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This application claims priority under 35 U. S. C. § 119 to USSN 60/822,545, filed August 16, 2006. the contents of which are hereby incorporated by reference.

The disclosure relates to polymer particles including a covalently bonded chemical species, as well as related compositions and methods.

Agents, such as therapeutic agents, can be delivered systemic-ally, for example, by injection through the vascular system or oral ingestion, or they can be applied directly to a site where treatment is desired, In some cases, particles are used to deliver a therapeutic agent to a target site. Additionally or alternatively, particles may be itsed to perform embolization procedures and/or to perform radiotherapy procedures.

Summary in one aspect, the invention features a particle that includes & polymer a chemical species covalently bonded to the polymer. The polymer includes vinyl alcohol monomer units, and the chemical species is selected from polymers, oligomers and monomers. The particle has a maximum dimension Of S ₅ OOO microns or less. fn another aspect, the invention features a particle that includes a polymer, a chemical species covalently bonded to the polymer and a therapeutic agent. The polymer includes at least five weight percent vinyl alcohol monomer units and at least five weight percent vinyl formal monomer units. The chemical species is selected from polymers, oligomers and monomers and the particle has a maximum dimension of 5,000 microns or less.

In a further aspect, the invention features a composition that includes a carrier ikiid and a plurality of particles in the carrier fluid. At least some of the plurality of particles have a maximum dimension of 5,000 microns or less and include a polymer and a chemical species eovaiently bonded to the polymer, The polymer includes vinyl alcohol monomer units, and the chemical species is selected from polymers, oligomers and monomers. in an additional aspect, the invention features a method that includes forming a particle that includes a polymer. The polymer has vinyl alcohol monomer units. The method also includes contacting the polymer with a chemical species selected from polymers, oligomers and monomers. The method further Includes ex.pos.ing the polymer and lhe chemical species to radiation to bond the chemical species to the polymer to form a particle having a maximum dimension of 5,000 microns or less and including the chemical species bonded to the polymer. in another aspect, the invention features a method that includes forming a particle that, has a polymer. The polymer includes at least five weight percent vinyl alcohol monomer units and at least live weight percent vinyl formal monomer units. The method also includes contacting the polymer with a chemical species selected from polymers, oligomers and monomers. The method ferther includes exposing the polymer and the chemical species to radiation to bond the chemical species to the polymer to form a particle with the chemical .species bonded to the polymer. In addition, the method includes contacting a therapeutic agent with the particle. The particle has a maximum dimension of 5,000 microns or less.

Embodiments can include one or more of the following features.

The polymer can include at least five weight percent vinyl alcohol monomers, The polymer can further include vinyl formal monomer units (e.g., at least five weight percent vinyl formal monomer units).

The polymer can further include vinyl acetate monomer units.

The polymer can include pores. For example, the chemical species can be at. leas? partially disposed m the pores of the polymer. The chemical species can be coated on a surface of the polymer.

The panicle can further include a therapeutic agent. For example, the therapeutic agent can be preferentially associated with the chemical species,

The polymer can be cross-linked.

The chemical species comprises a polymer, .such as, for example, polystyrene sulfonic acid, polyvinyl sulfonic acid, polydiaϊkylarnino alky! (xneth) acryhute, and/ør any hydrops lie or hydrophobic polymer that alters the chemical character of the particle to change the way a therapeutic is preferentially absorbed and released.

The method can use, for example, radiation is selected .from electron beam radiation, CJV radiation and gamma radiation (e.g., UV radiation), Exposing the polymer and the chemical species to radiation can cross-sink the polymer. For example, it can cause chemical bonds to form between the polymer in the particle and the additional polymer (chemical species) added to modify the chemical character of the particle.

Embodiments can include one or more of the following advantages, The chemical species (polymer, oligomer, monomer) can be used io manipulate in a desired fashion the release characteristics (e.g., liming, quantity) of one or mure therapeutic agents. For example, the chemical species may be associated (e.g., iomeally bonded) or associated with (e.g., via van der waals forces or by solubility of die therapeutic in) the chemical species with the therapeutic agent such that, for example, the therapeutic agent can he released by a particle as the environment in which the particle is present changes.

The particles can optionally be used to deliver therapeutic agents within a body lumen, alone or m combination with an embolization procedure.

Features ami advantages are in the description, drawings, and claims,

Brief Description. oC.fee.. Drawings

FIG, IA is side a side view of an embodiment of a particle. FIG. IB is a cross-sectional view of the particle of FIG, IA taken along line I B- IB.

FIG, 2 A. is a schematic illustrating an embodiment of a method of injecting a composition including particles into a vessel.

FIG, 2B is a greatly enlarged view of region 2B in FICi 2A. FIG. 3 is a cross-sectional view of an embodiment of a particle. FIGS, 4A-4C are an illustration of an embodiment of a system and method for producing particles. FIG 5 is an illustration of an embodiment, of a drop generator.

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FIGS, IA and i B show a particle 100 that can be used, for example, to in an embolization procedure. Particle 100 includes a cavity 102 surrounded by a matrix 104 Including pores 106. The matrix 104 is formed of a matrix polymer. Particle 100 also includes a chemical species that is covalently bonded to the matrix polymer (e.g., cos'aientiy bonded to the outer surface of particle 100 and/or eovalentiy bonded to the surface of one or more pores 104). The chemical species is orse or more monomers, oligomers and/or polymers.

In general, the matrix polymer is formed of a biocompatible material Examples include polymers that include vinyl alcohol monomers, vinyl forma! monomers and/or vinyl acetate monomers, As referred to herein, a vinyl formal monomer unit has the following structure:

As referred to herein, a vinyl alcohol monomer unit has the following structure:

H

^■ ' ^" ' ^"ii: H2C C J

OH

As referred to herein, a vinyl acetate monomer unit has the following structure:

Iii general, the monomer units can be arranged m a variety of different ways, As an example, in some embodiments, the polymer can include different monomer units that alternate with each other. For example,, the polymer can include repeating blocks, each block including s vinyl formal monomer unit, a vinyl alcohol monomer unit, and a vinyl acetate monomer unit. As another example, in certain embodiments, ώe polymer can include blocks including multiple monomer units of the same type,

In some embodiments, the polymer can have the formula that is schematically represented below, in which x, y and z each are integers that arc greater than zero. The individual monomer units that are shown can be directly attached to each other, and/or can include one or more other monomer units (e.g., vinyl formal monomer units, vinyl alcohol monomer units, vinyl acetate- monomer units) between them:

vinyl formal monomer unit vinyl alcohol moαørner unit vkxyl acetate ssionomer imλ

Optionally, formal lingaes can occur between PVA molecules giving crosslinks.

In some embodiments, the polymer can include at least live percent by weight {e.g., at least ! 5 percent by weight at least 25 percent by weight, at least 35 percent by weight) vinyl alcohol monomer units, and/or at most 80 percent by weight (e.g., at most 50 percent by weight, at most 25 percent by weight, at most 10 percent by weight) vinyl

alcohol monomer units. The weight percent of a monomer unit m a polymer can be measured using solid-state NMR spectroscopy. hi some embodiments, the polymer can include at least five percent by weight (e.g., at least 25 percent by weight, at least 50 percent by weight, at least 7.5 percent by weight, it least 85 percent by weight) vinyl formal monomer units, and/or at moss. 90 percent by weight (e.g., ai .most 75 percent by weight, at most 50 percent by weight, at most 25 percent by weight) vinyl formal monomer units. As used herein, the weight percent of a monomer unit in a polymer is measured using solid-stste NMR spectroscopy as described above, Ln some embodiments, the polymer can include at least one percent by weight

(e.g., at least two percent by weight, at least live percent by weight at least IO percent by weight, -it least 15 percent by weight) vinyl acetate monomer units, and/or at most 20 percent by weight (e.g., at most ! 5 percent by weight, at most 10 percent by weigh!, at mast βve percent by weight) vinyl acetate monomer units, As used herein, the weight percent of a monomer unit in a polymer is measured using solid-stste NIVtR spectroscopy as described above.

