Materials for conformable fillable medical balloons

Abstract

In some aspects, the present disclosure provides balloon implantation kits that comprise: (a) a conformable, fillable balloon configured to be implanted in a mammalian body, the conformable, fillable balloon comprising a hydrophilic polymer hydrogel comprising crosslinked hydrophilic polymer chains; and (b) a reservoir containing a filler material that is configured to be introduced into the conformable, fillable balloon.

Description

BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 MATERIALS FOR CONFORMABLE FILLABLE MEDICAL BALLOONS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No.63 / 673,063 filed on July 18, 2024, the disclosure of which is incorporated herein by reference. FIELD

[0002] The present disclosure pertains to conformable fillable balloons that are configured to be implanted in a mammalian body for various medical uses. BACKGROUND

[0003] Various solutions presently exist for spacing, lifting, and embolic applications. However, injectable materials, including in-situ crosslinking materials and shear thinning materials, can have some potential inconveniences that include asymmetric localized deployment of the implanted material, potential for off-target embolization due to delayed reaction or migration of the implanted material, and complexity associated with removal of material if complete removal of the material is desired.

[0004] The present disclosure addresses these and other inconveniences by employing conformable, fillable balloons to confine injectable materials at the implantation site. SUMMARY

[0005] The present disclosure is directed to conformable, fillable balloons that are suitable for implantation in a mammalian body.

[0006] In some aspects, the present disclosure provides balloon implantation kits that comprise: (a) a conformable, fillable balloon configured to be implanted in a mammalian body, the conformable, fillable balloonBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 comprising a hydrophilic polymer hydrogel comprising crosslinked hydrophilic polymer chains; and (b) a reservoir containing a filler material that is configured to be introduced into the conformable, fillable balloon.

[0007] In some embodiments, which can be used in conjunction with the above aspects, the crosslinked hydrophilic polymer chains are crosslinked by crosslinks that comprise hydrolysable linkers. For example, the hydrolysable linkers may be selected from a carbonate linker, an acid anhydride linker, an imide linker, a ketal linker, a carbamate linker, an organophosphate ester linker, a silane linker, an amide linker, a hydrozonium linker, an acylhydrozone linker, an oxime linker, an amidohydrozone linker, and combinations thereof.

[0008] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the crosslinks further comprise an activating group positioned adjacent to the hydrolysable linkers, which increases a rate of hydrolysis of the hydrolysable linkers. In some of these embodiments, the activating group is selected from a hydrogen bond donor, a hydrogen bond acceptor, a lone pair donor, a lone pair acceptor, a silicon containing group, a boron containing group, a phosphonate group, a sulfonate group, and combinations thereof. In some of these embodiments, the activating group is selected from a urea linker, a urea pendant group, a thiourea linker, a thiourea pendant group, an amine linker, an amine pendant group, an alcohol pendant group, a silicon- containing linker, a silicon-containing pendant group, a boron-containing linker, a boron-containing pendant group, a phosphonate linker, a phosphonate pendant group, a sulfonate pendant group, and combinations thereof.

[0009] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the hydrophilic polymer hydrogel comprises hydrophilic polymer chains that are crosslinked by crosslinks that comprise immolative linkers or by crosslinks that contain reversible covalent linkers that incorporate a reactive dimeric linker. In some of these embodiments, the kits further comprise a cleavage composition thatBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 contains a singly reactive molecule that acts to break the crosslinks at a position of the immolative linkers within the crosslinks or the cleavage composition contains a singly reactive molecule that acts to break the crosslinks at a position of the dimeric linkers within the crosslinks.

[0010] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the balloon implantation kits comprise a syringe barrel that contains the cleavage composition. In some of these embodiments, the balloon implantation kits further include a needle, a flexible tube, or both, and the syringe barrel is configured for coupling to the needle, the flexible tube, or both.

[0011] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the hydrophilic polymer hydrogel comprises hydrophilic polymer chains that are crosslinked by crosslinks that comprise immolative linkers, and the hydrogel cleavage composition contains the singly reactive molecule that acts to break the crosslinks at the position of the immolative linkers within the crosslinks. In some of these embodiments, the crosslinks comprise imidosydnone groups as immolative linkers and the singly reactive molecule is a strained alkyne reactive molecule. In some of these embodiments, the crosslinks comprise 1- (methyloxidoamino) cyclooctene groups as immolative linkers and the singly reactive molecule is a diboron molecule.

[0012] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the hydrophilic polymer hydrogel comprises hydrophilic polymer chains that are crosslinked by crosslinks that contain reversible covalent linkers that incorporate a reactive dimeric linker, and the hydrogel cleavage composition contains the singly reactive molecule that acts to break the crosslinks at the position of the dimeric linkers within the crosslinks. In some of these embodiments, each of the reversible covalent linkers each comprises two thioester groups, the singly reactive molecule is a thiol molecule, and the reactive dimeric linker is a bis-thiol linker.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0013] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the hydrophilic polymer chains are selected from polyalkylene oxide chains, polyester chains, polyoxazoline chains, polydioxanone chains, polypeptide chains, polypeptiod chains, polyacrylate chains, and polyacrylamide chains or combinations thereof.

[0014] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the filler material comprises an imaging agent.

[0015] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the filler material is a biostable filler material or a degradable filler material.

[0016] In some embodiments, which can be used in conjunction with the above aspects and embodiments the filler material comprises an injectable hydrogel or comprises hydrogel precursors that form a hydrogel when combined.

[0017] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the filler material is a lower critical solution temperature material.

[0018] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the filler material is contained in a syringe barrel.

[0019] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the balloon implantation kits further comprise an elongate filling tube that is configured to be removably coupled to the conformable, fillable balloon, the elongate filling tube having a lumen that is configured for fluid communication with an interior of the conformable, fillable balloon.

[0020] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the balloon implantation kits further comprise and elongate filling tube that is removably coupled to the conformable,BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 fillable balloon, the elongate filling tube having a lumen that is in fluid communication with an interior of the conformable, fillable balloon.

[0021] In some embodiments, which can be used in conjunction with the above aspects and embodiments, the balloon implantation kits further comprise a delivery sheath. In some of these embodiments, the conformable, fillable balloon is removably disposed in the delivery sheath.

[0022] In some embodiments, which can be used in conjunction with the above aspects and embodiments, balloon implantation kits comprise sterile packaging within which components of the conformable, fillable balloon implantation kits are removably packaged in a sterile state.

[0023] In other aspects, the present disclosure pertains to methods that comprise contacting an implant, the implant comprising (i) a conformable, fillable balloon that comprises a hydrophilic polymer hydrogel comprising crosslinked hydrophilic polymer chains that are crosslinked by crosslinks that comprise immolative linkers or by crosslinks that contain reversible covalent linkages that incorporate reactive dimeric linkers and (ii) a filler disposed within the conformable, fillable balloon, with a cleavage composition that contains a singly reactive molecule that acts to break the crosslinks at a position of the immolative linkers within the crosslinks or at a position of the dimeric linkers within the crosslinks, thereby accelerating breakdown of the conformable, fillable balloon.

[0024] Potential advantages of the present disclosure include one or more of the following, among others: reduced chance of unconfined localized deployment of injected material, reduced chance of asymmetric or uncontrolled distribution of injected material, reduced chance of off-target embolization, the use of a wider spectrum of injectable filler materials beyond those that are currently injected into subjects, and the ability of completely remove injected material from a subject if removal of the material is desired.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figs.1A-1D schematically illustrate a method of implanting a conformable, fillable balloon in a subject, in accordance with an embodiment of the present disclosure.

[0026] Figs.2A-2C schematically illustrate a method of breaking down a conformable, fillable balloon in a subject, in accordance with an embodiment of the present disclosure.

[0027] Fig.3A schematically illustrates a process for forming boc-protected 4- imidosyndonebenzoic acid chloride, in accordance with an embodiment of the present disclosure.

