, lower shear rate, and a second, lower viscosity at a second, higher shear rate. The viscosity of a material under shear can be measured via any suitable technique, such as using an oscillatory parallel plate rheometer (e.g., 8 mm plate diameter) operating in shear mode at a suitable temperature (e.g., 37 °C).

[0115] Alternatively, or in combination, the embolic composition can have a storage modulus within the linear viscoelastic region that is less than 100 kPa, 50 kPa, 10 kPa, 5 kPa, 1 kPa, or 500 Pa for at least 15 seconds, 30 seconds, 45 seconds, 60 seconds, 90 seconds, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, or 10 minutes after mixing of the precursor compositions. In some embodiments, the maximum force to inject the embolic composition within 15 seconds, 30 seconds, 45 seconds, 60 seconds, 90 seconds, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO minutes, or 10 minutes after mixing of the precursor compositions is less than or equal to 20 N, 15 N, 10 N, 5 N, or 1 N. The injection force can be measured using any suitable technique, such as based on the amount of force to inject the embolic composition through a 25-gauge needle at an injection speed of 0.3 mL / min at 22 °C.

[0116] Optionally, the embolic composition can be used in combination with another device, such as an occlusive device for an aneurysm (e.g., as described in Section I above). In such embodiments, the occlusive device can be positioned within the aneurysm before the embolic composition is delivered into the aneurysm. The embolic composition can have sufficient stiffness and cohesive strength such that when the embolic composition is delivered into the aneurysm, the embolic composition pushes downward against the occlusive device to ensure that the interior cavity of the aneurysm is substantially completely filled, without leaking through the occlusive device.

[0117] In some embodiments, Parts A and B are loaded in a dual barrel syringe that is serially connected to a static mixer and a microcatheter via Luer locks. Actuating the plunger of the syringe results in Parts A and B to simultaneously enter a static mixer in equal amounts. Further pressure on the plunger forces Parts A and B to mix and then exit the mixer into the microcatheter. The distal end of the microcatheter directs the resulting embolic composition to the treatment site.

[0118] In some embodiments, the method does not require a static mixer. Instead mixing Parts A and B is accomplished by repeatedly pumping the components between a first and second connected syringe to form a homogeneous mixture and then collecting the mixture in the first syringe. The method further comprises disconnecting the empty second syringe, followed by attaching a microcatheter via a Luer lock to the filled first syringe, placing the distal end of the microcatheter near a treatment site, and then applying pressure to the barrel of the first syringe to deliver the embolic composition to the treatment site.III. Miscellaneous

[0119] Where the context permits, singular or plural terms may also include the plural or singular term, respectively. As used herein, the terms “generally,” “substantially,” “about,” and similar terms are used as terms of approximation and not as terms of degree, and are intended to account for the inherent variations in measured or calculated values that would be recognized by those of ordinary skill in the art. As used herein, the term “about” is used synonymously with the term “approximately.” Illustratively, the use of the term “about” withMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO regard to an amount indicates values slightly outside the cited values, e.g., plus or minus 10%, plus or minus 5%, plus or minus 2%, plus or minus 1%, plus or minus 0.5%, plus or minus 0.2%, or plus or minus 0.1%.

[0120] Moreover, unless the word “or” is expressly limited to mean only a single item exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list.

[0121] Additionally, the term "comprising" is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and / or additional types of other features are not precluded.IV. Examples

[0122] The following examples are included to further describe some aspects of the present technology and should not be used to limit the scope of the technology.A. Example 1 : Preparation and Characterization of Embolic Compositions

[0123] This example describes the preparation and characterization of embolic compositions composed of covalently crosslinked polymers.1. Part A and Part B

[0124] Parts A and B comprise trimethylsilyloxy-terminated methylhydrosiloxanedimethylsiloxane copolymer and vinyl-terminated polydimethylsiloxane, respectively, which were prepared and obtained from Gelest and Nulsil at three different molecular weights as analyzed by size-exclusion chromatography (SEC), where the instrument is equipped with a Multi-angle Light Scattering paired with an RI detector. The polymers and the corresponding molecular weights (Mn, g / mol), dispersity (D), and degree of polymerization (DOP) are summarized in Table 1, below.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0125] Table 1 : Polymers in Parts A and B.

[0126] The m / n ratio of trimethylsiloxy-terminated methylhydrosiloxanedimethylsiloxane copolymer ranges from 3:97 to 20:80. Accordingly, the amount of Si-H functionalization of the polymer ranges from 3% to 20% ( / .< ., about 3% to about 20% of the total number of monomer units are capable of covalent crosslinking via the Si-H functional group. In some embodiments, the percentage of the methylhydroxy siloxane monomer is 3%- 10%. In addition to molecular weight, the viscosity and Tg of each polymer was measured. The viscosity was measured using a cone & plate Brookfield viscometer. The instrument was equipped with a spindle in order to achieve optimal signal per the viscosity of the specimens (targeted torque: 10-90 Nm). After setting the gap of the viscometer, 0.5 ml of the sample were loaded, and viscosity was measured at several speeds (shear rates). All measurements were conducted at room temperature 21.5 °C ± 1 °C.

[0127] The Tg of each polymer was measured via differential scanning calorimetry(DSC) using a TA DSC 2500 instrument. The measurement protocol involved cooling the polymer sample from room temperature to -180 °C at a rate of 10 °C / min. After equilibrating the sample at -180 °C, the temperature was increasingly ramped to room temperature at a rate of 10 °C / min. The Tg was determined during the heating cycle.