Alternatively or in addition, other polymers may also be used as a matrix polymer in particle 100. Examples of polymers include polyvinyl alcohols, polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates, carboxymeihyl celluloses, hyάroxyethyj celluloses, substituted celluloses, poiyaerylamides, polyethylene glycols, poiyamides, polyurias, polyureihanes, polyesters, poiyethers, polystyrenes, polysaccharides, polylaetic acids, polyethylene;*, polymethylmethacrylates, poiycaprolactoπes, poiyglycdic acids, polyOaetic-eo-giyeαHe) acids (e.g., polyfd-laetk.~co~glyeohc) acids) and copolymers or mixtures thereof. Polymers are described, for example, in Lanphere et ai., U.S. Patent Application Publication No. US 2004/0096662 Al , published on May 20. 2004, ami entitled "Embolization"; Song et al _> U.S. Patent Application Serial No. 11/314,056, Bled on December 2.1 , 2005, and entitled "Block Copolymer Particles"; and Song et a!., U.S. Patent Application Serial No. 1 1/314,557, tiled on December 21, 2005, and entitled "Block Copolymer Particles", all of which are incorporated herein by reference,

Examples of monomers thai can be covalently bonded to the matrix polymer?; s) oi ^" particle 100 include monomers of the polymers disclosed above. As an example, if the matrix, polymer is formed of formalized or imformalized FVA, styrene sulfonic acid can be cøvalently bonded to the matrix polymer. As another example, if the matrix polymer is formed of formalized or unformalized PVA ₅ dhraethylaminoethylacrylate can be covalenily bonded to the matrix polymer. As a further example, if the matrix polymer is formed of formalized or ynfornialized PVA, styrene can be eovaiently bonded to the matrix polymer. As an additional example, if the matrix polymer is formed of formalized or unfornialixed PVA, acrylic acid can be covalently bonded to the matrix polymer. Examples of oligomers that can be covalently bonded to the matrix polymer(s) of particle 100 include PEG aerylate oligomers, and low molecular weight versions of the polymers mentioned above. As an example, if the matrix polymer is formed of formalized or unfomialrzed PVA, PLA can be covalently bonded to the matrix polymer. As another example, if the matrix polymer is formed of formalized or unfoπn&lized PVA, PEG can be covalently bonded to the matrix polymer.

Examples of polymers that can be covalently bonded to the matrix polwier(s) of particle 100 include the polymers disclosed above. As an example, if the matrix polymer is formed of formalized or uiiforaialized PVA, a polystyrene (e.g., polystyrene sulfonic acid) can be covalentiy bonded to the matrix polymer. As another example, if the matrix polymer is formalized or unformalizεd PVA ₅ polystyrene sulfonic can be covalently bonded to the matrix polymer. As another example, if the matrix polymer is formalized or unføπnaiiml PVA, polydimethylaminoethylaerylate can be covalently bonded to the matrix polymer. As a farther example, if the matrix polymer is formalized or unformaib.ed PVA, polyacrylic acid can be covaienlly bonded to me matrix polymer. In general, the chemical species can be covalently bonded to the matrix polymery's) using any desired method. The process can involve, for example, bringing them into contact. In some embodiments, this can be achieved by coating the matrix polymer with the chemical species, In certain embodiments, the chemical species can be diffused into the pores of the particle. Subsequently, the chemical species can be covakntiy bonded to the matrix polymer. For example, the chemical species and matrix polymer can be exposed to appropriate radiation (e.g., electron beam radiation, gamma

radiation). An exemplary dose range for gamma or electron beam radiation is a minimum of one An exemplary dose range for UV radiation is 250 xim for S minutes. Exposure to radiation can, for example, cross-link the matrix polymer.

As an example, a gamma or an electron beam can be used to covalently bond polystyrene sulfonic acid to formalized or uπformalized PVA. As another example, a gamma or an electron beam can be used to covaϊently bond polyaciyiic acid to formalized or iinformalked PVA. As a further example, a gamma or an electron beam can be used to covaleπtly bond polydimeiliylaminoethylacrylate to formalized or unforøϊ&lføed PVA, As an additional example, a gamma or an electron beam can be used to covalently bond PEG acrylate oligomer to formalized or unformalized PVA.

Alternatively or in addition, a chemical species can be eovalently bonded to a matrix polymer by reaction between a free radical initiator incorporated into the matrix polymer and one of more monomers exposed to such matrix. ϊn general, the maximum dimension of particle 100 is 5,000 microns or less (e.g.. from two microns to 5,000 microns; from 10 microns to 5,000 microns; from 40 microns to 2,000 microns; from 100 microns to 700 microns; from 500 microns to 700 microns; from H)C) microns to 500 microns; from 100 microns to 300 microns; from 300 microns to 500 microns; from 500 microns to 1,200 microns; from 500 microns to 700 microns; from 700 microns to 900 microns; from 900 microns to 1,200 microns; from 1 ,000 microns to 1 ,200 microns). Ln some embodiments, the maximum dimension of particle HK) Is 5,000 microns or less (e.g., 4,500 microns or less, 4,000 microns or less, 3,500 microns or less, 3,000 microns or less, 2,500 microns or less; 2,000 microns or less; 1,500 microns or less; 1,200 microns or less; 1, 150 microns or less; 1,100 microns or less; 1,050 microns or less; 1 ,000 microns or less; 900 microns or less; ^" 00 microns or less; 500 microns or less; 400 microns or less; 300 microns or less; K)O microns or less; 50 microns or less; 10 microns or less; five microns or less) and/or one micron or more (e.g., five microns or more; 10 microns or more; 50 microns or more; 100 microns or more; 300 microns or more; 400 microns or more; 500 microns or more; 700 microns or more; 900 microns or more; 1 ,000 microns or more; 1.050 microns or more; 1 , 100 microns or more; 1,150 microns or more; 1 ,200 microns or more; 1 ,500 microns or more;

2,000 microns or more; 2,500 microns or more}, in some embodiments, the maximum dimension of particle 100 is less than 100 microns (e.g., less than 50 microns).

In some embodiments, particle 100 can be substantially spherical. in certain embodiments, particle 100 can have a sphericity of 0.8 or more (e.g., 0.85 or more, 0.9 or 5 more, 0.95 or more, 0.97 or more). Particle 100 can be, for example, .manually compressed, essentially flattened, while wet to 50 percent or less of its original diameter and then, upon, exposure to fluid, regain a sphericity of 0.8 or more (e.g., 0.85 or more, 0.9 or more, 0.95 or more, 0.97 or more). The sphericity of a particle can be determined using a Beckman Coulter RapidVUE Image Analyzer version 2.06 (Beckman Coulter, 0 Miami, FL). Briefly, the RapidVUE takes an image of continuous-tons (gray-scale) form and converts it to a digital form through the process of sampling and quantization. The system software identifies and measures particles in an image in the form of a fiber, rod or sphere. The sphericity of a particle, which is computed as Da/Dp (where Da ^{™ λ} i(4A/'<i); Dp ~ P/st ; A ^™ pixel area; F ^™ pixel perimeter), is a value from zero io one. with S one representing a perfect circle.

Multiple particles can be combined with a carrier fluid (e.g., a pharmaceutically acceptable carrier, such as a saline solution, a contrast agent, or both) to form a composition, which cats then be delivered to a site and used to embolize the site. FIGS. 2A and 2B illustrate the use of a composition including particles to emooHxe a lumen αf a 0 subject. As shown, a composition including particles 100 and a carrier fluid is injected into a vessel through an instrument such as a catheter 250. Catheter 250 is connected to a syringe barrel 210 with a plunger 260. Catheter 250 is inserted, for example, into a femora! artery 220 of a subject. Catheter 250 delivers the composition to, for example, occlude a uterine artery 230 leading to a fibroid 240 located in the uterus of a female 5 subject. The composition is initially loaded into syringe 210. Plunger 260 of syringe 210 is then compressed to deliver the composition through catheter 250 into a i urn en 265 of uterine artery 230.