[0028] Fig.3B schematically illustrates a process for forming an imidosydnone- functionalized trilysine-derived crosslinker, in accordance with an embodiment of the present disclosure.

[0029] Fig.3C schematically illustrates a process for forming a succinimidyl- ester-terminated multi-arm polymer, in accordance with an embodiment of the present disclosure.

[0030] Fig.3D schematically illustrates a process for forming a hydrophilic polymer hydrogel from the imidosydnone-functionalized trilysine-derived crosslinker of Fig.3B and the succinimidyl-ester-terminated multi-arm polymer of Fig.3C, in accordance with an embodiment of the present disclosure.

[0031] Fig.3E schematically illustrates a process for cleaving crosslinks in the hydrophilic polymer hydrogel of Fig.3D by contact with a strained alkyne, in accordance with an embodiment of the present disclosure.

[0032] Fig.3F schematically illustrates a process for forming an imidosydnone- functionalized trilysine-derived crosslinker, in accordance with a further embodiment of the present disclosure.

[0033] Fig.4A schematically illustrates a process for forming a cyclooctyne- terminated multi-arm polymer, in accordance with an embodiment of the present disclosure.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0034] Fig.4B schematically illustrates a process for forming an N- methylhydroxylamine-functional lysine-derived crosslinker, in accordance with an embodiment of the present disclosure.

[0035] Fig.4C schematically illustrates a process for forming a hydrophilic polymer hydrogel from the cyclooctyne-terminated multi-arm polymer of Fig.4A and the N-methylhydroxylamine-functional lysine-derived crosslinker of Fig.4B, in accordance with an embodiment of the present disclosure.

[0036] Fig.4D schematically illustrates a process for cleaving crosslinks in the hydrophilic polymer hydrogel of Fig.4C by contact with a diboron compound, in accordance with an embodiment of the present disclosure.

[0037] Fig.5 schematically illustrates a device for filling a conformable, fillable balloon, among other uses, in accordance with an embodiment of the present disclosure. DETAILED DESCRIPTION

[0038] The present disclosure is directed to conformable, fillable balloons that are suitable for implantation in a mammalian body, typically, a human body.

[0039] The implantable balloons are useful for a number of medical procedures including spacing, lifting, bulking, embolization and backfill procedures. Spacing procedures include soft tissue spacing procedures wherein one or more fillable balloons are placed, for example, between the rectum and the prostate and filled to prevent damage during radiation therapy or between other organs and / or tissues to protect them from potential side effects of a particular treatment, and joint spacing procedures where one or more fillable balloons are placed in the space of a joint, such as a shoulder, hip, knee or ankle joint and filled to provide mechanical support for the joint. Lifting procedures include procedures where one or more fillable balloons are placed and filled to lift a sinus membrane for sinus augmentation or others. Bulking procedures include procedures wherein one or more fillable balloons are implanted in or adjacent to a bodily sphincter, such as an anal sphincter or a urethral sphincter, to address intrinsic sphincterBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 deficiency or others. Embolization procedures include those where one or more fillable balloons are placed in a target blood vessel and filled to block blood flow to an area of the body. Backfill procedures include procedures wherein one or more fillable balloons are implanted and filled in a left atrial appendage after the introduction of a closure device such as the Watchman® left atrial appendage closure device available from Boston Scientific Corporation, Marlborough MA, USA or the balloon as a closure device for the left atrial appendage with no additional support or devices.

[0040] Conformable, fillable balloons in accordance with the present disclosure may be provided in a variety of shapes and dimensions depending on the target implantation site for the balloon. Balloon shapes include spheroidal balloon shapes, including spheres, various elongated balloon shapes including cylindrical balloon shapes which may have, for example, partial spheroidal ends (e.g., sausage-shaped balloons) or cone-shaped ends or prolate spheroids (e.g. football-shaped balloons), pear-shaped balloons, torus-shaped balloons (e.g., doughnut-shaped balloons) , flattened balloon shapes including oblate spheroids (e.g., balloons shaped like lentils or M&M’S® candies) and other disk shaped balloons, among others.

[0041] Conformable, fillable balloons in accordance with the present disclosure include conformable, fillable balloons having a longest dimension (e.g., diameter for a sphere, the width for a disk, length for an elongated balloon such as a sausage-shaped balloon, etc.) ranging anywhere from 1 mm or less to 40 mm or more, for example, ranging from 1 mm to 2.5 mm to 5 mm to 10 mm to 20 mm to 40 mm, among other possibilities, when filled.

[0042] Conformable, fillable balloons in accordance with the present disclosure include conformable, fillable balloons having a volume ranging anywhere from 0.1 ml or less to 250 ml or more, for example, ranging anywhere from 0.1 ml to 0.2 ml to 0.5 ml to 1.0 ml to 2.5 ml to 5 ml to 10 ml to 25 ml to 50 ml to 100 ml to 250 ml, among other possibilities, when filled.

[0043] Conformable, fillable balloons in accordance with the present disclosure include conformable, fillable balloons having a wall thickness rangingBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 anywhere from 10 or less micrometers to 5000 micrometers or more, for example, ranging from 10 micrometers to 25 micrometers to 50 micrometers to 100 micrometers to 250 micrometers to 500 micrometers to 1000 micrometers to 5000, among other possibilities, when filled.

[0044] Conformable, fillable balloons in accordance with the present disclosure commonly have a feature that allows a filler material to be injected into the balloon, while preventing outflow of the filler material after the balloon is filled. For example, the balloons may be provided with a check valve such as a duckbill valve that allows flow of filler material into the balloon while preventing reverse flow of filler material out of the balloon. As another example, the balloon may be provided with an aperture which allows flow of filler material into the balloon and a plug that is configured to seal the aperture to prevent flow of filler material out of the balloon once filled. As another example, the balloon may be provided with an aperture through which a small tube such as a hypotube is inserted for filling the balloon, which aperture is resealed upon withdrawal of the tube from the aperture (e.g., due to elastic recovery of the aperture or a constricting device that constricts the aperture, such as a clamp or elastic ring), preventing flow of filler material out of the balloon.

[0045] Conformable, fillable balloons in accordance with the present disclosure are formed from a variety of materials, depending on the target implantation site of the balloon, including biostable balloon materials, which remain intact and retain the filler material for at least 20 years after implantation, and degradable materials which are configured to break down and be removed from the body after a time period ranging from 1 day to 24 months (e.g., ranging anywhere from 1 day to 3 days to 1 week to 2 weeks to 1 month to 3 months to 6 months to 12 months to 24 months). Degradation may occur due to various mechanisms that include hydrolysis by interaction with water in the body, enzymatic degradation by enzymes that are naturally occurring in the body, oxidation by oxidants produced by the body and / or degradation brought above by substances such as enzymes that are introduced into the body.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0046] Balloon materials for use herein include biostable polymeric materials and degradable polymeric materials, including biodegradable polymeric materials. Degradable polymeric materials may undergo bond cleavage, resulting in reduced molecular weight and solubilization of the smaller polymer chains in biological fluids. The dissolved polymer chains may be completely metabolized, excreted by the kidneys, and / or absorbed via other physiological mechanisms.

[0047] Balloon materials for use herein are generally biocompatible with the space in which they are implanted. In some embodiments, the balloon materials are compliant (stretchable) materials such as those that comprise elastomeric polymers. In some embodiments, the balloon materials are thermoplastic polymers. In some embodiments, the balloon materials are in the form of crosslinked networks, including hydrogel crosslinked networks.

[0048] Biostable polymeric materials may be selected, for example, from the following polymers, among others: polyamides, polyolefins including polypropylene, polybutadienes including hydrogenated polybutadienes, polydimethylsiloxane (PDMS), polyurethanes, styrene block copolymers, including styrene-isobutylene-styrene triblock copolymers, styrene- isoprene-styrene triblock copolymers, styrene-butadiene-styrene triblock copolymers, and styrene-isoprene / butadiene-styrene triblock copolymers (e.g., Kraton™ polymers from Kraton Corporation, The Woodlands, TX, USA).

