Composite embolic systems for treating vascular defects

Abstract

Compositions and methods for treating vascular defects are provided. In some embodiments, a system for treating a vascular defect includes a first precursor composition including a first polymer having a first reactive group, and a second precursor composition including a second polymer having a second reactive group. Mixing of the first and second precursor compositions can cause a covalent crosslinking reaction between the first reactive group of the first polymer and the second reactive group of the second polymer to form a hydrogel. At least one of the first precursor composition or the second precursor composition can include a plurality of silicate nanoparticles that interact non-covalently with each other such that the mixture of the first and second precursor compositions has shear-thinning properties before the covalent crosslinking reaction is complete.

Description

COMPOSITE EMBOLIC SYSTEMS FOR TREATING VASCULAR DEFECTSCROSS-REFERENCED TO RELATED APPLICATION(S)[0001| The present application claims the benefit of priority to Greek Patent Application No. 20240100469, filed June 27, 2024, which is incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] The present technology generally relates to biocompatible materials, and in particular, to composite embolic systems for treating vascular defects.BACKGROUND

[0003] An intracranial aneurysm is a portion of an intracranial blood vessel that bulges outward from the blood vessel’s main channel. This condition often occurs at a portion of a blood vessel that is abnormally weak because of a congenital anomaly, trauma, high blood pressure, or for another reason. Once an intracranial aneurysm forms, there is a significant risk that the aneurysm will eventually rupture and cause a medical emergency with a high risk of mortality due to hemorrhaging. When an unruptured intracranial aneurysm is detected or when a patient survives an initial rupture of an intracranial aneurysm, vascular surgery is often indicated. One conventional type of vascular surgery for treating an intracranial aneurysm includes using a microcatheter to dispose a platinum coil within an interior volume of the aneurysm. Over time, the presence of the coil should induce formation of a thrombus. Ideally, the aneurysm’s neck closes at the site of the thrombus and is replaced with new endothelial tissue. Blood then bypasses the aneurysm, thereby reducing the risk of aneurysm rupture (or re-rupture) and associated hemorrhaging. Unfortunately, long-term recanalization (i.e., restoration of blood flow to the interior volume of the aneurysm) after this type of vascular surgery occurs in a number of cases, especially for intracranial aneurysms with relatively wide necks and / or relatively large interior volumes.

[0004] Another conventional type of vascular surgery for treating an intracranial aneurysm includes deploying a flow diverter within the associated intracranial blood vessel. The flow diverter is often a mesh tube that causes blood to preferentially flow along a main channel of the blood vessel while blood within the aneurysm stagnates. The stagnant blood within the aneurysmshould eventually form a thrombus that leads to closure of the aneurysm’s neck and to growth of new endothelial tissue, as with the platinum coil treatment. One significant drawback of flow diverters is that it may take weeks or months to form aneurysmal thrombus and significantly longer for the aneurysm neck to be covered with endothelial cells for full effect. This delay may be unacceptable when risk of aneurysm rupture (or re-rupture) is high. Moreover, flow diverters typically require antiplatelet therapy to prevent a thrombus from forming within the main channel of the blood vessel at the site of the flow diverter. Antiplatelet therapy may be contraindicated shortly after an initial aneurysm rupture has occurred because risk of re-rupture at this time is high and antiplatelet therapy tends to exacerbate intracranial hemorrhaging if re-rupture occurs. For these and other reasons, there is a need for innovation in the treatment of intracranial aneurysms. Given the severity of this condition, innovation in this field has immediate life-saving potential.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] 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.

[0006] FIG. 1A is a partially schematic view of a treatment system configured in accordance with embodiments of the present technology.

[0007] FIG. IB is an enlarged cross-sectional view of a distal portion of the treatment system of FIG. 1A.

[0008] FIG. 1C is a partially schematic view of an embolic kit of the treatment system of FIG. 1A.

[0009] FIGS. 2A-2E illustrate an example method of treating an aneurysm using the treatment system of FIGS. 1A-1C, in accordance with embodiments of the present technology.

[0010] FIG. 3A illustrates a neck cover configured in accordance with embodiments of the present technology.

[0011] FIGS. 3B-3D illustrate an example method of treating an aneurysm using the neck cover of FIG. 3 A, in accordance with embodiments of the present technology.

[0012] FIGS. 4A-4C are schematic illustrations of an embolic composition configured in accordance with embodiments of the present technology.

[0013] FIGS. 5A and 5B are graphs illustrating viscosity measurements for precursor compositions of an embolic composition before mixing.

[0014] FIGS. 6A-6D are graphs of storage modulus over time for different embolic compositions.

[0015] FIG. 7 is a graph illustrating rheological measurements for an embolic composition at various strain amplitudes.

[0016] FIGS. 8A and 8B illustrate occlusion of a simulated brain arteriovenous malformation model with an embolic composition.DETAILED DESCRIPTION

[0017] The present technology relates to compositions configured for delivery to a treatment site in a patient’s body, such as an aneurysm, an arteriovenous malformation, or other vascular defect, and associated methods. In some embodiments, for example, a system for treating a vascular defect includes a first precursor composition including a first polymer having a first reactive group, and a second precursor composition including a second polymer having a second reactive group. Mixing of the first and second precursor compositions can cause a covalent crosslinking reaction between the first reactive group of the first polymer and the second reactive group of the second polymer to form a hydrogel. At least one of the first precursor composition or the second precursor composition can include a plurality of silicate nanoparticles that interact non- covalently with each other such that the mixture of the first and second precursor compositions has shear-thinning properties before the covalent crosslinking reaction is complete.

[0018] The present technology can provide many advantages over conventional approaches for aneurysm treatment. For example, conventional treatment methods typically use either a low viscosity embolic agent that gels or solidifies in situ when exposed to physiological conditions at the treatment site, or separate precursor components that are mixed immediately before delivery to form the final embolic agent. However, these approaches may present challenges with timing. For example, if the agent gels too quickly, it may clog the delivery device. If the agent gels too slowly, it may leak out of the treatment site, which can have catastrophic results in certainapplications such as the treatment of cerebral aneurysms. The risk of leakage may be increased in situations where the treatment site is proximate to a parent vessel having relatively high blood flow rates. In contrast, the compositions of the present technology have shear-thinning properties before the crosslinking reaction is complete, thus providing injectability while also mitigating the issue of leakage, e g., the composition flows like a liquid during injection and forms a cohesive solid mass once delivered into the treatment site. The covalent crosslinking mechanism further ensures that no fragmentation or unintended embolization takes place after delivery. Moreover, the compositions herein can avoid the use of small molecule covalent crosslinkers and 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).

[0019] 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.

[0020] 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. Overview of Treatment Systems and Methods

[0021] FIG. 1A shows a treatment system 100 (“system 100”) configured in accordance with embodiments of the present technology. Although the system 100 is described herein in the context of treating aneurysms such as cerebral aneurysms, this is not intended to be limiting, and the system 100 can also be used in the treatment of other types of vascular defects, and / or in any other application involving delivery of an embolic composition into a space within a patient’s body.

[0022] As shown in FIG. 1A, the system 100 includes a delivery system 102, a neck cover 104 (also referred to herein as an “occlusive member,” “occlusive device,” or a “neck protection device”), and an embolic kit 150. The neck cover 104 (shown schematically) is configured to bedetachably coupled to the delivery system 102, and the delivery system 102 is configured to intravascularly position the neck cover 104 within an aneurysm. Representative examples of neck covers 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.

[0023] The embolic kit 150 includes an embolic composition 152 (e.g., a shear-thinning curable hydrogel 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 the aneurysm cavity. The embolic composition 152 can be any material suitable for forming a solid or semi-solid viscoelastic structure (e.g., a hydrogel) that partially or completely occludes the interior cavity of the aneurysm. The embolic composition 152 can be delivered to a space between the neck cover 104 and the dome of the aneurysm to fill and occlude the aneurysm cavity. The neck cover 104 prevents migration of the embolic composition 152 into the parent vessel, and together the neck cover 104 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 neck cover 104 may cause the aneurysm wall to fully degrade, leaving behind a successfully remodeled (aneurysm free) region of the blood vessel.

[0024] Referring next to FIG. 1C, 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. The 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 solid, cohesive hydrogel suitable for occluding the aneurysm cavity (or other treatment site such as a vessel, lesion, etc ). The time for the chemical crosslinking reaction can be sufficiently long to allow the resulting embolic composition 152 be delivered to the aneurysm or other treatment site before becomingtoo viscous for injection, but sufficiently short enough to reach a target deployed viscosity within a reasonable time after delivery. In some embodiments, the first precursor composition 156a and / or the second precursor composition 156b can include a plurality of nanoparticles that confer shearthinning properties to the embolic composition 152 before the crosslinking reaction is complete. Optionally, the first precursor composition 156a and / or the second precursor composition 156b can include one or more additional components, such as a contrast agent, or a third precursor composition can be provided with the contrast agent and / or additional component(s). 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.