FlG, 2B, which is an enlarged view of section 2B of FiG. 2 A, shows uterine artery 230, which is subdivided into smaller uterine vessels 270 (e.g., having a diameter 0 of two millimeters or less) that feed fibroid 240, The particles 100 in the composition

partially or totally fill the lumen of uterine artery 230, either partially or completely occluding the lumen of the uterine artery 230 that feeds uterine fibroid 240,

Compositions including particles such as particles 100 can be delivered to various sites hi the body, including, for example, sites having cancerous lesions, such as the breast, prostate, lung, thyroid, or ovaries. The compositions can be used irs, for example, neural, pulmonary, and/or AAA (abdominal sortie aneurysm) applications. The compositions can be used in the treatment of, tor example, fibroids, tumors, internal bleeding, arteriovenous malformations (AVMs), and/or hypervascular tumors. The compositions can be used as, for example, tillers for aneurysm sacs, AAA sac ( ^' Type II endolcaks), endoleak sealants, arterial sealants, and/or puncture sealants, and/or can be used to provide occlusion of other lumens such as fallopian tubes. Fibroids can include uterine fibroids which grow within the uterine wall (Intramural type), on the outside of the uterus (subserosai type), Inside the uterine cavity (submucosal type), between the layers of broad ligament supporting the uterus (mterϋgamentoαs type), attached to another organ (parasitic type), or on a mushroom-like stalk (pedunculated type). Internal bleeding .includes gastrointestinal, urinary, renal and varicose bleeding. AVKIs are, for example, abnormal collections of blood vessels (e.g. in the brain) which shunt blood from a high pressure artery to a low pressure vein, resulting in hypoxia and malnutrition of those regions from which the blood is diverted. In some embodiments, a composition containing the panicles can be used to prophyiacticaiiy treat a condition.

The magnitude of a dose of a composition can vary based on the nature, location and severity of the condition to be treated, as well as the route coadministration. A physician treating the condition, disease or disorder can determine an effective amount of composition. An effective amount of embolic composition refers io the amount sufficient to result in amelioration of symptoms and/or a prolongation of survival of the subject; or the amount sufficient to prophylactically treat a subject. The compositions can be administered as pharmaceutically acceptable compositions to a subject in any therapeutically acceptable dosage, including those administered to a subject intravenously, subcutaneous! y\ percutaneously, intratrachealy, intramuscularly, imramucosaly, intraoutaπeously, intra-articularly, orally or parεnterally.

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A composition can. Include a mixture of particles (e.g., particles .fanned of polymers including different weigh! percents of vinyl alcohol monomer units, particles including different types of therapeutic agents), or can include particles thai arc all of the same type. In some embodiments, a composition can be prepared with a calibrated concentration of particles for ease of delivery by a physician. A physician can select a coaiposUioii of a particular concentration based on, for example, the type of procedure to be performed. In certain embodiments, a physician can use a composition with a relatively high concentration of particles during one part of an embolization procedure, and a composition with a relatively low concentration of particles during another part of the embolization procedure.

Suspensions of particles in saline solution can be prepared to remain stable (e.g., to remain suspended in solution and not settle and/or float) over a desired period of time. A suspension of particles can be stable, for example, for from one minute to 20 minutes (e.g. from one minute to 10 minutes, from two minutes to seven minutes, from three minutes to sk minutes).

Ia some embodiments, particles can be suspended in a physiological solution by matching the density of the solution to the density of the particles, ϊn certain embodiments, the particles and/or the physiological solution can have a density of from one grain per cubic centimeter to 1,5 grams per cubic centimeter (e.g., from 1.2 grams per cubic centimeter to 1.4 grams per cubic centimeter, from 1 ,2 grams per cubic centimeter to 1.3 grams per cubic centimeter).

In certain embodiments, the carrier fluid of a composition can include a surfactant. The surfactant can help the particles to mix evenly in the carrier fluid and/or can decrease the likelihood of the occlusion of a delivery device (e.g., a catheter) by the particles. In certain embodiments, the surfactant can enhance delivery of the composition (e.g., by enhancing the wetting properties of the particles and facilitating the passage of the particles through a delivery device), ϊn some embodiments, the surfactant can decrease the occurrence of air entrapment by the particles in a composition (e.g., by porous particles in a composition). Examples of liquid surfactants include Tweer^ ^' SO (available from Sigma-AIdrieh) and Creniophor EL* (available from Sigma- Atdrieh), An example of a powder surfactant is Pluronic* Fl 27 NF (available from BASF). In

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certain embodiments, a composition can include from 0.05 percent by weigh! to one percent by weight {e.g., OJ percent by weight, 0,5 percent by weight) of a surfactant, A surfactant cao be added to the carrier ilukl prior to mixing with the particles and/or can be added to the panicles prior to mixing with the carrier fluid. In some embodiments, among the particles delivered to a subject (e.g., in a eoπφositiofi), the majority (e.g., 50 percent or more, 60 percent or more, 70 pcreem or more, 80 percent or more, 90 percent or more) of the particles can have a maximum dimension of 5,000 microns or less (e.g., 4,500 microns or less, 4,000 microns or less, 3,500 microns or less, 3,000 microns or less, 2,500 microns or less; 2,000 microns or less; 1 ,5(H) microns or less; 1 ₅ 200 microns or less; 1,150 microns or less; 1 , 100 microns or less; 1,050 microns or less; 1,000 microns or less; 900 microns or less; 700 microns or less; 500 microns or less; 400 .microns or less; 300 microns or less; 100 microns or less; 50 microns or less; 10 microns or less; five microns or less) and/or one microti or more (e.g., microns or more; 10 microns or more: 50 microns or more; K ⁾ O microns or more; 300 microns or more; 400 microtis or more; 500 microns or more; 700 microns or more; 900 microns or more: 1,000 microns or more; 1,050 microns or more; 1,100 microns or more; 1 , 150 microns or more; 1 ,200 microns or more; 1 ,500 microns or more; 2,000 microns or more; 2,500 microns or more), ϊn some embodiments, among the particles delivered to a subject, the majority of the particles can have a maximum dimension of less than 100 microns (e.g., less than 50 microns).

In certain embodiments, the particles delivered to a subject (e.g., in a composition _. } can have an arithmetic mean maximum dimension of 5,000 microns or less (eg,, 4,500 microns or less, 4,000 microns or less, 3,500 microns or less, 3,000 microns or less, 2,500 microns or less; 2,000 microns or less; 1 ,500 microns or less; 1 ,200 microns or less; K 150 microns or less; 1 , 100 microns or less; 1 ,050 microns or less;

1 ,000 microns or less; 900 microtis or less; 700 microns or less; 500 microns or less; 400 microns or less; 300 microns or less; 100 microns or less; 50 microns or less; 10 microns or less; five microns or less) and/or one micron or more (e.g., five microns or more; 10 microns or more; 50 microns or more; 100 microns or more; 300 microns or snore; 400 microns or more; 500 microns or more; 700 microns or more; 900 microns or more;

1 ,000 microns or more; ! ,050 microns or more; 1 ,100 microns or more; LI 50 microns or

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more; 1.200 microns or more; 1,500 microns or more; 2,000 microns t>r more; 2,500 microns or more), in some embodiments, the particles delivered to a subject can have an arithmetic mean maximum dimension of less than 100 microns (e.g., less than. 50 microns), Exemplary ranges for the arithmetic mean maximum dimension of particles delivered to a subject include from 100 microns to SOO microns; from 100 microns to 3(K) microns; from 300 microns to 500 microns; from 500 microns to 700 microns; from 700 microns io SH)O microns; from 900 microns to 1,200 microns; and from 1,000 microns to 1,200 microns, In general, the particles delivered to a subject (e.g.. in a composition) can have an arithmetic mean maximum dimension in approximately the middle of the range of the diameters of the individual particles, and a variance of 20 percent or less (e.g. 15 percent or less, 10 percent or less).