[0049] Degradable polymeric materials may be selected, for example, from the following polymers, among others: polyesters including polylactones such as polyvalerolactone and poly(l-lactide-co-ɛ-caprolactone), polycarbonates such as poly(hexamethylene carbonate) (polyHMC), polydioxane, poly(lactide co-glycolide), polyethylene glycol, polyvinyl alcohol, water- soluble polyacrylates (e.g. polyacrylic acid), polyoxazolines, polypeptides, polypeptoids, and proteins.

[0050] Degradable polymeric materials may be selected, for example, from hydrophilic polymer hydrogels that comprise crosslinks between polymerBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 chains within the hydrophilic polymer hydrogel. The polymer chains are generally hydrophilic polymer chains that are soluble in water and can be cleared from the body, for example, by metabolic processes, clearance through the kidneys and / or other physiological processes. Various polymers for use as polymer chains are listed below.

[0051] As used herein, a “hydrogel” is a crosslinked polymer that contains water or can absorb water but does not dissolve when placed in water, although hydrogels may degrade in vivo over time or be degraded by introduction of ex vivo substances.

[0052] In some embodiments, degradable polymeric materials for use herein are formed from hydrophilic polymer chains that are linked to one another by crosslinks that contain hydrolysable linkers that degrade upon contact with water, including the tunable-rate hydrolysable linkers described below.

[0053] In some embodiments, degradable polymeric materials for use herein are formed from hydrophilic polymer chains that are linked to one another by crosslinks that contain immolative linkers, including those described below, whose degradation in situ (i.e., within a subject) is triggered by contact with a cleavage composition as described below.

[0054] Turning first to hydrolysable balloons, in some embodiments, the balloons are formed from hydrophilic polymer hydrogels that comprise crosslinks between hydrophilic polymer chains within the hydrophilic polymer hydrogels, which crosslinks contain hydrolysable linkers that are dispersed throughout the hydrophilic polymer hydrogels. Such hydrophilic polymer hydrogels can be degraded in situ by hydrolysis, among other possible mechanisms.

[0055] In some embodiments, the hydrolysable linkers may be selected from the following groups, among others: a carboxylic acid ester linkage,, , an acid anhydride linkage,BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111, a carbamate linkage,, an organophosphate ester linkage,, an amide linkage,hydrozonium linkage,amidohydrozone linkage,.

[0056] In some embodiments, the crosslinks may further comprise an activating group that is positioned proximate to the hydrolysable linker in order to tune the rate of hydrolysis of the hydrolysable linker and, in particular embodiments, increase the rate of hydrolysis of the hydrolysable linker. Examples of activating groups include electron donating activating groups and electron withdrawing activating groups that can promote hydrolysis, either through binding and orienting water for subsequent attack, or through binding directly to the hydrolysable linker to accelerate and tune the reaction rate. These activating groups can function, for example, via hydrogen bond donation, electrostatic stabilization, metal / ligand interactions, and / or lone-pair donation, among other mechanisms.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0057] Particular examples of activating groups include hydrogen bond donor / acceptors or lone pair donors, which can complex with hydrogen bond acceptors / donors or lone pair acceptors. In this regard, it is noted that water is both a hydrogen bond donor and a hydrogen bond acceptor, with each water molecule having two lone pairs that can serve as hydrogen bond acceptors and two O-H bonds that provide a pair of hydrogen bond donors. Particular examples of such activating groups are ureas, thioureas, alcohols and amines, which may be provided in the form of a urea linkage,where R is H, a thiourea linkage,, where R is H, an amine linkage ,, where R is H, an amine pendantgroup,, where R is H, and an alcohol pendant group, such as a hydroxyalkyl group having from 1 to 7 carbon atoms.

[0058] Particular examples of activating groups also include lone pair acceptors in the form of uncharged moieties that can complex with lone pair donors, including water molecules. Particular examples of such activating groups are silicon- and boron-containing groups, for example, and may beprovided in the form of a silicon-containing linkage,where R ismethyl, a silicon-containing pendant group,, where R is methyl, aboron-containing linkage, , where R is an aryl or alkyl group, and aBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 boron-containing pendant group , where R is an aryl or alkyl functional group, most favorably an electron deficient aryl or alkyl group.

[0059] Particular examples of activating groups further include water complexing or electrostatic stabilizers (e.g., charged moieties, which can position water in an adjacent position). Particular examples of such activating groups are phosphonate and sulfonate groups, which may be provided in the form of aphosphonate linkage,, a phosphonate pendant group, , where R is OH, alkyl or aryl, and a sulfonate pendant group,.

[0060] In some embodiments, the activating groups are incorporated such that they complex with the hydrolysable linker in a cyclic transition state, specifically, a 4-9 atom cyclic transition state. For example, the activating groups may be appended via aromatic ring spacers, cycloaliphatic ring spacers, aliphatic spacers, or heteroatom spacers. This spacing, leading to a 4-9 atom cyclic transition state, may be 1-6 atoms in length.

[0061] Polymer chains for use herein may be selected from any of a variety of synthetic, natural, or hybrid synthetic-natural polymer chains. Examples of polymer chains include those that are formed from one or more monomers selected from the following, among others: C1-C6-alkylene oxide monomers (e.g., ethylene oxide, propylene oxide, tetramethylene oxide, etc.), cyclic ester monomers (e.g. glycolide, lactide, β- propiolactone, β-butyrolactone, γ-butyrolactone, γ-valerolactone, δ- valerolactone, ε-caprolactone, etc.), oxazoline monomers (e.g., oxazoline and 2-alkyl-2-oxazolines, for instance, 2-(C1-C6alkyl)-2-oxazolines, including various isomers, such as 2-methyl-2-oxazoline, 2-ethyl-2- oxazoline, 2-n-propyl-2-oxazoline, 2-isopropyl-2-oxazoline, 2-n-butyl-2- oxazoline, 2-isobutyl-2-oxazoline, 2-hexyl-2-oxazoline, etc.), and 2-BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 phenyl-2-oxazoline, polar aprotic vinyl monomers (e.g. N-vinyl pyrrolidone, acrylamide, N-methyl acrylamide, dimethyl acrylamide, N- vinylimidazole, 4-vinylimidazole, sodium 4-vinylbenzenesulfonate, etc.), dioxanone, N-isopropylacrylamide, amino acids, peptoids (e.g. N- substituted glycines, including N-methyl glycine or sarcosine) and sugars.

[0062] Polymer chains may be selected, for example, from the following polymer chains, among others: polyether chains including poly(C1-C6-alkylene oxide) chains such as poly(ethylene oxide) (PEO) chains (also referred to as polyethylene glycol chains or PEG chains), poly(propylene oxide) chains, poly(ethylene oxide-co-propylene oxide) chains, poly(tetramethylene oxide) chains, polyester chains including polyglycolide chains, polylactide chains, poly(lactide-co-glycolide) chains, poly(β-propiolactone) chains, poly(β-butyrolactone) chains, poly(γ- butyrolactone) chains, poly(γ-valerolactone) chains, poly(δ-valerolactone) chains, and poly(ε-caprolactone ) chains, polyoxazoline chains including poly(2-C1-C6-alkyl-2-oxazoline chains) such as poly(2-methyl-2- oxazoline) chains, poly(2-ethyl-2-oxazoline) chains, poly(2-propyl-2- oxazoline) chains, poly(2-isopropyl-2-oxazoline) chains, and poly(2-n- butyl-2-oxazoline) chains, poly(2-phenyl-2-oxazoline) chains, polymer chains formed from one or more polar aprotic vinyl monomers, including poly(N-vinyl pyrrolidone) chains, poly(acrylamide) chains, poly(N-methyl acrylamide) chains, poly(dimethyl acrylamide) chains, poly(N- vinylimidazole) chains, poly(4-vinylimidazole) chains, and poly(sodium 4- vinylbenzenesulfonate) chains, polydioxanone chains, poly(N- isopropylacrylamide) chains, polypeptide chains, polypeptoid chains (e.g., poly(N-substituted glycines), including polysarcosine) and hydrophilic polymer chains.