[0025] In some embodiments, the embolic kit 150 includes a mixing system suitable for mixing the first precursor composition 156a and the second precursor composition 156b. The mixing system can include a first syringe 158a containing the first precursor composition 156a, a second syringe 158b containing the second precursor composition 156b, the injector 154, and a coupler 160. The first and second syringes 158a, 158b can each include a plunger and a barrel in which the plunger is slidably received. The first syringe 158a, second syringe 158b, and injector 154 can be connected to each other via the coupler 160 (e.g., a three-way stopcock). To mix the first and second precursor compositions 156a, 156b, the plungers of the first syringe 158a and second syringe 158b can be alternately depressed, thereby causing the first and second precursor compositions 156a, 156b to move repeatedly between the barrels of the first and second syringes 158a, 158b. Optionally, the injector 154 may be provided with a third precursor composition (e.g., containing a contrast agent — not shown) that may be mixed with the first and second precursor compositions 156a, 156b in any suitable sequence, e.g., the first and second precursor compositions 156a, 156b may be mixed with each other before being mixed with the third precursor composition. The resulting embolic composition 152 can then be collected into the injector 154.

[0026] Referring again to FIG. 1A, the delivery system 102 has a proximal portion 106a configured to be extracorporeally positioned during treatment and a distal portion 106b configured to be intravascularly positioned at or within an aneurysm. 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. The delivery system 102 and / or the third elongate shaft 114 is configured to be detachably coupled at its distal end portion to the neck cover 104 via a connector 122 (see FIG. IB) of the neck cover 104. In some embodiments, the delivery system 102 does not include the first elongate shaft 110.

[0027] The second elongate shaft 112 is generally constructed to track over a conventional guidewire in the cervical anatomy and into the cerebral vessels associated with the brain. 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 more particularly may be between about 125 cm and about 175 cm long. The lumen of the second elongate shaft 112 is configured to slidably receive the neck cover 104 in a radially constrained state. 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).

[0028] The third elongate shaft 114 can be movable within the first and / or second elongate shafts 110, 112 to position the neck cover 104 at a desired location. The third elongate shaft 114 can be sufficiently flexible to enable manipulation (e.g., advancement and / or retraction) of the neck cover 104 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)

[0029] The injector 154 can be configured to pressurize the embolic composition 1 2 to a pressure that is sufficiently high to push the embolic composition 152 through the components of the delivery system 102 (e.g., through the lumen of the third elongate shaft 114). As described further in Section II below, the embolic composition 152 can have shear-thinning properties 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.

[0030] The system 100 can further include a conduit configured to guide the embolic composition 152 delivered from the injector 154 to a space between at least a portion of the neck cover 104 and the aneurysm dome. In some embodiments, the conduit is incorporated into the delivery system 102. For example, as depicted in the enlarged cross-sectional view of the distal portion 106b shown in FIG. IB, the conduit can comprise a combination of the third elongate shaft 114 and an extension 116 fixed to a distal end portion of the third elongate shaft 114. The extension 116 can be a tubular member that extends distally from the third elongate shaft 114, through the connector 122, and through the neck cover 104, at least when the neck cover 104 is in an expanded state. When the neck cover 104 is collapsed within the lumen of the third elongate shaft 114 during delivery, a portion of the neck cover 104 may extend distally of the extension 116. The length of the extension 116 can be such that, when the distal portion 106b of the delivery system 102 is positioned at the aneurysm with the neck cover 104 in an expanded state (for example, as shown in FIG. 2A), a distal terminus of the extension 116 is even with the distal end of the connector 122, distal of the connector 122 but proximal of a distal end of the neck cover 104, or even with or distal of the distal end of the neck cover 104. It may be beneficial for the extension 116 to be as short as possible to ensure the extension 116 remains sufficiently spaced apart from the fragile aneurysm wall.

[0031] In some embodiments, the extension 116 comprises an atraumatic member, such as a soft, flexible coil. In other embodiments, the extension 116 comprises a flexible tube having a continuous sidewall (e.g., not formed of a coiled member). In any case, 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. The pressure generated at the injector 154 can cause the embolic composition 152 to flow through the lumen of the third elongate shaft 114, through the lumen of the extension 116, and into the aneurysm cavity. Once the embolic composition 152 has sufficiently filled the aneurysm cavity, the neck cover 104 and extension 116 can be detached via electrolytic detachment that severs a region of the extension 116 exposed between the third elongate shaft 114 and the neck cover 104.

[0032] According to several embodiments, the conduit may comprise an additional elongate shaft (not shown). The additional elongate shaft can be delivered to the aneurysm through one or more of the first, second, and / or third elongate shafts 110, 112, 114, or may be delivered separately (e.g., outside of) the delivery system 102. In such embodiments, a proximal end portion of the elongate shaft is configured to be fluidly coupled to the injector 154 via the port 118. Methods for delivering the embolic composition 152 through a separate elongate shaft are discussed below.

[0033] The neck cover 104 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 aneurysm and an expanded, deployed state for positioning within the aneurysm. In some embodiments the neck cover 104 comprises a mesh 120 (shown schematically in FIG. IB) and a connector 122 coupled to the mesh 120. The connector 122 is configured to be coupled to one or more components of the delivery system 102, such as the third elongate shaft 1 14 and / or extension 116. The mesh 120 can be formed of a resilient material and shape set such that upon exiting the second elongate shaft 112, the mesh 120 self-expands to a predetermined shape. The mesh 120 can have any shape or size in the expanded state that enables the mesh 120 to cover the aneurysm neck. In some embodiments, for example as shown in FIG. 2A, the mesh 120 can be configured to assume a bowl shape. Other shapes are possible, e.g., as described in connection with FIGS. 3A-3D below. The mesh 120 can have a porosity sufficient to prevent leakage of the embolic composition 152 into the parent vessel.

[0034] In some embodiments, the mesh 120 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 120 may be formed of metal wires, polymer wires, or both, and the wires may have shape memory and / or superelastic properties. The mesh 120 may be formed of 24,32, 36, 48, 64, 72, 96, 128, or 144 filaments. The mesh 120 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 120 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.

[0035] In some embodiments, the mesh 120 can be a non-braided structure, such as a lasercut stent. Moreover, while the mesh 120 shown in FIGS. 2A-2E is a dual-layer mesh, in some embodiments the mesh 120 may comprise more or fewer layers (e.g., a single layer, three layers, four layers, etc.).

[0036] FIGS. 2A-2E illustrate an example method for treating an aneurysm using the system 100, in accordance with embodiments of the present technology. Referring first to FIG. 2A, a physician may begin by intravascularly advancing the second elongate shaft 112 towards an intracranial aneurysm A with the neck cover 104 in a low-profile, collapsed state and coupled to a distal end portion of the third elongate shaft 114. A distal portion of the second elongate shaft 112 may be advanced through a neck N of the aneurysm A to locate a distal opening of the second elongate shaft 112 within an interior cavity of the aneurysm A. The third elongate shaft 114 may be advanced distally relative to the second elongate shaft 112 to push the neck cover 104 through the opening at the distal end of the second elongate shaft 112, thereby releasing the neck cover 104 from the shaft 114 and enabling the neck cover 104 to self-expand into an expanded, deployed state.

[0037] FIG. 2A shows the neck cover 104 in an expanded, deployed state, positioned in an aneurysm cavity and still coupled to the third elongate shaft 114. In the expanded, deployed state, the neck cover 104 may generally conform to the curved inner surface of the aneurysm A. In some embodiments the neck cover 104 assumes a predetermined shape that is concave towards the aneurysm dome and encloses an interior region 124.

[0038] As illustrated in FIG. 2B, the embolic composition 152 can be injected through the third elongate shaft 114 and extension 116 to a space between the neck cover 104 and an inner surface of the aneurysm wall. In other embodiments, the embolic composition 152 can be delivered through another elongate shaft (not shown) separate from the third elongate shaft 114 and extension 1 16. As additional embolic composition 152 is delivered, it fdls the interior region 124 and all or a portion of the volume of the aneurysm cavity. It may be beneficial to fill as much space in the aneurysm as possible, as leaving voids within the aneurysm sac may cause delayed healing and increased risk of aneurysm recanalization and / or rupture. While the scaffolding provided by the neck cover 104 across the neck helps thrombosis of blood form in any gaps and healing at the neck N, the substantial filling of the cavity can prevent rupture acutely and does not rely on the neck cover 104. In some embodiments, the embolic composition 152 may fill greater than 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the aneurysm sac volume.

[0039] FIG. 2C is a cross-sectional view of the neck cover 104 still attached to the delivery system just after completion of delivery of the embolic composition 152. During and after delivery, the embolic composition 152 exerts a substantially uniform downward pressure (e.g., towards the parent vessel) on the neck cover 104 that further seals and stabilizes the neck cover 104 around the neck N of the aneurysm A. Moreover, the embolic composition 152 along the distal wall provides additional occlusion. In some embodiments, the embolic composition 152 completely or substantially completely occludes the pores of the adjacent layer or wall of the neck cover 104 such that blood cannot flow past the embolic composition 152 into the aneurysm cavity. It may be desirable to occlude as much of the aneurysm as possible, as leaving voids of gaps can enable blood to flow in and / or pool, which may continue to stretch out the walls of aneurysm A. Dilation of the aneurysm A can lead to recanalization and / or herniation of the neck cover 104 and / or embolic composition 152 into the parent vessel and / or may cause the aneurysm A to rupture. Both conditions can be fatal to the patient.