[0128] The viscosity and Tg measurements of the polymers are summarized in Table 2.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0129] Table 2: Viscosity of Polymers.2. Preparation of Embolic Composition

[0130] Polymer B (vinyl-terminated PDMS), was mixed with a platinum catalyst in divinyltetramethyldisiloxane to form the precursor composition Part B with 2-6% platinum.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WOPolymer A (trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer), without catalyst, formed the precursor composition Part A. Part A and Part B were each loaded into separate compartments of a dual barrel syringe. The dual barrel syringe was connected via a Luer lock to a static mixer, which in turn was linked to a microcatheter via a Luer lock. Upon depressing the plunger, Parts A and B were pushed out of the syringe into the static mixer in a 1 : 1 volume ratio. The liquid mixture exited the static mixer into the microcatheter. A soft and solid composition was formed within a 5-minute curing period.

[0131] In an alternative method, two syringes that are each filled with Part A or Part B are connected to each other through their Luer lock ends. The syringes were alternately pumped through several cycles, thereby mixing Parts A and B. After the mixture was sufficiently homogeneous, the syringes were disengaged from each other and a microcatheter was fitted onto the syringe containing the liquid mixture. The syringe was actuated by hand, and the liquid mixture exited the microcatheter as a liquid. A solid soft and compliant composition was formed within a 5-minute curing period.3. Rheological Characteristics of Embolic Composition

[0132] To measure the rheological properties of the embolic compositions, Part A and Part B for each formulation was mixed and immediately injected into an oscillatory parallel plate rheometer (8 mm plate diameter) at 37 °C. Storage modulus measurements over time were obtained at a frequency of 10 rad / s and 5% strain. Storage and loss modulus measurements over varying strains were obtained for strain amplitudes from 0% to 100%.

[0133] The curing time is determined by the point at which G’ and G” cross and was found to range from about 22-141 seconds. The storage modulus of the cured compositions ranged from about 8.1-155.3 kPa. The loss modulus of the cured compositions ranged from about 1.4-4.6 kPa. The tan delta of the cured compositions ranged from about 0.009-0.571. The rheological characteristics of each composition and the standard deviation is summarized in Table 3.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0134] Table 3. Summary of Curing Time, Storage Modulus, Loss Modulus, and TanDelta of Cured Embolic Compositions.

[0135] Sample 1 has lower molecular weight components (1.9 kDa and 3.6 kDa) than Samples 2 and 3 (5.2 kDa-5.9 kDa) and results in a softer solid as characterized by a comparatively low storage modulus (G1) and high tan delta (approaching 1). This softness may be attributed to reduced chain entanglement due to the shorter molecular chains. Solidification of Sample 1 is delayed by 1.7x to 6.4x, compared to the higher molecular weight Samples 2 and 3.

[0136] In general, the different amounts of functionalization (e.g., Si-H ) results in different degrees of crosslinking, which affects the properties of the crosslinked material.

[0137] Other examples of Polymer A and Polymer B are provided elsewhere in the description. An alternative method was also used to mix Compositions A and B, followed by collecting the mixture into one syringe and then injecting the mixture through a microcatheter. This method resulted in a liquid mixture exiting the microcatheter followed by curing with 5 minutes to form a soft and compliant embolic composition.V. Clauses

[0138] The present technology is illustrated, for example, according to various aspects described below. Various examples of aspects of the present technology are described as numbered clauses (1, 2, 3, etc.) for convenience. These various aspects are provided as examples and do not limit the subject technology.

[0139] Clause 1-1: A system for occluding a treatment site, the system comprising: a composition Part A comprising a Polymer A having at least one Reactive Group A; and a composition Part B comprising a Polymer B having at least one Reactive Group B; wherein combining Part A and Part B results in the formation of an embolic composition, Part A andMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WOPart B are solvent-free, Polymer A and Polymer B are hydrophobic, the molecular weight (Mn) of Polymer A is 900 Da to 15 kDa, 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa, and the molecular weight (Mn) of Polymer B is 900 Da to 15 kDa, 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa.

[0140] Clause 1-2: The system of Clause 1-1, wherein Part A and Part B each have a viscosity at 21 °C that is less than 100 cP, less than 80 cP, or less than 50 cP.10141] Clause 1-3: The system of Clause 1-1 or 1-2, wherein Polymer A and Polymer B each have a glass transition temperature (Tg) of less than -100 °C, less than -110 °C, or less than -120 °C.

[0142] Clause 1-4: The system of any one of Clauses I-1-I-3, wherein Polymer A is a siloxane-based polymer.

[0143] Clause 1-5: The system of any one of Clauses I- 1-1-4, wherein Polymer A comprises two or more monomer units substituted with one or more substituents selected from the group consisting of C1-C4 alkyl and vinyl groups.

[0144] Clause 1-6: The system of any one of Clauses I-1-I-5, wherein Polymer A is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof

[0145] Clause 1-7: The system of any one of Clauses I- 1-1-6, wherein Polymer A is selected from the group consisting of methylhydrosiloxane-dimethylsiloxane copolymer and polydimethylsiloxane.

[0146] Clause 1-8: The system of any one of Clauses I- 1-1-7, wherein Polymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxanedimethylsiloxane copolymer and hydride-terminated polydimethylsiloxane.

[0147] Clause 1-9: The system of any one of Clauses I- 1-1-8, wherein Polymer B is a siloxane-based polymer.