[0063] Polymer chains for use in the present disclosure typically contain between 10 and 20000 monomer units or more, for example, ranging from 10 monomer units to 20 monomer units to 50 monomer units to 100 monomer units to 200 monomer units to 500 monomer units to 1000 monomer units to 5000 monomer units to 10000 monomer units to 20000 monomer units, among other possibilities.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0064] Turning triggerable-degradation balloons, in some embodiments, the balloons are formed from hydrophilic polymer hydrogels that comprise crosslinks between hydrophilic polymer chains within the hydrophilic polymer hydrogels, which crosslinks contain reversible covalent linkages that incorporate reactive dimeric linkers or contain immolative linkers that are dispersed throughout the hydrogels. Such hydrophilic polymer hydrogels can be degraded in situ by contacting the hydrophilic polymer hydrogel with a cleavage composition that contains a singly reactive molecule, which acts to break the crosslinks at the positions of the dimeric reactive linkers or immolative linkers within the crosslinks.

[0065] As used herein an “immolative linker” is defined as a transient covalent bond that can be cleaved through the addition of a triggering molecule.

[0066] As used herein a “singly reactive compound” is defined as a compound that will only undergo one reaction with a desired substrate.

[0067] In some embodiments, the hydrophilic polymer hydrogel comprises crosslinks between hydrophilic polymer chains within the hydrophilic polymer hydrogel, which crosslinks contain reversible covalent linkages that incorporate reactive dimeric linkers, and the hydrophilic polymer hydrogel may be degraded by contacting the hydrophilic polymer hydrogel with a cleavage composition that contains a singly reactive molecule, which acts to break the crosslinks at the position of the dimeric linkers within the crosslinks.

[0068] The cleavage compositions of the present disclosure may be supplied in a syringe, vial, ampule or other reservoir. The cleavage compositions may be provided, for example, in dry form (e.g., powder form) or in fluid form, such as in a solution form or as an aqueous dispersion.

[0069] The cleavage compositions may further include one or more additional agents, including therapeutic agents, imaging agents, colorants, tonicity adjusting agents, and pH adjusting agents as described below.

[0070] Contact of the cleavage composition with the hydrophilic polymer hydrogel may include, for example, applying the cleavage compositionBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 onto a surface of the balloon, injecting the cleavage composition into the wall of the balloon, and so forth.

[0071] With regard to hydrogels having crosslinks that contain reversible covalent linkages that are based on reactive dimeric linkers, a general schematic representation is provided below, which shows two reversible covalent linkages, represented by X-Y. The covalent linkages. X-Y, reversibly break down resulting (a) a dimeric reactive linker, represented by X-B-X, where B represents a polymer chain and where X represents a reactive group attached to the polymer chain, B, and (b) two polymer chains, represented by AY, where Y represents a reactive group attached to a polymer chain, represented by A, that forms reversible covalent bonds with the reactive X groups of the dimeric reactive linker X-B-X. When a singly reactive molecule, represented by X-D, is introduced, the singly reactive molecule can react with Y groups of each of the AY polymer chains to form further polymer chains, represented by A-Y-X-D, which do not reversibly react with the dimeric reactive linker, X-B-X. In doing so, the singly reactive molecule, X-D, outcompetes the reverse reaction of the dimeric reactive linker, X-B-X, for the polymer chains, AY, which would otherwise reform the reversible covalent linkages. The overall result of this process is that the singly reactive molecule, XD, acts to cleave the reversible covalent linkages.

[0072] Several specific examples follow. In a first specific example, a crosslink that contains two thioester linkages as reversible covalent linkages is shown being cleaved with a singly reactive molecule, cysteine, or another thiol containing small molecule, to yield two polymer chains, each having a thioester group, and a telechelic dithiol reactive linker having two -SH groups:BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0073] In another specific example, a crosslink that contains two disulfide linkages as reversible covalent linkages is shown being cleaved by a singly reactive molecule, such as cysteine, or another thiol containing small molecule, to yield two polymer chains, each with a disulfide group and a dithiol dimeric reactive linker having two -SH groups:

[0074] In another specific example, a crosslink that contains two linkages composed of disuccinimide as reversible covalent linkages is shown which reversibly break down into a bismaleimide type reactive linker and two polymer chains, each containing a furyl group. The polymer chains containing the furyl group then react with a singly reactive molecule, poly(N-malimide) to form two polymer chains, each with a succinimide group:BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0075] In another specific example, a crosslink that contains two borate ester linkages as reversible covalent linkages is shown which reversibly breaks down into a dimeric reactive linker containing two vicinal diol groups, and two polymer chains, each containing a boronic acid group. The polymer chains then react with a singly reactive molecule, containing a vicinal diol, to form two polymer chains, each with borate ester groups:

[0076] In another specific example, a crosslink that contains two linkages as reversible covalent linkages is shown which reversibly breaks down into a dimeric reactive linker containing two primary amine groups and two polymer chains, each containing an aldehyde group. The polymer chains then react with a singly reactive molecule, for example, lysine, or another primary amine containing small molecule, to form two polymer chains:

[0077] Turning now to hydrogels having crosslinks that contain immolative linkers, several schematic representations of crosslinks between polymer chains follow, which show an immolative linker disposed between two polymer chains, each represented by the letter A, within a crosslinked hydrogel. As will be appreciated from the description to follow, in various embodiments, instead of a single immolative linker as schematically represented, two immolative linkers may be disposed between the chains, with one immolative linker attached to each polymer chain, which immolative linkers are linked to one another through a crosslinker residue. The schematic representations also illustrate the introduction of a singly reactive molecule, which acts to cleave the immolative linker and therefore cleaves the polymer chains from one another.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0078] In one example, a crosslink that contains an imidosydnone group as an immolative linker is shown being cleaved by a strained alkyne reactive molecule to yield one polymer chain with a primary amide group and another polymer chain with a tricyclic group:

[0079] In another example, a crosslink that contains a 1-(methyloxidoamino) cyclooctene group as an immolative linker is shown being cleaved by a diboron reactive molecule to yield one polymer chain with a hydroxyl group and another polymer chain with an imminium group:

[0080] In another example, a crosslink that contains a silyl diether group as an immolative linker, where R is an alkane, cycloalkane, or aromatic side chain is shown being cleaved by a singly reactive molecule, aminophenylethyl trifluoroborate to yield two polymer chains with hydroxyl groups:BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0081] In another example, a crosslink that contains an immolative linker is shown being cleaved by a singly reactive molecule, benzene-1,2-dithiol, to yield one polymer chain with an amine or alcohol group and another polymer chain with a dithiobenzene incorporated into the final aromatic end group of the polymer chain:

[0082] In another example, a crosslink that contains a tetrazine group as an immolative linker is shown being cleaved by a singly reactive molecule, such as a derivatized transcyclooctene, where R is an alkyl group or a 3- hydroxy-cyclooct-1-yne, to yield one polymer chain with a primary amine group and another polymer chain with a pyridazine group:

[0083] In another example, a crosslink that contains a 4-azidobenzene group as an immolative linker is shown being cleaved by a singly reactive molecule, such as (E)-cyclooct-4-enol, or through reaction with phenyl-2-carboxyl diphenylphosphine to yield one polymer chain with a carboxylate group and another polymer chain with an oxidized aromatic group bound to an amide:BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0084] In another example, a crosslink that contains a transcyclooctene group as an immolative linker is shown being cleaved by a singly reactive molecule, such as a tetrazine derivative, where R1 and R2 are alkyl functional groups, to yield one polymer chain with a primary amine group and another polymer chain with a pyridazine group:

[0085] In another example, a crosslink that contains an aryl enol ether group as an immolative linker is shown being cleaved by a singly reactive molecule, such as a tetrazine derivative, where R1 and R2 are alkyl functional groups, to yield one polymer chain with a hydroxyl group and another polymer chain with an alpha beta unsaturated cyclic ketone:

[0086] In another example, a crosslink that contains an 1,1 azide ether group as an immolative linker is shown being cleaved by a singly reactive phosphineBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 derivative where R is alkyl or aryl, to yield one polymer chain with an aldehyde group and another polymer chain with a hydroxyl group:

[0087] Polymer chains for use herein, including those schematically represented in the preceding schemes with the letter “A,” may be selected from any of a variety of synthetic, natural, or hybrid synthetic-natural polymer chains. Particular examples of polymer chains include those described above, among others.

