NON-DEGRADABLE, LOW SWELLING, WATER SOLUBLE RADIOPAQUE HYDROGEL POLYMER

Abstract

Hydrogel compositions prepared from amine components and glycidyl ether components are provided which are biocompatible and suitable for use in vivo due, in part, to their excellent stability.

Claims

1-30. (canceled)

31. A method of forming a material in situ comprising: providing a delivery system comprising: a first container comprising a first water soluble reactive component having a molecular weight between about 200 and about 10,000; a second container comprising a second water soluble reactive component having a molecular weight between about 100 and about 2500; and a delivery tube in fluid communication with the first container and the second container the tube having a first end and a second end; and placing the second end of the delivery tube at a desired space for placement of a solid material; combining the first water soluble reactive component and second water soluble reactive component to form a mixture; introducing the mixture into the first end of the delivery tube; introducing the mixture into the desired space through the delivery tube; and forming a solid material in the mixture, wherein formation of the solid material comprises initiating a chemical reaction of functional groups on said first water soluble reactive component with functional groups on said second water soluble reactive component at a first pH to form said solid material, said chemical reaction consisting essentially of chemical covalent bonding, wherein the mixture comprises a viscosity of between about 20 cp and about 100 cp such that it maintains fluidity upon introduction into the delivery tube in order to travel through the length of the delivery tube, and wherein the solid material comprises a swellability of less than about 30% within about 3 minutes to about 30 minutes of initiating the chemical reaction of the functional groups to form the solid material.

32. The method of claim 31, wherein the first pH is at least about 7.4 to form the solid.

33. The method of claim 31, wherein the mixture remains fluid for more than about 3 minutes after formation.

34. The method of claim 31, wherein the first water soluble reactive component comprises an epoxide moiety.

35. The method of claim 31, wherein the second water soluble reactive component comprises at least two amine moieties.

36. The method of claim 31, wherein the solid material comprises a hydrogel.

37. The method of claim 31, further comprising adding an additive to the mixture to increase the cure rate of the material.

38. The method of claim 31, wherein the first or second container is a syringe.

39. The method of claim 31, comprising forming the solid material inside a mammal.

40. The method of claim 39, wherein the solid material is a bulking agent.

41. A method of forming a material in situ comprising: providing a delivery system comprising: a first container comprising a first water soluble reactive component having a molecular weight between about 200 and about 10,000; a second container comprising a second water soluble reactive component having a molecular weight between about 100 and about 2500; and a delivery tube in fluid communication with the first container or the second container the tube having a first end and a second end; and placing the second end of the delivery tube at a desired space for placement of a solid material; combining the first water soluble reactive component and second water soluble reactive component to form a mixture; introducing the mixture into the first end of the delivery tube; introducing the mixture into the desired space through the delivery tube; and forming a hydrogel material in the mixture, wherein formation of the hydrogel material comprises initiating a chemical reaction of functional groups on said first water soluble reactive component with functional groups on said second water soluble reactive component at a first pH to form said hydrogel material, said chemical reaction consisting essentially of chemical covalent bonding, wherein the mixture comprises a viscosity of between about 10 cp and about 100 cp such that it maintains fluidity upon introduction into the delivery tube in order to travel through the length of the delivery tube, and wherein the solid material comprises a swellability of less than about 30% within about 3 minutes to about 30 minutes of initiating the chemical reaction of the functional groups to form the solid material.

42. The method of claim 41, wherein the first pH is at least about 7.4 to form the solid.

43. The method of claim 41, wherein the mixture remains fluid for more than about 3 minutes after formation.

44. The method of claim 41, wherein the first water soluble reactive component comprises an epoxide moiety.

45. The method of claim 41, wherein the second water soluble reactive component comprises at least two amine moieties.

46. The method of claim 41, wherein the solid material comprises a hydrogel.

47. The method of claim 41, further comprising adding an additive to the mixture to increase the cure rate of the material.

48. The method of claim 41, wherein the first or second container is a syringe.

49. The method of claim 41, comprising forming the solid material inside a mammal.

50. The method of claim 49, wherein the solid material is a bulking agent.

51. A delivery system for forming a material in situ comprising: a first container comprising a first water soluble reactive component having a molecular weight between about 200 and about 10,000; a second container comprising a second water soluble reactive component having a molecular weight between about 100 and about 2500; and a delivery tube in fluid communication with the first container and the second container the tube having a first end and a second end; and the second end of the delivery tube being configured to be placed at a desired space for placement of a solid material; the first water soluble reactive component and second water soluble reactive component are combinable to form a mixture that can flow from the first end of the delivery tube to the second end of the delivery tube to the desired space for placement of the solid material; wherein solid material is formed by initiating a chemical reaction of functional groups on said first water soluble reactive component with functional groups on said second water soluble reactive component at a first pH to form said solid material, said chemical reaction consisting essentially of chemical covalent bonding, wherein the mixture comprises a viscosity of between about 20 cp and about 100 cp such that it maintains fluidity upon introduction into the delivery tube in order to travel through the length of the delivery tube, and wherein the solid material comprises a swellability of less than about 30% within about 3 minutes to about 30 minutes of initiating the chemical reaction of the functional groups to form the solid material.

Description

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

[0035] As used herein, the term “biocompatible” describes the characteristic of a polymer or other material to not have a toxic or injurious effect (i.e., does not cause infection or trigger an immune attack, or adversely affect the biological function in the expected conditions of use) in a mammalian biologic system.

[0036] As used herein, the term “radiopaque” or “contrast agent” is used to describe a material that is not transparent to X-rays or other forms of radiation. Radiopaque materials include but are not limited to sodium iodide, potassium iodide, barium sulfate, gold, tungsten, platinum, metrizamide, iopamidol, iohexol, iothalamate sodium, meglumine, Visipaque 320, Hypaque, Omnipaque 350, Hexabrix and tantalum powder).

[0037] As used herein, the term “embolization device” describes a substance that is introduced into a space, a cavity, or lumen of a blood vessel or other like passageway that partially or totally fills the space or cavity or partially or totally plugs the lumen. For example, an embolic composition can be used for occlusion of a vessel leading to a tumor or fibroid, occlusion of a vascular malformation, such as an arteriovenous malformation, occlusion of a left atrial appendage, as a filler for an aneurysm sac, as an endoleak sealant, as an arterial sealant, as a puncture sealant, or for occlusion of any other lumen such as, for example, a fallopian tube.

[0038] As used herein, the term “lumen” or “luminal” refers to various hollow organs or vessels of the body such as veins, arteries, intestines, fallopian tubes, trachea and the like. Lumen is also used to refer to the tubes present in a catheter system (i.e., “multi-lumen” catheter).

[0039] As used herein, the term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which can be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C.sub.1-C.sub.10 means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds.