[0148] Clause I- 10: The system of any one of Clauses I-1-I-9, wherein Polymer B is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof.

[0149] Clause 1-11 : The system of any one of Clauses I-1-I-10, wherein Polymer B is selected from the group consisting of polydimethylsiloxane, diethylsiloxane-dimethylsiloxane copolymer, and vinylmethylsiloxane-dimethylsiloxane copolymer.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0150] Clause 1-12: The system of any one of Clauses I-l-I-l 1, wherein Polymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer

[0151] Clause 1-13: The system of any one of Clauses I-1-I-12, wherein at least one of Polymer A and Polymer B is an olefin-based polymer.

[0152] Clause 1-14: The system of Clause 1-13, wherein the olefin-based polymer is selected from the group consisting of polypropylene, polyethylene, polybutadiene, polyisoprene, polyisobutylene, polyoctene, and polyhexene, and copolymers thereof.

[0153] Clause 1-15: The system of Clause 1-13 or 1-14, wherein the olefin-based polymer is selected from the group consisting of poly(styrene-butadiene-styrene), and poly(styrene-ethylene-butylene-styrene).

[0154] Clause 1-16: The system of Clause 1-13 or 1-14, wherein the olefin-based polymer is selected from the group consisting of 1,2-polybutadiene, 1,4-polybutadiene, poly(l- octene), poly(l -hexene), and copolymers thereof.

[0155] Clause 1-17: The system of any one of Clauses I- 13-1- 16, wherein the olefin- based polymer is liquid at room temperature, hydrophobic, and has a Tg of less than -5 °C, less than -10 °C, less than -20 °C; less than -30 °C; or less than -60 °C.

[0156] Clause 1-18: The system of any one of Clauses I-1-I-17, wherein at least one of Polymer A and Polymer B is an olefin-based polymer and at least one of Polymer A and Polymer is a siloxane-based polymer.

[0157] Clause 1-19: The system of any one of Clauses I-1-I-18, wherein the at least one Reactive Group A is selected from the group consisting of silicone hydride, acrylate, methacrylate, epoxy, maleic anhydride, alcohol, isocyanate, mercapto, and oxalate.

[0158] Clause 1-20: The system of any one of Clauses I-1-I-19, wherein the at least one Reactive Group B is selected from the group consisting of vinyl, amine, acetoxy, enoxy, oxime, alkoxy, and alcohol.

[0159] Clause 1-21 : The system of any one of Clauses I- 1-1-20, wherein the at least one Reactive Group A and the at least one Reactive Group B react to form a covalent crosslink, and the reactive pair is selected from the group consisting of (a-i) listed below:MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0160] Clause 1-22: The system of any one of Clauses I-1-I-21, wherein the at least one Reactive Group A and the at least one Reactive Group B react to form a covalent crosslink, and the reactive pair is selected from the group consisting of (a-i) listed below:

[0161] Clause 1-23 : The system of any one of Clauses I-1-I-22, wherein the at least one Reactive Group A reacts with the at least one Reactive Group B, wherein the reaction is selected from the group consisting of Aza-Michael addition, hydrosilylation, anhydride-amine reaction, silanol condensation, and epoxy-amine reaction.

[0162] Clause 1-24: The system of any one of Clauses I-1-I-23, wherein the at least one Reactive Group A is part of a non-chain end monomer unit of Polymer A and the at least one Reactive Group B is at each chain end of Polymer B.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0163] Clause 1-25: The system of any one of Clauses I-1-I-23, wherein the at least one Reactive Group A is at the chain-end of Polymer A and the at least one Reactive Group B is at the chain-end of Polymer B.

[0164] Clause 1-26: The system of any one of Clauses I-1-I-23, wherein the at least one Reactive Group A is part of a non-chain end monomer unit of Polymer A and the at least one Reactive Group B is part of a non-chain end monomer unit of Polymer B.

[0165] Clause 1-27: The system of any one of Clauses I-1-I-23, wherein the at least one Reactive Group A is at the chain-end of Polymer A and the at least one Reactive Group B is part of a non-chain end monomer unit of Polymer B.

[0166] Clause 1-28: The system of any one of Clauses I- 1-1-27, wherein at least one of Part A or Part B, further comprises a catalyst.

[0167] Clause 1-29: The system of Clause 1-28, wherein the catalyst is a platinum catalyst.

[0168] Clause 1-30: The system of Clause 1-28 or 1-29, wherein the amount of catalyst is 1-10%, 1-8%, or 2-6% by weight.

[0169] Clause 1-31 : The system of any one of Clauses I-1-I-30, wherein at least one of Part A or Part B further comprises at least one additive.

[0170] Clause 1-32: The system of Clause 1-31, wherein the at least one additive is selected from the group consisting of contrast agent, filler, and crosslinker.

[0171] Clause 1-33: The system of Clause 1-32, wherein the contrast agent is selected from the group consisting of tantalum, bismuth, tungsten, barium, gadolinium, iodized oil, iohexol, iopamidol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoate, iothalamate, ioxaglate, iopromide, meglumine iothalamate, meglumine ioxaglate, meglumine diatrizoate, iodamide sodium, or metrizamide

[0172] Clause 1-34: The system of Clause 1-32 or 1-33, wherein the contrast agent is selected from the group consisting of tantalum, bismuth, tungsten, and barium.

[0173] Clause 1-35: The system of any one of Clauses 1-32-1-34, wherein the contrast agent is tungsten carbide or bismuth oxide.