[0088] In various embodiments, polymer chains, including those schematically represented in the preceding schemes with the letter A, are part of a multi- arm polymer residue where three or more polymer arms that comprise the polymer chains extend from a core region. The multi-arm polymers have three or more polymer arms (e.g., between three and fifteen polymer arms). General classes of core regions include residues of polyols, including sugars (monosaccharides, disaccharides, trisaccharides, etc.) and sugar alcohols, calixaranes, polyhedral oligomeric silsesquioxanes (POSS), cyclodextrin, polyhydroxylated polymers, catechins, flavanols, anthocyanins, stilbenes, and polyphenols, among many others.

[0089] In various embodiments, the polymer chains are crosslinked by multifunctional crosslinkers that contain two or more functional groups (e.g., between two and ten functional groups).

[0090] In some of these embodiments, the multifunctional crosslinkers are dimeric reactive linkers, and functional groups at the ends of the polymer chains are reversibly crosslinked with the dimeric reactive linkers as described above.

[0091] In some of these embodiments, the multifunctional crosslinkers have functional groups that irreversibly crosslink with functional groups at ends of the polymer chains.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0092] In some of these embodiments, the multifunctional crosslinkers have functional groups that irreversibly crosslink with functional groups at ends of the polymer chains, forming crosslinks that contain immolative linkers as described above. Two examples will be described in more detail here.

[0093] The first example provides hydrogels having crosslinks that contain imidosydnone groups as immolative linkers. In the presence of strained alkynes, imidosyndones will rapidly undergo sydnone-alkyne click chemistry reactions.

[0094] With reference now to Fig.3A, in a first step, the amino group of 4- aminobenzoic acid methyl ester (310) is cyanomethylated with chloroacetonitrile in the presence of NaI and K2CO3to yield 4- cyanomethylaminobenzoic acid methyl ester (312), which is then reacted with iso-amyl nitrite (314) to yield intermediate compound (316), followed by treatment with 4N HCl to form 4-(2-aminonitrosoethylnitrile) benzoic acid methyl ester (318), which is then sequentially treated with NaOH and HCl to form 4-imidosyndonebenzoic acid chloride (320), which is further reacted with di-tert-butyl dicarbonate (Boc2O) to form boc-protected 4-imidosyndonebenzoic acid chloride (322).

[0095] Turning to Fig.3B, a trilysine alkyl ester (324), where R is an alkyl group, heterocycle group, etc., that does not contain a carboxylic acid, halide, amine, alcohol, or other functional groups that can interfere with the following coupling reaction, is reacted with boc-protected 4- imidosyndonebenzoic acid methyl ester chloride (322) from Fig.3A in the presence of a carbodiimide coupling agent such as N,N'- dicyclohexylcarbodiimide (DCC), followed by treatment in HCl to form imidosydnone-functionalized trilysine (328). Note that the terminus of only a single functionalized side chain of the three side chains of the trilysine is shown. Although trilysine is used as a multi-functional amine in this specific instance, other multi-functional amines may be used including 1,3-propanediamine, tris(3-aminopropyl)amine, 3-(2- aminoethyl)pentane-1,5-diamine, N,N',N'-tetrakis(2-aminoethyl)-1,2- ethanediamine, 1,3,5-tris-(2-aminoethyl)-[1,3,5]triazinane-2,4,6-trione,BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 N,N,N'-Tris(2-aminoethyl)ethylenediamine, and adamantane-1,3,5,7- tetraamine, among many others.

[0096] With reference to Fig.3C, a hydroxyl-terminated multi-arm PEG (330) (only one arm is illustrated) is reacted with acrylic acid ethyl ester (332) followed by treatment with base to yield a carboxyl-terminated multi-arm PEG (334), which is reacted with N-hydroxy succinimide (336) in the presence of a carbodiimide coupling agent such as DCC to yield succinimidyl-ester-terminated multi-arm PEG (338). Although a hydroxyl-terminated multi-arm PEG is employed in Fig.3C, it will be appreciated that other hydroxyl terminated multi-arm polymers may be used including those containing the polymer chains described above.

[0097] With reference to Fig.3D, the activated succinimidyl ester groups of the succinimidyl-ester-terminated multi-arm PEG (338) of Fig.3C can be rapidly reacted with the primary amine groups of the imidosydnone- functionalized trilysine (328) of Fig.3B to form a crosslinked hydrogel product (340) with crosslinks that contain imidosyndoneamide linkages.

[0098] Because the resulting hydrogel contains crosslinks that comprise sydnone groups, which connect the multi-arm polymer residue and the trilysine- based crosslinker residue, when the hydrogel is no longer desired, it can be degraded on demand by treatment with a strained alkyne. In a particular example shown in Fig.3E, the crosslinked hydrogel product (340) of Fig. 3D is contacted with a strained alkyne, in particular, (1R,8S,9s)- bicyclo[6.1.0]non-4-yn-9-ylmethanol, also known as BCN-OH, thereby breaking the crosslinks, and forming a free amido-terminated arm (344), which is associated with a residue of the incorporated multi-arm PEG, and a cyclooctapyrazole group (346), which is associated with a residue of the incorporated trilysine-based crosslinker. Although BCN-OH is used in this particular example, strained alkynes can be functionalized with different groups or added to polymers to increase their biocompatibility.

[0099] As an alternative to the synthesis shown in Figs.3A and 3B, and with reference to Fig.3F, in a first step the amino groups of the methyl ester of trilysine (324), or amino groups of any other suitable polyamineBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 compound, is cyanomethylated with chloroacetonitrile in the presence of NaI and K2CO3to yield cyanomethylamino functionalized trilysine (350) in which the groups of the trilysine have been converted to cyanomethylamino groups. The cyanomethylamino groups of the cyanomethylamino functionalized lysine (350) are then reacted with iso- amyl nitrite (314) to a further yield intermediate compound (352), followed by treatment with 4N HCl to form imidosydnone-functionalized trilysine (328). Although trilysine is used as a multi-functional amine in this specific instance, other multi-functional amines may be used including 1,3-propanediamine, tris(3-aminopropyl)amine, 3-(2-aminoethyl)pentane- 1,5-diamine, N,N',N'-tetrakis(2-aminoethyl)-1,2-ethanediamine, 1,3,5-tris- (2-aminoethyl)-[1,3,5]triazinane-2,4,6-trione, N,N,N'-Tris(2- aminoethyl)ethylenediamine, and adamantane-1,3,5,7-tetraamine, among many others.

[0100] The second example is based on bioorthogonal click and release chemistry using a diborane.

[0101] Turning now to Fig.4A, a hydroxyl-terminated multi-arm PEG (410) (only one arm is illustrated) is reacted with acrylic acid ethyl ester (412) followed by treatment with base to yield a carboxyl-terminated multi-arm PEG (414). The carboxyl-terminated multi-arm PEG (414) is reacted with N-boc-1,2-diaminoethane (416), also known as tert-butyl N-(2- aminoethyl)carbamate, in the presence of a carbodiimide coupling agent such as DCC, followed by treatment in acid to form aminoethylaminocarbonyl-terminated multi-arm PEG (418), which is reacted with 2-(cyclooct-2-yn-1-yloxy)acetic acid (420) to form ethyl(cyclooct-2-yn-1-yloxy)aminocarbonyl-terminated multi-arm PEG (422) in which the multi-arm PEG is functionalized with a strained alkyne. Although a hydroxyl-terminated multi-arm PEG is employed in Fig.4A, it will be appreciated that other hydroxyl terminated multi-arm polymers may be used including those containing the polymer chains described above.

