WO2007073548A2

WO2007073548A2 - Embolic coils coated with alginate and polyvinylalcohol

Info

Publication number: WO2007073548A2
Application number: PCT/US2006/062241
Authority: WO
Inventors: Marcia S. Buiser; Elaine Lee
Original assignee: Boston Scientific Scimed, Inc.
Priority date: 2005-12-19
Filing date: 2006-12-18
Publication date: 2007-06-28
Also published as: US8101197B2; US20070141099A1; WO2007073548A3

Abstract

Coils, such as embolic coils, and related methods, devices, and compositions, are disclosed.

Description

Coils

TECHNICAL FIELD

The invention relates to coils, such as embolic coils, as well as related methods, devices, and compositions.

BACKGROUND

Therapeutic vascular occlusions (embolizations) are used to prevent or treat pathological conditions in siiu. Embolic coils can be used to occlude vessels in a variety of medical applications. Delivery of embolic coils (e.g., through a catheter) can depend c-n the size and/or shape of the coils.

SUMMARY

In one aspect, the invention features a method of coating a coil The method includes injecting a material into a container containing the coil, and forming the materia! into a coating that is supported by the coil.

In another aspect, the invention features a method of coating a coil. The method includes contacting the coil with a composition, including a first polymer and a gelling precursor, and forming the composition into a coating that is supported by the coil.

In an additional aspect, the invention features an article that is in the shape of a coil The article includes a substrate and a porous material supported by the substrate, In a further aspect, the invention features an article that is in the shape of a coil. The article includes a substrate and a materia! supported by the substrate. The materia! includes a first polymer and a gelling precursor.

In another aspect, the invention features an article that is in the shape of a coil. The article includes & substrate and a material supported by the substrate. The material includes at least two different polymers. m an additional aspect, the invention features a method that includes administering at least one article to a subject. The article is in fee shape of a coil and includes a substrate and a porous material supported by the substrate. In a farther aspect, the invention features a method that includes administering at least one article to a subject. The article is in the shape of a coil, and the article includes a substrate and a material supported by the substrate. The material includes a first polymer and a gelling precursor. In another aspect, the invention features a method that includes administering at least one article to a subject. The article is in the shape of an embolic coil and the article includes a substrate and a material supported by the substrate. The material includes at least two different polymers.

Embodiments can also include one or moτe of the following. The coll can be an embolic coil (e.g., the article can be in the shape of an embolic coil }.

The material can include a polymer. The polymer can be a polysaccharide (e.g., alginate) or polyvinyl alcohol In certain embodiments, the material can include at least two different polymers, in some embodiments, the material can include a polymer {a,g , pcslyviny] alcohol) and a gelling precursor. The gelling precursor can include a polymer (e.g., that is different from another polymer in the material). In certain embodiments, the gelling precursor can include a polysaccharide, such as alginate. In some embodiments, the material can include polyvinyl alcohol and alginate, hi certain embodiments, the materia! can include a therapeutic agent In some embodiments, the materia! can include a protein, such as collagen.

The method can include lyophilizing the material and/or contacting the material with starch and/or sodium chloride.

Forming the coating can include eross-linkmg the polymer and/or removing at least a portion of the gelling precursor, In some embodiments, forming the coating can include contacting the material with a gelling agent. The gelling agent can include calcium chloride. Contacting the material with a gelling agent can include delivering the gelling agent into the container and/or delivering the coil from the container into the gelling agent. Forming the coating can include contacting the material with a cross-Unking agent. The cross-linking agent cam include an aldehyde, an acid, and/or a salt (e.g., a salt including a multivalent cation, such as calcium chloride). In certain embodiments, contacting the material with a cross-linking agent can include delivering the cross-linking agent into the container arsd/or delivering the coil from the container into the cross-unking agent.

The coating can be in direct contact with an outer surface of the coil, in certain embodiments, the coating can be supported by only a portion of the coil hi some embodiments, the coating can be porous.

Tbe article can include a therapeutic agent In some embodiments, the method can include delivering the therapeutic agent from the article, in some embodiments, the method can include contacting the material with a therapeutic agent (e.g., by delivering the therapeutic agent into the container). Hie container can include a tabular member. IB certain. embodiments, the tuhukvr member can have art inner diameter of at least 0.008 inch (e.g., at least 0.021 inch) and/or at most 0.038 inch (e.g., at most 0.021 inch), in some embodiments, the tubular member can have an outer diameter of at least 0.01 inch (e.g., at least 0.015 inch, at least 0.042 inch) and/or at most 0,06 inch (e.g., at most 0.042 inch, at most 0.01 5 inch). The tubular member can be cylindrical, in certain embodiments, the tubular member can have a non-circular cross-section (e.g., a polygonal cross- section). In some embodiments, the container can include an introducer sheath. In certain embodiments, the container can include a catheter that is configured to fit within a lumen of a subject, The method can include removing the coil from the container (e.g., by cutting the container and/or by peeling the container away from the coil). In some embodiments, the container can include a hioerαdible and/or bioabsorhabk material. The method can include removing the coil from the container by eroding and/or absorbing the container. In certain embodiments, removing the coil from the container can include contacting the container with an agent that is adapted to dissolve the container, in some embodiments, removing the coil from the container can include pushing and/or pulling the coil out of the container.

Ln certain embodiments, the coil can be contacted with a composition including a polymer and a gelling precursor by adding the composition inttj a container containing the coil, hi some embodiments, tbe composition can he in the form of a solution. In certain embodiments, the porous materia! can include a lϊrst portion having one density of pores and a second portion having another density of pores that is different from the density of pores in the first portion, In some embodiments, the first portion of the porous materia! cars be disposed between (he substrate and the second portion of die porous material and the density of pores in the second portion can be greater than the density of pores in the tϊrsi portion, In certain embodiments, the porous material can include a first portion having one average pore size and a second portion having another average pυre sise that is different from the average pore size in the iirst portion, In some embodiments, the first portion of the porous materia] can be disposed between the wire and the second portion of the porous material and the average pore size in the first portion cats, be greater than the average pore size in the second portion.

'Hit porous materia! can include a polymer, such as polyvinyl alcohol. In some embodiments, the porous material can .include a polysaccharide (e.g., alginate). in certain embodiments, the porous material can include at least two different polymers, Irs some embodiments, the porous materia! ears include a therapeutic agent. The porous materia] can he in direct contact with an outer surface of the substrate, In certain embodiments, the porous material can form a coaling on the substrate. The coaling can have a thickness of at least about five microns (e.g., at least about H) microns, at least about 50 microns, at least about 100 microns, at least about 250 microns) and/or at most about 500 microns (e.g., ai most about 250 microns, ai most about 100 microns, at most about 50 microns_., at most about 10 microns).

The substrate can include a metal (e.g.. piatiaure, gold, rhenium, palladium, rhodium, ruthenium, tungsten), a metal alloy (e.g., Nitinoi, stainless steel, a platinum/tungsten alloy), and/or a polymer (e.g., a polyamino acid, a polynuclek acid, a polysaccharide, a potyhydrαxyaJkanoate, a polyanhydride). In certain embodiments, ihe substrate can include at least one of the following materials; a polyurethane, a poiyetjier, a polyimide, an acrylaie, an epoxy adhesive material an olefin, a polydsmethyt siioxane-hased polymer, Rayon, cellulose, a cellulose derivative, a natural rubber, a polyester, hydroxybuiyrate, polyhydroxyvaierate, a pdyether ester, an anhydride, or a mixture or copolymer of at least two of these materials, The substrate can be in the form of a wire. In some embodiments, the wire can have a diameter of from 0 0005 inch to 0.005 inch.

1« certain embodiments, the method can include using a catheter to administer tilt- article to the subject. In some embodiments, the method can include using a device to administer the article to the subject. The device can have ars internal opening and/or can be configured to fit within a lumen of a subject. In certain embodiments, the article can be disposed within the internal opening of the device.

The method can include using a pusher wire to deliver the article from the device. In some embodiments, the article can he attached to the pusher wire, and the method can include detaching (e.g., mechanically, chemically, electrolytically, thermal Iy, hydraulieaJly} the article from the pusher wire to deliver the article from the device. The method can include treating at (east one of the following: an aneurysm, an arteriovenous formation, a traumatic fistula, a tumor. In some embodiments, the method can include emboli zing a lumen of a subject. Embodiments can include one or more of the following advantages.

In some embodiments, a coil that includes a coating can exhibit relatively good occlusive properties when delivered to a target site within a subject This can, for example, allow the coil to be used to occlude a vessel (e.g., to emboike a rumor), treat an aneurysm, treat an arteriovenous malformation, and/or treat a traumatic fistula, in certain embodiments, a coil that includes a coating can he used to ehcit thrombosis at a target site, which can enhance the occlusion of the target site, in some embodiments, a coil that, includes a coating can he used to deliver one or more therapeutic agents to a target site. In certain embodiments, the coil can he used to deliver a metered dose of a therapeutic agent to a targe! site over a period of time. In some embodiments, the release of a therapeutic agent from the coil can he delayed until the coil has reached a target site. For example, the coating can be a hioerodiW e coating thin, erodes during delivery, such that when the coil reaches the target site, the coil can begin to release the therapeutic agent,

In certain embodiments, a coil that includes a coating can be used to deliver multiple therapeutic agents, either to the same target site, or to different target sites.

For example, the coil can deliver one type of therapeutic agent (e.g., an aπU- inflammatory agent an anti-thrømbαtie agent) as the coil is being delivered to a target site, and another type of therapeutic agent, (e.g., a growth factor) once the coil has reached the target site.

In some embodiments, a coil that includes a coating can be used both to s occlude a target site and to deliver one or more therapeutic agents to the target site.

In certain embodiments, a coil that includes a coating can experience enhanced protection of its coil body. As an example, in some embodiments, the coating can protect the coil body as the coil is delivered into a subject irom. a delivery device. As aiunhcr example, in certain embodiments, the coating can protect the coil body during 0 storage of the coi L hi some embodiments, a coil that includes a coating can exhibit relatively good deliverabiliiv. For example, in certain embodiments, the coi) can experience relatively little friction with the walls of a delivery device if the cod contacts the vvalSs of the delivery device during delivery. The coating can enhance the lubricity of the S coil, .making it relatively easy to deliver the coil from a delivery device. l.n sorrso embodiments, a coi! that includes a coating can have a relatively smooth outer surface, in certain embodiments, the relatively smooth outer surface can enhance the deliverabihiy of the coil from a delivery device (e.g., by limiting the likelihood that the coil will become caught on the delivery device during delivery). 0 Other aspects, features, and advantages are in the description, drawings, and claims.

DESCRIPTION OF DRAWINGS

PICl I A is a side view of an embodiment of an embolic coil,

FIG LB is a cross-sectional view of the embolic coil of FIG I A. taken along 5 line ! B- I B.

Fl(I 1 C is a cross-sectional view of the embolic coil of FKl I A, taken along lirse 1 C- 1 C,

FIG 2 A is a side view of an embodiment of an embolic coil.

F(G 2B is a cross-seetional view of the embolic cod of FJG 2A. taken along (5 line 2B-2B. FIG 20 is a cross-sectional view of the embolic coil of FIG 2 A, taken along line 2C-2C

FIGS. 3A-3E illustrate the delivery of an embodiment of an embolic coil to the- site of an aneurysm. FIG 4 is a perspective view of an embodiment of an embolic coil

FIG 5 is a perspective view of an embodiment of an embolic coil.

FlG 6 is a perspective view of an embodiment of an embolic coil.

FIG ? is a. perspective view of an embodiment of an embolic coil.

FiG. 8 A is a side view of an embodiment of a process for forming an embolic coil,

FIG SB is a side view of an embodiment of a mandrel used in the process of FlG 8A,

FIG BC is a cross-sectional view of the mandrel of FIG. SB, taken along line SC-SC. FlG 9 A is a side view of an embodiment of a mandrel.