[0040] As shown in FIG. 2D, once delivery of the embolic composition 152 is complete, the delivery system 102 and / or third elongate shaft 114 can be detached from the neck cover 104 (electrolytically or mechanically) and withdrawn from the patient’s body. In those embodiments comprising a separate elongate shaft for delivering the embolic composition 152, the elongate shaft can be withdrawn before, during, or after detachment of the third elongate shaft 114 from the neck cover 104.

[0041] Over time natural vascular remodeling mechanisms and / or bioabsorption of the embolic composition 152 (in embodiments where the embolic composition 152 is biodegradable) may lead to formation of a thrombus and / or conversion of entrapped thrombus to fibrous tissue within the internal volume of the aneurysm A. These mechanisms also may lead to cell death at a wall of the aneurysm and growth of new endothelial cells between and over the filaments of the neck cover 104. Eventually, the thrombus and the cells at the wall of the aneurysm may fully degrade, leaving behind a successfully remodeled region of the blood vessel.

[0042] In some embodiments, contrast agent can be delivered during advancement of the neck cover 104 and / or embolic composition 152 in the vasculature, deployment of the neck cover 104 and / or embolic composition 152 at the aneurysm A, and / or after deployment of the neck cover 104 and / or embolic composition 152 prior to initiation of withdrawal of the delivery system. The contrast agent can be delivered through the second elongate shaft 112, the conduit, or through another catheter or device commonly used to deliver contrast agent. The aneurysm (and devices therein) may be imaged before, during, and / or after injection of the contrast agent, and the images may be compared to confirm a degree of occlusion of the aneurysm. Alternatively, the contrast agent may be incorporated into the embolic composition 152, e.g., as described in Section II below.

[0043] As shown in FIG. 2E, in some embodiments, the system 100 may comprise two separate elongate shafts (e.g., microcatheters), with one elongate shaft dedicated to delivery of the embolic composition 152 (e.g., a fourth elongate shaft 126), and the other elongate shaft dedicated to the delivery of the neck cover 104 (e.g., the third elongate shaft 114). In such embodiments, the fourth elongate shaft 126 can be fluidly coupled to the injector 154 to form at least part of the conduit for conveying the embolic composition 152 into the aneurysm A. The fourth elongate shaft 126 may be intravascularly advanced to the aneurysm A and through the neck N such that that a distal tip of the fourth elongate shaft 126 is positioned within the aneurysm cavity. In someembodiments, the fourth elongate shaft 126 may be positioned within the aneurysm cavity such that the distal tip of the fourth elongate shaft 126 is near the dome of the aneurysm A.

[0044] The third elongate shaft 114 containing the neck cover 104 may be intravascularly advanced to the aneurysm A and positioned within the aneurysm cavity adjacent the fourth elongate shaft 126. The neck cover 104 may then be deployed within the aneurysm sac. As the neck cover 104 is deployed, it pushes the fourth elongate shaft 126 outwardly towards the side of the aneurysm A, and when fully deployed the neck cover 104 holds or “jails” the fourth elongate shaft 126 between an outer surface of the neck cover 104 and the inner surface of the aneurysm wall.

[0045] The embolic composition 152 may then be delivered through the fourth elongate shaft 126 to a position between the inner surface of the aneurysm wall and the outer surface of the neck cover 104. For this reason, it may be beneficial to initially position the distal tip of the fourth elongate shaft 126 near the dome (or more distal surface) of the aneurysm wall. This way, the “jailed” fourth elongate shaft 126 will be secured by the neck cover 104 such that the embolic composition 152 gradually fills the open space in the aneurysm sac between the dome and the neck cover 104.

[0046] FIG. 3A illustrates a neck cover 302 configured in accordance with embodiments of the present technology, and FIGS. 3B-3D illustrate an example method for treating an aneurysm using the neck cover 302, in accordance with embodiments of the present technology. The neck cover 302 may be generally similar to the neck cover 104 of FIGS. 1 A and IB, and may incorporate any of the features of the neck cover 104 described herein. For example, the neck cover 302 may comprise an expandable element (e.g., a mesh 304) having a low-profile or constrained state while positioned within a catheter (such as the second elongate shaft 112) for delivery to the aneurysm and an expanded, deployed state for positioning within the aneurysm.

[0047] Referring first to FIG. 3A, the neck cover 302 can be deployed within an aneurysm, e.g., using the system 100 of FIGS. 1A and IB. The proximal end of the neck cover 302 can be detachably coupled to a distal end of the third elongate shaft 114. For example, the third elongate shaft 114 can include a first connector 306, and the distal end of the neck cover 302 can include a second connector 308 configured to detachably couple with the first connector 306. The distal end of the neck cover 302 can be detachably coupled to a fourth elongate shaft 310 that is slidablydisposed within the third elongate shaft 114. One or more connectors (not shown in FIG. 3A) can be included at the proximal end of the neck cover 302 and the fourth elongate shaft 310 to permit deformation and inversion of a portion of the neck cover 302, as discussed in more detail below.

[0048] The fourth elongate shaft 310 can be inserted into the system 100 before the neck cover 302 is expanded, while the neck cover 302 is expanded, or after the neck cover 302 has been expanded and then retracted to a partially inverted state, as discussed in more detail below. In some embodiments, the fourth elongate shaft 310 is configured to deliver an embolic composition 152 (e.g., received from the embolic kit 150 of FIG. 1A) though exit port 312 to a position beyond the proximal end of the partially inverted neck cover 302. As such, the embolic composition 152 can become positioned between the neck cover 302 and an inner wall of the aneurysm cavity, as described in greater detail below.

[0049] In FIG. 3B, the neck cover 302 has expanded to substantially fill the interior volume of aneurysm A. In FIG. 3C, the interior volume of aneurysm A has been largely filled with an embolic composition 152 injected through the exit port 312 at the end of the fourth elongate shaft 310. The embolic composition 152 can occupy the interior volume left by the retraction and partial inversion of the neck cover 302. As shown in FIG. 3C, an annular ridge 314 can separate an outer first portion 316 of the neck cover 302 from an inverted inner second portion 318, thereby forming a concave (e.g., bowl) shape. In the embodiment shown in FIG. 3C, pressure exerted by the embolic composition 152 can help invert the proximal end of the neck cover 302. However, the neck cover 302 can alternatively or additionally be manually retracted using a suitable wire or other member (not shown in FIG. 3C) prior to injection of the embolic composition 152. FIG. 3D shows the aneurysm A after it has been completely filled with the embolic composition 152. The embolic composition 152 can form a cohesive, solid hydrogel mass that seals the aneurysm A and facilitates healing thereof.

[0050] Although certain embodiments of the systems herein are described in connection with the treatment of aneurysm, such as cerebral aneurysms, this is not intended to be limiting, and the systems of the present technology can also be used in the treatment of other types of vascular defects, and / or in any other application involving delivery of an embolic composition into a space within a patient’s body (e.g., middle meningeal artery embolization) or a lesion (e.g., a brain arteriovenous malformation or dural fistula). In such embodiments, the system may be modifiedas appropriate for the particular use case, e.g., the neck cover may be replaced with a different type of occlusion device (e.g., a flow diverter) or the embolic composition can be used without any occlusion device (e.g., if physiological fluid flow at the treatment site is expected to be sufficiently low such that leakage of the embolic composition is not a significant concern).II. Embolic Compositions

[0051] The present technology provides embolic compositions that form an injectable hydrogel suitable for partially or fully occluding an aneurysm or other space within the body. In some embodiments, the embolic composition includes a first polymer that is covalently crosslinked with a second polymer to produce a cohesive hydrogel, and a plurality of nanoparticles mixed with the first and second polymers. The covalent crosslinks between the first and second polymers can be formed via a chemical crosslinking reaction that is initiated immediately before delivery of the embolic composition into the aneurysm (e.g., via mixing of a first precursor composition and a second precursor composition). The chemical crosslinking reaction can continue during and after delivery of the embolic composition into the aneurysm, thereby resulting in formation of a solid mass within the aneurysm to occlude the aneurysm cavity. The nanoparticles can be noncov alently crosslinked with each other and / or with the first and / or second polymers to confer shear-thinning properties to the embolic composition, e.g., the viscosity of the embolic composition decreases when shear stress is applied to the composition and increases when the shear stress is removed. The shear-thinning properties can prevent the embolic composition from leaking out of the aneurysm cavity and / or moving further distally in a vessel or lesion and causing unintended embolization before the chemical crosslinking reaction between the first and second polymers is complete, while maintaining injectability of the embolic composition.