In some embodiments, the arithmetic mean maximum dimension of the particles delivered io a subject (e.g., in a composition) can vary depending upon the particular condition to be treated. As an example, in certain embodiments in which the particles are used to embolize a liver tumor, the particles delivered io the subject can have an arithmetic mean maximum dimension of 500 microns or less (e.g., from 100 microns to 300 microns; from 300 microns to 500 microns). As another example, in some embodiments in which the particles are used to embolize a uterine fibroid, the particles delivered to the subject east have an arithmetic mean maximum dimension of 1 ,200 microns or less (e.g., from 500 microns to 700 microns; from 700 microns to 900 microns; from 900 microns to 1 ,200 microns). As an additional example, in certain embodiments in which the particles are used to treat a neural condition (e.g., a brain tumor) aαd/or head trauma (e.g., bleeding in the head), the particles delivered to the subject can have an arithmetic mean maximum dimension of less than 100 microns (e.g., less than SO microns). As a further example, in some embodiments in which the particles are used to treat, a lung condition, the particles delivered to fee subject can have an arithmetic mean maximum dimension of less than 100 microns (e.g., less than 50 microns). As another example, in certain embodiments in which the particles are used to treat thyroid cancer, the particles can have an arithmetic maximum dimension of 1 ,200 microns or less (e.g., from 1,000 microns to 1,200 microns}. As an additional example.

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in some embodiments in which the particles are used only for therapeutic agent delivery, the particles can have an arithmetic mean maximum dimension of less than 100 microns (e.g., less than 50 microns, less than 10 microns, less than five microns).

The arithmetic mean maximum dimension of a group of particles can be determined losing a Beckman Coulter IlapidVUE Image Analyzer version 2.06 (tteekman Coulter. Miami, FL), described above. The arithmetic mean maximum dimension of a group of particles (e.g., in a composition) can be determined by dividing the sum of the diameters of all. of the particles in the group by the number of particles in the group.

ITS SOUS embodiments, particle 100 can have pores. For example, the polymer can form a matrix in which the pores are present. Additionally or alternatively, particle 100 can have one or more cavities. For example, particle 1.00 can be formed so thai the polymer surrounds one or more cavities,

A pore has a maximum dimension of at least 0,01 micron (e.g., at least 0.05 micron, at least 0, 1 micron, at least 0.5 micron, at least one micron, at least five microns, at least. 10 microns, at least 15 microns, at least 20 microns, at least 2.5 microns, at least 30 microns, at least 35 microns, at least 50 microns, at least 100 microns, at least 1.50 microns, at least 200 microns, at least 250 microns), and/or at most 300 microns (e.g., at most 250 microns, at most 200 microns, at most 150 microns, at most 100 microns, at most 50 microns, at most 35 microns, at most 30 microns, at most 25 microns, at roost 20 microns, at most ] 5 microns, at most 10 .microns, at most five microns, at most one micron, at most 0.5 micron, at most 0,1 micron, at most 0.05 micron}.

A cavity has a maximum dimension of at least one micron (e.g., a least five microns, at least 10 microns, at least 25 microns, at least 50 microns, at least 100 microns, at least 250 microns, at least 500 microns, at least 750 microns) and/or at most LOOO microns (e.g., at most 750 microns, at most 500 microns, at most 250 microns, at most 100 microns, at most 50 microns, at most 25 microns, at most 10 microns, at most five microns), hi some embodiments (e.g., when the particle is used to deliver a therapeutic agent within a body lumen, independent of whether embolization is desired), the particle can also include a therapeutic agent. In some embodiments, the therapeutic- agent can be present on the surface of the particle and/or in the pores of the particles.

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Optionally, the therapeutic agent can be bonded to or associated with the chemical species and/or matrix polymer. Examples of such bonding include ionic bonding, oovalent bonding, van άer waals bonding or solubility between the therapeutic and the chemical species. Therapeutic agents include genetic therapeutic agents, non-genetic therapeutic agents, and cells, and can be negatively charged, positively charged, amphoteric, or neutral Therapeutic agents can be, for example, materials thai are biologically active to treat physiological conditions; pharmaceutically active compounds; proteins; gene therapies; nucleic acids with and without carrier vectors (e.g., recombinant nucleic acids, DNA (e.g., naked DNA), cDNA, RNA, genomic DNA ₅ cDNA or UNA in a noninfectious vector or in a viral vector which may have attached peptide targeting sequences, antisense nucleic acids (RNA, DNA)); oligonucleotides; gene/vector systems (e.g., anything that allows for the uptake and expression of nucleic acids); DINA chimeras (e.g., DNA chimeras which include gene sequences and encoding for ferry prαieins such as membrane translocating sequences ("MTS") and herpes simplex virus-! ("VP22"}}; compacting agents (e.g., DNA compacting agents); viruses; polymers; hyaluronic acid; proteins (e.g., enzymes such as ribozymes, asparaginase); immunologic species; nonsteroidal anti-inflammatory medications; oral contraceptives; progestins; gonadotiOphin-releasing hormone agonists; chεmotherapeutic agents; and radioactive species (e.g., radioisotopes, radioactive molecules). Examples of radioactive species include yttrium C ⁰ Y), holraium ( ^{<λ 'Ho), phosphorus ('" ^' P). luietium ( ^{! ;} Xu), actinium ("" ⁵ Ac), praseodymium, astatine (" ⁸¹ At), rhenium ( ^!K "R.e), bismuth ( ² '~Bi or " ⁵³ Bi),). samarium ('" ⁵ Sm), iridium ( ^I9 %), rhodium ( ^J'λv Rh), iodine ( ^Ku I or ^i2'" lχ indium ('' 'In), technetium ( 'Tc), phosphorus ( ^''' "P), sulfur ( ^" "S), carbon ( ^: "C), tritium (/ ¹ H) ₁ chromium ( ⁵¹ Cr), chlorine ( ^3fe CI), cobalt ( ^i? Co or ³¹³ Co), iron ( ³⁹ Fe), selenium ( ^/: 'Se), and/or gallium C'Ga). in some embodiments, yttrium ( ^W Y), ϊutetium C ^K'' Xu) ₅ actinium C ^'" " ^" 'Ac), praseodymium, astatine ( ^2t 'At), rhenium ( ^iSt) Re), bismuth ( ^' " ² Bi or ^' ^ ^"1 Bi), hoimium ( ⁵ ^ ⁶ Ho) ₁ samarium (° ^J Sm), iridium ( ¹ ^ ² Ir), and/or rhodium ( ^!<jS R.h) can be used as therapeutic agents, in certain embodiments, yttrium ( ^% Y), lutetsurn ( ^{! ;} XuX actinium C ¹²⁵ Ac), praseodymium, astatine ( ^{i! 5} At), rhenium ( ^U6 Re), bismuth C ^{2i 2} Bi or ^i!l> Bi),

IiolrniuRS ('""Bo). samariufn ( ^{! x"} Sm), iridium ( ^1Vji !r), rhodium ( ^lW5 Rh). iodine V ^' "l or "" ^' Ik

S S

indium ( ^{π i} inj, technetium ( ¹ ^Te), phosphorus ( ³² P), carbon ( ^N C), and/or tritium (Ii) cεui be used as a radioactive label (e.g., for use in diagnostics}, io some embodiments, a radioactive species can be a radioactive molecule that ^" includes antibodies containing one or more radioisotopes, lor example, a radiolabeled antibody. Radioisotopes that can be bound to antibodies include, for example, iodine { ^Kn I or ^m ϊ), yttrium ( ^W1 Y), Iutetium