[0174] Clause 1-36: The system of any one of Clauses I-32-I-34, wherein the contrast agent is bismuth trioxide or bismuth oxychlorideMDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0175] Clause 1-37: The system of any one of Clauses 1-32— 1-36, wherein the amount of contrast agent is 10-30% by weight.

[0176] Clause 1-38: The system of Clause 1-32, wherein the filler is a shear-thinning filler.

[0177] Clause 1-39: The system of Clause 1-38, wherein the shear-thinning filler is a nanoparticle.

[0178] Clause 1-40: The system of any one of Clauses 1-32, and 1-38— 1-39, wherein the filler is selected from the group consisting of fumed silica, precipitated silica, and MQ resin.

[0179] Clause 1-41 : The system of any one of Clauses 1-32, and I-38-I-40 wherein the surface area of the filler is 60-350 m2 / g.

[0180] Clause 1-42: The system of Clause 1-32, wherein the crosslinker is a multifunctional vinyl siloxane.

[0181] Clause 1-43: The system of Clause 1-42, wherein the at least one additive is selected from the group consisting of fumed silica, MQ resin, and non-functional silicone oil.

[0182] Clause 1-44: The system of any one of Clauses I-1-I-43, wherein the dispersity (D) of Polymer A is 1.4 to 2.7, or 1.4 to 2.5.

[0183] Clause 1-45: An embolic composition formed by: combining a composition Part A and a composition Part B, wherein:Part A comprises a Polymer A having at least one Reactive Group A,Part B comprises a Polymer B having at least one Reactive Group B, and reacting at least one Reactive Group A and at least one Reactive Group B to form a covalent crosslink, wherein the reaction time is within a range from 10 seconds to 90 seconds; wherein:Part A and Part B are solvent-free,Polymer A and Polymer B are hydrophobic, the embolic composition is immiscible with blood, and the Tg of the embolic composition is less than -100°C.

[0184] Clause 1-46: The embolic composition of Clause 1-45, wherein the embolic composition has a Shore hardness of less than 40 A.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0185] Clause 1-47: The embolic composition of Clause 1-45 or 1-46, wherein the embolic composition has a curing time that is at least 15 seconds, at least 30 seconds, or at least 60 seconds.

[0186] Clause 1-48: The embolic composition of any one of Clauses I-45-I-47, wherein the embolic composition has a storage modulus at 37 °C within a linear viscoelastic region of the embolic composition that is within a range from 5 kPa to 225 kPa, 10 kPa to 200 kPa, 10 kPa to 180 kPa.

[0187] Clause 1-49: The embolic composition of any one of Clauses I-45-I-48, wherein the curing time is no more than 30 seconds, 1 minute, 2 minutes, 3 minutes, 4 minutes, or 5 minutes.

[0188] Clause 1-50: The embolic composition of any one of Clauses I-45-I-49, wherein at least one covalent crosslink is formed between the Polymer A and Polymer B.

[0189] Clause 1-51 : The embolic composition of any one of Clauses I-45-I-50, at least 80%, 85%, 90%, 95%, or 99% of the final total crosslinking value are formed 0.5-20 minutes, 1-20 minutes, 2-20 minutes, 3-20 minutes, 4-20 minutes, 5-20 minutes, 7-20 minutes, 10- 20 minutes, or 15-20 minutes after Parts A and B are combined.

[0190] Clause 1-52: The embolic composition of any one of Clauses 1-45— 1-51, wherein at least 80% of the final total crosslinking value are formed 1-10 minutes after Parts A and B are combined.

[0191] Clause 1-53 : The embolic composition of any one of Clauses I-45-I-52, wherein Part A and Part B each have a viscosity at 21 °C that is less than 100 cP, less than 80 cP, or less than 50 cP.

[0192] Clause 1-54: The embolic composition of any one of Clauses 1-45— 1-53 , wherein Polymer A and Polymer B each have a glass transition temperature (Tg) of less than -100 °C, less than -110 °C, or less than -120 °C.

[0193] Clause 1-55: The embolic composition of any one of Clauses I-45-I-54, wherein Polymer A is a siloxane-based polymer.

[0194] Clause 1-56: The embolic composition of any one of Clauses 1-45— 1-55, wherein Polymer A comprises two or more monomer units substituted with one or more substituents selected from the group consisting of C1-C4 alkyl and vinyl groups.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0195] Clause 1-57: The embolic composition of any one of Clauses 1-45— 1-56, whereinPolymer A is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof

[0196] Clause 1-58: The embolic composition of any one of Clauses 1-45— 1-57, whereinPolymer A is selected from the group consisting of methylhydrosiloxane-dimethylsiloxane copolymer and polydimethylsiloxane.

[0197] Clause 1-59: The embolic composition of any one of Clauses 1-45— 1-58, whereinPolymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxane-dimethylsiloxane copolymer and hydride-terminated polydimethylsiloxane.

[0198] Clause 1-60: The embolic composition of any one of Clauses 1-45— 1-59, wherein Polymer B is a siloxane-based polymer.

[0199] Clause 1-61 : The embolic composition of any one of Clauses I-45-I-60, wherein Polymer B is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof.

[0200] Clause 1-62: The embolic composition of any one of Clauses 1-45— 1-61 , whereinPolymer B is selected from the group consisting of polydimethylsiloxane, diethylsiloxanedimethylsiloxane copolymer, and vinylmethylsiloxane-dimethylsiloxane copolymer.