[0052] In some embodiments, the present technology provides a system for preparing an embolic composition for occluding an aneurysm or other space within the body. The system can include a first precursor composition including a first polymer having a first reactive group, and a second precursor composition including a second polymer having a second reactive group. The first precursor composition, the second precursor composition, or both can include a plurality of nanoparticles. Mixing of the first precursor composition and the second precursor composition can cause a covalent crosslinking reaction between the first reactive group of the first polymer and the second reactive group of the second polymer, e.g., the first reactive group of the first polymerforms a covalent bond with the second reactive group of the second polymer, thereby producing a hydrogel. The nanoparticles can interact non-covalently with each other such that the mixture of the first and second precursor compositions has shear-thinning properties before the covalent crosslinking reaction is complete.A. Polymers

[0053] The embolic compositions described herein can be composed of one or more polymers that are covalently crosslinked with each other to form a hydrogel network. The polymer(s) can be biocompatible (e.g., produces little or no toxicity, inflammatory response, or other undesirable side effects in vivo), and may or may not be biodegradable. The polymer(s) can be branched polymers, linear polymers, or combinations thereof. The embolic composition can be composed of any suitable number of polymers, such as one, two, three, four, five, or more polymers.

[0054] In some embodiments, the embolic composition includes at least one synthetic polymer. Examples of synthetic polymers that may be used include poly(ethylene glycol) (PEG), (e.g., linear PEG, branched PEG, PEG diacrylate, PEG acrylate, PEG amine), polyethyleneimine (PEI) (e.g., linear PEI, branched PEI, partially ethoxylated PEI), polyacrylamide, poly(vinylamine), poly(allylamine), poly(4-aminostyrene), poly(N-methylvinylamine), poly(vinyl pyrrolidone), poly(ethylene oxi de)-poly (propylene oxide) copoplymers, poly (propylene oxide) diamine, polypropylene dioxide) diacrylate, poly(hydroxyethyl methacrylate), poly(hydroxypropyl methacrylate), poly(hydroxybutyl methacrylate), poly(2-hydroxyethyl methacrylate), poly(vinyl alcohol), poly(vinyl acetate), poly(acrylic acid), and poly(maleic acid), and combinations (e.g., copolymers) thereof. Alternatively or in combination, the embolic composition can include at least one naturally occurring polymer, such as a protein, peptide, or polysaccharide. Examples of naturally occurring polymers include alginate, cellulose, chitosan, collagen, dextran, dextrin, gelatin, hyaluronic acid, and poly(L-lysine) (PLL), and derivatives thereof. In some embodiments, the naturally occurring polymer is an oxidized polysaccharide, e.g., dextran, dextrin, cellulose, and hyaluronic acid may be converted to their oxidized forms via reaction with NalO-r

[0055] The polymers described herein can include or be modified to include a reactive group (e.g., a reactive group of a repeating unit or an end group) that is capable of forming covalentbonds with a reactive group of another polymer. Examples of reactive groups include acyl groups, acrylate groups, acrylamide 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, furan 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), malonate groups, nitroalkane groups, succinimide groups (e.g., N-hydroxysuccinimide groups), and thiol groups. 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. In some embodiments, a branched polymer with three or more reactive groups is used (e.g., branched PEG, branched PEI), where each branch of the polymer includes at least one reactive group.

[0056] 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.

[0057] In some embodiments, the covalent crosslinking reaction is an aza-Michael addition reaction. The aza-Michael addition reaction can involve a reaction between an amine group (Michael donor) on a first polymer and an electrophilic group (Michael acceptor) on a second polymer. Nucleophilic primary and secondary amines of the first polymer can function as a Michael donor and react with the Michael acceptor of the second polymer. The nucleophilicity of the amine group can increase or decrease depending on a variety of factors, including the ability to form resonance structures, negative charge character, nearby electron withdrawing or electron donating groups, s-orbital character, and steric effects. The electrophilic group can be a a,P- unsaturated compound conjugated to an electron withdrawing group, and can have the structure of Formula (I) below:Formula (I) where EWG is the electron withdrawing group. Examples of electron withdrawing groups include carbonyl (e.g., enone, enal), nitro, CF3, ester, amide, and nitrile groups. When a ketone, nitrile, ester, or other pi-acceptor is adjacent to the alkene in Formula (I), the P carbon of Formula (I) is electrophilic and a negative charge can be delocalized through resonance to the oxygen or nitrogen. In some cases, the electrophilicity of the P carbon is the result of strong inductive effects of electron withdrawing group. In some embodiments, the second polymer includes an a, -unsaturated carbonyl group. In some embodiments, the second polymer includes an acrylate group.

[0058] In some embodiments, the covalent crosslinking reaction involves an aza-Michael addition reaction between an amine group on a first polymer and an electrophilic group on a second polymer. The first polymer having the amine group can be PEI (e g., branched PEI, linear PEI, partially ethoxylated PEI), PEG amine (e g., a branched PEG amine such as 4-arm PEG amine, 8- arm PEG amine, etc.), polyacrylamide, poly(vinylamine), poly(allylamine), poly(4-aminostyrene), poly(N-methylvinylamine), poly(L-lysine), chitosan, gelatin, or a combination thereof. In some embodiments, the second polymer having the electrophilic group can be PEG diacrylate or PEG acrylate (e.g., a branched PEG acrylate such as a 4-arm PEG acrylate, 8-arm PEG acrylate, etc.).

[0059] In some embodiments, the covalent crosslinking reaction involves a reaction between a first reactive group on a first polymer and a second reactive group on a second polymer, where the first reactive group is a maleic anhydride, a succinic anhydride, an aldehyde, or an N- hydroxysuccinimide, and the second reactive group is an amine (e.g., a primary or a secondary amine) or a thiol.

[0060] In some embodiments, the covalent crosslinking reaction involves a reaction between a first reactive group on a first polymer and a second reactive group on a second polymer, where the first reactive group is a diene or a furan, and the second reactive group is a substituted alkene.

[0061] In some embodiments, the covalent crosslinking reaction involves a reaction between a first reactive group on a first polymer and a second reactive group on a second polymer, where the first reactive group is an alkyne, and the second reactive group is an azide.

[0062] The molecular weight of the polymers herein can be selected to provide desired hydrogel properties, e.g., higher molecular weight polymers can produce stiffer, more cohesive, and more viscous hydrogels, while lower molecular weight polymers can produce softer and less viscous hydrogels. In some embodiments, the molecular weight of the polymer (weight average, number average, or viscosity average molecular weight) is greater than or equal to 100 Da, 200 Da, 250 Da, 300 Da, 350 Da, 400 Da, 450 Da, 500 Da, 550 Da, 600 Da, 700 Da, 800 Da, 900 Da, 1 kDa, 2 kDa, 5 kDa, 10 kDa, 25 kDa, 50 kDa, 75 kDa, 100 kDa, 250 kDa, 500 kDa, 1 MDa, or 5 MDa; and / or is less than or equal to 5 MDa, 1 MDa, 500 kDa, 250 kDa, 100 kDa, 75 kDa, 50 kDa, 25 kDa, 10 kDa, 5 kDa, 2 kDa, 1 kDa, 900 Da, 800 Da, 700 Da, 600 Da, 500 Da, 450 Da, 400 Da, 350 Da, 300 Da, 250 Da, 200 Da, or 100 Da. The molecular weight of the polymer can be within a range from 100 Da to 10 kDa, 100 Da to 1 kDa, 100 Da to 500 Da, 500 Da to 10 kDa, 500 Da to 5 kDa, 1 kDa to 10 kDa, 1 kDa to 5 kDa, 10 kDa to 50 kDa, 50 kDa to 100 kDa, 100 kDa to 200 kDa, 200 kDa to 500 kDa, 500 kDa to 1 MDa, or 1 MDa to 5 MDa.

[0063] The concentration of the polymer in the embolic composition can be varied as desired. Higher concentrations of polymer may produce stiffer, stronger, and more viscous hydrogels, while lower concentrations of polymer may produce softer and less viscous hydrogels. In some embodiments, the concentration of the polymer(s) in the embolic composition as expressed in % w / w, individually or collectively, is greater than or equal to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%; and / or is no more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%. The concentration of the polymer(s) in the embolic composition, individually or collectively, can be within a range from 1% to 50%, 1% to 25%, 1% to 10%, 10% to 50%, 10% to 25%, 25% to 75%, 25% to 50%, or 50% to 75%.

[0064] In some embodiments, the embolic composition is formulated by mixing a first precursor composition including a first polymer with a second precursor composition including a second polymer to form a hydrogel. The concentration of the first polymer in the first precursor composition (% w / w) is greater than or equal to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%; and / or is no more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%. The concentration of the first polymer in the first precursor composition can be within a range from 1% to 50%, 1% to 25%, 1% to 10%, 10% to 50%, 10% to 25%, 25% to 75%, 25% to 50%, or 50% to 75%. The concentration of the second polymer in the second precursor composition (% w / w) is greater than or equal to 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%; and / or is no more than 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%. The concentration of the second polymer in the second precursor composition can be within a range from 1% to 50%, 1% to 25%, 1% to 10%, 10% to 50%, 10% to 25%, 25% to 75%, 25% to 50%, or 50% to 75%.B. Nanoparticles

[0065] The embolic compositions described herein can include a plurality of 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. The hydrogel can include a single type of nanoparticle or can include multiple different types of nanoparticles (e.g., two, three, four, five, or more different polymers).