[0040] As used herein, the term “does not degrade” or “non-degradable” refers to the characteristic of a substance, such as a polymeric material, to resist being physically, chemically, or enzymatically decomposed (metabolized) into smaller molecular weight fragments, in a physiological environment to a degree that it impacts the function or biocompatibility of the material. Generally, a composition that does not degrade in an in vivo environment is one that is stable in aqueous pH 10 solution for at least 18 days which is equivalent to 10 years in vivo. The amount of degradation will typically be less than about 5% by weight, more preferably less than 4%, still more preferably less than 2%, even more preferably less than 1%, and most preferably less than about 0.5% by weight, relative to the overall weight of the polymer composition.

[0041] As used herein, the term “weight percent” refers to the mass of one component used in the formulation of a polymer composition divided by the total mass of the polymeric product and multiplied by 100%.

EMBODIMENTS OF THE INVENTION

I. Compositions

[0042] In one aspect, the present invention provides hydrogel polymer compositions that are biocompatible, pose no embolic risk, are non-degradable, and are stable in blood contact for >10 years. The gel compositions of the present invention are suitable for a variety of in vivo applications, including but not limited to, use in an intraluminal graft, as a luminal embolization device, in an inflatable occlusion member, and as a tissue bulking device, among others.

[0043] In its broadest concept, the hydrogel polymer compositions of the present invention are formed from at least two monomer components, i.e., a diamine and a polyglycidyl ether. The resulting gel composition of the invention does not contain a hydrolyzable group such as an ester group or amide group, among others. As a result, the present compositions exhibit increased stability in a physiological environment, and reduce the likelihood of breakdown in vivo.

[0044] Turning first to the diamine component of the present compositions, a suitable diamine monomer can be essentially any diamine compound in which each nitrogen atom is independently either an amino or an alkylamino group, and is sterically free to react with an epoxide moiety on a polyglycidyl ether. Typically, the diamine monomer has a molecular weight of between about 100 to about 2500; and in certain embodiments the diamine monomer is biocompatible. In one group of embodiments, the diamine is a polyoxyalkylene compound having amino or alkylamino termini. In a preferred embodiment, the polyoxyalkylene compound has amino termini. Suitable diamine monomers for the hydrogel polymer composition include, but are not limited to, polyethylene glycol diamine (also referred to as PEG-diamine or O,O′-Bis(2-aminoethyl)polyethylene glycol; CAS No. 24991-53-5), di-(3-aminopropyl) diethylene glycol (also referred to as O,O′-Bis(3-aminopropyl)diethylene glycol, diethylene glycol di-(3-aminopropyl)ether or 3-{2-[2-(3-Amino-propoxy)-ethoxy]-ethoxy}-propylamine; CAS No. 4246-51-9), polyoxypropylenediamine (available from Huntsman Performance Products, Texas, USA; CAS No. 9406-10-0), polyetherdiamine (available from Huntsman Performance Products, Texas, USA; CAS No. 194673-87-5), polyoxyethylenediamine (available from Huntsman Performance Products, Texas, USA; CAS No. 65605-36-9), triethyleneglycol diamine (also known as 3,6-dioxa-octamethylenediamine; CAS No. 929-59-9), and mixtures thereof. In one embodiment, the diamine compound is di-(3-aminopropyl) diethylene glycol (available from Aldrich Chemical Company, Wisconsin, USA). In another embodiment, the diamine is a mixture of polyethylene glycol (400) diamine (available from Polypure Inc., Oslo, Norway; or from Tomah Inc., Wisconsin, USA) and di-(3-aminopropyl)diethylene glycol. In yet another embodiment, the diamine a mixture of polyoxyethylenediamine and di-(3-aminopropyl)diethylene glycol. Other suitable diamine monomers for the present composition will be apparent to those skilled in the art.

[0045] A second component for the gels of the present invention is a polyglycidyl ether. As used herein, the polyglycidyl ether monomer is any compound possessing at least two glycidyl ether functional groups, and preferably at least three glycidyl ether functional groups. In some embodiments, the polyglycidyl compound has at least two glycidyl ether groups and a molecular weight between 100 and 2000. Polyglycidyl ethers having two glycidyl ether groups are alternatively referred to in the art as diglycidyl ethers; while polyglycidyl ethers having three glycidyl groups are referred to as triglycidyl ethers. In most embodiments of the present invention, the polyglycidyl ether is biocompatible. Suitable polyglycidyl ethers for use in the composition include, but are not limited to, bis[4-(glycidyloxy)phenyl]methane (CAS No. 2095-03-6), 2,2-bis[4-(glycidyloxy)phenyl]propane (CAS No. 1675-54-3), bisphenol A propoxylate diglycidyl ether (CAS No. 106100-55-4), 1,4-butanediol diglycidyl ether (CAS No. 2425-79-8), 1,3-butanediol diglycidyl ether (CAS No. 3332-48-7), 1,4-cyclohexanedimethanol diglycidyl ether (CAS No. 14228-73-0), diethylene glycol diglycidyl ether (CAS No. 4206-61-5), ethylene glycol diglycidyl ether (CAS No. 2224-15-9 and CAS No. 72207-80-8), glycerol diglycidyl ether (CAS No. 27043-36-3), neopentyl glycol diglycidyl ether (CAS No. 17557-23-2), poly(dimethylsiloxane)-diglycidyl ether terminated (CAS No. 130167-23-6), polyethylene glycol diglycidyl ether (CAS No. 26403-72-5), poly(propylene glycol) diglycidyl ether (CAS No. 26142-30-3), resorcinol diglycidyl ether (CAS No. 101-90-6), sorbitol polyglycidyl ether (CAS No. 68412-01-1), polyglycerol polyglycidyl ether, pentaerythritol polyglycidyl ether (CAS No. 3126-63-4), diglycerol polyglycidyl ether (CAS No. 68134-62-3), glycerol polyglycidyl ether (CAS No. 25038-04-4), polyproylene glycol diglycidyl ether (CAS No. 26142-30-3), resorcinol diglycidyl ether (CAS No. 101-90-6), glycidyl ester ether of p-hydroxy benzoic acid (CAS No. 7042-93-5), neopentyl glycol diglycidyl ether (CAS No. 17557-23-2), 1,6-hexanediol diglycidyl ether (CAS No. 16096-31-4), bisphenol A (PO).sub.2 diglycidyl ether (available from Nagase ChemteX Corp., Osaka, Japan), o-phthalic acid diglycidyl ester (CAS No. 7195-45-4), hydroquinone diglycidyl ether (CAS No. 2425-01-6), bisphenol S diglycidyl ether (CAS No. 13410-58-7), terephthalic acid diglycidyl ester (CAS No. 7195-44-0), trimethylolpropane triglycidyl ether (CAS No. 30499-70-8), glycerol propoxylate triglycidyl ether (CAS No. 37237-76-6), trimethylolethane triglycidyl ether, triphenylolmethane triglycidyl ether (CAS No. 106253-69-4), as well as mixtures thereof. Other polyglycidyl ethers suitable for use in the present invention will be apparent to one skilled in the art.