[0201] Clause 1-63 : The embolic composition of any one of Clauses I-45-I-62, whereinPolymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl-terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer

[0202] Clause 1-64: The embolic composition of any one of Clauses 1-45— 1-63 , wherein at least one of Polymer A and Polymer B is an olefin-based polymer.

[0203] Clause 1-65: The embolic composition of Clause 1-64, wherein the olefin-based polymer is selected from the group consisting of polypropylene, polyethylene, polybutadiene, polyisoprene, polyisobutylene, polyoctene, and polyhexene, and copolymers thereof.

[0204] Clause 1-66: The embolic composition of Clause 1-64 or 1-65, wherein the olefin-based polymer is selected from the group consisting of poly(styrene-butadiene-styrene), and poly(styrene-ethylene-butylene-styrene).MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0205] Clause 1-67: The embolic composition of Clause 1-64 or 1-65, wherein the olefin-based polymer is selected from the group consisting of 1,2-polybutadiene, 1,4- polybutadiene, poly(l -octene), poly (1 -hexene), and copolymers thereof.

[0206] Clause 1-68: The embolic composition of any one of Clauses I-64-I-67, wherein the olefin-based polymer is liquid at room temperature, hydrophobic, and has a Tg of less than -5 °C, less than -10 °C, less than -20 °C; less than -30 °C; or less than -60 °C.

[0207] Clause 1-69: The embolic composition of any one of Clauses I-45-I-68, wherein at least one of Polymer A and Polymer B is an olefin-based polymer and at least one of Polymer A and Polymer is a siloxane-based polymer.

[0208] Clause 1-70: The embolic composition of any one of Clauses I-45-I-69, wherein the at least one Reactive Group A is selected from the group consisting of silicone hydride, acrylate, methacrylate, epoxy, maleic anhydride, alcohol, isocyanate, mercapto, and oxalate.

[0209] Clause 1-71 : The embolic composition of any one of Clauses I-45-I-70, wherein the at least one Reactive Group B is selected from the group consisting of vinyl, amine, acetoxy, enoxy, oxime, alkoxy, and alcohol.

[0210] Clause 1-72: The embolic composition of any one of Clauses 1-45— 1-71 , wherein the at least one Reactive Group A and the at least one Reactive Group B react to form a covalent crosslink, and the reactive pair is selected from the group consisting of (a-i) listed below:

[0211] Clause 1-73 : The embolic composition of any one of Clauses I-45-I-72, wherein the at least one Reactive Group A and the at least one Reactive Group B react to form a covalent crosslink, and the reactive pair is selected from the group consisting of (a-i) listed below:MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0212] Clause 1-74: The embolic composition of any one of Clauses 1-45— 1-73 , wherein the at least one Reactive Group A reacts with the at least one Reactive Group B, wherein the reaction is selected from the group consisting of Aza-Michael addition, hydrosilylation, anhydride-amine reaction, silanol condensation, and epoxy-amine reaction.|0213] Clause 1-75: The embolic composition of any one of Clauses I-45-I-74, wherein the at least one Reactive Group A is part of a non-chain end monomer unit of Polymer A and the at least one Reactive Group B is at each chain end of Polymer B.

[0214] Clause 1-76: The embolic composition of any one of Clauses 1-45— 1-75, wherein the at least one Reactive Group A is at the chain-end of Polymer A and the at least one Reactive Group B is at the chain-end of Polymer B.

[0215] Clause 1-77: The embolic composition of any one of Clauses I-45-I-76, wherein the at least one Reactive Group A is part of a non-chain end monomer unit of Polymer A and the at least one Reactive Group B is part of a non-chain end monomer unit of Polymer B.

[0216] Clause 1-78: The embolic composition of any one of Clauses I-45-I-77, wherein the at least one Reactive Group A is at the chain-end of Polymer A and the at least one Reactive Group B is part of a non-chain end monomer unit of Polymer B.

[0217] Clause 1-79: The embolic composition of any one of Clauses I-45-I-78, wherein at least one of Part A or Part B, further comprises a catalyst.

[0218] Clause 1-80: The embolic composition of Clause 1-79, wherein the catalyst is a platinum catalyst.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0219] Clause 1-81 : The embolic composition of Clause 1-79 or 80, wherein the amount of catalyst is 1-10%, 1-8%, or 2-6% by weight.

[0220] Clause 1-82: The embolic composition of any one of Clauses 1-45— 1-81, wherein at least one of Part A or Part B further comprises at least one additive.

[0221] Clause 1-83 : The embolic composition of claim 82, wherein the at least one additive is selected from the group consisting of contrast agent, filler, and crosslinker.

[0222] Clause 1-84: The embolic composition of Clause 1-83, wherein the contrast agent is selected from the group consisting of tantalum, bismuth, tungsten, barium, gadolinium, iodized oil, iohexol, iopamidol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoate, iothalamate, ioxaglate, iopromide, meglumine iothalamate, meglumine ioxaglate, meglumine diatrizoate, iodamide sodium, or metrizamide

[0223] Clause 1-85: The embolic composition of claim 83 or 84, wherein the contrast agent is selected from the group consisting of tantalum, bismuth, tungsten, and barium.

[0224] Clause 1-86: The embolic composition of any one of Clauses 1-83— 1-85, wherein the contrast agent is tungsten carbide or bismuth oxide.

[0225] Clause 1-87: The embolic composition of any one of Clauses 1-83— 1-86, wherein the contrast agent is bismuth trioxide or bismuth oxychloride

[0226] Clause 1-88: The embolic composition of any one of Clauses 1-83— 1-87, wherein the amount of contrast agent is 10-30% by weight.