[0066] In some embodiments, the nanoparticles have an average particle size within a range from 1 nm to 100 nm, 1 nm to 75 nm, 1 nm to 50 nm, 1 nm to 25 nm, 1 nm to 10 nm, 1 nm to 5 nm, 5 nm to 100 nm, 5 nm to 75 nm, 5 nm to 50 nm, 5 nm to 25 nm, 5 nm to 10 nm, 10 nm to 100 nm, 10 nm to 75 nm, 10 nm to 50 nm, 10 nm to 25 nm, 25 nm to 100 nm, 25 nm to 75 nm, 25 nm to 50 nm, 50 m to 100 nm, 50 nm to 75 nm, or 75 nm to 100 nm. The size of a particle can correspond to its diameter (for spherical or disk-shaped particles) or to its maximum linear dimension (for other particle shapes).

[0067] The nanoparticles can have any suitable form factor, such as disks, spheres, cubes, rods, tubes, fibers, etc. In some embodiments, the nanoparticles have an anisotropic shape. For example, the nanoparticles can be disk-shaped nanoparticles having a pair of planar faces and an edge connecting the faces. The diameter of the disk can be within a range from 10 nm to 50 nm, 15 nm to 35 nm, 20 nm to 30 nm, or 20 nm to 25 nm. The thickness of the disk can be within a range from 0.1 nm to 5 nm, 0.5 nm to 2 nm, 0.75 nm to 1 nm, or 1 nm to 1.25 nm.

[0068] In some embodiments, the nanoparticles form non-covalent crosslinks with each other. For example, the nanoparticles can be charged nanoparticles (e.g., at least at physiological pH (e.g., pH 7.4)) that are capable of interacting electrostatically with each other. The charged nanoparticles can include at least one charged portion, such as a cationic portion, an anionic portion, or both. The charge distribution of the nanoparticles can be anisotropic. For example, in embodiments where the nanoparticles are disk-shaped, the disk faces can be anionic while the disk edge is cationic, or vice-versa. The charged portion(s) of the nanoparticles can facilitate electrostatic interactions with other nanoparticles, e.g., a cationic portion of a nanoparticle can be attracted to an anionic portion of another nanoparticle, an anionic portion of a nanoparticle can be attracted to a cationic portion of another nanoparticle, a cationic portion of a nanoparticle can repel a cationic portion of another nanoparticle, and / or an anionic portion of a nanoparticle can repel an anionic portion of another nanoparticle. In embodiments where the polymer(s) of the embolic composition are charged, the charged portion(s) of the nanoparticles can optionally facilitate electrostatic interactions with the charged polymer(s), e.g., the cationic portion can be attracted to anionic functional groups on the polymer and / or the anionic portion can be attracted to cationic functional groups on the polymer. In other embodiments, however, the nanoparticles may not interact electrostatically with the polymer(s), e.g., if the polymer(s) are not charged.

[0069] In some embodiments, the nanoparticles are laponite nanoparticles. Laponite has a disk-shaped structure with a diameter within a range from 20 nm to 30 nm, and a thickness of approximately 1 nm. Laponite has an anisotropic charge distribution, with the disk faces being anionic and the disk edge being cationic; due to the larger surfaces area of the faces, the overall charge is negative.

[0070] The concentration of the nanoparticles in the embolic composition can be varied as desired. Higher concentrations of nanoparticles can increase the stiffness and strength of thehydrogel, while lower concentrations of nanoparticles can increase the injectability of the hydrogel. In some embodiments, the concentration of the nanoparticles in the embolic composition(% w / w), individually or collectively, is greater than or equal to 0.5%, 1%, 1.5%, 2%, 2.5%, 3%,3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25%; and / or is no more than 25%,20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%. The concentration of the nanoparticles in the embolic composition, individually or collectively, can be within a range from 1% to 10%, 1% to 5%, 2% to 5%, 4% to 6% 5% to 10%, or 10% to 20%.

[0071] In some embodiments, the embolic composition is formulated by mixing a first precursor composition including a first polymer with a second precursor composition including a second polymer, where at least one of the first or second precursor compositions further includes a plurality of nanoparticles. The concentration of the nanoparticles in the first precursor composition (% w / w) can be greater than or equal to 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25%; and / or no more than 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%. The concentration of the nanoparticles in the first precursor composition can be within a range from 1% to 10%, 1% to 5%, 2% to 5%, 4% to 6% 5% to 10%, or 10% to 20%. The concentration of the nanoparticles in the second precursor composition (% w / w) can be greater than or equal to 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, or 25%; and / or no more than 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, or 0.5%. The concentration of the nanoparticles in the second precursor composition can be within a range from 1% to 10%, 1% to 5%, 2% to 5%, 4% to 6% 5% to 10%, or 10% to 20%.

[0072] In some embodiments, the first precursor composition includes a plurality of first nanoparticles, and the second precursor composition includes a plurality of second nanoparticles. The first nanoparticles may be the same as the second nanoparticles, or the first nanoparticles may be different than the second nanoparticles. The concentration of the first nanoparticles in the first precursor composition may be the same as the concentration of the second nanoparticles in the second precursor composition, or the concentration of the first nanoparticles in the first precursor composition may be different than the concentration of the second nanoparticles in the second precursor composition. In some embodiments, the first precursor composition includes a plurality of nanoparticles and the second precursor composition does not include any nanoparticles. In someembodiments, the second precursor composition includes a plurality of nanoparticles and the first precursor composition does not include any nanoparticles.C. Contrast Agents

[0073] 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., OMNIPAQUE™ from GE Healthcare), iopamidol (e.g., ISOVUE™ from Bracco Diagnostics, Inc.), ioxilan, iopamide, iodixanol (e.g., VISIPAQUE™ from GE Healthcare), iobitridol, ioversol, diatrizoate (e.g., HYPAQUE™ from GE Healthcare), metrizoate, iothalamate (e.g., CONRAY™ from Covidien), ioxaglate, iopromide, iothalamate / meglumine, ioxaglate / meglumine, diatrizoate / meglumine, iodomide sodium, metrizamide, or combinations thereof. The hydrogel 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).

[0074] 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 hydrogel, 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%.

[0075] In some embodiments, the embolic composition is formulated by mixing a first precursor composition including a first polymer with a second precursor composition including a second polymer, where at least one of the first or second precursor compositions further includes a contrast agent. The concentration of the contrast agent in the first precursor composition (% 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 the first precursor composition 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 the second precursor composition (% 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 the second precursor composition 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%.

[0076] In some embodiments, the first precursor composition includes a first contrast agent, and the second precursor composition 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.

[0077] In some embodiments, neither the first precursor composition nor the second precursor composition 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. The third precursor composition may be mixed with the first precursor composition before the first precursor composition is mixed with the second precursor composition, or the third precursor composition may be mixed with the second precursor composition before the second precursor composition is mixed with the first precursor composition, or the third precursor composition may be mixed with the first and second precursor compositions after the first and second precursor compositions are mixed with each other.

[0078] Optionally, after the embolic composition is delivered into the treatment site and forms a hydrogel, the contrast agent may gradually diffuse out of the hydrogel, thus resulting in diminishing radiopacity over time. This approach may be advantageous where the contrast agent produces imaging artifacts that may interfere with subsequent imaging of the treatment site. In some embodiments, the hydrogel is configured to release at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the initial loading contrast agent within a target time period after implantation, where the target time period is at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, or 3 months after implantation. In other embodiments, however, the contrast agent may remain within the hydrogel without leaching out after implantation.

[0079] 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 neck cover by the embolic composition (e.g., as discussed above with respect to FIGS. 3A-3D).D. Solvents

[0080] The embolic composition disclosed herein can also include at least one solvent. The solvent can be a biocompatible aqueous solution, such as water (e.g., distilled water, deionized water), a saline solution (e.g., normal saline, Ringer’s lactate solution, phosphate-buffered saline), etc. The solvent can optionally be supplied as a part of other components of the embolic composition, such as the contrast agent.

[0081] The concentration of the solvent in the embolic composition (% 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%. In some embodiments, the concentration of the solvent in the embolic composition 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%.

[0082] In some embodiments, the embolic composition is formulated by mixing a first precursor composition including a first polymer with a second precursor composition including asecond polymer, where at least one of the first or second precursor compositions further includes a solvent. The concentration of the solvent in the first precursor composition (% 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%. In some embodiments, the concentration of the solvent in the first precursor composition 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%. The concentration of the solvent in the second precursor composition (% 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%. In some embodiments, the concentration of the solvent in the second precursor composition 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%.