FIGS, vB and 90 are illustrations of an embodiment of a process for forming an embolic coil using the mandrel of FlG. 9A.

FlCsS. K)A- 1 OE illustrate an embodiment of a process for forming an embolic coil. FIGS. 11 A- 11 D illustrate an embodiment of a process for forming an embolic coil.

FfGS. 12-16 are micrographs of embodiments of embolic coils.

FiG, 17 is a scanning electron microscope (SEM) image of embodiments of embolic coils. FIGS. 18A-I.8F are SEM images of a location on one of the embolic coils of

FfG 17, taken at different levels of magnification.

FIGS. 19A-19E arc SEM images of a location on one of the embolic coils of FIG 17_; takers at different levels of magnification.

FIGS. 20A-20E are SEM images of a location on one of the embolic coils of FiG 17, taken ai different levels of magniiϊcaύon. FfGS. 21 A-21 D arc SEM images of a location on one of the embolic colls of FIG 17, taken at different levels of magnification.

FIG. 22 is a side cross-sectional view of an embodiment of on embolic coil.

FiG. 23 A is a side view of an. embodiment of an embolic coil. FIG 23B is a cross-sectional view of the embolic coil of FlG 23 A, taken along

Hne 23B-23B.

FfG. 23C is a cross-scetiona! view of the embolic coil of FIG 23 A, taken along hne 23C,-23C.

FIG, 24A is a Side cross-sectional view of an embodiment of an embolic coil FIG, 248 is a side cross-sectional view of an embodiment of an embolic coil.

FIG 25 A is a eross-sectionai view of art embodiment of an embolic coil.

FlG 258 is a cross-sectional view of an embodiment of a device kt? coating a coil body,

FfG 26 illustrates the delivery of an embodiment of an embolic coil from an introducer sheath into a deliver}' device.

FIG. 2?A is an illustration of an embodiment of an introducer sheath.

FlG. 2?B is an enlarged view of region 278 of FIG. 27A.

DETAILED DESCRIPTION

FIGS. IA-IC show the primary shape of an embolic coil 10 thai includes a coil body 12 formal of windings (e.g., windings 14, I S. and \u) of a wire 18 (e.g., a platinum wire). Embolic coil 10 also includes a cuatmg 20 (e.g., a polyvinyl alcohol coaling) disposed an the exterior surface 22 of coil body 12. Coating 20 includes pores 24. Embolic coil 10 can be used, for example, in an embolization procedure, and/or can be used to deliver one or more therapeutic agents to a target sue. As shown in FlCJ. 1C, coating 20 has a thickness Tl , In general thickness Tl can be selected based on the application of embolic coil 10, As an example, in some embodiments in which coating 20 contains a therapeutic agent and embolic coil i 0 is used to deliver the therapeutic agent to a target site, thickness Tl can be selected to effect a specific delivery rate of the therapeutic agent to the target site. As another example, in certain embodiments in which coating 20 is an credible coating that Ls used Io protect exterior surface 22 of embolic coil IO during deliver)' of embolic coil IO to a target site, thickness Tl can be selected so that the coating is present during delivery but has eroded once embolic coil 10 has reached the target site, hi certain embodiments, thickness Tl can be selected based on multiple considerations (e.g., 5 tleii very of a therapeutic agent and protection of surface 22). In some embodiments, thickness Tl can be at least about five microns (e.g., at least about 10 microns, at least about 25 microns, at least about 50 microns, at least about 75 microns, at least about i OO mkrons, at least about 200 microns, at least about 250 microns, at least about 300 microns, at least about 400 microns) and/or at most about 5(.K) microns (e.g., at .most

1C about 400 microns, at most about 300 microns, at most about 250 microns, at most about 200 microns, at most about 100 microns, at most about 75 microns, at most abotu 50 microns, at most about 25 microns, at most, about 10 microns).

Embolic coil 10 in its primary shape has a length 1,1 , an inner diameter IDl, and an outer diameter OO I , Generally, these dimensions can be selected as desired. ig In some embodiments, length Li can be at. least about one centimeter (e.g., at least about five centimeters, at least about 10 centimeters, at least about 20 centimeters, at least about 30 centimeters, at least about 40 centimeters, at least about 50 centimeters), and/or at most about 60 centimeters (e.g., at most about 50 centimeters, at most about 40 centimeters, at most about 30 centimeters, at most about 20

20 centimeters, at .most about H) centimeters, at most about five centimeters}, (n certain embodiments, inner diameter IDI can be at least 0.001 inch (e.g.. at least 0.002 indi, at least 0.006 inch, at least 0.01 inch, at least 0.015 inch, at least 0.02 inch, at feast 0.t)25 inch, at least 0,03 inch) and/or at most 0.036 inch (e.g., a! most 0.03 inch, at HKist 0.025 inch, at most 0.02 inch, at roost 0.015 inch, at most 0.01 inch, at most

25 0,005 inch, at most 0.002 inch). In some embodiments, taster diameter OD 1 can be at least 0.003 inch (e.g , at least 0.008 inch, at least 0.015 inch, at least 0.02 ! inch, at least 0.03 inch) and/or atπϊost 0.038 inch (e.g., at most 0.03 inch, at most 0.021 inch, at mast 0.01 5 inch, at most 0,008 inch). For example, in certain embodiments, outer diameter ODl can be 0,010 inch or 0.015 inch.

X> hi certain embodiments, carter diameter ODl can be selected based on the intended use of embolic coil 10. As an example, in certain embodiments in which embolic coil K) can be used to treat intracranial aneurysms, outer diameter ODl can be relatively small (e.g., at most 0.016 inch). As another example, in some embodiments in which embolic coil 10 can be used to treat arteriovenous malformations, outer diameter GDI can be relatively large (e.g., at least 0.021 inch). 5 In some embodiments, outer diameter ODl can be selected based on the size of a delivery system that will be used to deliver the coil (e.g., a catheter .having an inner diameter of 0.010 inch, 0.018 inch, or 0,035 inch).

When embolic coil SO is m its primary shape, coil body 12 has a length L.2 that js equal to length Ll of embolic coil 10, an inner diameter ID2 that is equal Kt inner 0 diameter IDl of embolic coil 10, and an outer diameter OD2. In some embodiments, outer diameter 01)2 can be at least 0.003 inch (e.g., at bast 0.008 inch, at least 0.0! 5 inch, at least 0.021 inch, at least 0.03 inch) and/or at most 0,038 inch (e.g.. at most 0.03 inch, at most 0.021 inch, at .most 0.015 inch, at most 0.008 inch).

The pitch of a coil body, such as coil body 12, is the sum of the thickness of s one winding of the coil body (e.g., winding 14) and the amount of space between that winding and « consecutive winding of the coil body (e.g., winding 15). FlG. I B shows the pitch Pl of coil body 12. Because the windings of coil body 12 are flush with each other, pitch Pl is equal to the thickness of a winding of coil body 12. In some embodiments, pitch Pl can be at most 0.01 inch (e.g., at most 0.005 inch), 0 and/or at least 0,0005 inch (e.g., at least 0.005 inch). While the windings of coil body 1.2 are shown as being Hush with each other, in certain embodiments, a coil csn include windings that are not flush with each other and that have space between them. Coating 20 eau include (e.g., can be formed of) one or more materials. Ifi some embodiments, coating 20 can include one or more polymers (e.g., at 5 least two polymers, ai least three polymers, at least four polymers, at least five polymers). Examples of polymers include polyvinyl alcohols (PVA), pølyacrytie acids, polyammo acids, pαlyoleims, polyanhydrides, polymethacryiie acids, poly vinyl sulfonates, carboxy.met.hyj celluloses, bydroxyethyi celluloses, substituted celluloses, polyacrylamides, polyethylene glycols, polyarmdes (e.g., nylon), D polyureas, polyuretlianes, polyesters, pdyethers, polystyrenes, polysaccharides (e.g.. alginate, agarose), polylactic acids, polyethylenes, polymethylmethacrylates, polyethyiacrylate, polycaprolactones, polyglycolic acids, poiy{Iaetk-eo-giyeαiic} acids (e.g., po!y(d-laetie~eo~glycϋ!ic) acids), and copolymers or mixtures thereof. An example of a copolymer is a poiyglycolic acid/lactide copolymer, hi certain embodiments, the polymer can be a highly wafer insoluble, high molecular weight polymer. An example of such a polymer is a high molecular weight polyvinyl alcohol (PVA) thai has been acetalized. The polymer can be substantially pure intrachain 1 ,3- acetalized PVA and substantially free of animal derived residue such as collagen.

In some embodiments, coaling 20 can include one or more gelling precursors. Examples of gelling precursors include alginates, alginate salts (e.g. sodium alginate), xaπthan gums, natural gum, agar, agarose, chiiosam cartageenan, ilscokiars, turcellaran, larninaran, hypnea, eucheuma. gum aπtbic, gum gliatli, gum karaya, gum tragacaoth, hyaluronic acid, locust beam gum, arahinogalaclan, pectin, amylopeetm, other water soluble polysaccharides and other ionically cross-linkable polymers, A particular gelling precursor is sodium alginate. An example of sodium alginate is high guJuronie acid, stem-derived alginate (e.g., about 50 percent or more, about 60 percent or more guiinτmie acid) with a low viscosity (e.g., from about 20 centrpoise to about 80 cenlipoise at 20³C), which can produce a high tensile, robust gel.

In some embodiments, coating 20 can include one or more bioerodibfe aiul/or bio absorb able materials. In certain embodiments, coating 20 can be formed entirely of bioerodibie and/or bioabsorbable materials. This can, for example, allow coating 20 to erode and/or to be absorbed during and/or after delivery of embolic coil 10 to a target site. Examples of bioerodibie and/or bioabsorbable materials include polysaccharides (e.g., alginate); polysaccharide derivatives; inorganic, ionic salts; water soluble polymers (e.g., polyvinyl alcohol, such as polyvinyl alcohol that has not been cross-linked); biodegradable poly DL-iaetide-poly ethylene glycol (PEl-A); hydrogels (e.g., poivaerylic acid, hyaluronic acid, gelatin such as gelatin loam, carboxyniefhyl cellulose}; polyethylene glycol (PEG); chitosan; polyesters (e.g., poiycsproketones); po Iy(I aetie-co-gly colic) acid (e.g., a polytd-ketic-eo-giyeolic} acid); poiyammo acids, polynucleic acids; polyhydxoxyalkanoat.es; poly anhydrides; ami combinations thereof. In some embodiments, coating 20 can include sodium alginate. in certain embodiments, coating 20 can include one or more proieirss. Examples of proteins include collagen, enzymes, and growth factors.

Irs so.oui embodiments, coating 20 can include one or more gelled materials, and/or can be in & gel form. For example, coating 20 can be formed of a gelling 5 precursor (s.g,, alginate) that has been gelled by being contacted with a gelling agent (e.g., calcium chloride).

In certain embodiments, coaling 20 can include one or more radiopaque materials. As used herein, a radiopaque material refers Io a material having a density of about ten grams per cubic centimeter or greater (e.g., about 25 grams per cubic

10 centimeter or greater, about 50 grams per cubic centimeter or greater). Lo some embodiments in which coating 20 includes one or more radiopaque materials, embolic coil 10 can exhibit enhanced visibility under X-ray fluoroscopy, such as when embolic coil 10 is in a subject. In certain embodiments. X-ray fluoroscopy can be performed without the use of a radiopaque contrast agent Radiopaque materials are

15 described, tor example, in Rioux et a!., U.S. Patent Application Publication No. US 2004/0101564, published on May 27, 20(54, which is incorporated herein by reference.