[0046] In one embodiment, the polyglycidyl ether is a mixture of trimethylolpropane triglycidyl ether and polyethylene glycol diglycidyl ether (both available from Aldrich Chemical Company, Wisconsin, USA). In another embodiment, the polyglycidyl ether is a mixture of polyethylene glycol (600) diglycidyl ether (available from Polysciences, Inc., Pennsylvania, USA) and trimethylolpropane triglycidyl ether. In yet another embodiment, the polyglycidyl ether is a sorbitol polyglycidyl ether (available from Nagase ChemteX Corp., Osaka, Japan). In yet another embodiment, the polyglycidyl ether is a mixture of sorbitol polyglycidyl ether and polyglycerol glycidyl ether. In yet another embodiment, the polyglycidyl ether is a mixture of pentaerythritol polyglycidyl ether and trimethylolpropane polyglycidyl ether. One of skill in the art will appreciate that the properties of the resultant gel composition can be carefully controlled by varying the amount of polyglycidyl ether or combinations of polyglycidyl ethers to control the amount of cross-linking in the gel, the hydrophilic or hydrophobic character of the gel, as well as the cure time and viscosity of the pre-cure combination.

[0047] Optionally, the hydrogel polymer comprises at least one radiopaque material. Radiopaque materials suitable for the present invention include but are not limited to sodium iodide, potassium iodide, barium sulfate, gold, tungsten, platinum, Visipaque 320, Hypaque, Omnipaque 350, Hexabrix, metrizamide, iopamidol, iohexol, iothalamate sodium, meglumine, gold and tantalum powder. In some instances, it is preferable to use a blend of radiopaque material, as is in the case when it desired that the gel composition loses radiopacity over time. For instance, a blend of a soluble contrast agent such as an iodinated aqueous solution and an insoluble contrast agent such as barium sulfate can serve this purpose. The soluble contrast agent will leach out of the composition resulting in a progressive decrease in radiopacity of the composition over time.

[0048] The utility of the inventive gel compositions for many in vivo applications is attributed, in part, to the ease in which the mechanical properties of the pre- and post-cure gel composition can be modified, as noted above, simply through the judicious selection of the diamine and polyglycidyl ether components, and the curing conditions. For example, the cure rate is affected, in part, by the molecular weight of the monomer components used, and the concentration of the curing solution. In more detail, using a polyglycidyl ether having more glycidyl ether groups per monomer unit will provide a faster cure rate; using a higher concentration of monomer components in the pre-cure gel composition will provide a faster cure rate; and having a higher pH composition will provide a faster cure rate. Other methods of modifying the cure rate of the inventive composition will be readily apparent to a skilled artisan.

[0049] In another example, the firmness/hardness property of the final gel composition will be determined, in part, by the hydrophilic/hydrophobic balance of the monomer components. A higher proportion of hydrophobic monomers can provide a firmer gel composition. The firmness is also affected by the molecular weight of the monomer (i.e., a lower molecular weight provide a firmer gel), and the length of the monomer backbone of the polyglycidyl ether component (i.e., shorter polyglycidyl ether backbone provides a firmer gel). Other methods of modifying the hardness/firmness property of the final gel composition will be readily apparent to a skilled artisan.

[0050] In one embodiment, the composition comprises a hydrophilic diamine and a hydrophilic polyglycidyl ether. In another embodiment, the composition comprises a hydrophilic diamine and a hydrophobic polyglycidyl ether. In yet another embodiment, the composition comprises a hydrophobic diamine and a hydrophilic polyglycidyl ether.

[0051] The gel composition can optionally incorporate water or another aqueous fluid to result in increased volume (or swelling) of the final gel composition. The swelling of the final gel composition is inversely related to the firmness of the final gel. Depending of the proposed application, it is desirable that the inventive gel swells less than about 30 percent. In certain applications, such as in a embolization device, minimal swelling can be preferred.

[0052] The hydrogel polymer composition can optionally comprise various additives that can alter the mechanical or physical properties of the pre- or post-cure gel composition, e.g., to increase cure rate, to reduce viscosity, to introduce radiopacity. In one illustrative example, hydroxide can be added to the pre-cure gel mixture to catalyze rate of formation (cure rate) of the hydrogel polymer. In another illustrative example, fumed silica can be added to the pre-cure gel mixture to give it a thixiotropic character desirable for certain embolization applications. Other comonomers and additives can be incorporated to the gel composition to alter the thermoresponsiveness, elasticity, adhesiveness and hydrophilicity of the final gel composition.

[0053] Optionally, the gel compositions of the present invention can be used to deliver drugs to the target site. The drugs can be mixed in or attached to the gel composition using a variety of methods. Some exemplary drugs and methods for attaching the drugs to the embolic composition are described in J. M. Harris, “Laboratory Synthesis of Polyethylene Glycol Derivatives,” Journal of Macromolecular Science-Reviews in Macromolecular Chemistry, vol. C-25, No. 3, pp. 325-373, Jan. 1, 1985; J. M. Harris, Ed., “Biomedical and Biotechnical Applications of Poly(Ethylene Glycol) Chemistry”, Plenum, N.Y., pp. 1-14, 1992; Greenwald et al., “Highly Water Soluble Taxol Derivatives: 7-Polyethylene Glycol Carbamates and Carbonates:”, J. Org. Chem., vol. 60, No. 2, pp. 331-336, 1995, Matsushima et al., “Modification of E. Coli Asparaginase with 2,4-Bis(O-Methoxypolyethylene Glycol)-6-Chloro-S-Triazine (Activated PEG.sub.2); Disappearance of Binding Ability Towards Anti-Serum and Retention of Enzymic Activity,” Chemistry Letters, pp. 773-776, 1980; and Nathan et al., “Copolymers of Lysine and Polyethylene Glycol: A New Family of Functionalized Drug Carriers,” Bioconjugate Chem. 4, 54-62 (1993), each of which are incorporated herein by reference in its entirety.

[0054] As previously stated, the selection of monomer components for the gel composition will depend largely on the desired physical properties of the pre-cure monomer mixture and the final gel material, which is in turn is dependent on its intended application in vivo. Specific uses for the gels of the present invention (including preferred monomers and amounts of monomers) are provided below as select embodiments of the invention.

Stent Graft or Intralumenal Graft:

[0055] The present gel compositions are useful in a polymeric stent-graft or intraluminal graft (e.g., as described in U.S. Pat. No. 6,395,019) located in a mammal for the purpose of inflating the channels and cuffs of the graft to conform to the morphology of the lumen, and to impart sufficient strength to the graft to resist to kinking. As used herein, the term “stent graft” interchangeably refers to inflatable intraluminal grafts as well as inflatable intraluminal stent grafts. For application in a stent graft or intraluminal device, it is preferable that the pre-cure gel composition comprise monomer components that are hydrophilic and biocompatible so as to minimize the embolic risk and toxicity that can result in the event of accidental release of the monomeric components in the bloodstream during addition of the pre-cure composition into the stent graft. Should accidental release occur, normal blood flow would then rapidly disperse the monomeric components and their concentration would fall below the level required to form a solid. Preferably, the pre-cure gel composition is soluble for at least 3 minutes in the bloodstream; more preferably for at least 5 minutes; even more preferably for at least 8 minutes or until just before cure.