[0102] With reference now to Fig.4B, trilysine (424) (the terminus of only a single aminobutyl side chain out of the three aminobutyl side chain of theBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 trilysine is shown) is reacted with N-Methyl-N-(phenylmethoxy)glycine (426) in the presence of a carbodiimide coupling agent such as DCC, followed by reaction sodium methoxide (NaOMe) to form an N- methylhydroxylamine-functional compound (428) in which N- methylhydroxylamine groups are linked to a trilysine residue through amide linkages. Although trilysine is used as a multi-functional amine in this specific instance, other multi-functional amines may be used, including those set forth above.

[0103] With reference to Fig.4C, the cyclooctyne groups of the cyclooctyne- terminated multi-arm PEG (422) of Fig.4A can be rapidly reacted with the N-methylhydroxylamine groups of the N-methylhydroxylamine- functionalized trilysine (428) of Fig.4B to form a crosslinked hydrogel product (430) with crosslinks that contain enamine N-oxide groups, specifically, 1-(methyloxidoamino) cyclooctene groups.

[0104] Because the resulting hydrogel contains crosslinks that comprise enamine N-oxide groups, which connect the multi-arm polymer residue and the trilysine-based crosslinker residue, when the hydrogel is no longer desirable, it can be degraded on demand by treatment with a diboron compound. In a particular example shown in Fig.4D, the crosslinked hydrogel product (430) of Fig.4C is contacted with a diboron compound, specifically, bis(pinacolato)diboron (432), thereby breaking the crosslinks and forming a free N-(2-hydroxyethyl)amide-terminated arm (434), which is associated with a residue of the incorporated multi-arm PEG, and an imminium group (436), which is associated with a residue of the incorporated trilysine-based crosslinker.

[0105] In some embodiments, the present disclosure pertains to methods that comprise contacting a balloon, which comprises a hydrophilic polymer hydrogel that comprises hydrophilic polymer chains that are crosslinked by crosslinks that comprise immolative linkers or by crosslinks that contain reversible covalent linkages that incorporate reactive dimeric linkers, with a cleavage composition that comprises a singly reactive molecule. For example, in the event that it is desirable to remove the balloon from a subject (e.g. because therapy is complete, because theBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 balloon is causing discomfort, because the hydrophilic polymer hydrogel is improperly placed, etc.), the crosslinked hydrophilic polymer may be contacted with the cleavage composition, degrading the balloon.

[0106] In some embodiments, the cleavage composition contains a singly reactive molecule that acts to break the crosslinks at the position of the immolative linkers within the crosslinks. In some embodiments, the cleavage composition contains a singly reactive molecule that acts to break the crosslinks at the position of the dimeric linkers within the crosslinks.

[0107] In addition to one or more singly reactive molecules, the cleavage compositions of the present disclosure may contain one or more additional agents such as therapeutic agents, imaging agents, colorants, tonicity adjusting agents, suspension agents, wetting agents, and pH adjusting agents as detailed below.

[0108] In some embodiments, the conformable, fillable balloons may be surface functionalized. For example, the conformable, fillable balloons may be surface functionalized to promote thrombus or to promote binding to tissue surfaces. For example, in some embodiments, the balloon surface may be functionalized with N-Hydroxysuccinimide (NHS) esters to bind to biomolecules including proteins in bodily fluid and surface proteins, thereby promoting thrombus formation and tissue adhesion, reducing the risk of migration of the balloon. In some embodiments, the balloon surface may be functionalized with plastic antibodies to selectively bind to proteins that promote thrombogenicity.

[0109] In other cases, the conformable, fillable balloons may be surface functionalized to limit thrombus. For example, in some embodiments, the balloon surface may be treated with a fluoropolymer such as polyvinylidene fluoride (PVDF) or riveroxoban to limit thrombus formation.

[0110] A variety of filler materials may be used in conjunction with conformable, fillable balloons of the present disclosure, including biostable and degradable filler materials.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0111] In some embodiments the filler materials may be in the form of aqueous liquids including aqueous solutions and aqueous dispersions, particular examples of which include normal saline, phosphate buffered saline, 5% dextrose in water (D5W), contrast media including radiographic contrast media such as iodinated contrast media (e.g., Lipiodol® Guerbet LLC, Princeton, NJ, USA), iohexol (Omnipaque™, GE HealthCare Technologies, Inc., Chicago, IL, USA), iodixanol (Visipaque™, GE HealthCare Technologies, Inc.), iopamidol, ioversol, etc.) and barium sulfate, magnetic resonance imaging (MRI) contrast media including gadolinium-containing contrast media, near-infrared (NIR) contrast media such as those containing indocyanine green, methylene blue, sodium fluorescein, and 5-aminolevulinic acid (5-ALA), and positron emission tomography (PET) contrast media such as those containing [18F]fluorodeoxyglucose (FDG) or [18F]sodium fluoride (Na18F).

[0112] In some embodiments the filler materials may be in the form of a polymeric solutions, for example, solutions of a water-soluble polymer selected from polysaccharides (e.g., solutions of hyaluronic acid, gelatin, pectin, alginate, cellulose, gellan gum, etc.), polyethylene glycol, polyoxazolines, polypeptides, polypeptoids, polyacrylates, polyacrylamides, copolymers of polyethylene glycol, and polyvinyl alcohol.

[0113] In some embodiments the filler materials may be in the form of a shear thinning hydrogel, which is able to temporarily fluidize under shear stress and recover its original mechanical properties after release of the applied stress, based on natural polymers such as gelatin (e.g., Obsidio™ Conformable Embolic from Boston Scientific, a pre-hydrated bioresorbable mixture of gelatin and layered silicate particles, either with or without tantalum powder for radiocontrast), collagen, hyaluronic acid, alginate, and chitosan. Such hydrogels are generally crosslinked based on physical crosslinking mechanisms such as electrostatic interactions or hydrogen bonding.

[0114] In some embodiments the filler materials may be in the form of a lower critical solution temperature (LCST) material, where the LCST refers toBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 the temperature at which the transition from a liquid phase to a hydrogel phase occurs. When the LCST material is injected into a body, the temperature of the LCST material is below the LCST and increases due to heat transfer from the body. Once the temperature of the LCST material reaches the LCST, the transition from the liquid phase to the hydrogel phase takes place. Such LCST materials can be configured or prepared to remain in a liquid phase, with a low viscosity, at an injection temperature below the body temperature (e.g., room temperature or below) and to transform to a gel phase when increased in temperature to body temperature. Examples of such materials include polyoxyethylene- polyoxyproplyene (PEO-PPO) block copolymers, such as Pluronic acid F127 and F108, and N-Isopropyl acrylamide (IPAAm) copolymers.

[0115] In some embodiments the filler materials may form crosslinked hydrogels in vivo. An example of such a crosslinked hydrogel is SpaceOAR®, which is based on a multi-arm polyethylene glycol (PEG) polymer functionalized with succinimidyl glutarate as activated end groups which further react with trilysine to form crosslinks. During use, a solution of the multi-arm polymer and the lysine is simultaneously injected with a buffer solution. When mixed, the buffer solution increases the pH and dramatically accelerates the rate of reaction between the multi-arm polymer and the lysine, forming a crosslinked hydrogel within seconds. Another example of such a crosslinked hydrogel is SpaceOAR Vue®, which, like SpaceOAR®, is based on a multi-arm polyethylene glycol (PEG) polymer functionalized with succinimidyl glutarate as activated end groups which further react with trilysine to form crosslinks. In SpaceOAR Vue®, some of the succinimidyl glutarate end groups are functionalized with 2,3,5-triiiodobenzamide groups, providing radiopacity. In other embodiments, systems of these types can be used to form hydrogels ex vivo, after which the hydrogels are broken down into particles and suspended in an aqueous solution to form an injectable pre-formed hydrogel.