U) certain embodiments, coauπg 20 can include one or more MRf-visible materials. As used herein, an MRI-visible materia! refers to a material that hss a

20 magnetic susceptibility of at most about one or less (e.g., at most about 0.5 or less; at most about zero or less) when measured at 2S°C. In some embodiments in. which coating 2(5 includes one or more MEI- visible materials, embolic coil 10 can exhibit enhanced visibility under MRL such as when embolic coil 10 is in a subject (see discussion below), In certain embodiments, M RJ can be performed without the use of

;?5 an MlU contrast agent. svlRI -visible materials are described, for example, in Rioux et aL U.S. Patent Application Publication No. US 2004/0101564, published on May 27, 2004, which is incorporated herein by reference, hi certain embodiments, coating 20 can include one or more ferromagnetic materials. As used herein, a ferromagnetic materia! refers to a material that has a

30 .magnetic susceptibility of at least about 0.075 or more (e.g., at least about 0.1 or

.more; at least about 0.2 or more; at least about 0.3 or more; at least about 0.4 or more; at least aboiu 0.5 or more; at least about one or more; at least about Jen or more; at least about 100 or more; at least about i ,000 or more; at least about i OJ)OO or more) when measured at 25''C, in some embodiments in which coating 20 includes one or more ferromagnetic materials, a magnetic source can be used to move or direct 6 embolic coil 10 tø a treatment site. The magnetic source can be external to the subject's body, or can be used internally, in certain embodiments, both an externa! magnetic scarce and an internal magnetic source can be used to move embolic coil 10. An example of an internal magnetic source is a magnetic catheter. Magnetic catheters are described, for example, in Freyman, U.S. Patent Application Publication iθ No, US 2003/0187320 AI . published on October 2, 2003, which is incorporated herein by reference. An example of an externa! magnetic source is a magnetic wand. Ferromagnetic materials are described, lor example, in Rioux et a!., U.S. Patent Application Publication No. US 2004/0101564, published on May 27. 2004. winch is incorporated herein by reference.

15 In some embodiments, coating 20 can include one or more materials thai are neither bioerodible nor hioabsorbahle.

In certain embodiments, coating 20 can include two or more of any of the above materials. For example, in some embodiments, coating 20 can. include one or more polymers and one of more gelling precursors. 0 While FIG I C shows that embolic coil 10 ears have a coating 20 with a relatively uniform thickness Tl around coil body 12, in some embodiments, an embolic coil can have a coating with a non-uniform thickness. For example, FIGS. 2A-2C .show the primary shape of an embolic coil 50 including a coil body 52 formed of windings (e.g., windings 54 and 56} of a wire 58, and a coating 60 disposed on the 5 exterior surface 62 of coil body 52. Coaling 60 includes pores 66. The thickness of coating 60 o.n coil body 52 varies in different regions of embolic coil 50. For example, as shown in FiG 2C, in one region Rl of embolic coil 50, coating 60 has a thickness ?2, In some embodiments, thickness T2 can be at least about five microns (e.g., at (east about 10 microns, at least about 50 microns, at least about K⁾O microns, 0 at least about 250 microns, at least, about 500 microns, at leasi about 750 microns) and/or at most about 1000 microns (e.g., at most about 750 microns, st most about SOO microns, at most about 250 microns, at most about 100 microns, at most about 50 microns, at roost about 10 microns). In another region R2 of embolic coil SO, coaling 60 has a thickness T3. In certain embodiments, thickness T3 can be at least about one micron (e.g., at least about 10 microns, at least about 25 microns, at least about 50 S microns, at least about 75 microns) and/or at most about 100 microns (e.g., at most about 75 microns, at most about 50 microns, at most about 25 microns, at most about 10 microns), hi certain regions of embolic coil 50, there may be no coating on coil body 52. For example, in region R3 of embolic coil 5O₅ there is no coating on co.0 body 52. 0 Typically; a wire (e.g., wire 18, wire 58) that is used to form a coil body can mciiide (e.g., can be formed of) one or more materials .hat are capable of being shaped into a coil Form. For example, a wire can include one or more materials that have sufficient, flexibility and/^'or malleability to be shaped into a coil ibrm. in some embodiments, a wire can include one or more metals or metal alloys, such as 5 platinum, a platinum alloy (e.g., platinum-tungsten alloy), stainless steel, Nitiool, and/or ElgiKsy*^' alloy (from Eigiloy Specialty Materials).

Irs certain embodiments, a wire cars include one or more polymers. The polymers can include synthetic polymers, natural polymers, cross-linked polymers, πoπ-crosx-iHiked polymers, thermosetting polymers, and/'or thermoplastic polymers. 0 Examples of polymers include polyolefms ; polyurethanes; block copolymers (e.g., block copolymers with segments including esters, ethers and/or carbonates); polyetbers; polyimkles; acrylates (e.g., oyanoacryiales); cpoxy adhesive materials (e.g., one-part epoxy-arnine materials, two-part epoxy-amiπe materials); polymers and/or copolymers of ethylene, propylene, butadiene, styrene, and/or thermoplastic ?; olefin elastomers; poly-dimethyl siloxaπe-based polymers; Rayon; cellulose; cellulose derivatives; (e.g., nitrocellulose); natural rubbers; polyesters (e.g., polyethylene terephihaUste); polyiactides; polygiycoHdes; polycaprolactones; copolymers of lactides, gjycolidcs, and/or caprolactoncs; polyhydroxybutyrate, polyhydroxyvalerate, and copoi yiTiers of hydroxybutyrate and hydroxyvaleraie; pc$lyether esters (e.g., 0 polyclioxaπone); poiyaxiliydridcs, such as polymers and copolymers of sebacie acid, hexadecandiok acid and other di acids; ortlioesters; polyamiπo acids; pυlynucleii; acids; polysaccharides; and polyhydroxyalkanoates. In some embodiments, a wire can include one or more mixtures and/or copolymers (e.g., block copolymers, random copolymers) of these materials_^

Ln some embodiments, a wire can include one or more shape-memory s materials. Examples of .shape-memory materials include Nitinol and shape-memory polymers (e.g., Verϊilex™ shape-memory polymers, available from CRG Industries (Dayωn, OH)).

In certain embodiments, a wire can include (e.g., encapsulate) one or more radiopaque materials. Radiopaque materials are described, for example, m flioux et 0 al, U.S. Patent Application Publication No. US 2004/0101564 Al , published on May 27, 2.004, which is incorporated herein by reference.

In some embodiments, a wire that is used to form a cot! body am have a diameter of at least 0.0005 inch (e.g., at least 0.00 i inch, at least 0.002 ijieb, at least 0,003 inch, at least 0.004 inch) and/or at most 0.005 inch (e.g., at most 0.004 inch, at s most 0.003 inch, at most 0.002 inch, at most 0.00 i inch).

Embolic coils can generally be used in a number of different applications, such as neurological applications and/or peripheral applications. Ln some embodiments, embolic coils can be used to emboli ze a lumen of a subject (e.g., to occlude a vessel), and/or to treat an aneurysm (e.g.. an intereraniai aneurysm), an arteriovenous 0 maiibrmatioπ (AVM), and/or a traumatic fistula, In certain embodiments, embolic coils can be used to etnbo&e a tumor (e.g., a liver tumor). In some embodiments, embolic coils can be used in transarterial eherπoεmboUzation (TACE),

FK}S. 3A-3E show the use of embolic coil IQ to fill and occlude an aneurysmal sac 104 of & subject As shown in FIG. 3 A. aneurysmal sac 104 is formed 5 in a wait 103 of a vessel ! 0O₅ and is connected to vessel K)O by a neck 102.

As shown in FIG 3B, a catheter 106 containing embolic coil 10 is delivered .into vessel 100, FIG 3C shows a cross-sectional view of catheter 106 containing embolic coil 10. Embolic coil 10 is disposed within a lumen. 105 of catheter 106, and is in us primary shape, in some embodiments, embolic coil 10 can he disposed within 0 a pharmaceutically acceptable carrier (e.g., a saline solution, a contrast agent, a heparin solution, hepaπnized saline) while embolic coil 10 is within lumen 105 oi^' catheter 106, Catheter 106 includes a core wire 108 connected to a power supply 1.10. Power supply 110 has a negative pole 112 that can be placed in electrical contact with the skin of the subject

As shows in FiG. 3D, catheter 106 is used to deliver embolic coil 10 into aneurysmal sac 104. at least until a sacrificial link 124 between coil 10 and core wire 108 is exposed beyond the distal tip 126 of catheter 106, As shown in FIG 3 E, when an electrical current generated by power supply 110 flows through core wire 10S, the electrical current causes sacrificial link 124 to disintegrate, thereby eSec.rolyticaily detaching embolic coil 10 from core wire 108. Embolic coil 10 {ills aneurysmal sac 104, By tilling aneurysmal sac 1(14, embolic coil 10 helps to occlude aneurysmal sac 104. In some embodiments, coating 20 of embolic coil 10 can accelerate the occlusion of aneurysmal sac 104 (e.g., by enhancing thrombosis within aneurysmal sac 104). An accelerated embolization procedure can benefit the subject by, for example, reducing exposure time to fluoroscopy. Embolic coils and coil delivery are described, for example, in Gia et a!., U, S. Patent No, 6,589,230, and Elliott et a!., U.S. Patent Application Serial No, 1 1 /000,741 , filed on December 1, 2004, and entitled "'Embolic Coils", both of which are incorporated herein by reference. hi general, an embolic coil such as embolic coil H) has a primary shape and a secondary shape. Embolic coil 10 exhibits only its primary shape when embolic coil 10 is extended within lumen 105 of catheter 106 (as shown in FKi 3C). As embolic coil 10 exits catheter 106, however, embolic coil 10 further assumes its secondary shape, which allows embolic coil 10 to fill aneurysmal sac 104. Typically, the primary shape of embolic coil 10 can be selected for deliverability, and the secondary shape of embolic coil 1.0 can be selected for application (e.g., embolization of an aneurysm),

AiJ FIGS. 4-7 illustrate, an embolic coil can have any of a number of different secondary shapes, which cars depend on the particular application for the embolic coil. For example, FIG 4 shows a coated embolic coil 200 having a helix secondary shape, As shown in FlG. 4, in its secondary shape, embolic coil 200 has an outer diameter OD3, In some embodiments, outer diameter OD3 can be about six millimeters. An embolic coil with a hdix secondary shape can be used, for example, to provide & supportive framework along a vessel wall Alternatively or additionally, an embolic coil with a helix secondary shape can be used to hold other embolic coils that are subsequently delivered to the target site. F(G, 5 shows a coated embolic coil 210 having a vortex secondary shape. An embolic coil with a vortex secondary shape can be used, for example, to close the center of a target site (e.g., a vessel, an aneurysm) that is to be oeduded, and/or to occlude a target site in conjunction with an embolic coil such as embolic coil 200 (FIG 4). As shown in FIG 6, a coated embolic coil 22C) has a diamond secondary shape. Like an embolic coil with a vortex secondary shape, an embolic coil with a diamond secondary shape can be used, for example, to close the center of a target Site (e.g., a vessel, an aneurysm) that is to be occluded, and/or to occlude a target site in conjunction with an embolic coil such as embolic coil 2(K⁾ (FIG 4), FIG 7 shows a coated embolic coil 230 having a secondary shape in the form of a J. As embolic coi! having a secondary shape in the form of a J can be used. for example, to Ii 11 remaining space irt a« aneurysm that was not filled by other coils. In some embodiments, an operator (e.g., a physician) can hook the curved portion of embolic coil 23(5 into a eo.il or coil mass that has already been deployed at a target site, and then shape the straighter portion of embolic coil 230 to fill the target site.

FIGS. 8 A-SC illustrate a process for forming a coil body hi its primary shape, FIGS. 9A-9C illustrate a process for shaping the coil body into & secondary shape, and FIGS. 10A~l OE ami I ! A-I ID .illustrate processes for coating a coif body to form a coated embolic coil (e.g., embolic coil 10).