[0056] In a stent graft application, it is less desirable for the gel composition to cure quickly as the pre-cure mixture should remain fluid in order to travel through a delivery tube into the stent graft. After the addition of the gel composition to the stent-graft, it is preferable for the graft to remain initially less rigid, so that the filled graft material can adjust and conform to the morphology of the vessel or lumen space. In one embodiment, the gel composition has a cure time from about 5 minutes to about 20 minutes. In another embodiment, the cure time is from about 10 to about 17 minutes. As stated above, it is beneficial for the pre-cure composition be a flowable solution that can be delivered through a delivery tube (e.g., catheter, syringe). In one embodiment, the viscosity of the pre-cure mixture is between about 10 to about 500 cp (centipoise). In another embodiment, the viscosity of the pre-cure mixture is between about 20 to about 100 cp, more preferably about 30 cp.

[0057] After curing, the gel composition maintains its biocompatibility and is stable in the event of contact with blood. The cured gel composition provides desirable mechanical properties such as, an elastic modulus between about 60 and about 500 psi, more preferably about 100 to about 400 psi, even more preferably about 200 to about 300 psi. Still further, the gel compositions that are used in stent-graft will typically be low swelling compositions and exhibit a volume change upon curing between about 0 to about 30 percent. As can be appreciated the pre-cure properties and post-cure properties of the gel composition described above are merely examples and should not limit the scope of the present invention.

[0058] The inventive gel composition in a stent graft typically show little or no volume change after curing. In one embodiment, the gel composition swells or shrinks less than about 20 percent after curing and hydration. In another embodiment, the gel composition swells or shrinks less than about 10 percent after curing and hydration. In yet another embodiment, the gel composition swells or shrinks less than 5 percent after curing and hydration. Low volume change of the gel mixture after curing and hydration is important in a stent graft material application. Excessive volume change of the hydrogel polymer after curing and hydration can adversely affect the strength of the graft material located inside the body lumen, and possibly jeopardize the safety of the mammal.

[0059] The hydrogel polymer can be comprised of any diamine or mixture of thereof; however, in one embodiment, the diamine or mixture thereof is a hydrophilic diamine. In another embodiment, the diamine monomer is selected from the group consisting of polyoxyethyleuediamine, triethyleneglycol diamine, polyethylene glycol diamine, di-(3-aminopropyl)diethylene glycol, or a mixture thereof. It is desirable that the polyglycidyl ether component is also hydrophilic. In one embodiment, the polyglycidyl ether component is a mixture of a diglycidyl ether and a triglycidyl ether. In another embodiment the polyglycidyl ether component is mixture of polyethylene glycol diglycidyl ether and trimethylolpropane triglycidyl ether. In yet another embodiment, the polyethylene glycol diglycidyl ether is polyethylene glycol (600) diglycidyl ether. Furthermore, the hydrogel polymer can comprise a radiopaque material. In one embodiment, the radiopaque material is sodium iodide.

[0060] In one embodiment, the diamine is present in an amount of between about 4 to about 20 weight percent of the hydrogel polymer; and the polyglycidyl ether is present in an amount of between about 15 to about 60 weight percent of the hydrogel polymer. In another embodiment, diamine is present in an amount of between about 5 to about 15 weight percent of said polymer; and the polyglycidyl ether is present in an amount of between about 25 to about 40 weight percent of the hydrogel polymer.

[0061] In yet another embodiment, the diamine is di-(3-aminopropyl)diethylene glycol; the polyglycidyl ether is a mixture of polyethylene glycol diglycidyl ether and trimethylolpropane triglycidyl ether; and the radiopaque material is selected from the group consisting of sodium iodide, potassium iodide, barium sulfate, Visipaque 320, Hypaque, Omnipaque 350 and Hexabrix.

Embolic Compositions

[0062] In addition to the stent graft embodiments above, the present gel compositions can be constructed for use as an embolization device. Embolization devices block or obstruct flow through a body lumen. Numerous clinical applications exist for embolization of both vascular and nonvascular body lumens. The most prevalent uses for an embolization device include, but are not limited to, the neurological treatment of cerebral aneurysms, AVMs (arteriovenous malformations) and AVFs (arteriovenous fistula), and the peripheral treatment of uterine fibroids and hypervascular tumors. However, embolization devices are also useful in a variety of vascular or non-vascular body lumens or orifices, such as the esophagus, genital-urinary lumens, bronchial lumens, gastrointestinal lumens, hepatic lumens, ducts, aneurysms, varices, septal defects, fistulae, fallopian tubes, among others. Moreover, it should be appreciated that the gel composition as an embolization device can be used in conjunction with other components, such as endovascular grafts, stents, inflatable implants, fibers, coils, and the like. Other applications of embolization devices are described in co-pending U.S. patent application Ser. No. 11/031,311, titled “Methods, Materials, and Devices for Embolizing Body Lumens” to Whirley et al., the disclosure of which is incorporated herein by reference in its entirety.

[0063] For application in an embolic composition, it is preferable that the pre-cure gel composition is biocompatible and exhibit controllable solubility which is independent of the environment in which the embolic composition is delivered (e.g., in blood or other body fluid). More specifically, as the pre-cure gel mixture will be applied directly to the site for occlusion, in one aspect, it is be desirable for the pre-cure composition to be less soluble in blood or other body fluid and to remain relatively localized at the site of administration. In other embodiments, it is be desirable for the pre-cure gel composition to disperse through the vasculature as to provide a complete “cast” of a segment of the arterial tree after the gel composition cures (such as for a hypervascular tumor or an AVM), thereby reducing the opportunity for development of collateral perfusion. Typically, the present hydrogel polymer in an embolic application has a viscosity of 100 cp or higher, a controllable hydrophobicity and a faster cure rate than the compositions described above.

[0064] Applicants have found that for embolization applications it is desirable to increase the viscosity and hydrophobicity of the uncured material and thereby facilitate controlled placement without unintended embolization of distal vascular beds. This can be accomplished by reducing or eliminating saline or water from the gel composition. Reducing the saline and water prior to curing has been found to achieve the best viscosity for delivery into the body lumen, maximizes the degradation resistance of the cured polymer and maximizes the cohesiveness and hydrophobicity of the gel material.

[0065] Low viscosity formulations of the gel composition can also be used to deeply penetrate tumor vascular beds or other target embolization sites prior to curing of the composition. Occlusion balloons (such as a Swan-Ganz dual-lumen catheter or the EQUINOX™ Occlusion Balloon Catheter manufactured by Micro Therapeutics, Inc. of Irvine, Calif.) or other ancillary flow-blocking devices, such as brushes or other obstructive devices, some of which can be placed on a catheter or stent, such as those sometimes placed across a cerebral aneurysm to be embolized, can be used to prevent flow of the embolic composition beyond the target embolization site.