[0083] In some embodiments, the first precursor composition includes a first solvent, and the second precursor composition includes a second solvent. The first solvent may be the same as the second solvent, or the first solvent may be different than the second solvent. The concentration of the first solvent in the first precursor composition may be the same as the concentration of the second solvent in the second precursor composition, or the concentration of the first solvent in the first precursor composition may be different than the concentration of the second solvent in the second precursor composition.E. Properties

[0084] 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). 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 hydrogel within a reasonable timeframe after delivery into the treatment site. The reaction time can be thetime elapsed between when the precursor compositions 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. In some embodiments, the reaction time is 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; 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. The reaction time can be 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. The reaction time can be controlled based on the solvent content, the ratio between the two precursor compositions, the molecular weight of the polymers, and / or the degree of functionalization of the polymers . Optionally, either or both of the first and second precursor compositions can include a catalyst to accelerate the chemical crosslinking reaction.

[0085] Before the embolic composition reaches its final state, the embolic composition can 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 embolic composition hydrogel 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 semisolid 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.

[0086] FIGS. 4A-4C are schematic illustrations of an embolic composition 400 configured in accordance with embodiments of the present technology. Specifically, FIG. 4A is a side cross- sectional view of the embolic composition 400 in an injector 402 while no injection force is applied, FIG. 4B is a side cross-sectional view of the embolic composition 400 in the injector 402 while an injection force is applied, and FIG. 4C illustrates chemical crosslinking of the embolic composition 400 to form a hydrogel.

[0087] Referring first to FIG. 4A, the embolic composition 400 can be composed of a plurality of laponite nanoparticles 404, a first polymer 406a having a first reactive group (e.g., an amine group), a second polymer 406b having a second reactive group (e.g., an acrylate group), a contrast agent 408 (e.g., radiopaque particles such as tantalum), and a solvent 410 (e.g., water). When no force is being applied to the embolic composition 400, the laponite nanoparticles 404 can form a “house-of-cards” 3D structure due to electrostatic interactions between the cationic disk edges and the anionic disk faces (shown in inset view). Accordingly, the embolic composition 400 can exhibit solid-like behavior (e.g., the storage modulus of the embolic composition 400 is greater than the loss modulus of the embolic composition 400) with a relatively high viscosity.

[0088] Referring next to FIG. 4B, when force is applied to the embolic composition 400 during injection, the force can disrupt the electrostatic interactions between the laponite nanoparticles 404 and cause the laponite nanoparticles 404 to become aligned parallel with each other and to the direction of flow (this configuration can produce less resistance to flow and lower energy due to the anisotropic nanoparticle shape). Accordingly, the embolic composition 400 can exhibit liquid-like behavior (e.g., the loss modulus of the embolic composition 400 is greater than the storage modulus of the embolic composition 400) with a relatively low viscosity. The reaction time between the first polymer 406a and the second polymer 406b can be sufficiently long so that little or no chemical crosslinking occurs while the embolic composition 400 is within the injector 402, thus allowing the embolic composition 400 to remain flowable for injection.

[0089] Referring next to FIG. 4C, once the embolic composition 400 has been delivered into the treatment site and is no longer subjected to shear forces, the laponite nanoparticles 404 can transition back into the house-of-cards 3D structure, thus causing the embolic composition 400 to return to a solid-like state. Accordingly, the embolic composition 400 can remain in place within the treatment site without flowing. Over time, as the first polymer 406a and second polymer 406b can react with each, covalent crosslinks 412 are formed between the polymer chains, thereby producing forming a cohesive hydrogel to occlude the treatment site.

[0090] A precursor composition used to form the embolic compositions herein can have shear-thinning properties before mixing with another precursor composition to initiate the chemical crosslinking reaction for hydrogel formation. In some embodiments, the precursor composition has a first, higher viscosity at a first, lower shear rate, and a second, lower viscosityat a second, higher shear rate. For example, the precursor composition can have a viscosity greater than or equal to 10 Pa-s, 50 Pa-s, 100 Pa-s, 250 Pa-s, 500 Pa-s, 750 Pa-s, 1000 Pa-s, 2000 Pa-s, or 5000 Pa-s when the shear rate is less than or equal to 10° s'1, 10'1s'1, 1 O'2s'1, or 10'3s'1; and can have a viscosity less than or equal to 10 Pa-s, 5 Pa-s, 4 Pa-s, 3 Pa-s, 2 Pa-s, 1 Pa-s, 0.5 Pa-s, or 0.1 Pa-s when the shear rate is greater than or equal to 10° s'1, 101s'1, 102s'1, or 103s'1. The viscosity may change by at least 1, 2, 3, or 4 orders of magnitude across a range of shear rates from 10'3s'1to 103s'1. 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).

[0091] After mixing of the precursor compositions, the resulting embolic composition can exhibit shear-thinning properties 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. 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, 9 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.

[0092] Upon completion of the chemical crosslinking reaction, the embolic composition can form a solid, cohesive hydrogel. In some embodiments, the hydrogel has a storage modulus within the linear viscoelastic region that is within a range from 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 storage modulus of the hydrogel reaches at least 80%, 85%, 90%, 95%, or 99%of its final value 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. Alternatively or in combination, the storage modulus of the hydrogel 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. In some embodiments, the hydrogel 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. The ratio of the loss modulus to the storage modulus (tan(delta) of the hydrogel can be within a range from 0.005 to 0.1, 0.005 to 0.05, 0.01 to 0.05, or 0.05 to 0.1.

[0093] 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

[0094] In some embodiments, the present technology provides a method for preparing an embolic composition for occluding a treatment site, such as an aneurysm or other vascular defect. The method can include mixing a first precursor composition with a second precursor composition. The first precursor composition can include a first polymer having a first reactive group, and the second precursor composition can include a second polymer having a second reactive group. The mixing of the first and second precursor compositions can cause a covalent crosslinking reaction between the first reactive group of the first polymer and the second reactive group of the second polymer, thereby forming a hydrogel. In some embodiments, the first and second precursor compositions do not include a separate catalyst to initiate the covalent crosslinking reaction.

[0095] In some embodiments, the first precursor composition and / or the second precursor composition include a plurality of nanoparticles. The nanoparticles can interact non-covalentlywith each other such that the mixture of the first and second precursor compositions has shearthinning properties before the covalent crosslinking reaction is complete. Optionally, the first precursor composition and / or the second precursor composition can include additional components, such as a contrast agent and / or a solvent. The types and concentrations of polymers, nanoparticles, contrast agent, and solvent can be varied as desired, e.g., as discussed in Sections II.A-II.D above.

[0096] In some embodiments, the present technology provides a method for treating a patient using an embolic composition as described herein. The method can include preparing an embolic composition by mixing a first precursor composition and a second precursor composition as described herein, and delivering the embolic composition to a treatment site. For example, the embolic composition can be delivered into an aneurysm to partially or fully occlude the aneurysm. 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 have shear-thinning properties before the covalent crosslinking reaction is complete so that the embolic composition flows like a liquid during injection and forms a solid or semi-solid mass after delivery into the treatment site without leaking. The method can further include forming a hydrogel that occludes the treatment site, where the hydrogel is composed of the covalently crosslinked first polymer and second polymer and the plurality of nanoparticles.

[0097] Optionally, the embolic composition can be used in combination with another device, such as a neck cover for an aneurysm (e.g., as described in Section I above). In such embodiments, the neck cover 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 neck cover to ensure that the interior cavity of the aneurysm is substantially completely filled, without leaking through the neck cover.

[0098] In some embodiments, the methods herein can be used to treat other types of diseases or conditions besides aneurysms. Examples of diseases and conditions that are also applicable to the present technology include 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 ., 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.III. Examples

[0099] 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.Example 1 : Preparation and Characterization of Embolic Compositions

[0100] This example describes the preparation and characterization of embolic compositions composed of covalently crosslinked polymers and nanoparticles.

[0101] Embolic compositions were prepared by mixing a first precursor composition (“Part A”) with a second precursor composition (“Part B”) at a 1 :1 : volume ratio. For embolic compositions including a contrast agent, a solution of contrast agent (Omnipaque or 10% tantalum) was mixed with Part A, followed by mixing with Part B at a 1 : 1 : 1 volume ratio. Mixing took place at room temperature with 15 minutes of sonication to ensure homogeneity. The formulations the embolic compositions are listed in Tables 1A-1D below.

[0102] Table 1A: Formulation 1

[0103] Table IB: Formulation 2

[0104] Table 1C: Formulation 3

[0105] Table ID: Formulation 4

[0106] The viscosities of the precursor compositions (Part A and Part B) before mixing were measured using an oscillatory parallel plate rheometer (8 mm plate diameter) at 37 °C, 10 rad / s frequency, 5% strain, and three different shear rates (1 s’1, 10 s’1, and 100 s’1).

[0107] 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%.

[0108] FIGS. 5A and 5B are graphs illustrating viscosity measurements for Part A (FIG. 5A) and Part B (FIG. 5B) of Formulation 1 before mixing. As shown in FIGS. 5A and 5B, the viscosities of Part A and Part B both decreased with increasing shear rates. At the lowest shear rate (1 s'1), the viscosity values for Part A and Part B were both below 1100 Pa-s. At the highest shear rate (100 s'1), the viscosity values for Part A and Part B were both below 10 Pa-s. These results show that both Part A and Part B exhibited non-Newtonian properties with significant shearthinning behavior enabling hand injection through a syringe, and transitioned to a gel state upon removal of stress.