As shown in PKl 8 A, a eoil-formirsg apparatus 300 includes a mandrel 310 held by two rotatable chucks 320 and 330. A spool 340 of wire 1 S is disposed above mandrel 310, and is attached to a moving device 360. To form an embolic coil in its primary .shape, chucks 320 and 330 are activated so that they rotate in the direction of SΠΌWS A2 and A3, thereby rotating mandrel 310. Moving device 360 also is activated, and moves spool 340 in the direction of arrow Al . The rotation of mandrel 310 pulls wire 18 from spool 340 at, a predetermined pull-off angle, and causes wire I S to wrap around mandrel 310, forming coil body 1.2. The pull-off angle («) is the angle between axis PAl, which is perpendicular Jo longitudinal axis LAl of mandrel 310, and the portion 380 of wire 18 between spool 340 and coil body 12. In. some embodiments, a ears be from about one degree to about six degrees (e.g.. from about 1.5 degrees io about five degrees, from about 1.5 degrees to about 2.5 degrees, about two degrees), m certain embodiments, a controller (e.g., a programmable logic δ controller) can be used to maintain the puli-off angle in coil-forming apparatus 300. Because mandrel 310 is rotating as ϊi is pulling wire 18 from spool 340, and because moving device 360 is moving spool 340 in the direction of arrow AI , wire 18 forms coil body 12 in a primary shape around mandrel 310. Coil body 12 can be formed, for example, at room temperature (25⁰C). o Alter coil body 12 lias been formed, chucks 320 and 330, and moving deviee

360, are deactivated, and portion 380 of wire 1 S is out Mandrel 310 is then released from chuck 320, and coil body 12 is pulled off of .mandrel 310. While cod body 12 might lose some of its primary shape as it is pulled off of mandrel 310, eoil body 12 can generally return to its primary shape shortly mereaiter, because of memory s imparted to eoil body 12 during formation. In certain embodiments (e.g., in certain embodiments in which wire IS is formed of one or more polymers), eoil body 12 can be healed alter being formed on mandrel 310 and prior to being removed from mandrel 310. ^'This heating can help coil body 13 to retain its primary shape

removal of coil body 12 from mandrel 310. In some embodiments, after eoil body 12 0 has been removed from mandrel 310, one or both of the ends of coil body 12 can be heated and melted to form rounder, more biocompatible (e.g.. atraumatic) ends.

Mandrel 310 can be formed of, for example, a metal or a rnetai alloy, such as stainless steel. In some embodiments, mandrel 310 can be formed of one or more polymers, such as Teflon* (polytetraflυoroethylene) or De!rhi^A (polyoxyrnεihyiene). 5 hi certain embodiments, mandrel. 310 can be formed of a shape-memory material such as NitiπoL

Mandrel 310 has a diameter D! (FIGS. SB and SC), In some embodiments, diameter Di can be at least 0.00 ! inch (e.g., at least 0,002 inch, at bast 0.005 inch, at least 0.01 inch, at bast 0,015 inch, at least 0.02 inch, at least 0,025 inch, at least 003 0 inch, at least 0.035 inch) and/or at most 0,037 inch (e.g.. at most 0,035 inch, at most

s s 0.03 inch, at most 0,025 inch, at most 0.02 inch, at most 0.015 inch, at most 0.01 inch, at most. 0,005 inch, at most 0.002 inch),

^'The tension of mandrel 310 as it is held between chucks 320 and 330 preferably is suiϊkienily high Io avoid vibration of mandrel 310 during the winding process, and sufficiently low to avoid stretching of mandrel 310 during the winding process, hi some instances, significant stretching of mandrel 310 during the winding process could cause coil body 12 to has'e a smaller primary shape than desired, aτκi/or could make it relatively difficult to remove coil body 12 from mandrel 310. In certain embodiments, the tension of mandrel 310 can be from about i 00 grams to about 1 ,000 grams (e.g., from about 300 grama to about 600 grams, from about 400 grams to about 500 grams). For example, the tension of mandrel 310 can be about 506 grams, !n some embodiments, wire 18 can be wound around mandrel 310 at a tension of from about IQ grams to about 100 grams (e.g., from about four grams to about 50 grains, from about six grams to about 40 grams, from about 22 grams to about 32 grams, about 27 grams).

In certain erobodimenis, the length of coil body 1.2 in its primary shape and while under tension on mandrel 3 i0 can be from about 10 centimeters Jo about 250 centimeters (e.g., from about 50 centimeters to about 200 centimeters, from about 130 centimeters --.o about 170 centimeters, from about 144 centimeters to about 153 L-enti meters, from about 147 centimeters to about 153 centimeters.!. For example, the length of con⁵ body 12 in its primary shape and while under tension on mandrel 310 cars be about 132 centimeters or about 147 centimeters. Coil body 12 may recoil to some extent (e.g., by at most about five centimeters) when portion 380 of wire 18 is severed, such that coil body 12 will be somewhat smaller once it has been removed from mandrel 310. In some embodiments, coil body ] 2 can have a length of from about five centimeters to about 225 centimeters (e.g., from about 25 centimeters to about 170 centimeters, from about 120 centimeters \Q about 140 centimeters, from about 137 centimeters to about \ 40 centimeters) after being removed from mandrel 310. After coil body 12 has been removed from mandrel 310, coil body 12 csn be cui into smaller coils. Once coil body 12 has been formed in its primary shape, coil body 12 can be further shaped into a secondary shape, as shown in FiGS. 9A-9C.

FfG 9A shows a mandrel 390 used to form the secondary shape of coil body 12, While mandrel 390 is shaped to form a diamond, other types of mandrels can be used to form other secondary shapes. Mandrel 390 is formed of a diamond-shaped block 392 with grooves 394 cut into its surface. As shown in FIGS. 9B arsd 9€, eois body 12 m its primary shape is wrapped around mandrel 390, such that coil body 12 fills grooves 394, creating the secondary shape, ^'The ersds of coil body 12 are then attached (e.g., pinned) to mandrel 390. and coil body 12 is heat-treaied to impart memory to coil body 12. In sonic embodiments, coil body 12 can be heat-treated at a temperature of at least about 1000⁰C (e.g., at least about 1 OSG⁰C, at least about 1100⁰C₁ at least about 1 150⁰C), anci-^'or at most about 12QO⁰C (e.g., at raosi about HS(FC, at most about 1 100⁰C, at most about 1050⁰C), In certain embodiments, the heat treatment of coil body 12 can last for a period of from about 10 minutes to about 40 minutes (e.g., about 25 minutes). After being heat-treated, coil body 12 is unwrapped from mandrel 390. The removal of coil body 12 from mandrel 390 allows coil body 12 to reassume its secondary shape, hi some embodiments, after coil body 12 has been removed from mandrel 390, one or both of the ends of coil body 12 can be heated and melted to form rounder, more biocompatible (e.g., atraumatic) ends. Mandrel 390 can be formed of, for example, a metal or a metal, alloy (e.g., stainless steel}. In some embodiments, mandrel 390 can be formed of a plated metal or a plated .metal alloy (e.g., chrome-plated stainless steel),

FlOS, I OA-IOE illustrate an embodiment of a process that ean he used to coat- coil body 12 As shown in FIG. 10A, coil body ] 2 in its primary shape is placed within a rumen 402 of a cylindrical introducer sheath 400. At its distal end 404, introducer sheath 400 b sealed with a cap 406. and at its proximal end 408, introducer sheath 400 is connected to a female luer lock component 410. Cap 406 and/or female luer lock component 410 can include one or more gas outlets. For example, cap 406 and/or female luer lock component 410 can be shaped to include one or more gas outlets, The distal end 13 of coil body 12 is attached to cap 406, and the proximal end ! 5 of coil body 12 is attached to female luer lock component 410, so that coil body 12 is suspended within lumen 402 of introducer sheath 400. A syringe 412 containing a solution 414 including a polymer (e.g.. polyvinyl alcohol) and a gelling precursor (e.g., alginate) is then connected to introducer sheath 400 via female luer lock component 410. In some embodiments, solution 414 can include al most about 8.5 weight percent of the polymer (e.g., from about 7.5 weight percent to about 8.5 weight percent, about eight weight percent), and/or at most about 2.5 weight percent (e.g., from about 1.5 weight, percent to about 2.5 weight percent, about two weight percent) of the gelling precursor. Solution 414 is injected into lumen 402 of introducer sheath 400, so that solution 414 contacts coil body 12, and partial Iy fills

Hiiiien ^uz.

As shown in FlG 1OB, after solution 414 has been injected into lumen 402, i different syringe 416 containing a solution 418 including a gelling agent is attached to introducer sheath 400, In some embodiments, the concentration of gelling agent in solution 418 can be at least 0.01 weight percent (e.g., at least about two weight percent, at least about tlve weight percent) and/or ai most 10 weight percent (e.g., at most about live weighs, percent, at most about two weight percent, irom about one weight percent to about two weight percent). Solution 418 is then injected into lumen 402. When the gelling agent in solution 418 contacts solution 414 in lumen 402 of introducer sheath 400, the gelling agent can interact with the gelling precursor in solution 414 to form a gel coating 420 (FIG 10C) on coil body 12 that includes the gelled gelling precursor and the polymer.

Examples of gelling agents include agents including ions, such as multivalent cations (e.g., divalent cations). Examples of such agents include alkali metal sails, alkaline earth metal salts or transition metal salts that can ioπicaily cross-link with a gelling precursor. In some embodiments, an inorganic salt, such as a calcium, barium, ήnc or magnesium salt, can; be used as a gelling agent. In certain embodiments (e.g., embodiments in which a gelling precursor is alginate), a suitable gelling agent is calcium chloride. The calcium cations have an affinity for carhoxylic groups in the gelling precursor. The cations can complex with carboxylic groups in the gelling precursor, forming a gel

As shown in FKI K)C₅ cap 406 can then be removed frøra introducer sheath 400 and introducer sheath 400 can be cut (e.g., using a razor) and peeled sway; exposing a coated coil 422 formed of coil body 12 and gel coating 420. As introducer sheath 4(K) is peded away; coated coil 422 assumes its secondary shape. In some embodiments, coaled coil 422 can be used in a procedure, such as an embolization procedure.

While FIG 1 OC shows introducer sheath 400 being cut and peeled away, in certain embodiments, coated coil 422 can be removed from introducer sheath 400 using other methods. Aa an example, in some embodiments, introducer sheath 400 can be formed of one or .more bioerodibϊe and/or bioabsorbable materials, such as the mateπals described above. Coated coil 422 can be removed, for example, by eroding and/or absorbing at. least part of introducer sheath, As another example, in certain embodiments, introducer sheath 400 can be contacted with an agent (e.g., dimethyl sulfoxide (DMSO)) that causes the material of the introducer sheath to dissolve. As an additional example, in some embodiments, coaled coil 422 can be pushed aad/or pulled out of introducer sheath 400. As a rurther example, in certain embodiments, .introducer sheath 400 can include slits and/or perforations thai allow introducer sheath 400 to be peeled apart to remove coated coii 422,

In certain embodiments, after coated coii 422 has been removed irom introducer sheath 400, coated coil 422 can be further processed. As shown in FIG 10D, in some embodiments, coated coil 422 can be added into a reactor vessel 430 containing a mixture 432. Mixture 432 can include components that help to stabilize gel coating 420 by, for example, reacting with (e.g.. cross-linking with) the polymer (e.g., polyvinyl alcohol s m gel coating 420. In certain embodiments, mixture 432 can include one or more cross-linking agents. Examples of cross-linking agents include aldehydes (e.g., formaldehyde, glyoxal, ^'benzafdehyde, atercplithabkiehyde, suceina.ldehyde, glutaraldehydc). In some embodiments in which gel coating 420 includes polyvinyl alcohol one or more aldehydes can be used to react with the polyvinyl alcohol in an acetalization process. In certain embodiments, one or more acids can be used in conjunction with a cross-linking agent to react with gel coating 420. Examples of acids include strong acids (e.g.. sulfuric acid, hydrochloric acid, nitric acid) and weak acids (e.g., acetic acid, formic acid, phosphoric acid).