[0066] High viscosity and/or thixotropic (shear-thinning) formulations of these compositions can be used to limit the flow to the neighborhood of the delivery catheter and to facilitate the tendency of the gel composition to remain in the vicinity of the location in which it was delivered, sometimes even in the presence of substantial blood flow or other forces. Viscosity and/or thixotropy characteristics can be increased by adding bulking and/or thixotropic agents, such as fumed silica. The bulking agent can be added anytime during the formation of the gel composition, but is typically preloaded with one of the components, and preferably preloaded with the monomer/polymer or buffer solution.

[0067] Some examples of additives that are useful include, but are not limited to, sorbitol or fumed silica that partially or fully hydrates to form a thixotropic bulking agent, and the like. Desirable viscosities for the pre-cure gels range from about 5 centipoise (cP) for a low-viscosity formulation (such as might be used to deeply penetrate tissue in a hypervascular tumor) up to about 1000 cP or higher for a higher viscosity formulation (such as might be used to treat a sidewall cerebral aneurysm while minimizing the chance of flow disturbance to the embolic composition during the curing process). As can be appreciated, other embodiments of gels can have a higher or lower viscosity, and the gel composition is not limited to such viscosities as described above.

[0068] After curing, the embolic composition maintains its high biocompatibility and is stable in blood. The cured embolic composition provides desirable mechanical properties such as, a specific gravity between 1.15 to over 1.4, an elastic modulus between about 30 and about 500 psi, a strain to failure of about 25 percent to about 100 percent or more, a volume change upon curing between about 0 percent to about 200 percent or more, and a water content between less than 5 percent to greater than about 60 percent. In one embodiment, the volume change of the gel composition upon curing is less than about 20 percent. As can be appreciated the pre-cure properties and post-cure properties of the gel composition described above are merely examples and should not limit the scope of the embolic compositions of the present invention. The gel composition of the present invention can be modified to provide other pre-cure and post-cure mechanical properties, as desired.

[0069] The hydrogel polymer can be comprised of any diamine or mixture of thereof; however, in one embodiment, the diamine or mixture thereof is a hydrophilic diamine. In another embodiment, the diamine is a hydrophobic diamine. The polyglycidyl ether can be hydrophilic or hydrophobic. In one embodiment, in the gel composition, a hydrophilic diamine will be paired with a less water-soluble, hydrophobic polyglycidyl ether. Alternatively, in another embodiment, in the gel composition, a more water-soluble hydrophilic polyglycidyl ether will be paired with a more hydrophobic diamine. The selection of suitable diamine and polyglycidyl ether components for the purpose of modify the mechanical properties of the pre-cure or the post-cure composition will be readily apparent to a skilled artisan. For example, to increase the firmness of the final gel composition, a polyglycidyl ether, such as a triglycidyl ether, which functions as a crosslinking agent, can be included in the composition. A skilled artisan will also recognize that the firmness of the formed gel composition will also be determined in part by the hydrophobic and hydrophilic balance of the monomer components, e.g., a higher hydrophobic percent provides a firmer hydrogel. In one embodiment, the diamine component is selected form the group consisting of di-(3-aminopropyl)diethylene glycol, polyoxyethylenediamine and, and a mixture thereof. In another embodiment, the polyglycidyl ether is selected from the group consisting of sorbitol polyglycidyl ether, polyglycerol polyglycidyl ether, trimethylolpropane triglycidyl ether, and mixtures thereof. In another preferred embodiment, the gel composition includes a radiopaque agent.

[0070] In one embodiment, the diamine is present in an amount of between about 7 to about 60 weight percent of the hydrogel polymer; and the polyglycidyl ether is present in an amount of between about 7 to about 55 weight percent of the hydrogel polymer. In another embodiment, diamine is present in an amount of between about 10 to about 45 weight percent of said polymer, and the polyglycidyl ether is present in an amount of between about 14 to about 35 weight percent of the hydrogel polymer.

[0071] In one embodiment, the diamine is present in an amount of between about 5 to about 30 weight percent of the hydrogel polymer, and the polyglycidyl ether is present in an amount of between about 40 to about 90 weight percent of the hydrogel polymer. In another embodiment, diamine is present in an amount of between about 50 to about 75 weight percent of said polymer; and the polyglycidyl ether is present in an amount of between about 10 to about 20 weight percent of the hydrogel polymer.

[0072] In yet another embodiment, the diamine is di-(3-aminopropyl)diethylene glycol; and the polyglycidyl ether is a mixture of pentaerythritol polyglycidyl ether and trimethylolpropane polyglycidyl ether; and the radiopaque material is sodium iodide.

[0073] In yet another embodiment, the diamine is a mixture of di-(3-aminopropyl)diethylene glycol and polyoxyethylenediamine; the polyglycidyl ether is sorbitol polyglycidyl ether, and the radiopaque material is selected from the group consisting of sodium iodide, potassium iodide, barium sulfate, Visipaque, Hypaque, Omnipaque, and Hexabrix.

Tissue Bulking Device and Inflatable Occlusion Member:

[0074] The present gel compositions are useful for in vivo application in an inflatable occlusion member and as a tissue bulking device. The gel composition are useful in vivo in a number of tissue bulking applications (e.g., aiding functionality of various organs or structures, such as assisting in closing a stricture (including restoring competence to sphincters to treat fecal or urinary incontinence or to treat gastroesophageal reflux disease (GERD)), augmentation of soft tissue in plastic or reconstructive surgery applications (e.g., chin or cheek reshaping), replacing or augmenting herniated or degenerated intervertebral disks. The pre-cure composition can be directly contacted with the tissue material; or can be introduced into an inflatable bag located in vivo. Alternatively, the pre-cure gel mixture can be added to an inflatable bag ex vivo, followed by placement of the bag inside the body.

[0075] It is preferable for the pre-cure gel composition to be biocompatible and exhibit controllable solubility which is independent of the environment in which the pre-cure mixture is delivered (e.g., in blood or other body fluid). More specifically, it is desirable for the pre-cure composition to be less soluble in blood or other body fluid and to remain relatively localized at the site of administration. Alternatively, in some embodiments, it is desirable for the pre-cure gel composition to diffuse to an in vivo site distal to the point of administration. Typically, the hydrogel polymer in a tissue bulking application has a viscosity of 100 cp or higher and controllable hydrophobicity. The solubility of the pre- and post-cure composition of the invention can be modified by any means known to one skilled in the art (e.g., through the choice of the hydrophobic or hydrophilic monomer components).

[0076] Preferably, the gel composition will have a cure time that is long enough to allow the gel composition to fill and conform to the cavity to which it is administered and/or long enough so that a medical professional can sculpt or otherwise shape the composition prior to the completion of the gelling process. In one embodiment, the gel composition has a cure time of from about 10 seconds to about 30 minutes depending on its intended site of administration. In another embodiment, the gel composition has a cure time of between about 30 seconds to about 2 minutes.