[0109] FIGS. 6A-6D are graphs of storage modulus over time for four different embolic compositions: Formulation 2 (FIG. 6A), Formulation 3 (FIG. 6B), Formulation 4 (FIG. 6C) and Formulation 1 (FIG. 6D). The curing time for Formulation 2 (FIG. 6A) was too fast for injectability purposes — the composition was already solid (storage modulus above 10 kPa) when injected into the rheometer. The curing time for Formulation 3 (FIG. 6B) was approximately 15 seconds (there is a 10 second delay after injection before rheological measurement begin), which may also be too short for injectability. The curing time for Formulation 4 (FIG. 6C) was approximately 47 seconds, which was sufficiently long for injectability. The curing time for Formulation 1 (FIG. 6D) was approximately 66 seconds, which was also sufficiently long for injectability. These results show that the polymer concentrations in Part A and Part B can be tuned to achieve a specific curing time for the embolic composition.

[0110] FIG. 7 is a graph illustrating rheological measurements for Formulation 1 at various strain amplitudes. When fully cured, Formulation 1 had a storage modulus of 100 kPa ± 5 kPa and a loss modulus of 1 kPa ± 0.1 kPa over strain amplitudes from 0% to 100% (tan(delta) = 0.01 ± 0.01). The storage modulus remained higher than the loss modulus across this strain range, thus showing that the cured composition had primarily elastic behavior, did not flow under these conditions, and remained solid-like.

[0111] FIGS. 8A and 8B illustrate occlusion of a simulated brain arteriovenous malformation (bAVM) model with Formulation 1 (FIG. 8A is a photograph and FIG. 8B is an X- ray image). The embolic composition was injected into a silicone bAVM model having a vessel inner diameter less than 1 mm. The embolic composition included 10% tantalum for radi opacity. As shown in FIGS. 8A and 8B, the embolic composition successfully occluded most of the nidus forming a cohesive, radiopaque cast, while the increased flow control of the embolic composition did not allow occlusion of the draining vessel, which may be important in a clinical setting for avoiding unintended embolization.

[0112] Overall, these results demonstrate that the two-part, shear-thinning embolic composition can be used to treat complex lesions, particularly where control of the injection is critical. The two-part gelation mechanism ensures easy delivery of the composition, while also mitigating risks with cast fragmentation and unintended embolization.IV. Additional Examples

[0113] Various examples of aspects of the subject technology are described as numbered clauses (1, 2, 3, etc.) for convenience. These are provided as examples and do not limit the subject technology.

[0114] Clause 1. A system for treating a vascular defect, the system comprising: a first precursor composition comprising a first polymer having a first reactive group; and a second precursor composition comprising a second polymer having a second reactive group, wherein mixing of the first and second precursor compositions causes a covalent crosslinking reaction between the first reactive group of the first polymer and the second reactive group of the second polymer to form a hydrogel, and wherein at least one of the first precursor composition or the second precursor composition comprises a plurality of silicate nanoparticles that interact non- covalently with each other such that the mixture of the first and second precursor compositions has shear-thinning properties before the covalent crosslinking reaction is complete.

[0115] Clause 2. The system of Clause 1, wherein the first reactive group is an acrylate group, and the second reactive group is an amine group.

[0116] Clause 3. The system of Clause 1 or 2, wherein the first polymer comprises poly(ethylene glycol) acrylate or poly(ethylene glycol) diacrylate, and the second polymer comprises polyethyleneimine, poly(ethylene glycol) amine, polyacrylamide, poly(vinylamine), poly(allylamine), poly(4-aminostyrene), polyQM-methylvinylamine), poly(L-lysine), chitosan, or gelatin.

[0117] Clause 4. The system of any one of Clauses 1 to 3, wherein the first and second polymers are each independently selected from the group consisting of poly(ethylene glycol), polyethyleneimine, polyacrylamide, poly(vinylamine), poly(allylamine), poly(4-aminostyrene), poly(N-methylvinylamine), poly(vinyl pyrrolidone), poly(ethylene oxide)-poly(propylene oxide) copoplymers, polypropylene oxide) diamine, polypropylene dioxide) diacrylate, poly(hydroxyethyl methacrylate), polypydroxypropyl methacrylate), poly(hydroxybutyl methacrylate), poly(2-hydroxyethyl methacrylate), poly(vinyl alcohol), poly(vinyl acetate), poly(acrylic acid), and polypialeic acid), alginate, cellulose, chitosan, collagen, dextran, dextrin, gelatin, hyaluronic acid, and poly(L-lysine).

[0118] Clause 5. The system of any one of Clauses 1 to 4, wherein the silicate nanoparticles comprise one or more of the following: laponite, montmorillonite, bentonite, kaolinite, chlorite, illite, saponite, or hectorite.

[0119] Clause 6. The system of any one of Clauses 1 to 5, wherein each silicate nanoparticle comprises a cationic portion and an anionic portion, and wherein the silicate nanoparticles are non-covalently crosslinked with each other via electrostatic interactions between the cationic portions and the anionic portions of the silicate nanoparticles.

[0120] Clause 7. The system of Clause 6, wherein the silicate nanoparticles are diskshaped nanoparticles, the cationic portions comprise disk edges of the disk-shaped nanoparticles, and the anionic portions comprise disk faces of the disk-shaped nanoparticles.

[0121] Clause 8. The system of any one of Clauses 1 to 7, wherein the first precursor composition and the second precursor composition each include the plurality of silicate nanoparticles.

[0122] Clause 9. The system of any one of Clauses 1 to 7, wherein the plurality of silicate nanoparticles are present only in the first precursor composition, or wherein the plurality of silicate nanoparticles are present only in the second precursor composition.

[0123] Clause 10. The system of any one of Clauses 1 to 9, wherein the first polymer is poly(ethylene glycol) diacrylate, the second polymer is polyethyleneimine, and the silicate nanoparticles are laponite nanoparticles.

[0124] Clause 11. The system of any one of Clauses 1 to 10, wherein the covalent crosslinking reaction has a reaction time within a range from 10 seconds to 90 seconds.

[0125] Clause 12. The system of any one of Clauses 1 to 11, wherein before the mixing, the first and second precursor compositions each have a viscosity at 37 °C that is greater than 100 Pa-s at a shear rate less than or equal to 1 s’1and that is less than 0.1 Pa-s at a shear rate greater than or equal to 100 s’1.

[0126] Clause 13. The system of any one of Clauses 1 to 12, wherein the mixture of the first and second precursor compositions has a storage modulus at 37 °C that is less than 1 kPa for at least 30 seconds after the mixing of the first and second precursor compositions.

[0127] Clause 14. The system of any one of Clauses 1 to 13, wherein the hydrogel has a storage modulus at 37 °C within a linear viscoelastic region of the hydrogel that is within a range from 50 kPa to 200 kPa.

[0128] Clause 15. The system of any one of Clauses 1 to 14, further comprising a contrast agent.

[0129] Clause 16. The system of Clause 15, wherein the contrast agent comprises one or more of the following: tantalum, bismuth trioxide, bismuth oxychloride, tungsten, tungsten carbide, barium sulfate, gadolinium, iodized oil, iohexol, iopamidol, ioxilan, iopamide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoate, iothalamate, ioxaglate, iopromide, iothalamate / meglumine, ioxaglate / meglumine, diatrizoate / meglumine, iodomide sodium, or metrizamide.

[0130] Clause 17. A method for treating a vascular defect, the method comprising: preparing an embolic composition by mixing a first precursor composition and a second precursor composition, wherein:the first precursor composition comprises a first polymer having a first reactive group, the second precursor composition comprises a second polymer having a second reactive group, and the mixing of the first and second precursor compositions causes a covalent crosslinking reaction between the first reactive group of the first polymer and the second reactive group of the second polymer to form a hydrogel; and delivering the embolic composition into the vascular defect to occlude the vascular defect, wherein at least one of the first precursor composition or the second precursor composition comprises a plurality of silicate nanoparticles that interact non-covalently with each other such that the embolic composition has shearthinning properties before the covalent crosslinking reaction is complete.

[0131] Clause 18. The method of Clause 17, wherein the first reactive group is an acrylate group, and the second reactive group is an amine group.

[0132] Clause 19. The method of Clause 17 or 18, wherein the first polymer comprises poly(ethylene glycol) acrylate or poly(ethylene glycol) diacrylate, and the second polymer comprises polyethyleneimine, poly(ethylene glycol) amine, polyacrylamide, poly(vinylamine), poly(allylamine), poly (4-ami nostyrene), poly(N-methylvinylamine), poly(L-lysine), chitosan, or gelatin.