As FIG 1 OE shows, in certain embodiments, after gel coating 420 has been stabilised, coated coil 422 ears be added into a gel dissolution vessel 450 that contains a gel dissolution mixture 452, to form embolic coil 10. Upon contacting coated coil 423, gel dissolution mixture 452 cart remove She gelled gelling precursor from coaling 420 (e.g., by an ion-exchange reaction), thereby forming embolic coil 10. hi some embodiments (e.g., sonic embodiments in which the gelling precursor is sodium alginate), the gelling precursor can be removed from coating 42(J by ion-exchange wiih a soiisiioo of sodium hoxa-metaphosphale (e.g., from EMD Chemicals hie, Gibbstown, NJ). Ln certain embodiments, the solution can include ethvlenediarmneietraceiic acid (EiDTA), citric add, one or mere other acids, and/or one or more phosphates, hi some embodiments, the solution can have a concentration of sodi uπ? hexa-metaphosphate of at least about one weight, percent (e.g., at least about five weight percent, at least about 10 weight percent) and/or at most about 20 weight percent (e.g., at moat about H) weight percent, at most about five weight percent) in deionized water. After embolic coil 10 has been formed, embolic coil 10 can be removed from gel dissolution vessel 450, While I⁷IGS. !0A- H)E show certain methods of coating a coil body to form a coaled embolic coil, other methods can be used. For example. FIGS. 1 1 A-I l D illustrate methods that can be used to form an embolic coil such as embolic coil 50 (FIGS. 2A-2C).

As shown in FIGS, 1 1 A and H B, coil body 52 in its primary shape is placed into a lumen 502 of an introducer sheath 500, which has an inner diameter 1D3 and an outer diameter OD4.

In some embodiments, inner diameter ΪD3 can be at least 0.008 inch 5 e.g., at least 0.01 inch, at bast 0.01 5 indb, at least 0,02 inch, at least 0.021 inch, a! least 0.025 inch, at least 0.03 inch, at least 0.035 inch), and/or at most 0.038 inch (e.g., at most 0.035 inch, <H most 0,03 .mch, at most 0.025 inch, at most 0.021 inch, at most 0.02 inch, at most 0.015 inch, at most 0.01 inch). For example, in certain embodiments. inner diameter ΪD3 can be 0.01 S inch. In some embodiments, inner diameter I D3 can he 0,026 inch,

In certain embodiments, outer diameter OD4 can be at least 0.01 inch (e.g., at least 0.015 inch, at least 0.02 inch, at leas! 0,03 inch, at least 0,04 inch, at least 0.042 inch, ut least 0.05 inch) and/or ai most 0.06 inch (e.g., at most 0.05 inch, at most 0,042 inch, at mos; 0.04 inch, at .most 0.03 inch, at most 0,02 inch, at most 0.015 inch).

At its proximal end 504, introducer sheath 500 is connected to a fernsie luer lock component 506. As shown in FiG 1 IB, coil body 52 is .not suspended within lumen 502. Rather, coil body 52 is in some contact wife a wall 508 of introducer sheath 500,

As FIG. I l C shows, a syringe 510 containing a solution 514 including a polymer (eg., polyvinyl alcohol) and a gelling precursor (e.g , alginate) is then COi)BCCtC(I to introducer sheath 500 via Female luer lock component 506. Solution Shi- is partially injected into lumen 502 of introducer sheath 500, so thai solution 514 contacts coil body 52, As shown in FKI 11 D. after solution 514 ha^ Oo wed over at least a portion of coil body 52, syringe 510 is used to inject both solution 514 and coil body 52 into a vessel 520 containing a solution 524 including a gelling agent. As coil body 52 is delivered into solution 524, the interaction between solution 514 and solution 524 at the surface of coil body 52 results in the formation of a coated coil 530 formed out of coil boclv 52 and a gel coating 534. Coated coil 550 can be used in a procedure (e.g., an embolization procedure), or can be further processed (e.g., by being exposed to a reactor vessel and/or a gel dissolution vessel, as described above) io form an embolic coil such as embolic coil 50.

While FiGS. ! 0A~l OF, and 1 ϊ A-H D illustrate methods oϊ coating coil body 12 after cod body 12 has been formed into its secondary shape, in some embodiments, other methods can he used to form a coated coil As an example, in certain embodiments, coil body 12 can be coated prior to being formed into a secondary shape, As another example, irs some embodiments, wire I S cars include a coating. Th_:us, when wire ! S is used to form coil body 12, coil body 12 can also include the coating. Wire 18 can be coated using, for example, one or more spray coaling methods and/or dip coating methods. Embolic coils and methods of making embolic coils are described, for example, in Elliott et a!., U.S. Patent Application Serial No. 1 1/000,741, lϊlcd an December K 2004. and entitled "Embolic Coiis'\ which is incorporated herein by reference. Methods of forming gels, stabilizing polymers, and dissolving gels are described, for example, m Lanphere et at, U. S, Patent Application Publication No. US 2004/0096662 A I , published on May 20, 2004, and entitled "Embolization"; and iri DiCarlo et aL U.S. Patent Application Serial No. 11/11 KSl L filed on Apαi 21, 2005, and entitled "Particles'^", both of which are incorporated herein by reference, hi some embodiments, an embolic coil such as embolic coil 10 can include one or more therapeutic agents (e.g., drags). For example, coil body 12 and/or coaling 20 of embolic coil 10 can include one or more therapeutic agents. Embolic coil 10 can, for example, be used to deliver the therapeutic agents to a target site- in certain embodiments, one component of embolic coil IG (e.g., coil body 12) can include one or more therapeutic agents that arc the same as, or different from, one or more therapeutic agents in coating 20. hi some embodiments, therapeutic agents ears be dispersed within coating 20. in certain embodiments, coating 20 can be formed of one or more bioerodible and/or bioabsorhable materials, and can contain one or more therapeutic agents (e.g., heparin) that limit and/or prevent, thrombosis. When coating 20 k eroded and/or absorbed, thereby releasing the therapeutic agent into the body of the subject (e.g., during delivery), the therapeutic agent can iirøit or prevent premature thrombosis,

In some embodiments, embolic coil 10 can include one or more therapeutic agents that are coated onto coil body 12, and/or that are coated onto coating 20. In some embodiments, a therapeutic agent can be compounded with a polymer that is included in coating 20, In certain embodiments, a therapeutic agent can be applied to the surface of coil body 12 and/or to coating 20 by exposing coil body 12 and/or coating 20 to a high concentration solution of the therapeutic agent,

In some embodiments, a therapeutic agent-coated embolic coil can include a coating (e.g., a bioerodible and/or bioabsorbable polymer coating) over the surface the therapeutic agent. The coating can assist in controlling the rate at which therapeutic agent is released from the embolic coil. For example, the coating cars be in the form

2 S of a porous membrane. The coating can delay an initial hurst of therapeutic agent release. The coating can be applied by dipping or spraying the embolic coil The coating can include therapeutic agent or can be substantially free of therapeutic agent. The therapeutic agent in the coating can be the same as or different from an agent an a surface layer of the embolic coil body, and/or in a coating on she embolic coil body, and/or within the embolic coil body, A polymer coating (e.g., that is bioerodibie and/or biαabsorbabie) can be applied to an embolic coil body surface and/or to a coated embolic coil surface in embodiments in which a high concentration of therapeutic agent has not been applied to the embolic coil body surface or to the coated coil surface.

Coaimgs are described, for example, in DiMatteo et aL U.S. Patent Application Publication No. US 2004/0076582 Al₁ published on April 22. 2004, and entitled "Agent DeH very Particle", which is incorporated herein by reference. m some embodiments, one or more coils can be disposed in a therapeutic agent thai can serve as s pharmaceutically acceptable carrier.

Therapeutic agents include genetic therapeutic agents, non-genetic therapeutic agents, arsd ceils, and can he negatively charged, positively charged, amphoteric, or neutral. Therapeutic agents can be, for example, materials that are biologically active to treat physio logics I conditions; pharmaceutically active i-ompouαds; gene therapies; nucleic acids with and without carrier vectors (e.g.. recombinant nucleic acids, DMA (e.g.. naked DNA), cDN A, RNΛ_: genomic DNA, cDNA or RNA in a non-infectious vector or in a viral vector which may have attached peptide targeting sequences, antisense nucleic acids (RNA, DNA)); peptides (e.g., growth factor peptides, such as basic fibroblast growth factor (bFG F)); oligonucleotides; gene/vector systems (e.g., anything thai allows for the uptake and expression of nucleic acids): DNA chimeras (e.g., DNA chimeras which include gene sequences and encoding fur ferry proteins such as membrane translocating sequences (^tvMTS'\) and herpes simplex vims- 1 (^%tVP22"}>; compacting agents (e.g.. I)NA compacting agents); viruses; polymers; hyaluronic aiud; proteins (e.g., enzymes such, as ribozyrnes, asparaginase, and/or matrix metal ioprøtemases; cytokines such as growth factors and/or IL-I); immunologic species; nonsteroidal anti-inflammatory medications; eherausgents; pain management therapeutics; oral contraceptives; progestins; gonadotrophin-ref easing hormone agonists; chemotherapeuiie agents, and radioactive species (e.g., radioisotopes, radioactive molecules). Non~Hmiting examples of therapeutic agents include anti-thrombogenk agents; thrαmbogeπic agents; antioxidants; angiogenic and αnti-aiigiogenie agents and Factors; antiproliferative agents (e.g., agents capable of blocking smooth muscle eel! proliferation); calcium entry blockers; and survival genes which protect against cell death (e.g., anti-apoptotic BcI -2 family factors and AkI kinase). Additional example of therapeutic agents include cell fragments and cell components, such as cell membranes and cell surface receptors. Further examples of iherapeuUe agents include tissue fragments and tissue components, such as extracellular matrix and endothelial sheets.

Exemplary non-genetic therapeutic agents include: anti-thromboiic agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanirie proline argimne chloromethyiketooe); thrombus-stabilizing agents such as Factor Xi i I; antiinflammatory agents such as dexamethasone, prednisolone, eortkøsieroπe, budcsoπide, estrogen, acetyl salicylic acid, sulfasalazine and niesalamine; antineoplastic/ antiproliferative/ants-mitotic agents such as paclitaxel, 5-Ωuorouracϋ, crisp; a tin, methotrexate, doxorubicin, vinblastine, vincristine, epothiiones, cπdostatm, angiostatm, angiopeptin, monoclonal antibodies capable of blocking smooth rnuscle cell proliferation, and thymidine kinase inhibitors; anesthetic agents such as Iktocamt;, bupivacaine and ropivacaiπe; ants-coagυlants such as D-Phe-Pro-Arg chioromethy! ketone, m^ RCJD pcptide-containing compound, heparin, hirudin, amithrombin compounds, platelet receptor antagonists, aiitt-lhrombiπ antibodies, anti-piatelct receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors and ϋek antiplatelet factors or peptides; vascular cell growth promoters such as growth factors, transcriptional activators, and translational promoters; vascular ceil growth inhibitors such as growth factor inhibitors (e.g., PDOF iαhibitnr-Trapidil), growth factor receptor antagonists, transcriptional repressors, translatiβna! repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, birunetionai molecules consisting of a growth factor and a eyiotoxin, bi functional molecules consisting of an antibody and a eytoloxin; protein kinase and tyrosine

01 kinase inhibitors (e.g., tyrphostins, genistein, quinoxalin.es); prostacyclin analogs; cholesterol-lowering agents; angiopoielins; antiπύerυbiaS agents such as triclosan, cephalosporins, aminoglycosides snό nitrofurantoin; cytotoxic agents, cytostatic agents and cdl proliferation affectors; vasodilating agents; and agents that interfere with endogenous vasoactive mechanisms.