[0116] In some embodiments the filler materials may comprise a hydrophilic polymer hydrogel that comprises crosslinks between hydrophilic polymerBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 chains within the hydrophilic polymer hydrogels, which crosslinks contain hydrolysable linkers, as described above.

[0117] In some embodiments the filler materials may comprise a hydrophilic polymer hydrogel that comprises crosslinks between hydrophilic polymer chains within the hydrophilic polymer hydrogels, which crosslinks contain immolative linkers that are dispersed throughout the hydrogels, as described above. Such hydrogels can be degraded in situ by contact with a suitable cleavage composition, as described above.

[0118] Filler materials for use in the present disclosure may also contain one or more additional agents such as therapeutic agents, imaging agents, colorants, tonicity adjusting agents, and pH adjusting agents. In embodiments where the balloon permits release (e.g., by allowing diffusion through the balloon), such agents (e.g., therapeutic agents, imaging agents, etc.) may be released from the balloon over time.

[0119] Examples of therapeutic agents include antithrombotic agents, anticoagulant agents, antiplatelet agents, thrombolytic agents, antiproliferative agents, anti-inflammatory agents, hyperplasia inhibiting agents, anti-restenosis agent, smooth muscle cell inhibitors, antibiotics, antimicrobials, analgesics, anesthetics, growth factors, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, anti- angiogenic agents, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, immune modulatory cytokines, T-cell agonists, STING (stimulator of interferon genes) agonists, antimetabolites, alkylating agents, microtubule inhibitors, hormones, hormone antagonists, monoclonal antibodies, antimitotics, immunosuppressive agents, tyrosine and serine / threonine kinases, proteasome inhibitors, mRNA, matrix metalloproteinase inhibitors, Bcl-2 inhibitors, DNA alkylating agents, spindle poisons, poly (DP-ribose)polymerase (PARP) inhibitors, and combinations thereof.

[0120] Examples of imaging agents include (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g. green, blue, cyan fluorescent proteins), (b) contrast agents for use in conjunction withBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 magnetic resonance imaging (MRI), including contrast agents that contain elements that form paramagnetic ions, such as Gd(III), Mn(II), Fe(III) and compounds (including chelates) containing the same, such as gadolinium ion chelated with diethylenetriaminepentaacetic acid, (c) contrast agents for use in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (i.e., particles that result in an increase in the reflected ultrasonic energy) or organic and inorganic echolucent particles (i.e., particles that result in a decrease in the reflected ultrasonic energy), (d) contrast agents for use in connection with near-infrared (NIR) imaging, which can be selected to impart near-infrared fluorescence to the hydrogels of the present disclosure, allowing for deep tissue imaging and device marking, for instance, NIR-sensitive nanoparticles such as gold nanoshells, carbon nanotubes (e.g., nanotubes derivatized with hydroxy or carboxyl groups, for instance, partially oxidized carbon nanotubes), dye-containing nanoparticles, such as dye-doped nanofibers and dye-encapsulating nanoparticles, and semiconductor quantum dots, among others, and NIR- sensitive dyes such as cyanine dyes, squaraines, phthalocyanines, porphyrin derivatives and boron dipyrromethane (BODIPY) analogs, among others, (e) imageable radioisotopes including 99mTc, 201Th, 51Cr, 67Ga, 68Ga, 111In, 64Cu, 89Zr, 59Fe, 42K, 82Rb, 24Na, 45Ti, 44Sc, 51Cr and 177Lu, among others, and (f) radiocontrast agents, for example, particles of tantalum, tungsten, rhenium, niobium, molybdenum, and their alloys, which metallic particles may be spherical or non-spherical. Additional examples of radiocontrast agents include non-ionic radiocontrast agents, such as iohexol, iodixanol, ioversol, iopamidol, ioxilan, or iopromide, ionic radiocontrast agents such as diatrizoate, iothalamate, metrizoate, or ioxaglate, and iodinated oils, including ethiodized poppyseed oil (available as Lipiodol®).

[0121] Examples of colorants include brilliant blue (e.g., Brilliant Blue FCF, also known as FD&C Blue 1), indigo carmine (also known as FD&C Blue 2), indigo carmine lake, FD&C Blue 1 lake, and methylene blue (also known as methylthioninium chloride), among others.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111

[0122] Examples of tonicity adjusting agents include sugars (e.g., dextrose, lactose, etc.), polyhydric alcohols (e.g., glycerol, propylene glycol, mannitol, sorbitol, etc.) and inorganic salts (e.g., potassium chloride, sodium chloride, etc.), among others.

[0123] Examples of pH adjusting agents include various buffer solutes.

[0124] In some aspects of the present disclosure, methods are provided that comprise: implanting a balloon in a subject at a target location and subsequently introducing a filler material into the balloon. In some embodiments, the balloon is implanted with the assistance of a delivery sheath. For example, the delivery sheath can first be inserted into the subject after which the balloon is inserted through the sheath to the target location, after which the filler material is introduced into the balloon. As another example, the balloon may be disposed within the delivery sheath while the delivery sheath is inserted into the subject. Then, the balloon is advanced from the delivery sheath to the target location and filled with the filler material. In various embodiments, the filler material is introduced into the balloon through an elongate filling tube, or catheter, which is removably coupled to the balloon, the elongate filling tube having a lumen that is in fluid communication with an interior of the balloon. After filling the balloon, the filling tube is detached from the balloon and withdrawn from the subject, along with the delivery sheath, if employed. As described above, outflow of the filler material from the balloon may be prevented, for example, through the use of a check valve, a resealable aperture, or a plug. In some embodiments, the plug is located inside the balloon and is detachably connected to a distal end of the filling tube, such that when the filling tube is withdrawn, the plug is fitted within the aperture inside the balloon.

[0125] In a particular embodiment shown in Figs.1A-1E, a balloon 120 is inserted at a target site in body lumen, such as a blood vessel 110 while in substantially uninflated state. The balloon 120 is removably coupled to a distal end of a filling tube 130 (e.g., a catheter), which is in fluid communication with an interior of balloon 120. In some embodiments, the balloon may be rolled or folded for this purpose. In the embodimentBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 shown, the balloon is inserted with the assistance of a delivery sheath 140. As shown in FIG.1B, the filling tube 130 is then used to inflate the balloon 120 within the blood vessel 110 with a filler material 125, such that the balloon 120 occludes the blood vessel 110. The filling tube 130 is then decoupled from the balloon 120 as shown in FIG.1C and the filling tube 130 and delivery sheath 140 removed from the subject, completing the implantation procedure.

[0126] In some embodiments, the filler material 125 of the present disclosure can be imaged during or after administration using a suitable imaging technique such as ultrasound or an X-ray-based imaging technique, such as computerized tomography or X-ray fluoroscopy.

[0127] When desired, cleavage of the hydrophilic polymer hydrogel that forms the balloon can be initiated by contacting the hydrophilic polymer hydrogel compositions with a cleavage composition as described herein.

[0128] As previously indicated, in some embodiments, balloons are provided that comprise a hydrophilic polymer hydrogel, which comprises hydrophilic polymer chains that are crosslinked by crosslinks that comprise immolative linkers or reversible covalent linkages that incorporate reactive dimeric linkers, and which can be degraded in situ by contact with a cleavage composition that comprises a singly reactive molecule. For example, in the event that it is desirable to remove the balloon from a subject (e.g. because therapy is complete, because the balloon is causing discomfort, because the balloon is improperly placed, etc.), the balloon may be contacted with the cleavage composition to accelerate the breakdown of the balloon.