( ¹⁷⁷ Lu), actinium (" ^''''5 Ac), praseodymium, astatine ( ^{2f 1} At), rhenium ( ^i!λ R.e), bismuth ( ^{" !~} Bi or "'' ^' Bi), indium (' ' ¹ In), technetium ( ⁹⁹ Tc), phosphorus C ² P);, rhodium ( ^ωλ Kh)» sulfur f'SX carbon (^C) ₅ tritium (Hi), chromium ( ⁵⁵ Cr) ₅ chlorine ( ³ Vi), cobalt ( ⁵⁷ Co or ⁵ *Co), iron ( ^s& Fe), selenium { '^Se), and/or gallium ( ^tJI Ga). Examples of antibodies include monoclonal and polyclonal antibodies including RS7, Movi 8, MN-14 IgG, CC49, COL- !, tnAB A33, NP-4 F(ab')2 anti~CEA, anli-FSMA, ChL6, xn-170, or antibodies to CD20, CD74 or CD52 antigens. Examples of radioisotope/aπtibody pairs include m~l?0 MAB with ⁹⁰ Y. Examples of commercially available radioisotope/antibody pairs include Zevaiin ⁵ ^ (IDEiC pharmaceuticals, San Diego, CA) and Bexxar ^{] M} (Corixa corporation, Seattle, WA). Further examples of radioisotope/aπtibody pairs can be found in i _. . _... Nucl. Med. 2003, Apr: 44(4): 632-40,

Non-limiting examples of therapeutic agents include anti-thrombogenie agents; throffibogenic agents; agents that promote clotting; agents that inhibit clotting; antioxidants; angiogenic and anti-angiogenic agents and factors; antiproliferative agents (e.g., agents capable of blocking smooth muscle cell proliferation, such as r&pamyein); calcium entry blockers (e.g., verapamil, dihiazem, nifedipine); targeting factors (e.g., polysaccharides, carbohydrates); agents that can stick to the vasculature (e.g., charged moieties) (e.g., gelatin, chitosn, collagen, polymers contain g bioactive groups like RGD peptide?); and survival genes which protect against cell death (e.g., anti-apoptotic Bel-2 family factors and Akt kinase).

Examples of non-genetic therapeutic agents include; anti-tlironibotie agents such as heparin, heparin derivatives, urokinase, and P Pack (dextrophenyl alanine proline arginine ohioromethylkeione); anti-inflammatory agents such as dexamethasone, prednisolone, coiticosterone, budesonide, estrogen, acetyl salicylic acid, sulfasalazine and mesalamine; antineoplastic/antiproliferative/anli-raitotic agents such as paeJitaxel 5- Iiuorouracil, cϊsplatin, methotrexate, doxorubicin, vinblastine, vincristine, epothiioaes,

endosiatin, angiostatin, angiopeptin, monoclonal antibodies capable of blocking smooth muscle cell proliferation, and thymidine kinase inhibitors; anesthetic agents such as iidoeaine, bupivacalne and ropivacaine; anti-coagulants such as D-Phe-Pro-Arg chioromemyl ketone, an RGD peptide-containing compound, heparin, hirudin, antithrømbin compounds, platelet receptor antagonists, anti-thrombin antibodies, antiplatelet receptor antibodies, aspirin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet factors or peptides; vascular cell growth promoters such as growth factors;, transcriptional activators, and translations! promoters; vascular ceil growth inhibitors such as growth factor inhibitors (e.g., PDGF inhibitor-Trapid.il), growth factor receptor antagonists, transcriptional repressors, translationa! repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxic, bifunctional molecules consisting of an antibody and a cytotoxic; protein kinase and tyrosine kinase inhibitors (e.g., tyrphosuns, geπistein, qusooxalis.es); prostacyclin analogs; choiester.ol~lowef.rng agents; angiop-oietms; antimicrobial agents such as triclαsan, cephalosporins, aminoglycosides and nitrofurantoin; cytotoxic agents, cytostatic agents and cell proliferation afϊ ^' eciors; vasodilating agents; and agents that interfere with endogenous vasoactive mechanisms.

Examples of genetic therapeutic agents include: anti-sense DNA and RNA; DNA coding for anti-sense RNA, tRNA or rRNA 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 a and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor a, hepatocyte growth factor, and insulin like growth factor, cell cycle inhibitors including CD inhibitors, thymidine kinase ("TK") and other agents useful for interfering with eel! proliferation, and the family of bone morphogenie proteins C ^l BMP ^! s"), including BMP2, BMP3, BMP4, BMP5, BMP6 (Vgrl), BMP? (OPI), BMP8, BMP9, BMPIO, BMI L BMP12, BMPl 3, BMP 14, BMP15, and BMPI6. Currently preferred BMP's are any of BMP2, BMP3, BMP4, BMP5, BMP6 and BMP7. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively or additionally, molecules

π

capable of inducing an. upstream or downstream effect of a BMP 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: plasmlds: viral vectors such as adenovirus (AVj, adenoassocmted virus (AAV) and lεmivirus; and non- viral veeiors such as lipids. Liposomes and cationic lipids.

Cells include ceils of human origin (autologous or allogeneic), including 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 are disclosed in

10 Kunz et al, _> U, S, Patent No, 5,733,925, which is incorporated herein by reference. Therapeutic agents disclosed hi this patent include the following:

"Cytostatic agents" (Le,, agents that prevent or delay ceil division in proliferating cells, for example, by inhibiting replication of DNA or by inhibiting spindle Bber formation). Representative examples of cytostatic agents include modified toxins,

15 methotrexate, adtianiyein, radionuclides (e.g., such as disclosed in Fritzbεrg et al, U.S. Patent No, 4,897,255), protein kinase inhibitors, including staurospo ^ή n, a protein kinase C Inhibitor of the following formula:

as well as 36 dϊrndoioaikatoids having one of the ^" following general structures:

as well as stimulators of the production or activation of TGF-beta, including Tamoxifen and derivatives of functional equivalents (e.g., plasmin, heparin, compounds capable of reducing the level or inactivating the lipoprotein Lp(a) or the glycoprotein apoϋpoρrotem(a)) thereof, TGF-beta or functional equivalents, derivatives or analogs thereof ^' suramin, nitric oxide releasing compounds (e.g., nitroglycerin) or analogs or functional equivalents thereof, paelϋaxef or analogs thereof (e.g., taxotere), inhibitors of specific enzymes (such as the nuclear enzyme DNA topoisomerase Il and DNA

polymerase, RNA polymerase, adenyi guanyl cyclase), superoxide disrautase inhibitors, terminal dcoxyiuicleotidyi-traiisferase, reverse transcriptase, antisense oligonucleotides thai 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 non-competπive inhibitors) of cellular factors that may (e.g., in the presence of extracellular matrix) trigger proliferation of smooth muscle ceils or pericytes: e.g., cytokines (e.g., iπterleukins such as Ih-I), growth factors (e.g., FDGF, TGF-alpha or — beta, tumor necrosis factor, smooth muscle- and endotheliaj-derived growth factors, i.e., endothelial, FGF), homing receptors (e.g., for platelets or leukocytes), and extracellular matrix receptors (e.g., integrins). Representative examples of useful therapeutic agents in this category of cytostatic agents addressing smooth muscle proliferation include: subtragments of heparin, triazolopyrimidine (trapidil; a PDGF ^' antagonist), lovastatin, and prostaglandins El or 12.

Agents lhat inhibit the intracellular increase in cell volume (i.e., the tissue volume occupied by a cell), such as eytosketetal inhibitors or metabolic inhibitors.

Representative examples of cytoskeletal inhibitors include colchicine, vmblastin, cytochalasiss, paelitaxel and fee like, which act on microtubule and micro 0 lament networks within a cell Representative examples uf metabolic inhibitors include staurospϋrin ₅ iτichσtliecenes, and modified diphtheria and ricin toxins, Pseudomonas exotoxin and the like, Trichothecenes include simple triehotJieeenes (i.e., those that have only a central sesquiterpenoid structure) and rnacrocyclic trichotheeenes (i.e., those that have an additional macrocyclic ring), e.g., a verrucarins or roridins, including Verπicarin A, Verrucarin B, Verruearin J (Satratoxin C), Roridiπ A, Roridio C, Roridiπ D ₅ Roridin E (Satra toxin D), Roridin B. Agents acting as an inhibitor that blocks cellular protein synthesis sad/or secretion or organization of extracellular matrix (i.e., an "anti-matrix agent"). 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 eross- linking collagen), and matrix remodeling (e.g., following wound healing). A representative example of a useful therapeutic agent in this category of anti-matrix agents

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 welt as dinnmsh smooth muscle cell proliferation following angioplasty. The organization or stabilization may stern from the blockage of vascular smooth muscle ceil maturation in to a pathologically proliferating form.