Exemplary genetic therapeutic agents include: an ti -sense DNA and RNA; DNA coding for anti-sense RNA, tRNA or fRN A to replace defective or deficient endogenous molecules, angiogenic factors including growth factors such as acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor u and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor a. hepatocyte growth factor, and insulin like growth fector, cell cycle inhibitors including CD inhibitors, thymidine kinase CTR'') and other agents useful for interfering with cell proliferation, and the family of bone morphogenic proteins CBMPV), including BMP2, BMP3, BMP4, BMP5, BMPC (Vgrl ), BMP? (OPl ), BMP8, BMP9, BMPI O, BMH , BM P 12,

BMP13, BMP14. BMPI 5, and BMP16. Currently preferred BMP's arc any of BMP2, BMP3, BMP4₅ BMP5, BMP6 and BMP7. These dinierie proteins can be provided as hornodmiers, heferodimers, or combinations thereof, alone or together with other molecules. Alternatively or additionally, molecules capable of inducing an upstream or downstream effect of a 3MP can be provided. Such molecules include any of the "hedgehog" proteins, or the DNA's encoding them.

Vectors of interest for delivery of genetic therapeutic agents include: plasrrrids; viral vectors such as adenovirus (AV), adenoassociated virus (AAV) and lenfivirus; and non-viral vectors such as lipids, liposomes and eaikmic Lipids. Cells include cells of human origin (autologous or allogeneic), including platelets and stem cells, or from an animal source (xenogeneic), which can be genetically engineered if desired to deliver proteins of interest.

Several of the above and numerous additional therapeutic agents appropriate for the practice of the present invention are disclosed in ICαnz et a!., U. S. Patent No, 5,733,925, assigned to NeoRx Corporation, which is incorporated herein by reference. ^'Therapeutic agents disclosed in this patent include the following:

2S "Cytostatic agents" (i.e., agents that prevent or delay eel! division m proliferating ceils, for example, by inhibiting replication of DMA or by inhibiting spindle fiber formation). Representative examples of cytostatic agents include modified toxins, methotrexate, adriamycin, radionuclides (e.g., such as disclosed in Fritzberg ei a!,, U.S. Patent Na. 4,897,255), protein, kinase inhibitors, including staurosporøi, a protein kinase C inhibitor of the following formula:

as well as diindoioaikaloids having one of the following genera! structures

as well as slhsulatisrs of the production or activation of FGF-bcta, including ^'Tamoxifen and derivatives of functional equivalents (e g., plasmin, heparin, compounds capable of reducing the level or inactivating the lipoprotein Lρ(a) or the glycoprotein δpolipoprotein(a)) tiiereof, TGF-beta <u" functional equivalents, derivatives or analogs thereof, .suramin, nitric oxide releasing compounds (e.g., nitroglycerin) or analogs or functional equivalents thereof, pacHtaxeϊ or analogs thereof (e.g., taxotere). inhibitors of specific enzymes (such as the nuclear enzyme L)NA topoisomεrase 1! and DNA polymerase, UNA polymerase, adeπyi guaiiyl cyclase), superoxide disrnutase inhibitors, terminal deoxynucleotidyl-transierase, reverse transcriptase, an.ti sense oligonucleotides that suppress smooth muscle cell proliferation and the like. Other examples of "cytostatic agents" include peptidic or mimetic inhibitors (i.e., antagonists, agonists, or competitive or πoπ-comρeiitive mhibitors) of eel hilar factors that may (e.g., in the presence of extracellular matrix) trigger proliferation of smooth muscle cells or pericytes; e.g., cytokines s_ve,g.._s interieukins such as IL- i }_; growth factors (e.g., PDOF, TGF-alpha or -beta, tumor necrosis factor, smooth muscle- and eπdothelial-derived growth factors, i.e., cπdothclin, FGF), homing receptors (e.g., for platelets or leukocytes)_., and extraccHular matrix receptors (e.g., integrins). Representative examples of useful therapeutic agents in this category of cytostatic agents addressing smooth muscle 5 proliferation include: subfragments of heparin, ttiazolopyπniidmε (trapidil; a PDGF antagonist^'}, iovastatin, and prostaglandins ^"EJ or 12.

Agents that inhibit the intracellular increase in eel! volume (i.e., the tissue volume occupied by a ceil), such as cytoskeletal inhibitors ur metabolic inhibitors. Representative examples of cytoskeletal inhibitors include colchicine, vinblastin,

10 eytochalasins. paclitaxcl and the like, which act on microtubule and microfilament .networks within a cell. Representative examples of metabolic inhibitors include staurosporin. iricholhecenes. and modified diphtheria and ricin toxins, Pseικloraonas exotoxin and the like. Trichoiheeenes include simple trichothcceπcs (Le., those that have only a centra! xesquiterpenoid structure) and macrocy ic trichotheeenes (i.e.,

H> those that have an additional rnacroeydie ring), e.g., a verruearins or roridins. including Verruearin A. Verruc-arin B, Verrucarin J (Satraioxm C), Roridiα A, Roridia C, Rυridin D, Roridm E (Satratoxin D), Roridin H.

Agents acting as an inhibitor that blocks cellular protein synthesis and/or secretion or organization of extracellular matrix (i.e., an "anti -matrix agent^"5).

20 Representative examples of "anti-matrix agents" include inhibitors (i.e., agonists and antagonists and competitive and non-competitive inhibitors) of matrix synthesis, secretion and assembly, organizational cross-linking (e.g., transglutaminases cross- linking collagen), and matrix remodeling (e.g., following wound healing). A representative example of a issefui therapeutic agent in this category of ant i -matrix 5 agersis is colchicine, an inhibitor of secretion of extracellular matrix. Another example is tamoxifen for which evidence exists regarding its capability to organize and/or stabilize as well as diminish smooth muscle cell proliferation following angioplasty. The organization or stabilization may stem from the blockage of vascular smooth muscle cell maturation in to a pathological! y proliferating form,

30 Agents that are cytotoxic to cells, particularly cancer cells. Preferred agents arc Roridin A, Pseudomonas exotoxin and the like or analogs or ftmctional equivalents thereof. A plethora uf sueh therapeutic agents, including radioisotopes and the like, have been identified and are known m the art. In addition, protocols for the idenulkation of cytotoxic moieties are known and employed routinely in the art. A number of the above therapeutic agents and several others have also been 5 identified as candidates for vascular treatment^' regimens, for example, as agents targeting restenosis. Such agents include one or more of the following: ealeium- chatvnel blockers, including benzoihiazapmes (e.g.. diltiazem, elerttlazem}; dihydropyridiπes (e.g., nifedipine, amlodipine, nicardapine); phenylalkyl amines (e.g., verapamil): serotonin pathway modulators, including 5-HT antagonists (e.g.. iθ ketanserin, naltidrofuryl) and 5-ilT uptake inhibitors (e.g., fluoxetine-}; cyclic

.nucleotide pathway agents, including phosphodiesterase inhibitors (e.g., cilosiaxole, dipyridamole), adenyiate/guanylate cyclase stimulants (e.g., forskolirt), and adenosine analogs; catecholamine modulators, including α-antagomsls (e.g., prazosin, bunazosine), β-aatagoϊiists (e.g.. propranolol), and α/β-antagonists (e.g., labetaloK ii> ciu'vcthiol); cjκiothelin receptor aiHagoπists; nitric oxide d(.πκ>rs/rdeasiog molecules, including orgajiic nitrates/nitrites (e.g., nitroglycerin, isosorbide dinitrate, sπiyl nitriie), iπorganie niiroso compounds (e.g., sodium niiropnisside), sydnorsiniines (e.g., molsidomine, Ihisidomine), nonoaies (e.g., diazeniuiϊϊ dictates, NO adducls of alkanedianiines), S~nitroso compounds, including low molecular weight compounds

20 (e.g., S-nitRBO derivatives of captopril, glutatliione and N -acetyl penicillami e} and hi gb molecular wtight compounds (e.g., S-nitroso derivatives of proteins, peptides, oligosaccharides, polysaccharides, synthetic polymers/oligomers and natural poh'T?iers/oligoniers), C~ni.roso~, O-nitτoso- and N-nif.roso~ct>mpounds, and L- argiπine; ACE inhibitors (e.g., cilazapril, fosinopril, enalapril); ATll-receptor

26 antagonists (e.g., saraiasin, losaitin): platelet adhesion inhibitors (e.g., albumin, polyethylene oxide): platelet aggregation inhibitors, including aspirin and thienopyridme (ticlopidine, clopidogiel) and GF ϊlb/IIIa inhibitors (e.g., abeiximab, epiiifibatide, tiroriban, ■ritergrslin); coagulation pathway modulators, including heparinoids (e.g., heparin, low molecular weight heparin, dextran sulfate, β-

30 cyelodextrin tetradecasul&te), thrombin inhibitors (e.g., hirudin, hirulog, PPACK. (I)- phe~I.-propyl-L-arg-chloromethyikc.one}, argalroban), FXa inhibitors (e.g., an.iislatin, TAP (tick, anticoagulant peptide)}, vitamin K. inhibitors (e.g., warfarin}, and activated protein C; eyclooxygenase pathway inhibitors (e.g., aspirin, sbuprolen, flurbiprofen, iπdomeihaciii, sulfinpyrazone); natural and synthetic corticosteroids (e.g., dexamεtliasoπe, prednisolone, methprednisαlone, hydrocortisone); lipoxygenase pathway inhibitors (e g., nordibydrogυairetic acid, caffeic acid: leukotriene receptor antagonists; antagonists of f:- and P-selecifna; inhibitors of VCAM-! and ICAM-I interactions; prostaglandins and analogs thereof, including prostaglandins such as PGE! and FG12; prostacyclin analogs (e.g., ciprostene, epoprosteπoL carbacyclin, iloprost, beraprost); macrophage activation preventers (e.g.. bisphosphoπaies); IiMG- CoA reductase inhibitors (eg., lovastatin, pravastatin, fhrvastatin, simvastatin, eerivasiatm); llsh oils and αmega-3- fatty acids; free-radical scavengers/antioxidanLs (e.g., prohucoL vitamins C and E, ebseien. relinoic acid (e.g., trans-retimπc acid), SC)D miniics); agents affecting various growth factors including FCJF pathway agents (e.g., bPGF antibodies, chimeric fusion proteins), PDGF receptor antagonists (e.g., trapidil), IGF pathway agents (e.g., somatostatin analogs such as angiopcptin and ocreoride), TGP-β pathway agents such as poiyanionie agents (heparin, fucoidin). decoTin, and TGF-β antibodies, EGF pathway agents (e.g., EGF antibodies, receptor antagonists, chimeric fusion proteins), TNF-α pathway agents (e.g., thalidomide and analogs thereof), thromboxane A2 (TXA2) pathway modulators (e.g.. sulotroban, vapiprost, dazoxiben, πdogrel), protein tyrosine kinase inhibitors (e.g., tyrphostin, genistdn, and quinoxalinG derivatives); MMF pathway inhibitors (e.g., rrsariraastai, jlomastai, metastat), and cell motility inhibitors (e.g., cytochalasin B); antiproliferative/ antineoplastic agents including antimetabolites such as purine analogs (e.g., 6-mereaptopurme), pyriπiidine analogs (e.g., eyiarabiπe and S- iluorouracil) and methotrexate, nitrogen mustards, a iky! sulfonates, ethyleniraines, antibiotics (e.g., daimorubicin. doxorubicin, daunomyein, bleomycin, mitomycin, penicilliuϋ, cephalosporins, ciprofaixin. vancomycins, aminoglycosides, quinolones, polymyxins, eτythτomycins, tertacyelines, chloramphetαicols, clindamycins, linomycins, sulfonamides, and their homologs, analogs, fragments, derivatives, and pharmaceutical salts), nitrosoureas (e.g., carmustine, lomustinc) and cisplatiπ. agents affecting microtubule dynamics (e.g.. vinblastine, vincristine, colchicine, paclitaxci, epothikme), caspase activators, proteasome inhibitors, angiogenesis inhibitors (e.g., endosiatin, angiostatiri and squalarøine), and rap&myeϊtk cerivasiatin, fiawpiridol and suramin; matrix deposiϋoa/organization pathway inhibitors (e.g., hakvfugioone or other quinnzolinone derivatives, tranilast); endothelialization facilitators (e.g., VEGF and RGD peptide); and blood rheology modulators (eg., pentoxifylline).