[0077] After curing, the gel composition remains biocompatible and is stable in blood. The cured polymer provides desirable mechanical properties such as, an elastic modulus between about 30 and about 500 psi, a strain to failure of about 25 percent to about 100 percent or more, a volume change upon curing between about 0 to about 30 percent or more, and a water content of about less than 60 percent. The volume change of the cured composition is preferably less than about 15 percent, and more preferably less than about 10 percent. As can be appreciated the pre-cure properties and post-cure properties of the gel composition in an embolic application described above are merely examples and should not limit the scope of the gel compositions of the invention. In one embodiment, the gel time is between about 30 seconds to about 25 minutes. In another embodiment, the gel time is between about 1 to about 3 minutes.

[0078] The hydrogel polymer can be prepared from any diamine or mixture thereof (as described generally above). However, in one embodiment, the diamine or mixture thereof is a hydrophilic diamine. In another embodiment, the diamine is a hydrophobic diamine. Similarly, the polyglycidyl ether can be hydrophilic or hydrophobic. In one embodiment, in the gel composition, a hydrophilic diamine will be paired with water-soluble, hydrophilic polyglycidyl ether. In another embodiment, the diamine is di-(3-aminopropyl)diethylene glycol. In another embodiment, the polyglycidyl ether is sorbitol polyglycidyl ether. In yet another embodiment, the gel composition comprises a radiopaque agent. In yet another embodiment, the radiopaque agent is Omnipaque, Visipaque, or a combination thereof. In yet another embodiment, the diamine is di-(3-aminopropyl)diethylene glycol; the polyglycidyl ether is sorbitol polyglycidyl ether; and the radiopaque material is a mixture of Visipaque and Omnipaque.

[0079] In one embodiment, the diamine is present in an amount of between about 4 to about 20 weight percent of the hydrogel polymer, and the polyglycidyl ether is present in an amount of between about 15 to about 60 weight percent of the hydrogel polymer. In another embodiment, diamine is present in an amount of between about 5 to about 15 weight percent of said polymer; and the polyglycidyl ether is present in an amount of between about 25 to about 40 weight percent of the hydrogel polymer.

Preparation of the Polymeric Hydrogels:

[0080] The gel composition can be made by combining the monomeric components in any order, as well as any additional monomers (comonomers) and other additives, under conditions suitable for formation of the polymer. The reaction is carried out in a suitable solvent; that being any solvent that dissolves the monomer components. For example, water, alcohols, such as ethanol or methanol, also carboxylic amides, such as dimethylformamide, dimethylsulfoxide, and also a mixture thereof, are all solvents suitable for the reaction to make the hydrogel polymer. In one embodiment, the reaction is carried out in a substantially aqueous solution, e.g., in a basic sodium hydroxide solution (pH=7.4). Alternatively, the reaction can be carried out in under anhydrous conditions. Additionally, the skilled artisan will recognize that the mechanical properties of the final hydrogel product can be modified by changing at least the following variables: the choice of monomer components, the ratio of the monomer components (e.g. high or low molecular weight monomers), the concentration of the monomer(s), the pH of the reaction medium, the reaction time, and the rate of addition of the individual monomer components. For example, adding a triglycidyl ether in the composition, which can function as a crosslinking agent, can result in a gel material having increased hardness. Details are provided in the examples below to guide one of skill in the art in the preparation of the present gel compositions.

II. Method of Use

[0081] The hydrogel composition of the invention can be used in any medical application, in which the presence of a non-degradable, biocompatible hydrogel polymer is desired. More specifically, the present invention is particularly suited for applications that benefit from the in situ gelling characteristics. The present gel composition is especially useful in an inflatable occlusion member, an intraluminal graft, a tissue bulking device, and an embolization device.

[0082] In one aspect of the invention, the gel composition can be used in an in vivo environment, for example, as an intraluminal graft, such as, in a polymeric stent graft, as described in U.S. Pat. No. 6,395,019, the entirety of which is incorporated herein by reference, to improve the mechanical integrity of the stent graft. The '019 patent, describes that monomer components are added into the cuffs and channels of a stent graft, which upon curing, the final gel composition imparts additional strength to and conforms to the stent graft sealing cuffs.

[0083] In another aspect of the invention, the gel composition is also be useful as a tissue bulking (augmentation) device, such as, for augmentation of dermal support within intradermal or subcutaneous regions for the dermis, for breast implants, or for sphincter augmentation (i.e., for restoration of continence), among others. In this application, the pre-cure gel composition can be added to an inflatable bag located inside the body, or the pre-cure gel composition can be added to an inflatable bag ex vivo, which is then placed inside the body.

[0084] In yet another aspect of the invention, the gel composition can be formed directly on the tissue surface in an in vivo environment. Medical applications in which direct contact of body tissue with the inventive material is beneficial include, but are not limited to, as a puncture or wound sealant, and as an embolization device.

[0085] In one aspect, the gel composition can be used as an embolization device to form a plug for a variety of biological lumens. The compositions can be used to occlude blood vessels and other body lumens, such as, fallopian tubes and vas deferens, filling aneurysm sacs, and as arterial sealants. The embolization of blood vessels is useful for a number of reasons; to reduce the blood flow and encourage atrophy of tumors such as in the liver; to reduce blood flow and induce atrophy of uterine fibroids; for the treatment of vascular malformations, such as AVMs and AVFs; to seal endoleaks in aneurysm sacs; to stop uncontrolled bleeding; and to slow bleeding prior to surgery.

Method of Delivery:

[0086] The gel composition can be delivered to an in vivo site using any delivery devices generally known to those skilled in the art. The selection of the delivery device will depend on a number of factors, including the location of the in vivo site and whether a quick or slow curing gel is desired. In most cases, a catheter or syringe is used. In some cases, a multi-lumen catheter is used to deliver the hydrogel composition to the intended in vivo location, wherein the components of the composition are maintained in separate lumens until the time of administration. For example, a polyglycidyl ether component can be delivered in the first lumen, while the diamine compound is delivered through a second lumen. A third lumen can be used to deliver a contrast agent or other comonomers and/or additives to the in vivo site.

[0087] Alternatively, the components of the gel composition can be added to a multi-barrel syringe, wherein the barrels of the syringe are attached to a multi-pronged connector which is fitted to a spiral mixer nozzle (e.g., static mixer). As the components of the composition are pressed out of the syringe, they mix together in the nozzle and can be directly applied to tissue as needed in a relatively uniform, controlled manner. Additionally, the mixed components can be injected directly into tissue if the nozzle is further connected to a needle.

[0088] Injectable reaction mixture compositions also could be injected percutaneously by direct palpation, such as, for example, by placing a needle inside the vas deferens and occluding the same with the injected embolizing composition, thus rendering the patient infertile. The composition can be injected with fluoroscopic, sonographic, computed tomography, magnetic resonance imaging or other type of radiologic guidance. This would allow for placement or injection of the in situ formed hydrogel either by vascular access or percutaneous access to specific organs or other tissue regions in the body.