[0227] Clause 1-89: The embolic composition of Clause 1-83, wherein the filler is a shear-thinning filler.

[0228] Clause 1-90: The embolic composition of claim 89, wherein the shear-thinning filler is a nanoparticle.

[0229] Clause 1-91 : The embolic composition of any one of Clauses 1-83, and 1-89— I-90, wherein the filler is selected from the group consisting of fumed silica, precipitated silica, and MQ resin.

[0230] Clause 1-92: The embolic composition of any one of Clauses 1-83 and 1-89— I-91, wherein the surface area of the filler is 60-350 m2 / g.

[0231] Clause 1-93: The embolic composition of Clause 1-83, wherein the crosslinker is a multifunctional vinyl siloxane.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0232] Clause 1-94: The embolic composition of Clause 1-83, wherein the at least one additive is selected from the group consisting of fumed silica, MQ resin, and non-functional silicone oil.

[0233] Clause 1-95: The embolic composition of any one of Clauses I-45-I-94, wherein the dispersity (D) of Polymer A is 1.4 to 2.7, or 1.4 to 2.5.

[0234] Clause 1-96: A method for occluding a treatment site, the method comprising: combining a composition Part A and a composition Part B to form an embolic composition; and delivering the embolic agent into or near the treatment site to occlude the treatment site; wherein:Part A comprises a Polymer A having at least one Reactive Group A,Part B comprises a Polymer B having at least one Reactive Group B, the combining of Part A and Part B results in the formation of covalent crosslinks between Polymer A and Polymer B,Part A and Part B are solvent-free, the embolic composition is hydrophobic, the embolic composition is immiscible with blood, and the Tg of the embolic composition is less than -100°C

[0235] Clause 1-97: The method of Clause 1-96, wherein the treatment site comprises a feature selected from the group consisting of an aneurysm, an arteriovenous malformation, an arteriovenous fistula, a tumor, a chronic subdural hematoma, a perivascular leak, a varicose vein, a hemorrhoid, and an endoleak.

[0236] Clause 1-98: The method of Clause 1-96 or 1-97, wherein Part A and Part B each have a viscosity at 21 °C that is less than 100 cP, less than 80 cP, or less than 50 cP.

[0237] Clause 1-99: The method of any one of Clauses I-96-I-98, wherein Polymer A and Polymer B each have a glass transition temperature (Tg) of less than -100 °C, less than - 110 °C, or less than -120 °C.

[0238] Clause I- 100: The method of any one of Clauses I-96-I-99, wherein Polymer A is a siloxane-based polymer.

[0239] Clause 1-101 : The method of any one of Clauses I-96-I-100, wherein Polymer A comprises two or more monomer units substituted with one or more substituents selected from the group consisting of C1-C4 alkyl and vinyl groups.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0240] Clause 1-102: The method of any one of Clauses 1-96— 1-101, wherein Polymer A is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof

[0241] Clause 1-103: The method of any one of Clauses I-96-I-102, wherein Polymer A is selected from the group consisting of methylhydrosiloxane-dimethylsiloxane copolymer and polydimethylsiloxane.

[0242] Clause 1-104: The method of any one of Clauses 1-96— 1-103, wherein Polymer A is selected from the group consisting of trimethylsiloxy-terminated methylhydrosiloxanedimethylsiloxane copolymer and hydride-terminated polydimethylsiloxane.

[0243] Clause 1-105: The method of any one of Clauses I-96-I-104, wherein Polymer B is a siloxane-based polymer.

[0244] Clause 1-106: The method of any one of Clauses 1-96— 1-105, wherein Polymer B is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof.

[0245] Clause 1-107: The method of any one of Clauses I-96-I-106, wherein Polymer B is selected from the group consisting of polydimethylsiloxane, diethylsiloxanedimethylsiloxane copolymer, and vinylmethylsiloxane-dimethylsiloxane copolymer.

[0246] Clause 1-108: The method of any one of Clauses I-96-I-107, wherein Polymer B is selected from the group consisting of vinyl-terminated polydimethylsiloxane, vinyl- terminated diethylsiloxane-dimethylsiloxane copolymer, and trimethylsiloxy-terminated vinylmethylsiloxane-dimethylsiloxane copolymer

[0247] Clause 1-109: The method of any one of Clauses 1-96— 1-108, wherein at least one of Polymer A and Polymer B is an olefin-based polymer.

[0248] Clause 1-110: The method of Clause 1-109, wherein the olefin-based polymer is selected from the group consisting of polypropylene, polyethylene, polybutadiene, polyisoprene, polyisobutylene, polyoctene, and polyhexene, and copolymers thereof.

[0249] Clause 1-111: The method of Clause 1-109 or I- 110, wherein the olefin-based polymer is selected from the group consisting of poly(styrene-butadiene-styrene), and poly(styrene-ethylene-butylene-styrene).MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0250] Clause 1-112: The method of Clause 1-109 or 1-110, wherein the olefin-based polymer is selected from the group consisting of 1,2-polybutadiene, 1,4-polybutadiene, poly(l- octene), poly(l -hexene), and copolymers thereof.

[0251] Clause 1-113: The method of any one of Clauses 1-109— 1-112, wherein the olefin-based polymer is liquid at room temperature, hydrophobic, and has a Tg of less than -5 °C, less than -10 °C, less than -20 °C; less than -30 °C; or less than -60 °C.