Other examples of therapeutic agents include anti-ttrroor agents, such as doeetaxcL alkylating agents (e.g., mechlorethamine, chlorambucil cyclophosphamide, meiphalan, ifosfamide), plant, alkaloids (e.g., etoposkle), inorganic ions (e.g., eisplatm), biological response modifiers (e.g., interferon)_* and hormones (e.g., tamoxifen, flutaniide), as well as their bomologs, analogs, fragments, derivatives, and pharmaceutical, salts.

Additional examples of therapeutic agents include organic-soluble therapeutic agents, such as πiithramycin, cyelosporine, and pϋcamycin. Further examples of therapeutic agents include pharmaceutically active compounds, anti-sense genes, viral, liposomes and eatioπie polymers (e.g., seleeted based on. the application_.^ bioiogicuUy active solutes (e.g., heparin), prostaglandins, prosteyclins, L-arginine> nitric oxide (NO) donors (e.g., Hsidonime, molsidomine, NO-proteiα adducts, NQ- poiysacchaπde adducts, polymeric or oligoraeric NO adducts or chemical complexes), enoxapaπn, Warafin sodium, dicumaroi, inie.rfero.ns, cliymase iahibitors (e.g., Tranilast}, ACE inhibitors (e.g., Eaalapril), serotonin antagonists, 5-HT uptake inhibitors, and beta blockers, and other antitumor and/or chemotherapy drugs, such as BiCNU, busuifan, carboplatinum, cisplatinυni, Cytoxan, DTK.?, iludarabine, niiioxantrone, velban, VP-16, herceptin, ieustatin, navelbine, rituxan, and taxotere. Therapeutic agents are described, for example, in DLMatteo et ai., Li, S. Patent Application Publication No. US 2004/0076582 AL published on April 22, 2004, and entitled "Ageat Delivery Particle", in Pinchuk et ai., U.S. Patent No. 6,545,097, and in Schwarz et ai., U.S. Patent No.. 6,368,658, all of which are incorporated herein by reference. Examples

The following examples are illustrative and not intended to be limning.

.e l :

5 Nine embolic coils were prepared. The following procedure was used tor preparing each coil.

Λ piatimuxi helical coil (a GDC*-Ϊ8 Standard coil, UPN MOO335O83O4O, from Boston Scientific Corp.) having an outer diameter of 0,015 inch (0.381. millimeter} hi its primary shape, an outer diameter of six millimeters in its secondary shape, and a 0 Sength of 200 millimeters in its primary shape, was cut so ihaf its primary shape length was about 100 millimeters. The coil from a VortX^{^'}-lS Diamond-Shaped Fibered Platinum Coil system (UPN MOOl 3822030, from Boston Scientific Corp.) was removed from the introducer sheath of the system. The GDC*- 18 Standard coil was then inserted into the dislal end of the introducer sheath. s A polymer solution including eight percent by weight polyvinyl alcohol (from

Sigma-Aldrieh) and two percent by weight sodium alginate (from FMC Biopolymcr, Philadelphia, PA) in deionized water was prepared. The polymer solution was then autoekrved using a benehtop autoclave (from Tuitnauer Co. Ltd., Hauppauge, NY), The polymer solution was autoclaved for one standard cycle of 12PC for 30 minutes. D The polymer solution was allowed to cool to room temperature (25^''''C), and then was aspirated into a syringe (from Becton Dickinson),

^'The syringe was attached tα the iuer fitting of the coil introducer sheaih, and Che polymer solution was gently injected so that it filled the interslitiaf space of the coil introducer sheath, thereby surrounding the coil, 6 ^'The distal end of the coil introducer sheath was Inserted into a beaker containing a calcium chloride solution including one percent by weighs calcium chloride in ddonized water.

The polymer solution was forcefully injected into the calcium chloride solution from the syringe. The forceful ejection also caused the coil to he injected 0 into the calcium chloride solution.

J 3 The polymer solution formed a coating around the coil when the poi>τ.πer solution contacted the calcium chloride solution. Without wishing to be bound by theorv, it is believed that the coating was formed of cross-linked al ^ginate and polyvinyl alcohol. A reaction solution of including four percent by weight formaldehyde (from

EMD Chemicals inc. (formerly EM Industries, Inc. and EM Science), Gibbstovvn, NJ) and 20 percent by weigh! sulfuric acid (from EN4D Chemicals inc. (formerly EIv-¹I Industries, iπe. and EM Science), Gibbstown. Nj) in deionized water was prepared.

The reaction solution, which was contained in a flask, was hεatsd with shaking in a water shaker bath at 65^CC. The shaker hath was an orbital shaker bath that restrained the reaction flask during shaking.

The coated coil, was removed from the calcium chloride solution and. placed in the Il ask containing tiiε reaction solution, which was located in the shaker bath, The shaker bath was an orbital shaker bath that restrained the reaction flask during shaking. The coated coil remained in the flask for 20 minutes at 65°C, as the flask was being shaken by the orbital shaker bath, until the coating in the coil turned white. Without wishing to be hound hv theorv. it is believed that when the eoaun-i on the coil turns white, the formaldehyde in the reaction solution has cross-linked the polyvinyl alcohol in the coil coating. The coated coil was then removed from the flask and was rinsed m deionized water two times, for 15 minutes each time.

The coaled coiJ was stirred in a solution including deionized water and five percent sodium hexametaphosphate, at room temperature (25^"'1C-) for 30 minutes.

The coated coil was then removed from the sodium hexametaphosphate solution, and was rinsed in deioπb.ed water two times, for 15 minutes each time.

The above process was repeated to produce a total of nine embohc coils.

FIGS. 12- 16 are micrographs of some of the embolic coils produced by the above method, taken using & microscope. FIG. 12 is a micrograph of aα embolic coil at I Ox magnification, FIG 13 is a micrograph of an embolic coil at 3Ox magnification, FJG. 14 is a micrograph of an embohc coil at 1 Ox magnification, FiG. 15 is a micrograph of an embolic coil at !Ox magnification, and FI(X 16 is a micrograph of an embolic coil at 1Ox magnification.

FIG. i? is mi SEM image, at 20x magnification, of some of the embolic coils produced by the above method. FIGS. 18Λ-18F arc SEM images of a location ("Location #1") on one of the embolic coiis of PlG. 17, at 55x magnification (FIG 18A), H)Ox magnification (PIG. 18B), 250x magnification (FIG. 18C). 500s magnification (FIG 18D), 100Ox ioagnilkaiion (FIG. 18K). and 2000x magnification (FiG, ϊ 8F).

FIGS. Ϊ9A-19E are SEM iπiages of a location ("Location #2") on one of the embolic coils of FIG 1 7, at 55x magnification (FIG. 19A), 25Ox magnification (FIG 19B), 500x magnification (FIG. H)C)₅ 100Ox magnification (FIG. 19D), and 200Ox magnification (FIG. 19E).

FfGS. 20A-2OE are SEM images of a location ("Location #3") on oαe of the embolic coils of FIG. 17, at 55x magnification (FIG, 20A), 25Ox magnification (FIO. 20B), 50Ox magnification (FlG 20C), H)OOx magnification (FlG 20D), and 2000x rnagmlieation (FIG 20E).

FIGS. 2! A-21D are SEM images of a location ("Location $4"} on one of the embolic coils of FIG 17. at 50x magnification l FIG 2! A), KKk magnification (FIG 21 S), 250x magnification (FlG 2 ! C), and 500x magniiicaϋon (FIG 21 D).

Example 2:

One embolic coil was prepared according to the following procedure. A bare coil {a GlX^-18 Standard coil, UPN MOO335O83Q40, from Boston Scientific Corp.) was dip-coated in a solution including two percent by weight alginate (from FMC Biopolymer. Philadelphia, PA), at 25^fJC. The coil remained in the alginate solution fat K) seconds.

The coil was then dip-coated in a solution including one percent by weight calcium dilonde (Iron's BMD Chemicals inc. (formerly EM Industries, l.oc. and FM Science), Gibbstowri, Ni), at 25°C. The coil remained in the calcium chloride solution for 10 seconds. The resulting coated coil had an uneven coaling including beads of gelled alginate.

Example 3: Five embolic coils were prepared. The following procedure was used for preparing each coil.

The coil from a VαrtX^{^}-18 Diamond-Shaped Fibered Platinum Coil system (IJPN M OD 13822030_s from Boston Scientific Corp.) was removed from the introducer sheath of the system. A G ixf^'-l S Standard coil (UPN M00335083O40, from Boston Scientific Corp.) was then inserted into the distal end of the introducer sheath, which included a luer lock on its proximal end,

A syringe containing a solution including deiomzed water ami two percent by weight alginate (from FMC" Biopol>τner, Philadelphia, PA) was used to inject die alginate solution through the luer lock and into the introducer sheath, thereby surrounding the coil with the alginate solution.

The tip of the introducer sheath was then submerged into a bath of a solution including dcionizcd water and one percent by weight calcium chloride (from EMD Chemicals Inc. (formerly EM Industries, Inc. and EM Science), Gϊbbstown, NJ).

The syringe was then used to inject the alginate solution forcefully., thereby forcing both the coil and the alginate solution into the calcium chloride solution.

The above process was repeated to produce a total of five embolic coils.

The resulting coated coils bad relatively uniform coatings, each of which had an outer diameter that was equal to the inner diameter of the introducer sheath (0.024 inch),

Other Embodiment's

While certain embodiments have been described, other embodiments are possible.

As an example, m some embodiments, an embolic coil can include a coating having a certain pore structure. For example, FIG 22 shows an embolic coil 600 including a coil body 602 and a coating 604 including pores 606. Coating 604 includes an exterior regiors Rl with a thickness that is about 50 percent of the thickness of coating 604, and an interior region. R2 with a thickness that is about 50 percent of the thickness of coaling 604. in some embodiments, the density of pores 606 (the number of pores 606 per unit volume) in region R i can be higher than the density of pores 606 in region Rl In certain embodiments, the average size of pores 606 in region R2 can be higher than the average size of pores 606 in region R L

As another example, in some embodiments, an embolic coil can include a non- porous coating. For example, FIGS. 23 A -23 C show an embolic coil 700 including a coil body ^"702 and a non-porous coating 704, As a further example, in certain embodiments, an embolic coil can include a coil body thai is coated in certain portions and that is not coaled in other portions. As an example, PlCi. 24A shows an embolic coil 71.0 including a coil body 712. Two portions 714 ami 716 of embolic coil 710 include coatings 718 and 720, respectively, while a middle portion 722 of embolic coil 7 j 0 does not include any coatings. As another example, FKl 24B shows an embolic coil 730 including a coil body 732. A middle portion 734 of embolic coil 730 includes a coating 736 while two other portions 738 and 740 of embolic coil 730 do not include any coatings,

As another example, in some embodiments, an embolic, coil can include multiple (e.g., two, three, four, five, 10, 20) coatings. As a farther example, in certain embodiments, an embolic i-o.il, coil body, and/or wire can be coated by spraying the embolic coil, coil body, and/or wire with one or more compositions (e.g., solutions), In some embodiments, an embolic coil, coil body, and/or wire can be coated by dipping Ae embolic coil, coil body, and/or wire into one or more compositions, such as described above in Example 2. Ln certain embodiments, an embolic coil, coil body, and/or wire can be coated by disposing the embolic coil, eoiS body, and/or wire in a container (e.g., mi introducer sheath), and placing the container into a vessel containing a composition (e.g., a polymer solution, a gelling precursor solution). In some embodiments, ars embolic coil coil body, and/or wire can be coated by forming a sheath of a coating material and placing the sheath aroursd the embolic coil, coil body, and/or wire, in certain embodiments, the sheath can be shrunk (e.g., heat- shrunk) around the embolic coil, coil body, and/or wire.