Agents that are cytotoxic to cells, particularly cancer cells. Preferred agents arc tloridiπ A, Pseudumonas exotoxin and the like or analogs or functional equivalents thereof. A plethora of such therapeutic agents, including radioisotopes and the like, have been identified and are known in the art. In addition, protocols for the identification of cytotoxic moieties arc known and employed routinely in the art.

λ number of the above therapeutic agents and several others have also been identified as candidates for vascular treatment regimens, for example, as agents targeting restenosis. Such agents include one or more of the following; calcium-channel blockers, including benzothiazapiπεs (e.g., diltiazerπ, clentiazera); dihydropyridincs (e.g., nifedipine, amlodipine, nicardipine); phenylalkylamines (e.g., verapamil); serotonin pathway modulators, including S-HT antagonists (e.g., ketanserin, αafϋdrofiiryl) and 5- IfT uptake inhibitors (e.g., fluoxetine); cyclic nucleotide pathway agents, including phosphodiesterase inhibitors (e.g., cilostazok, dipyridamole), adenylate/guanylate cyclase stimulants (e.g., forskolin), and adenosine analogs; catecholamine modulators, including α-antagonists (e.g., prazosin, bunazosine), (^-antagonists (e.g., propranolol), and α/β-anlagonists (e.g., labetalol, carvedilol); endotnelfe receptor antagonists; nitric oxide donors/releasing molecules, including organic nitrates/nitrites {e.g., nitroglycerin, ϊsosorbide dinitrate, amyl nitrite), inorganic nitroso compounds (e.g., sodium nitropru&side), sydnonirøines (e.g., molsidomine, linsidomme), nonoaies (e.g., diazenkrni diolates. NO adducts of alkaαediamines), S-nitroso compounds, including low molecular weight compounds (e.g., S-nitroso derivatives of captopril, glutathione and N-acetyi penicillamine) and high molecular weight compounds (e.g., S-nitroso derivatives of proteins, peptides, oligosaccharides, polysaccharides, synthetic polymers/oligomcrs and natural polymcrs/oligoiners), C~nitxoso% O-nitroso~ and N-nitroso-cornpounds, and L- argininc; ACE inhibitors (e.g., eilazapril fosinopril enalapril); ATIl-receptor antagonists (e.g., saralasin, losartm); platelet adhesion inhibitors (e.g., albumin, polyethylene oxide);

platelet aggregation inhibitors, including aspirin and tfeienopyridine (ticlopidme, cJopidogrel) and GF lib/Ilia Inhibitors (e.g., abcixirøab, epiπ ^' libatkie, tiroilb&n, intergrilin); coagulation pathway modulators, including hepariπokte (e.g., heparin, low molecular weight heparin, dexiran sulfate, β~cyc!αdextrin tetradecasuifate), thrombin inhibitors (e.g., hirudin, hirulog, FPACK (D-phe-L-propyl-L-arg-ehloromethylketone), argatrobaa), Fxa inhibitors (e.g., antistatin, TAP (tick anticoagulant peptide)), vitamin K inhibitors (e.g., warfarin), ami activated protein C; cyclooxygenase pathway inhibitors (e.g., aspirin, ibuprofen, flurbiprofen, indomethacin, sulfinpyrazone); natural and synthetic corticosteroids (e.g., dexamethasone, prednisolone, methprednisolone, hydrocortisone); lipoxygenase pathway inhibitors (e.g., nordihydroguaireiic acid, caffeic acid; leukotriene receptor antagonists; antagonists of E- and P-selεetins; inhibitors of VCAM-I and ICAM- 1 interactions; prostaglandins and analogs thereof, including prostaglandins such as PGEl and PG 12; prostacyclins and prostacyclin analogs {e.g., ciprostene, epoprøstenoL carbacyclin, iloprost, beraprost); macrophage activation preventers (e.g., bisphosphonates); HMG-CoA reductase inhibitors (e.g.. lovastatm, pravastatin, ilavastatsn, simvastatin, cerivastatin); fish oils and oirjcga-34 ^' atty acids; free- radical scavcnger&'antioxidaiits (e.g., probucol, vitamins C and E ₅ ebselen, retinoic acid (e.g., trans-retinoic acid), SOD mimics); agents affecting various growth factors including FGF pathway agents (e.g., bFGF antibodies, chimeric fusion proteins). PDGF receptor antagonists (e.g., trapidil), IGF pathway agents (e.g., somatostatin analogs such as angiopeptin and oereotide), TGF-β pathway agents such as poiyanionic agents (heparin, fueoidin), decorin, and TGF-β antibodies, EGF pathway agents (e.g., EOF antibodies, receptor antagonists, chimeric fusion proteins), TNF-α pathway agents (e.g,> ihaiidoirade &nά analogs thereof), thromboxane A2 (TXA2) pathway modulators (e.g., sulofroban, vapiprost, daxoxlbe-n, ridogrel), protein tyrosine kinase inhibitors (e.g., tyrphostm, genisteia, and quinoxalme derivatives); MMP pathway inhibitors (e.g., marirnastiU, itomastat, metastat), and cell motility inhibitors (e.g., cytochalasin B); antiproliferative/antineoplastic agents including antimetabolites such as purine analogs (e.g., ό-mereaptoparineX pyrimidine analogs (e.g., cytarabine and S~fiuorouraci!) and methotrexate, nitrogen ir.ustards, alky! sulfonates, ethyknivnines, antibiotics (e.g., dauntimbicin, doxorubicin, daυnomyciπ, bleomycin, mitomycin, penicillins,

cephalosporins, ciproiMxiiix vancomycins, aminoglycosides, quboionεs, polymyxins, erythromycins, iertacyclmes, chloramphenicols, clindamycins, ϋαomycins, sulfonamides, and their homologs, analogs, fragments, derivatives, and pharmaceutical salts), nitrosoureas (e.g., carrnustine, lornustine) and eispiatiπ, agents affecting microtubule dynamics (e.g., vinblastine, vincristine, colchicine, paclitaxel, epothilone), caspase activators, protessome inhibitors, angiogenesis inhibitors (e.g., enctostatin, angiostalin and squalamine), and rapamycin, cerivastatiri, flavopiridol and suramin; matrix deposition/organization pathway inhibitors (e.g., halofuginone or other qiύϊϊ&YxAmom- derivatives, tranilast); eiidotheliaSization facilitators (e.g., VEGF and RGD peptide); and blood rheology modulators (e.g.. pentoxifylline).

Other examples of therapeutic agents include anti -tumor agents, such as docetaxei, alkylating agents (e.g., mechloretliamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), plant alkaloids (e.g., etoposide), inorganic ions (e.g., cisplatin}, biological response modifiers (e.g., interferon), and hormones (e.g., tamoxifen, flatamide), as well as their hoinologs, analogs, fragments,, derivatives, and pli armaceuticai salts.