[0089] The gel composition can be added to a stent-graft in an in vivo environment. For example, one method for inflating a stent graft in such an environment is as follows: after the graft has been placed in the patient's body, and it is time to inflate the graft, the monomer components which are contained in a sterile kit having separate syringes for each monomer or mixtures thereof and also a timer, will be thoroughly mixed to begin the curing process. The contents are then transferred to one of the syringes and that syringe is attached to an autoinjector which is connected to a tube that is in turn connected to a biopolymer delivery tube located on the proximal end of the catheter. At the appropriate time, the autoinjector is turned on and the contents of the syringe is moved through the tube in the catheter that is connected on the distal end to a port on the graft where it enters the series of cuffs and channels to inflate the graft material.

[0090] Additional methods of delivering the composition to an in vivo site are also described in co-pending U.S. application Ser. No. 11/031,311

[0091] The following examples are meant to illustrate certain embodiments (e.g., stent graft fill, embolic composition, and tissue bulking compositions) of the invention and should not be construed in any way as limiting the invention.

EXAMPLES

Abbreviations Used:

[0092] PEGGE: Polyethylene glycol glycidyl ether
TPTE: Trimethylolpropane triglycidyl ether
DCA or DCA-221: Di-(3-aminopropyl)diethylene glycol
cc: milliliters
DI: deionized water
1.5 N Gly-Gly: 1.5 N Glycine-glycine buffer
EX-411: pentaerythritol polyglycidyl ether
EX-321: trimethylpropane polyglycidyl ether (CAS No. 30499-70-8)

PBS: Phosphate Buffered Saline

Example 1

[0093] The following table shows formulations (1-7) that are useful, in one aspect of the invention, as stent graft fill material. These formulations can also find utility for other in vivo applications that require a hydrogel polymer having the properties as shown in Table 1.

TABLE-US-00001 TABLE 1 Wt % % Weight of Mol # of Gel % Wt Notes Formulation Material (g) Total Wt mmoles Time Swelling Gain Observations 1 Nal (50%) pH 9.00 59.0 20 cc, 4.00 10.50% 5.2 Hard 7.40 min; 1 cc, material PEGGE 2.25 14.8 600 3.75 12 min TPTE 2.50 16.4 302 8.28 DCA221 1.50 9.8 222.00 6.76 2 Nal (50%) pH 9.00 57.1 20 cc, 4 7 0.8 Hard 7.40 min; 1 cc, material PEGGE 2.25 14.3 600 3.75 12 min TPTE 3.00 19.0 302 9.93 DCA221 1.50 9.5 222.00 6.76 3 Nal (50%) pH 9.00 55.4 20 cc, 3.40 7 1.4 Hard 7.40 min; 1 cc, material PEGGE 2.25 13.8 600 3.73 11.20 min Epoxy Aldrich 3.50 21.5 302 11.59 DCA221 1.50 9.2 222.00 6.76 4 Nal (50%) pH 9.00 53.7 20 cc, 3.40 5.6 0.4 Hard 7.40 min; 1 cc, material PEGGE 2.25 13.4 600 5.25 11.20 min TPTE 4.00 23.9 302 13.25 DCA221 1.50 9.0 222.00 6.76 5 Nal (50%) pH 10.00 53.0 20 cc, 3.40 5.6 0 Hard 7.40 min; 1 cc, material PEGGE 2.25 13.0 600 3.75 11.20 min TPTE 3.50 20.3 302 11.59 DCA221 1.50 8.7 222.00 6.76 6 Nal (50%) pH 10.00 59.7 20 cc, 4.40 7 0 Hard 7.40 min; 1 cc, material PEGGE 2.25 13.4 600 3.75 12 min TPTE 3.00 17.9 302 6.93 DCA221 1.50 9.0 222.00 6.76 7 Nal (50%) pH 10.00 55.6 20 cc, 4.30  1.20% −14% Hard 7.40 min; 1 cc, material PEGGE 2.25 12.5 600 3.75 11.40 min TPTE 3.50 19.4 302 11.59 DCA221 1.50 8.3 222.00 6.76 PBS 0.75 4.2

Example 2

[0094] The following table shows formulations (8-15) that are useful, in one aspect of the invention, as a stent graft fill material. These formulations can also find utility for other in vivo applications that require a hydrogel polymer having the properties as shown in Table 2.

TABLE-US-00002 TABLE 2 Gel Weight Time Gel Observations Mol # of % 20 Times Notes Formulation Material Weight Wt mmoles Total 8 9.0 56.3 4.58 13.45 18 Hard DCA 0.5 221.0 gel polyoxyethylene 3.0 2000.0 1.50 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 21.9 ether 9 9.0 2.62 15.00 13.30 Soft gel DCA 0.5 221.0 2.26 3.4 polyoxyethylene 2.0 2000.0 1.50 20.7 diamine Sorbitol polyglycidyl 2.0 406.0 4.93 13.8 ether 10 9.0 62.1 5.72 11.00 14.00 5 soft gel DCA 0.5 221.0 2.26 polyoxyethylene 1.5 2000.0 0.75 10.3 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 24.1 ether 11 9.0 3.27 14.30 14.30 soft gel DCA 0.5 221.0 2.26 polyoxyethylene 1.5 2000.0 0.75 11.5 diamine Sorbitol polyglycidyl 2.0 406.0 4.93 ether 12 7.0 4.58 9.00 13.00 21 Hard DCA 0.5 221.0 gel polyoxyethylene 3.0 2000.0 1.50 21.4 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 25.0 ether 13 7.0 56.0 2.62 12.30 soft gel DCA 0.5 221.0 2.26 4.0 polyoxyethylene 3.0 2000.0 1.50 24.0 diamine Sorbitol polyglycidyl 2.0 406.0 4.93 16.0 ether 14 7.0 56.0 5.72 7.30 12.30 10 Hard DCA 0.5 221.0 2.26 gel polyoxyethylene 1.5 2000.0 0.75 12.0 diamine Sorbitol polyglycidyl 3.5 406.0 8.62 28.0 ether 15 7.0 3.27 10.30 12.00 8 Hard DCA 0.5 221.0 2.26 4.5 gel polyoxyethylene 1.5 2000.0 0.75 13.6 diamine Sorbitol polyglycidyl 2.0 406.0 4.93 18.2 ether indicates data missing or illegible when filed

Example 3

[0095] The following table shows formulations (16-24) that are useful, in one aspect of the invention, stent graft fill material. These formulations can also find utility for other in vivo applications that require a hydrogel polymer having the properties as shown in Table 3.