[0252] Clause 1-114: The method of any one of Clauses I-96-I-113, wherein at least one of Polymer A and Polymer B is an olefin-based polymer and at least one of Polymer A and Polymer is a siloxane-based polymer.

[0253] Clause 1-115: The method of any one of Clauses I-96-I-114, wherein the at least one Reactive Group A is selected from the group consisting of silicone hydride, acrylate, methacrylate, epoxy, maleic anhydride, alcohol, isocyanate, mercapto, and oxalate.

[0254] Clause 1-116: The method of any one of Clauses I-96-I-115, wherein the at least one Reactive Group B is selected from the group consisting of vinyl, amine, acetoxy, enoxy, oxime, alkoxy, and alcohol.

[0255] Clause 1-117: The method of any one of Clauses I-96-I-116, wherein the at least one Reactive Group A and the at least one Reactive Group B react to form a covalent crosslink, and the reactive pair is selected from the group consisting of (a-i) listed below:MDT Ref. No. A0012456W001 Fortem Ref. No. MDTNV.303WO

[0256] Clause 1-118: The method of any one of Clauses I-96-I-117, wherein the at least one Reactive Group A and the at least one Reactive Group B react to form a covalent crosslink, and the reactive pair is selected from the group consisting of (a-i) listed below:

[0257] Clause 1-119: The method of any one of Clauses I-96-I-118, wherein the at least one Reactive Group A reacts with the at least one Reactive Group B, wherein the reaction is selected from the group consisting of Aza-Michael addition, hydrosilylation, anhydride-amine reaction, silanol condensation, and epoxy-amine reaction.

[0258] Clause 1-120: The method of any one of Clauses I-96-I-119, wherein the at least one Reactive Group A is part of a non-chain end monomer unit of Polymer A and the at least one Reactive Group B is at each chain end of Polymer B.

[0259] Clause 1-121 : The method of any one of Clauses I-96-I-119, wherein the at least one Reactive Group A is at the chain-end of Polymer A and the at least one Reactive Group B is at the chain-end of Polymer B.

[0260] Clause 1-122: The method of any one of Clauses I-96-I-119, wherein the at least one Reactive Group A is part of a non-chain end monomer unit of Polymer A and the at least one Reactive Group B is part of a non-chain end monomer unit of Polymer B.

[0261] Clause 1-123: The method of any one of Clauses I-96-I-119, wherein the at least one Reactive Group A is at the chain-end of Polymer A and the at least one Reactive Group B is part of a non-chain end monomer unit of Polymer B.

[0262] Clause 1-124: The method of any one of Clauses 1-96— 1-123, wherein at least one of Part A or Part B, further comprises a catalyst.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0263] Clause 1-125: The method of Clause 1-124, wherein the catalyst is a platinum catalyst.

[0264] Clause 1-126: The method of Clause 1-124 or 1-125, wherein the amount of catalyst is 1-10%, 1-8%, or 2-6% by weight.

[0265] Clause 1-127: The method of any one of Clauses I-96-I-126, wherein at least one of Part A or Part B further comprises at least one additive.

[0266] Clause 1-128: The method of Clause 1-127, wherein the at least one additive is selected from the group consisting of contrast agent, filler, and crosslinker.

[0267] Clause 1-129: The method of Clause 1-128, wherein the contrast agent is selected from the group consisting of tantalum, bismuth, tungsten, barium, gadolinium, iodized oil, iohexol, iopamidol, ioxilan, iopromide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoate, iothalamate, ioxaglate, iopromide, meglumine iothalamate, meglumine ioxaglate, meglumine diatrizoate, iodamide sodium, or metrizamide

[0268] Clause 1-130: The method of Clause 1-128 or 1-129, wherein the contrast agent is selected from the group consisting of tantalum, bismuth, tungsten, and barium.

[0269] Clause 1-131 : The method of any one of Clauses 1-128— 1-130, wherein the contrast agent is tungsten carbide or bismuth oxide.

[0270] Clause 1-132: The method of any one of Clauses 1-128— 1-130, wherein the contrast agent is bismuth trioxide or bismuth oxychloride

[0271] Clause 1-133: The method of any one of Clauses 1-128— 1-132, wherein the amount of contrast agent is 10-30% by weight.

[0272] Clause 1-134: The method of Clause 1-128, wherein the filler is a shear-thinning filler.

[0273] Clause 1-135: The method of Clause 1-134, wherein the shear-thinning filler is a nanoparticle.

[0274] Clause 1-136: The method of any one of Clauses 1-128, and 1-134— 1-135, wherein the filler is selected from the group consisting of fumed silica, precipitated silica, and MQ resin.

[0275] Clause 1-137: The method of any one of Clauses 1-128 and I- 134-1- 136, wherein the surface area of the filler is 60-350 m2 / g.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0276] Clause 1-138: The method of Clause 1-128, wherein the crosslinker is a multifunctional vinyl siloxane.

[0277] Clause 1-139: The method of Clause 1-138, wherein the at least one additive is selected from the group consisting of fumed silica, MQ resin, and non-functional silicone oil.

[0278] Clause 1-140: The method of any one of Clauses 1-96— 1-139, wherein the dispersity (D) of Polymer A is 1.4 to 2.7, or 1.4 to 2.5.