Additional examples of therapeutic agents include organic-soluble therapeutic agents, .such as mithramycin, cyclosporine, and piicamycm. Further examples of therapeutic agents include pharmaceutically active compounds, anti-sense genes, viral, liposomes and catioiiic polymers (e.g., selected based on the application), biologically active solutes (e.g., heparin), prostaglandins, prosteyelms, L-arginme, riitric oxide (NO) donors (e.g., ϊisϊdomine, molsidomine, NO-protein adducts, NO-poiysaccharide adducts, polymeric or oligomeric NO adducts or chemical complexes ^' ), eisoxaparin, Warafin sodium, dicumarøl, interferons, interleukins, chyinasε inhibitors (e.g., Irani! ast), ACE inhibitors (e.g., Eπalapril), serotonin antagonists, 5-HT uptake inhibitors, and beta blockers, and other antitumor and/or chemotherapy drugs, such as BiCNU, buauifan, earbopiatmum, cisplatiauai, Cytoxan, DTlC, fludarabine, mitoxantrone, velbaa, VP- 16, hercepiin, leαstatin, isavelbinc, rituxan, and taxotere. in senile embodiments, a therapeutic agent can he hydrophilic. An example of a hyάrαphiiic therapeutic agent is doxorubicin hydrochloride. In certain embodiments, a therapeutic agent can be hydrophobic. Examples of hydrophobic therapeutic agents

include padltaxel, dsplatin, tamoxifen, and doxorubicin base. In some embodiments, a therapeutic agent can be lipophilic. Examples of lipophilic therapeutic agents include paclitaxei, other taxane derivative, dexamethasone, oilier steroid based therapeutics. Therapeutic agents are described, for example, in DiMatleo et al., U.S. Patent Application Publication No. US 2004/0076582 Al , published on April 22, 2004, and entitled "Agent Delivery Particle"; Schwarz εt al., U.S. Patent No. 6,368,658; Bαiser et al., U.S. Patent Application Serial No. 11/311,617, filed on December 19, 200S ₅ and entitled "Coils"; and Song, U.S. Patent Application Serial No. 11/355,301 , filed on February 15, 20(56, and entitled "Block Copolymer Particles", all of which are incorporated herein by reference. In certain embodiments, in addition to or as an alternative to including therapeutic agents, particle 100 can include one or more radiopaque materials, materials that are visible by magnetic resonance imaging (MRI- visibie materials), ferromagnetic materials, and/or contrast agents (e.g., ultrasound contrast agents). These materials can, for example, be bonded to the chemical species (monomer(s), oligomers(s), polymeria)). Radiopaque materials, M IU- visible materials, ferromagnetic materials, and contrast agents are described, for example, in Rioux et al., U.S. Patent Application Publication No. US 2004/0101564 Al ₅ published on May 27, 2004, and entitled "Embolization", which is incorporated herein by reference, hi certain embodiments, a particle can also include a coating. For example, FIG, 3 shows a particle 300 having a matrix i 04, pores 106 and, and a coating 310, Coating 310 can, for example, be formed of a polymer (e.g., alginate) that is different from the polymer in matrix 304. Coating 310 can, for example, regulate release of therapeutic agent from particle 300, and/or provide protection to the interior region of particle 300 (e.g., during delivery of particle 300 to a target site). In certain embodiments, coating 310 can be formed of a bioεrodϊbie and/or bioabsorbable material ihat can erode and/or be absorbed as particle 300 is delivered to a target site. This can. for example, allow the inferior region of panicle 300 to deliver a therapeutic agent to the target site once particle 300 has reached the target site. A bioerodible material ears be _s for example, a polysaccharide (e.g. _r alginate); a polysaccharide derivative; an inorganic, ionic salt; a water soluble polymer (e.g., polyvinyl alcohol, such as polyvinyl alcohol that has not been cross-linked); biodegradable poly DL-lactide-poly ethylene glycol (PELA); a

hydrαge! (e.g., polyacryiic acid, hyaluronic acid, gelatin, carboxymethyl cellulose); a polyethylene glycol. (PEG); chltosan; a polyester (e.g.. a polycaprolactone); a poly(ortho ester); a poiymihydxide; a pøly(]actϊc-co-glycoiic) acid (e.g., a poly(d-!actic-co-glycolic) acid); a polyllactic aeki) (PLA); a poly(glycoHc acid) (PGA.}; or a combination thereof. In some embodiments, coating 310 ears be formed of a sweliable material, such as a hydro gel (e.g., polyaerylamide co-acrylic acid). The sweliable material can be made to swell by, for example, changes in pH, temperature, and/or salt. In certain embodiments in which particle 300 is used in an embolization procedure, coating 310 can swell at a target site, thereby enhancing occlusion of the target site by particle 300, IB some embodiments _. , the coating can be porous. The coating can, for example, be formed of one or more of the above-disclosed polymers. in certain embodiments, a panicle can include a coating that includes one or more therapeutic agents (e.g., a relatively high concentration of one or more therapeutic agents). One or more of the therapeutic agents can also be loaded into the interior region of the particle. Thus, the surface of the particle can release an initial dosage of therapeutic agent, after which the interior region of the particle can provide a burst release of therapeutic agent. The therapeutic agent on the surface of the particle can be ihe same as or different from the therapeutic agent in the interior region of the particle. The therapeutic agent on the surface of the particle can be applied to the particle by, for example, exposing the particle to a high concentration solution of the therapeutic agent.

In some embodiments, a therapeutic agent coated particle can include another coating over the surface of the therapeutic agent (e.g., a bioerodible polymer which erodes when die particle is administered). The coating can assist in controlling the rate at which therapeutic agent is released from ihe particle. For example, the coating can be in the form of a porous membrane. The coating can. delay an initial burst of therapeutic agent release. In certain embodiments, the coating can be applied by dipping and/or spraying the panicle. The bioerodible polymer can be a polysaccharide (e.g., alginate). In some embodiments, the coating can be an inorganic, ionic salt. Other examples of bioerodible coating materials include polysaccharide derivatives, water-soluble polymers (such as polyvinyl alcohol,, e.g., that has not been cross-linked), biodegradable poly DL- laciide-poly ethylene glycol (PELA), hydrogels (e.g., poiyacryhe acid, hyaluronic acid,

gdafe\ carlx>xymethyl cellulose), polyethylene glycols (PEG) ₃ ehiiosaπ, polyesters (e.g., polyeaproiactones), pojy(oτtho esters), polyanhydrides, ρoly(!actic acids) (PtA), polygiycolk acids (PGA), poly(laetic-co-giycolie) adds (e.g., poly(d~lactie-co-glycoiic) acids), and combinations thereof. The coating can include therapeutic agent or can be substantially free of therapeutic agent. The therapeutic agent in ths coating can be the same as or different from an agent on a surface layer of the particle and/or within the particle. A polymer coating (e.g., a bioerodible coating) can be applied to the panicle surface in embodiments in which a high concentration of therapeutic agent has not been applied tc the particle surface. Coatings are described, for example, in DiMatteo el al, U.S. Patent Application Publication No. US 2004/0076582 A 1 , published on April 22, 2004. and eαthled "Agem Delivery Particle", which is incorporated herein by reference.

In general, an emulsion process, such as a single-emulsion process, can be performed with or without a droplet generator. As an example, in processes that do not involve a droplet generator, a solution of polymer in a water immiscible organic solvent. can be added to an aqueous solution containing a surfactant, and small particcs can be spontaneously formed. As another example, FIGS. 4A-4C show a single-emulsion process that can be used, for example, to make particles having vinyl alcohol monomer units and vinyl formal monomer units. As shown in FIGS. 4A-4C, a drop generator 500 (e.g., a pipette, a needle) forms drops 510 of an organic solution including an organic solvent, a therapeutic agent, and a polymer including vinyl alcohol monomer units and vinyl formal monomer units. .Examples of organic solvents include glacial acetic acid. N,N~dimethγlfoπ«&mide (DMF), ietrahyd.ro friran (TIIF), and diniethylsulfoxide (DMSO), In certain embodiments, the organic solvent can be an εφroiic polar solvent (e.g. _j DMf) ₅ which can dissolve both polar therapeutic agents and some non-polar therapeutic agents. In some embodiments, the organic solution can include at bast about five weight percent and/or at most about 100 weight percent of the organic solvent, in general, as the concentration of the polymer in the organic solution increases, the sizes and/or masses of the particles that arc formed from the organic solution can also increase. Typically, as the volume of organic solvent in the organic solution that is used to form drops SlO decreases, the rate at which particles form can increase. Generally, the rate of particle formation can increase as the volume of organic solvent that is used decreases.

Without wishing to be bound by theory, it is believed that this occurs because the organic solvent can evaporate from drops 510 more quickly during the particle formation process.