TABLE-US-00003 TABLE 3 Epoxy/ Gel Weight Time Gel Mol # of % inc 20 Times % Formulation Material Weight Wt mmoles Total ratio 16 Omnipaque 9.0 51.4 2.90 8.30 14.30  7.0% Buffer 1.5N 3.0 17.1 pH 7.6 DCA221 1.5 221 6.79 8.6 Sorbitol 4.0 406 9.85 22.9 polyglycidyl ether 17 Omnipaque 10.0 50.0 3.99 11.00 14.20 5.6- Buffer 1.5N 3.0 15.0  7.0% pH 7.6 DCA221 1.5 221 6.79 7.5 Sorbitol 5.5 406 13.55 27.5 polyglycidyl ether 18 Visipaque 12.0 60.0 3.63 11.13 12.56 2.80% DCA 1.5 221.0 6.79 7.5 1.5N 1.5 7.5 Gly—Gly Sorbitol 5.0 406.0 12.32 25.0 polyglycidyl ether 19 Visipaque 11.0 59.5 2.90 13 14.3 DCA 1.5 221.0 6.79 8.1 1.5N 2 10.8 Gly—Gly Sorbitol 4.0 406.0 9.85 21.6 polyglycidyl ether 20 Omnipaque 10.0 47.6 3.99 11.00 14.20 5.6- Buffer 1.5N 3.0 14.3  7.0% pH 7.6 DI 1.0 4.8 DCA221 1.5 221 6.79 7.1 Sorbitol 5.5 406 13.55 26.2 polyglycidyl ether 21 Omnipaque 10.5 48.3 3.81 11.00 20.00 5.6- Buffer 1.5N 4.5  7.0% pH 7.6 DCA221 1.5 221 6.79 6.9 Sorbitol 5.3 406 12.93 24.1 polyglycidyl ether 22 Visipaque 12.0 55.8 3.63 16 15.4 5.6- DI 1.0 4.7  7.0% DCA 1.5 221 6.79 7.0 1.5N 2 9.3 Gly—Gly Sorbitol 5.0 406.0 12.32 23.3 polyglycidyl ether 23 Visipaque 12.0 58.5 3.63 12.08 13.2   4% DI 0.5 2.4 in DCA 1.5 7.3 graft 1.5N 1.5 221.0 6.79 7.3 Gly—Gly Sorbitol 5.0 406.0 12.32 24.4 polyglycidyl ether 24 Visipaque 11.4 55.6 3.63 11 14.3 6.00% Omnipaque 0.6 2.9 DCA 1.5 221.0 6.79 7.3 1.5N 2 9.8 Gly—Gly Sorbitol 5.0 406.0 12.32 24.4 polyglycidyl ether indicates data missing or illegible when filed

Example 4

[0096] The following table shows formulations (EM1-EM12) that we useful, in one aspect of the invention, as embolic materials. These formulations can also find utility for other in vivo applications that require a hydrogel polymer having the properties as shown in Table 4.

TABLE-US-00004 # of Weight Reactive Weight Gel Components (g) FW mmoles Sites % Time Comments EM-1 1 EX-411 3.00 411 2.30 4 60.0  7:10 Some floating EX-321 0.50 321 1.56 3 10.0 syringe material. 2 Nal (100%) 1.00 20.0 Soft, non-elastic 3 DCA221 0.50 221 2.26 2 10.0 fractionating Total 5.00 100.0 slug. EM-2 1 EX-411 3.00 411 7.30 4 57.1  7:15 Floating EX-321 0.25 321 0.78 3 4.8 syringe material. 2 Nal (100%) 1.00 19.0 Slightly firm 3 DCA221 1.00 221 4.52 2 19.0 slug Total 5.25 100.0 EM-3 1 EX-411 3.00 411 7.30 4 54.5 10:27 Floating EX-321 1.00 321 3.12 3 18.2 syringe material. 2 Nal (100%) 1.00 18.2 Soft, wet, non- 3 DCA221 0.50 221 2.26 2 9.1 elastic slug. Total 5.50 100.0 EM-4 1 EX-411 3.00 411 7.30 4 50.0  6:12 Floating EX-321 1.00 321 3.12 3 16.7 syringe material. 2 Nal (100%) 1.00 16.7 Very hard 3 DCA221 1.00 221 4.52 2 16.7 slug. Total 6.00 100.0 EM-5 1 EX-411 2.00 411 4.87 4 53.3  6:20 Floating EX-321 0.25 321 0.78 3 6.7 syringe material. 2 Nal (100%) 1.00 26.7 Soft, 3 DCA221 0.50 221 3.26 3 13.3 elastic slug. Total 3.75 100.0 EM-6 1 EX-411 3.00 411 4.87 4 47.1 No cure Floating material. EX-321 0.25 321 0.78 3 5.9 time collected. Material in PBS 2 Nal (100%) 1.00 23.5 Extended, cure does not demontrate 3 DCA221 1.00 221 4.52 2 23.5 should have hydrophobicity. Total 4.25 100.0 re-mixed Slightly “grainy” texture. EM-7 1 EX-411 2.00 411 4.87 4 44.4  6:20 Floating material. EX-321 1.00 321 3.12 3 22.2 syringe Soft, non-elastic 2 Nal (100%) 1.00 22.2 fractionating 3 DCA221 0.50 221 2.26 2 11.1 slug. Total 4.50 100.0 EM-8 1 EX-411 2.00 411 4.87 4 40.0  4:25 Very small amount EX-321 1.00 321 3.12 3 20.0 syringe At floating material. Hot 2 Nal (100%) 1.00 20.0  4:00 exotherm, ~75 C. 3 DCA221 1.00 221 4.52 2 30.0 drops became Very hard slug. Total 5.00 100.0 strings. EM-9 1 EX-411 2.50 411 6.08 4 62.5  10:5  Material in PBS EX-321 0.20 321 0.62 3 5.0 syringe cured at 8:00 2 Nal (100%) 1.00 25.0 3 DCA221 0.30 221 1.36 2 7.5 Total 4.00 100.0 EM-10 1 EX-411 2.50 411 6.08 4 56.8  7:05 Drops became strings EX-321 0.40 321 1.25 3 9.1 syringe at 2:45. Soft, 2 Nal (100%) 1.10 25.0 fractionating 3 DCA221 0.40 221 1.81 2 9.1 slug. Total 4.40 100.0 EM-11 1 EX-411 3.00 411 7.50 4 47.6  5:36 At 1:37, drops became EX-321 1.00 321 3.12 3 15.9 syringe 1 cc strings. 5:50 material 2 Nal (100%) 1.70 27.0 @37 C. cure is PBS. Soft, 3 DCA221 0.60 221 2.71 2 9.5 cured at elastic slug. Total 6.30 100.0  7:36 EM-12 1 EX-411 3.00 411 7.30 4 44.1  4:45 Material cure in PBS @ EX-321 1.50 321 4.67 3 22.1 Syringe 5:47 2 Nal (100%) 1.70 25.0 1 cc @ Injected Ice in blood 3 DCA221 0.60 221 2.71 2 8.8  8:15 6.80 100.0

Example 5

[0097] Formulation 7 was prepared according to the following experimental procedure.

[0098] The mixture of polyethylene glycol diglycidyl ether and trimethylolpropane triglycidyl ether is added to a single syringe. Di-(3-aminopropyl)ether diethylene glycol is added to a second syringe. The two syringes are connected using a delivery tube and ping-ponged mixed between syringes for approximately 20 seconds, with the syringed emptied fully every time with each stroke (approximately 1 stroke/second). A two milliliter sample stored in a 20 milliliter syringe cures in approximately 13 minutes at room temperature. This corresponds to an in vivo cure time of 13 minutes in an inflatable endovascular graft.