[0129] Fig.2A illustrates a conformable, fillable balloon 120 that is inflated with a filler material 125 and occludes a blood vessel 110. The balloon 120 is formed from a polymeric material comprising hydrophilic polymer chains that are linked by crosslinks that contain immolative linkers or reversible covalent linkages that incorporate reactive dimeric linkers. Also shown in Fig.2A is catheter 150 having a distribution head 152 through which a cleavage composition 160 is distributed. When the cleavageBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 composition 160 contacts the polymeric material forming the balloon 120, the immolative linkers or the reversible covalent linkages that incorporate reactive dimeric linkers are cleaved, resulting in degradation of the balloon.

[0130] If the filler material 125 is a biostable or a biodegradable solid, the filler material 125 may remain, at least for a time, after the polymeric material forming the balloon degrades as shown in Fig.2B. If the filler material 125 is a biodegradable solid, the filler material 125 ultimately biodegrades leaving the blood vessel 110 non-occluded as shown in Fig. 2C.

[0131] Alternatively, if the composition 125 is a liquid, the filler material 125 will flow away from the balloon 120 as the polymeric material forming the balloon 120 degrades, leaving the blood vessel 110 non-occluded as shown in Fig.2C after degradation of the balloon.

[0132] Fig.5 illustrates a syringe 10 that includes a barrel 12, a plunger 14, and one or more stoppers 16. The barrel 12 may include a suitable adapter / connector such as a Luer adapter, e.g., at the distal end 18 of the barrel 12, for attachment to a flexible catheter 29. The proximal end of the catheter 29 may include a suitable adapter / connector 20 for receiving the adapter / connector of the barrel 12. In some embodiments, the distal end of the catheter 29 may be removably attached to a conformable, fillable balloon as described herein. In some embodiments, the distal end of the catheter 29 terminates at an outlet suitable for dispensing a cleavage composition as described herein. The syringe barrel 12 may serves as a reservoir for a fluid to be injected through the catheter such as a filler material or a cleavage composition as described herein.

[0133] In other aspects, the present disclosure provides balloon implantation kits that include one or more inflatable balloons configured to be implanted in a human body and one or more containers that include a filler material that is configured to be introduced into the one or more balloons or that include filler material precursors that, when combined, produce a filler material in the one or more balloons. Containers for the fillerBSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 material or the filler material precursors include, for example, vials, ampules, empty syringes, and preloaded syringes. In various embodiments, the one or more inflatable balloons further include features for preventing outflow of filler material such as check valves, plugs or constricting devices as described above.

[0134] In some embodiments, the balloon implantation kits include one or more filling tubes (e.g., catheter tubes) for introducing the filler material or filler material precursors into the one or more balloons. In some embodiments, the one or more filling tubes are releasably attached to the one or more balloons.

[0135] In some embodiments, the balloon implantation kits include one or more delivery sheaths through which the one or more balloons is / are implanted in the subject. In some of these embodiments, the one or more balloons is / are pre-loaded in the one or more delivery sheaths.

[0136] In some embodiments, the balloon implantation kits include one or more containers that contain a cleavage solution as described herein. Containers for the cleavage solution include, for example, vials, ampules, and preloaded syringes. In these embodiments, the balloon implantation kits may further include a catheter tube for delivering the cleavage solution. In some of these embodiments, a distribution head, such as a spray head, may be disposed at a distal end of the catheter tube.

[0137] In some embodiments, the balloon implantation kits further include sterile packaging in which the above-described the kit components are removably packaged in a sterile state.

Claims

BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 CLAIMS:

1. A balloon implantation kit comprising: (a) a conformable, fillable balloon configured to be implanted in a mammalian body, the conformable, fillable balloon comprising a hydrophilic polymer hydrogel comprising crosslinked hydrophilic polymer chains; and (b) a reservoir containing a filler material that is configured to be introduced into the conformable, fillable balloon.

2. The balloon implantation kit of claim 1, wherein the crosslinked hydrophilic polymer chains are crosslinked by crosslinks that comprise hydrolysable linkers.

3. The balloon implantation kit of claim 2, wherein the hydrolysable linkers are selected from a carbonate linker, an acid anhydride linker, an imide linker, a ketal linker, a carbamate linker, an organophosphate ester linker, a silane linker, an amide linker, a hydrozonium linker, an acylhydrozone linker, an oxime linker and an amidohydrozone linker.

4. The balloon implantation kit of any of claims 2-3, wherein the crosslinks further comprise an activating group positioned adjacent to the hydrolysable linkers, which increases a rate of hydrolysis of the hydrolysable linkers.

5. The balloon implantation kit of claim 4, wherein the activating group is selected from a hydrogen bond donor, a hydrogen bond acceptor, a lone pair donor, a lone pair acceptor, a silicon containing group, a boron containing group, a phosphonate group and a sulfonate group.

6. The balloon implantation kit of claim 4, wherein the activating group is selected from a urea linker, a urea pendant group, a thiourea linker, a thiourea pendant group, an amine linker, an amine pendant group, an alcohol pendant group, a silicon-containing linker, a silicon-containing pendant group, a boron-containing linker, a boron-containing pendant group, a phosphonate linker, a phosphonate pendant group, and a sulfonate pendant group.

7. The balloon implantation kit of any of claims 1-6, wherein the hydrophilic polymer hydrogel comprises hydrophilic polymer chains that are crosslinked by crosslinks that comprise immolative linkers or by crosslinks that contain reversible covalent linkers that incorporate a reactive dimeric linker.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 8. The balloon implantation kit of claim 7, wherein the kit further comprises a cleavage composition that contains a singly reactive molecule that acts to break the crosslinks at a position of the immolative linkers within the crosslinks, or wherein the kit further comprises a cleavage composition that contains a singly reactive molecule that acts to break the crosslinks at a position of the dimeric linkers within the crosslinks.

9. The balloon implantation kit of any of claims 7-8, wherein the hydrophilic polymer hydrogel comprises the hydrophilic polymer chains that are crosslinked by crosslinks that comprise immolative linkers and wherein the hydrogel cleavage composition contains the singly reactive molecule that acts to break the crosslinks at the position of the immolative linkers within the crosslinks.

10. The balloon implantation kit of claim 9, wherein the crosslinks comprise imidosydnone groups as immolative linkers and the singly reactive molecule is a strained alkyne reactive molecule, or wherein the crosslinks comprise 1- (methyloxidoamino) cyclooctene groups as immolative linkers and the singly reactive molecule is a diboron molecule.

11. The balloon implantation kit of any of claims 7-8, wherein the hydrophilic polymer hydrogel comprises the hydrophilic polymer chains that are crosslinked by crosslinks that contain reversible covalent linkers that incorporate a reactive dimeric linker and wherein the hydrogel cleavage composition contains the singly reactive molecule that acts to break the crosslinks at the position of the dimeric linkers within the crosslinks.

12. The balloon implantation kit of claim 11, wherein each of the reversible covalent linkers each comprises two thioester groups, wherein the singly reactive molecule is a thiol molecule, and wherein the reactive dimeric linker is a bis-thiol linker.

13. The balloon implantation kit of any of claims 1-12, wherein the polymer chains are selected from polyalkylene oxide chains, polyester chains, polyoxazoline chains, polydioxanone chains, polypeptide chains, polypeptoid chains, polyacrylate chains, and polyacrylamide chains or combinations thereof.BSC File No.: 24-0208WO01 Atty. Docket No.: 2001.3638111 14. The balloon implantation kit of any of claims 1-13, wherein the balloon implantation kit further comprising an elongate filling tube that is configured to be removably coupled to the conformable, fillable balloon, the elongate filling tube having a lumen that is configured for fluid communication with an interior of the conformable, fillable balloon, or wherein the balloon implantation kit further comprises an elongate filling tube that is removably coupled to the conformable, fillable balloon, the elongate filling tube having a lumen that is in fluid communication with an interior of the conformable, fillable balloon.

15. The balloon implantation kit of any of claims 1-14, wherein the kit further comprises a delivery sheath.

Images