[0279] Clause 1-141 : The method of any one of Clauses I-96-I-140, wherein the embolic composition is according to any one of Clauses 1-45— 1-95.Conclusion

[0280] The present technology is applicable to many applications and / or approaches. Such as treatment of saccular intracranial aneurysms, non-saccular intracranial aneurysms, abdominal aortic aneurysms, thoracic aortic aneurysms, renal artery aneurysms, arteriovenous malformations (e.g., brain arteriovenous malformations), arteriovenous fistulas, tumors (e.g., via occlusion of vessel(s) feeding a tumor), chronic subdural hematomas (e.g., via occlusion of the middle meningeal artery), perivascular leaks, varicose veins (e.g., via occlusion of one or more truncal veins such as the great saphenous vein), hemorrhoids, and sealing endoleaks adjacent to artificial heart valves, covered stents, and abdominal aortic aneurysm devices, among other examples. Additionally, several other embodiments of the technology can have different configurations, components, or procedures than those described herein. A person of ordinary skill in the art, therefore, will accordingly understand that the technology can have other embodiments with additional elements, or the technology can have other embodiments without several of the features shown and described above with reference to FIGS. 1 A-1C.

[0281] The descriptions of embodiments of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Where the context permits, singular or plural terms may also include the plural or singular term, respectively. Although specific embodiments of, and examples for, the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative embodiments may perform steps in a different order. The various embodiments described herein may also be combined to provide further embodiments.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO

[0282] To the extent any materials incorporated herein by reference conflict with the present disclosure, the present disclosure controls.

[0283] It will also be appreciated that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. Further, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein.

Claims

MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WOCLAIMSWhat is claimed is:

1. A system for occluding a treatment site, the system comprising: a composition Part A comprising a Polymer A having at least one Reactive Group A; and a composition Part B comprising a Polymer B having at least one Reactive Group B; wherein combining Part A and Part B results in the formation of an embolic composition,Part A and Part B are solvent-free,Polymer A and Polymer B are hydrophobic, the molecular weight (Mn) of Polymer A is 900 Da to 15 kDa, 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa, and the molecular weight (Mn) of Polymer B is 900 Da to 15 kDa, 1.2 kDa to 8 kDa, 3 kDa to 7 kDa, or 1.5 kDa to 7 kDa.

2. The system of claim 1, wherein Part A and Part B each have a viscosity at 21 °C that is less than 100 cP, less than 80 cP, or less than 50 cP.

3. The system of any one of claims 1-2, wherein Polymer A is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof4. The system of any one of claims 1-3, wherein Polymer B is selected from the group consisting of polymethylhydrosiloxane, polydimethylsiloxane, polydiethylsiloxane, polyvinylmethylsiloxane, and copolymers thereof.

5. The system of any one of claims 1-4, wherein the at least one Reactive Group A is selected from the group consisting of silicone hydride, acrylate, methacrylate, epoxy, maleic anhydride, alcohol, isocyanate, mercapto, and oxalate.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO6. The system of any one of claims 1-5, wherein the at least one Reactive Group B is selected from the group consisting of vinyl, amine, acetoxy, enoxy, oxime, alkoxy, and alcohol.

7. The system of any one of claims 1-6, wherein the at least one Reactive Group A reacts with the at least one Reactive Group B, wherein the reaction is selected from the group consisting of Aza-Michael addition, hydrosilylation, anhydride-amine reaction, silanol condensation, and epoxy-amine reaction.

8. The system of any one of claims 1-7, wherein at least one of Part A or Part B, further comprises a catalyst.

9. The system of any one of claims 1-8, wherein at least one of Part A or Part B further comprises at least one additive selected from the group consisting of contrast agent, filler, and crosslinker.

10. An embolic composition formed by: combining a composition Part A and a composition Part B, wherein:Part A comprises a Polymer A having at least one Reactive Group A,Part B comprises a Polymer B having at least one Reactive Group B, and reacting at least one Reactive Group A and at least one Reactive Group B to form a covalent crosslink, wherein the reaction time is within a range from 10 seconds to 90 seconds; wherein:Part A and Part B are solvent-free,Polymer A and Polymer B are hydrophobic, the embolic composition is immiscible with blood, and the Tg of the embolic composition is less than -100°C.

11. The embolic composition of claim 10, wherein the embolic composition has a storage modulus at 37 °C within a linear viscoelastic region of the embolic composition that is within a range from 5 kPa to 225 kPa, 10 kPa to 200 kPa, 10 kPa to 180 kPa.MDT Ref. No. A0012456W001Fortem Ref. No. MDTNV.303WO12. An embolic composition for use in occluding a treatment site, comprising: combining a composition Part A and a composition Part B to form an embolic composition; and delivering the embolic agent into or near the treatment site to occlude the treatment site; wherein:Part A comprises a Polymer A having at least one Reactive Group A,Part B comprises a Polymer B having at least one Reactive Group B, the combining of Part A and Part B results in the formation of covalent crosslinks between Polymer A and Polymer B,Part A and Part B are solvent-free, the embolic composition is hydrophobic, the embolic composition is immiscible with blood, and the Tg of the embolic composition is less than -100°C13. The embolic composition of claim 12, wherein Part A and Part B each have a viscosity at 21 °C that is less than 100 cP, less than 80 cP, or less than 50 cP.

14. The embolic composition of claim 12 or 13, wherein Polymer A and Polymer B each have a glass transition temperature (Tg) of less than -100 °C, less than -110 °C, or less than -120 °C.

15. The embolic composition of any one of claims 12-14, wherein the embolic composition has a storage modulus at 37 °C within a linear viscoelastic region of the embolic composition that is within a range from 5 kPa to 225 kPa, 10 kPa to 200 kPa, 10 kPa to 180 kPa.

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