[0133] Clause 20. The method of any one of Clauses 17 to 19, wherein the first and second polymers are each independently selected from the group consisting of poly(ethylene glycol), polyethyleneimine, polyacrylamide, poly(vinylamine), poly(allylamine), poly(4- aminostyrene), poly(N-methylvinylamine), poly(vinyl pyrrolidone), poly(ethylene oxide)- poly(propylene oxide) copoplymers, polypropylene oxide) diamine, polypropylene dioxide) diacrylate, poly(hydroxyethyl methacrylate), poly(hydroxypropyl methacrylate), poly(hydroxybutyl methacrylate), poly(2-hydroxyethyl methacrylate), poly(vinyl alcohol), poly(vinyl acetate), poly(acrylic acid), and polypialeic acid), alginate, cellulose, chitosan, collagen, dextran, dextrin, gelatin, hyaluronic acid, and poly(L-lysine).

[0134] Clause 21. The method of any one of Clauses 17 to 20, wherein the silicate nanoparticles comprise one or more of the following: laponite, montmorillonite, bentonite, kaolinite, chlorite, illite, saponite, or hectorite.

[0135] Clause 22. The method of any one of Clauses 17 to 21, wherein each silicate nanoparticle comprises a cationic portion and an anionic portion, and wherein the silicate nanoparticles are non-covalently crosslinked with each other via electrostatic interactions between the cationic portions and the anionic portions of the silicate nanoparticles.

[0136] Clause 23. The method of Clause 22, wherein the silicate nanoparticles are disk-shaped nanoparticles, the cationic portions comprise disk edges of the disk-shaped nanoparticles, and the anionic portions comprise disk faces of the disk-shaped nanoparticles.

[0137] Clause 24. The method of any one of Clauses 17 to 23, wherein the first precursor composition and the second precursor composition each include the plurality of silicate nanoparticles.

[0138] Clause 25. The method of any one of Clauses 17 to 23, wherein the plurality of silicate nanoparticles are present only in the first precursor composition, or wherein the plurality of silicate nanoparticles are present only in the second precursor composition.

[0139] Clause 26. The method of any one of Clauses 17 to 25, wherein the first polymer is poly(ethylene glycol) diacrylate, the second polymer is polyethyleneimine, and the silicate nanoparticles are laponite nanoparticles.

[0140] Clause 27. The method of any one of Clauses 17 to 26, wherein the covalent crosslinking reaction has a reaction time within a range from 10 seconds to 90 seconds.

[0141] Clause 28. The method of any one of Clauses 17 to 27, wherein before the mixing, the first and second precursor compositions each have a viscosity at 37 °C that is greater than 100 Pa-s at a shear rate less than or equal to 1 s'1and that is less than 0.1 Pa-s at a shear rate greater than or equal to 100 s’1.

[0142] Clause 29. The method of any one of Clauses 17 to 28, wherein the mixture of the first and second precursor compositions has a storage modulus at 37 °C that is less than 1 kPa for at least 30 seconds after the mixing of the first and second precursor compositions.

[0143] Clause 30. The method of any one of Clauses 17 to 29, wherein the hydrogel has a storage modulus at 37 °C within a linear viscoelastic region of the hydrogel that is within a range from 50 kPa to 200 kPa.

[0144] Clause 31. The method of any one of Clauses 17 to 30, further comprising a contrast agent.

[0145] Clause 32. The method of Clause 31, wherein the contrast agent comprises one or more of the following: tantalum, bismuth trioxide, bismuth oxychloride, tungsten, tungsten carbide, barium sulfate, gadolinium, iodized oil, iohexol, iopamidol, ioxilan, iopamide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoate, iothalamate, ioxaglate, iopromide, iothalamate / meglumine, ioxaglate / meglumine, diatrizoate / meglumine, iodomide sodium, or metrizamide.Conclusion

[0146] Although many of the embodiments are described above with respect to systems, devices, and methods for treating saccular intracranial aneurysms, the technology is applicable to other applications and / or other approaches. For example, suitable features of described systems, devices, compositions, and methods for treating saccular intracranial aneurysms can be implemented in the context of treating non-saccular intracranial aneurysms, abdominal aortic aneurysms, thoracic aortic aneurysms, renal artery aneurysms, arteriovenous malformations (e.g., brain arteriovenous malformations), 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. 1A-8B.

[0147] 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.

[0148] 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.

[0149] 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. As used herein, the phrase “and / or” as in “A and / or B” refers to A alone, B alone, and A and B. 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.

[0150] To the extent any materials incorporated herein by reference conflict with the present disclosure, the present disclosure controls.

[0151] 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

CLAIMSWhat is claimed is:

1. A system for treating a vascular defect, the system comprising: a first precursor composition comprising a first polymer having a first reactive group; and a second precursor composition comprising a second polymer having a second reactive group, wherein mixing of the first and second precursor compositions causes a covalent crosslinking reaction between the first reactive group of the first polymer and the second reactive group of the second polymer to form a hydrogel, and wherein at least one of the first precursor composition or the second precursor composition comprises a plurality of silicate nanoparticles that interact non- covalently with each other such that the mixture of the first and second precursor compositions has shear-thinning properties before the covalent crosslinking reaction is complete.

2. The system of claim 1, wherein the first reactive group is an acrylate group, and the second reactive group is an amine group.

3. The system of claim 1 or 2, wherein the first polymer comprises poly(ethylene glycol) acrylate or poly(ethylene glycol) diacrylate, and the second polymer comprises polyethyleneimine, poly(ethylene glycol) amine, polyacrylamide, poly(vinylamine), poly(allylamine), poly(4-aminostyrene), poly(N-methylvinylamine), poly(L-lysine), chitosan, or gelatin.

4. The system of any one of claims 1 to 3, wherein the first and second polymers are each independently selected from the group consisting of polyethylene glycol), polyethyleneimine, polyacrylamide, poly(vinylamine), poly(allylamine), poly(4-aminostyrene), poly(N-methylvinylamine), poly(vinyl pyrrolidone), polyethylene oxide)-poly(propylene oxide) copoplymers, poly(propylene oxide) diamine, poly(propylene dioxide) diacrylate,poly(hydroxyethyl methacrylate), poly(hydroxypropyl methacrylate), poly(hydroxybutyl methacrylate), poly(2 -hydroxyethyl methacrylate), poly(vinyl alcohol), poly(vinyl acetate), poly(acrylic acid), and poly(maleic acid), alginate, cellulose, chitosan, collagen, dextran, dextrin, gelatin, hyaluronic acid, and poly(L-lysine).

5. The system of any one of claims 1 to 4, wherein the silicate nanoparticles comprise one or more of the following: laponite, montmorillonite, bentonite, kaolinite, chlorite, illite, saponite, or hectorite.

6. The system of any one of claims 1 to 5, wherein each silicate nanoparticle comprises a cationic portion and an anionic portion, and wherein the silicate nanoparticles are non-covalently crosslinked with each other via electrostatic interactions between the cationic portions and the anionic portions of the silicate nanoparticles.

7. The system of claim 6, wherein the silicate nanoparticles are disk-shaped nanoparticles, the cationic portions comprise disk edges of the disk-shaped nanoparticles, and the anionic portions comprise disk faces of the disk-shaped nanoparticles.

8. The system of any one of claims 1 to 7, wherein the first precursor composition and the second precursor composition each include the plurality of silicate nanoparticles.

9. The system of any one of claims 1 to 7, wherein the plurality of silicate nanoparticles are present only in the first precursor composition, or wherein the plurality of silicate nanoparticles are present only in the second precursor composition.

10. The system of any one of claims 1 to 9, wherein the first polymer is poly(ethylene glycol) diacrylate, the second polymer is polyethyleneimine, and the silicate nanoparticles are laponite nanoparticles.

11. The system of any one of claims 1 to 10, wherein the covalent crosslinking reaction has a reaction time within a range from 10 seconds to 90 seconds.

12. The system of any one of claims 1 to 11 , wherein before the mixing, the first and second precursor compositions each have a viscosity at 37 °C that is greater than 100 Pa-s at a shear rate less than or equal to 1 s'1and that is less than 0.1 Pa-s at a shear rate greater than or equal to 100 s'1.

13. The system of any one of claims 1 to 12, wherein the mixture of the first and second precursor compositions has a storage modulus at 37 °C that is less than 1 kPa for at least 30 seconds after the mixing of the first and second precursor compositions.

14. The system of any one of claims 1 to 13, wherein the hydrogel has a storage modulus at 37 °C within a linear viscoelastic region of the hydrogel that is within a range from 50 kPa to 200 kPa.

15. The system of any one of claims 1 to 14, further comprising a contrast agent, optionally wherein the contrast agent comprises one or more of the following: tantalum, bismuth trioxide, bismuth oxychloride, tungsten, tungsten carbide, barium sulfate, gadolinium, iodized oil, iohexol, iopamidol, ioxilan, iopamide, iodixanol, iobitridol, ioversol, diatrizoate, metrizoate, iothalamate, ioxaglate, iopromide, iothalamate / meglumine, ioxaglate / meglumine, diatrizoate / meglumine, iodomide sodium, or metrizamide.

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