As an additional example, a coated embolic coil can have a circular cross- section and/or a non-circular cross-section. For example, a coated embolic coil can have a polygonal cross-section (a non-circular cross-section that is a defect plane ^■figure bounded by straight Sines). As an example, FiG 25A shows a coated embolic coil 750 including a coil body 752 and a coating 754. Coated embolic coil 750 has a square cross~.seef.ioo. As shown in FlG 2SB, a coated embolic coil sue!) as coated embolic coil ⁷50 can be formed, for example, by coating coil body 752 while coil body 752 is disposed within a lumen 758 of a container 756 (e.g., a sheath) having a square cross-section.

As a fbrther example, in some embodiments, a.n embolic coil including a coil body and a coating can be stored in saline and/or dekmivseti water, which can hydrate the coating. As anoiher example, in certain embodiments, a coated coil cars be dried.

Examples of methods that can be used to dry a coated coil include lyophilization. fieeze-drying, and allowing the coil to dry in the air. A coated coil can be dried, for example, to enhance the attachment of a delivery wire to the coil, and/or to enhance loading of the coil into a sheath and/or other delivery device (e.g., a catheter). As an additional example, while methods of eoatmg a coil using an introducer sheath have been described, in some embodiments, a coil can be coated while the coil is disposed within a different type of container. For example, a coil can be coated while the coil is disposed within a lumen of a catheter.

As a further example, while methods of coating a coil body by delivering certain solutions into a container (e.g., an introducer sheath) containing the coil body have been described, in some embodiments, a coil body can be coated by delivering one or more other materials into the container. .As an example, in certain embodiments, a coil body can be coated by delivering a cross-linking agent into a container containing the coil body. As another example, in some embodiments, & coil body can be coated by delivering a therapeutic agent, into a container containing the coif body. As another example, in certain embodiments, a mixture (e.g., a solution, such as a solution including polyvinyl alcohol and alginate) can be contacted with a porosHy-enhaπcing agent, such as starch, sodium chloride, or calcium chloride. Porosity-enhancing agents ears increase the number and/or sizes of pores in coatings that are formed irora the mixture.

As a further exam pie, in some embodiments, an embolic coil can have at least two (e.g., three, four, five, 10, 15, 20) different outer diameters. Embolic coils with different outer diameters are described, for example, in Elliott et a!.. U.S. Patent Application Serial No. i 1/000,741, filed on December 1 , 2004. and entitled "Embolic Coils", which is incorporated, herein by reference.

As an additional example, while embodiments have been shown m which the pitch of a coil body is substantially the same in different regions of the coil body, in certain embodiments, the pitch of a coil body can differ in different regions of the coil body. For example, some regions of a coil body cars have a pitch of 0.002 inch, while other regions of an embolic coil can have a pitch of 0.004 inch.

As a further example, in some embodiments, an embolic coil can he a pushable embolic coil. The embolic coil can be delivered, for example, by pushing the embolic coil oist of a delivery device (e.g., a catheter} using a pusher wire, Pushable embolic coils arc described, for example, in Elliott et a!.. U.S. Patent Application Serial No. 1 1/000,741, filed on December L 2004, and entitled "Embolic Coils", which is incorporated herein by reference,

As another example, while an electrolytically detachable embolic coil has been shown, in some embodiments, an embolic coi! can alternatively or additionally be a chemically detachable embolic coil and/or a mechanically detachable embolic coil, In certain embodiments, an embolic coil can be a Guglielmi Detachable Coil (GDC) or an Interlocking Detachable Coil (ΪDC), In some embodiments, an embolic coil car; be a thermally detachable coil. As an example, in certain embodiments, an embolic coil can be attached to a pusher wire by a plastic loop, At a target site, a heating element can be used to heal the plastic loop, thereby melting the loop miό releasing the coil into the target site. In some embodiments, an embolic coii can be a hydraiilically detachable coil. As an example, in certain embodiments, a proximal end

4i of an embolic coil can be attached to a holder on a pusher wire using an interference tit. Once the embolic coil is at a target site, saline can. be injected into the holder under high pressure, thereby causing the embolic coil to become detached from the holder and delivered into the target site. Detachable embolic coils arc described, tor example, in Twyford. Jr. et a!.. U.S. Patent No. 5,304, 195, and Gυglielmi et at, U.S. Patent No. 5,895,385. both of which are incorporated herein by reference.

As ixn additional example, while detachable embolic coils have beet^'s described, in. some embodiments, an embolic coil cars be injectable, Ln certain embodiments, an injectable embolic coil can be disposed within a delivery device (e.g., a catheter) that is used to deliver the embolic coil to a target site. Once at the target site, the injectable embolic coil cars be delivered into tbs target site using a high-pressure saline Hush thai pushes the embolic coil out the oi^' the ddivery device, In some embodiments, a pusher wire can be used in conjunction with a saline flush Io deliver an embolic coil to a target site. In certain embodiments, a pusher wire may not be used in conjunction with a saline flush to deliver an embolic coil to a target site.

As a further example, i.rs certain embodiments, a coil can bε at least partially delivered from a delivery device, and. then can be retracted back into the delivery device. As another example, irs certain embodiments, an embolic coil can be loaded into a delivery device using an introducer sheath. For example, FlG 26 illustrates the transfer of a coated embolic coil 800 from an introducer sheath 810 into a catheter 820. A hub 830 located at the proximal end 840 of catheter 820 directs the placemen! of introducer sheath H K). After introducer sheath H l O has been placed in hub 830, a pusher SSO is used to push embolic eoij 8Qf) out of introducer sheath S 10 and into catheter 820,

As an additional example, in some embodiments, multiple (e.g., two, three, four) embolic coils can be delivered using one delivery device.

As a further example, in certain embotiimenis. a treatment site can be occluded by using embolic coils in conjunction with other occlusive devices. For example, embolic cods cars be used with embolic particles, such as those described in Buiser et aL U.S. Patent Application Publication No. US 2003/0185896 A i, published on October 2, 2003, and in Lanphere et aL, U.S. Patent Application Publication No. US 2004/0096662 A L published on May 20. 2004, both of which are incorporated herein by reference, 1« some embodiments, embolic coils can be used irs conjunction with one or more embolic gels. Embolic gels are described, for example, in Richard et aL. U.S. Patent Application Serial No, 10/927,86S₅ filed cm August 27, 2004, and entitled "Embolization^ which is incorporated herein by reference,

As an additional example, in some embodiments, an embolic coil can imjUxie one or more radiopaque markers. The radiopaque markers can, for example, be attached to one or more windings of the embolic coil.

As a farther example, in certain embodiments, a tapered introducer sheath can be used to form a coated coil and/or io deliver a coil (e.g., a coated coil}. For example, F KJS. 27 A and 27B show a tapered introducer sheath 900 with a lumen 902. Introducer sheath 900 is attached to a hub 901 . As shown in FIG 27B, introducer sheath 900 has an inner diameter ID4, an outer diameter OD5 in one region. 904 of introducer sheath 900, and an outer diameter C)Do m another region 905 of introducer sheath 900. Region 904 is located at a distance D from the distal end 910 of introducer sheath 900, in certain embodiments, distance D can be about 0, 1 inch. l.π some embodiments, inner diameter LD4 can he at least 0,008 inch and/or at most 0.038 inch {e.g., 0,023 inch), In certain embodiments, outer diameter 01⁾5 can be at least 0.01 inch and/or at most QM inch {e.g., 0,0385 inch). In some embodiments, outer diameter ODό can he at least 0.01 inch and/or at most 0.059 inch (e.g., 0.0335 inch). An introducer sheath can include a tapered inner diameter, a tapered outer diameter, or both a tapered inner diameter and a tapered outer diameter. As another example, in some embodiments, an embolic coil coating can have a relatively smooth surface. An embolic coil coating with a relatively smooth surface can be formed, for example, by placing an embolic coil into the lumen oi^'an introducer sheath having a relatively smooth .interior surface, and coating the embolic coil while the embolic coil is in the introducer sheath. As an additional example, in some embodiments, an embolic coil coating can have a relatively rough surface, hi certain embodiments, as the roughness of the surface of an embolic coil coaling Increases, the embolic coil coating can become more thrombogenic. in some embodiments, an embolic coil coaling with a relatively rough surface can be formed by placing an embolic coil into the lumen of an introducer sheath having a relatively rough interior surface, and coating the embolic coil while the- embolic coi! is in the introducer sheath. The interior surface of an introducer sheath car. be roughened using, for example, a HIe to file materia! away from the interior surface, and/or a micrαbiasting method Sn certain embodiments, the surface of an embolic coating can be roughened after the coating has been formed For example, a micro blasting method and/or a filing method can be used to roughen the surface of the coaling.

Other embodiments are in the claims.

Claims

WHAT ΪS CLAIMED IS:

1 . A method of coaling a coil, the method comprising: injecting a materia) into a container containing the cosh and forming the material into a coating that is supported by the coil. s

2. The method of claim 1, wherein the coil is an embolic coil.

3. The method of claim 1 , wherein the material comprises a polymer.

o 4, Tlic method υi^' claim 3, wherein the polymer comprises a polysaccharide,

5. The method of claim 3, wherein the polymer comprises alginate.

s 6, The method of claim 3, wherein the polymer comprises polyvinyl alcohol.

7. The method of claim I, wherein the material comprises at least two di ffererit polymers. 0

S. The method of claim I, wherein the material composes a first polymer and a gelling precursor.

9. The method of claim 8, wherein forming the coating comprises cross- 5 hnking the first polymer.

10. The method of claim 8, wherein forming the coating further comprises removing at least a portion of the gelling precursor.

1 1. The method of claim 8, wherein forming the coating comprises contacting the material with a gelling agent.

12. The method of claim 1 1 , wherein contacting the material with a gelling agent comprises delivering the gelling agent into the container.

13. The method of claim 8, wherein forming the eoatirsg comprises eontaetirsg the materia! wit.li a cross-linking agent.

14, The method of claim 13, wherein contacting the materia! with a cross-

Linking agent, comprises delivering the cross-linking agent into the container.

15. The method of claim L further comprising contacting the material with a therapeutic agent

16. The method of claim IS, wherein contacting the .material with a therapeutic agent comprises delivering the therapeutic agent into the container.

1 ?. The method of claim L wherein the material comprises a therapeutic agent.

18. The method of claim 1 , wherein the coating is porous.

19. The method of claim 1 , wherein the container comprises a tubular member.

20. The method of claim i, further comprising removing die coil torn the container.

2 ! . The method of claim 20, wherein the container comprises a. bioerodible or bioabsorbable materia}, and removing the coil from the container comprises eroding or absorbing the container.

22, A method of coating a eoiL the method comprising: contacting the coii with a composition comprising a first polymer and a gelling precursor; and forming fee composition into a coating that is supported by the coil.

23. The method of claim 22, wherein the composition is in the form of a solution,

24, The method of claim 22, wherein contacting the coil with a composition comprising a. first polymer and a gelling precursor comprises adding the composition into a container containing the coil.

25. The method of claim 24, wherein the container comprises a tubular member.

26. A.TΪ article comprising: a substrate; and a porous material supported by the substrate, wherein the article is in the shape of a coil.

27, The article of claim 26, wherein the article is in the shape of at) embolic coii.

28. AvH article, comprising: a substrate; and a material supported by the substrate, the material comprising a first polymer and a gelling precursor, wherein the article is in the shape of a. coil.

29. The article of claim 28, wherein the article is in the shape of an embolic coil.