After they are formed, drops 510 fall from drop generator 500 into a vessel 520 that contains an aqueous solution including water (eg,, from about 50 milliliters to about ICK) milliliters of water) and a surfactant. Examples of surfactants include Usury! sulfate, polyvinyl alcohols, polyvinyl pyrrolidone) (PVP), and polysorbates (e.g., Tweer/ ^' 20, Twetnϊ ^8'' 80}. The concentration of the surfactant in the aqueous solution can be at least about 0.1 percent w/v, and/or al most about 20 percent w/v. For example, in some embodiments, the solution cars include about one percent w/v l&wyl sulfate. Generally, as the concentration of the surfactant in the aqueous solution increases, the sphericity of the particles that are produced from the drop generation process, and the rate of formation of the particles during the particle formation process, can also increase, In some embodiments, the aqueous solution can be at a temperature of at least about freezing temperature and/or at most about 100 ⁰ C. Typically, as the temperature of the aqueous solution increases, the rate at which particles (e.g., relatively rigid particles) form can also increase,

As FIG. 4B shows, after drops 510 ^" have fallen into vessel 520, the solution is mixed (e.g., homogenized} using a stirrer 530. In some embodiments, the solution can he mixed for a period of at least about one minute and/or at most about 24 hours. In certain embodiments, mixing can occur at a temperature of at least about freezing temperature and/or at most about ! 00 ⁰ C. The mixing results in a suspension 540 including particles 100 suspended in the solvent (FIG. 4C).

After particles 100 have been formal, they are separated from the solvent by, for example, .filtration (e.g., through a drop funnel, filter paper, and/or a wire mesh), ceutrifuging followed by removal of the supernatant, and/or decanting. Thereafter, particles 100 are dried (e.g., by evaporation, by vacuum drying, by air drying). to some embodiments, combinations of drying methods can be used. In certain embodiments, atkr being formed, panicles 100 can be stored in a carrier fluid, such as saline, in some embodiments, particles 100 can be stored in desonized water. Examples of such processes are disclosed, for example, in U.S. Patent Application (Attorney Docket: §H94-49500!| which is hereby incorporated by reference.

While pipettes and needles have been described as examples of drop generators that can be used m a particle formation process, in some embodiments, other types of drop generators or drop generator systems can be used in a particle formation process. For example, FIG. 5 shows a drop generator system 601 that includes a flow controller 600, a viscosity controller 60S, a drop generator 610, and a vessel 620. Flow controller 600 delivers a solution (e.g., a solution including a solvent; a therapeutic agent, and a polymer inclading -vinyl formal monomer units) to viscosity controller 605, which heats the solution to reduce its viscosity prior to delivery to drop generator 610. The solution then passes through an orifice in a nozzle in drop generator 610, resulting in the formation of drops of the solution. The drops are then directed into vessel 620, which contains, for example, an aqueous solution including a surfactant such as polyvinyl alcohol (PVA). Drop generators axe described, for example, in Larφhere et aL U.S. Patent Application Publication No, US 2004/0096662 AI , published on May 20, 2004, and entitled "Embolization", and in DiCario et al, LLS. Patent Application Serial No, 1 1 /1 1 1 ,51 1 , tiled on April 21 , 2005, and entitled "Particles", both of which are Incorporated herein by reference,

While certain embodiments have been described, other embodiments are possible. As another example, in some embodiments, particles can be used for tissue bulking. As an example, the particles can be placed (e.g., injected) into tissue adjacent to a body passageway. The particles can narrow the passageway, thereby providing bulk and allowing the tissue to constrict the passageway more easily. The particles can be placed in the tissue according to a number of different methods, for example, pereutaneσusly, laparoseopicaily. and/or through a catheter, In certain embodiments, a cavity can be formed in the tissue, and the particles can be placed in the cavity. Particle tissue bulking can be used to treat, for example, intrinsic sphincterie deficiency (ISD), vesicoureteral reflux, gastroesophageal reflux disease (GERD), &rκi'or vocal cord paralysis (e.g., to restore glottic competence in cases of paralytic dysphor a), In some embodiments, particle tissue bulking can. be used to treat urinary incontinence and/or fecal incontinence. The particles can be used as a graft material or a filler to fill and/or to smooth out soft tissue defects, such as for reconstructive or cosmetic applications (e.g., surgery). Examples of soft tissue defect applications include cleft lips, scars (eg,.

depressed scars from chicken pox or acne scars), indentations resulting from liposuction, wrinkles (e.g.. glabella frown wrinkles), and soft tissue augmentation of thin lips. Tissue bulking is described, for example, in Bourne et a!.. U.S. Patent Application Publication No, US 2003/0233150 Al ₅ published on December 18, 2003, and entitled "Tissue Treatment", which is incorporated herein by reference.

As an additional example, in certain embodiments, particles can be used to treat trauma and/or to fill wounds. In some embodiments, the particles can include one or more bactericidal agents and/or bacteriostatic agents,

As a further example, while compositions .including particles suspended in at least one carrier fluid have been described, in certain embodiments, particles may not be suspended in any carrier fluid. For example, particles alone can be contained within a syringe, and can be Injected from the syringe into tissue during a tissue ablation procedure and/or a tissue bulking procedure.

As an additional example, in some embodiments, particles having different shapes, sizes, physical properties, and/or chemical properties can be used together in a procedure (e.g., an embolization procedure). The different particles can be delivered inio the body of a subject in a predetermined sequence or simultaneously. In certain embodiments, mixtures of different particles can be delivered using a nuύti-kunen catheter and/or syringe. In some embodiments, particles having different shapes and/or sizes can be capable of interacting syncrgisticaily (e.g., by engaging or interlocking) to form a well-packed occlusion, thereby enhancing embolization, Particles with different shapes, sixes, physical properties, and/or chemical properties, arid methods of embolization using such particles are described, for example, in BeII et sL U.S. Patera Application Publication No. US 2004/0091543 Al, published on May 13, 2004, and entitled "Embolic Compositions", and m DiCarlo et aL, U.S. Patent Application

Publication No. US 2005/0095428 A!, published on May 5, ,2005, and entitled "Embolic Compositions", both of which are incorporated herein by reference,

As a further example, in some embodiments in which a particle including & polymer is used for embolization, the particle can also include (e.g.. encapsulate) one or more embolic agents, such as a sclerosing agent (e.g., etharso!}, a liquid embolic agent

as

(e.g., n-buty]-cyanoacrylate) _j and/or a fibrin agent The other embolic agent(s) can enhance the restriction of blood flow at a target site.

As another example, in some embodiments, a treatment site can be occluded by using particles in conjunction with other occlusive devices. For example, particles car* be used In conjunction with coils. Coils are described, for example, in Elliott et a!,, U.S. Patent Application Serial No, 1 1/000,741, filed on December i, 2004, and entitled "Embolic Coils'", and in Btriser et al. _; U.S. Patent Application Serial No. 1 1/311,617, filed on December 19, 2005, and entitled "Coils", both of which are incorporated herein by reference. Irs certain embodiments, particles can be used in conjunction with one or more gels. Gels are described, for example, in Richard et al,, U.S. Patent Application Publication No. US 2G06/Oθ4S900 Al, published on March 2, 2006, and entitled "Embolization", which is incorporated herein by reference. Additional examples of materials that can be used in conjunction with particles to txeat a target site in a body of a subject include gel foams, glues, oils, and alcohol As a further example, while particles including a polymer have been described, m some embodiments, other types of medical devices and/or therapeutic agent delivery devices can include such a polymer. For example, in some embodiments, a coil can include a polymer as described above. Ia certain embodiments, the coil can be formed by flowing a stream of the polymer into an aqueous solution, and stopping the Sow of the polymer stream once a coil of the desired length has been formed. Coils are described, for example, in Elliott et al, U.S. Patent Application Serial No. 1 1/000,741, filed on December 1, 2004, and entitled "Embolic Coils", and in Biu ^' ser et &!,, U.S. Patent Application Serial No. 11/311,617, filed on December 19, 2005, and entitled "Coils", both of which are incorporated herein by reference, In certain embodiments, sponges (e.g., for use as a hemostatic agent and/or in reducing trauma) can include & polymer as described above. In some embodiments, coils and/or sponges can be used as bulking agents and/or tissue support agents in reconstructive surgeries (e.g,, to treat trauma and/or congenita! delects).

Other embodiments are in the claims.