Patent Publication Number: US-2013251777-A1

Title: Brachytherapy Seed

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The present application claims the priority of U.S. provisional application No. 60/249,128 filed Nov. 16, 2000. 
    
    
     STATEMENT AS TO FEDERALLY SPONSORED RESEARCH 
     Not applicable. 
     FIELD OF THE INVENTION 
     The invention relates generally to the fields of medicine and delivery of therapeutically active substances. More particularly, the invention relates to implantable brachytherapy devices. 
     BACKGROUND 
     Radioactive seed therapy, commonly referred to as brachytherapy, is an established technique for treating various medical conditions, most notably prostate cancer. In a typical application of brachytherapy for treating prostate cancer, about 50-150 small seeds containing a radioisotope that emits a relatively short-acting type of radiation are surgically implanted in the diseased tissue. Because the seeds are localized near the diseased tissue, the radiation they emit is thereby concentrated on the cancerous cells and not on distantly located healthy tissue. In this respect, brachytherapy is advantageous over conventional external beam radiation. 
     A number of devices have been employed to implant radioactive seeds into tissues. See, e.g., U.S. Pat. Nos. 2,269,963 to Wappler; 4,402,308 to Scott; 5,860,909 to Mick; and 6,007,474 to Ryden. In a typical protocol for treating prostate cancer, an implantation device having a specialized needle is inserted through the skin between the rectum and scrotum into the prostate to deliver radioactive seeds to the prostate. The needle can be repositioned or a new needle used for other sites in the prostate where seeds are to be implanted. Typically, 20-40 needles are used to deliver between about 50-150 seeds per prostate. A rectal ultrasound probe is used to track the position of the needles. Once the end of a given needle is positioned in a desired location, a seed is forced down the bore of the needle so that it becomes lodged at that location. 
     As the seeds are implanted in the prostate as desired, the needles are removed from the patient. Over the ensuing several months the radiation emitted from the seeds kills the cancerous cells. Surgical removal of the seeds is usually not necessary because the type of radioisotope generally used decays over the several month period so that very little radiation is emitted from the seeds after this time. 
     Currently marketed radioactive seeds take the form of a capsule encapsulating a radioisotope. See, e.g., Symmetra® I-125 (Bebig GmbH, Germany); IoGold™ I-125 and IoGold™ Pd-103 (North American Scientific, Inc., Chatsworth, Calif.); Best® I-125 and Best® Pd-103 (Best Industries, Springfield, Va.); Brachyseed® I-125 (Draximage, Inc., Canada); Intersource® Pd-103 (International Brachytherapy, Belgium); Oncoseed® I-125 (Nycomed Amersham, UK); STM 1250 I-125 (Sourcetech Medical, Carol Stream, Ill.); Pharmaseed® I-125 (Syncor, Woodland Hills, Calif.); Prostaseee I-125 (Urocor, Oklahoma City, Okla.); and I-plant® I-125 (Implant Sciences Corporation, Wakefield, Mass.). The capsule of these seeds is made of a biocompatible substance such as titanium or stainless steel, and is tightly sealed to prevent leaching of the radioisotope. The capsule is sized to fit down the bore of one of the needles used in the implantation device. Since most such needles are about 18 gauge, the capsule typically has a diameter of about 0.8 mm and a length of about 4.5 mm. 
     The two radioisotopes most commonly used in prostate brachytherapy seeds are iodine (I-125) and palladium (Pd-103). Both emit low energy irradiation and have half-life characteristics ideal for treating tumors. For example, I-125 seeds decay at a rate of 50% every 60 days, so that using typical starting doses their radioactivity is almost exhausted after ten months. Pd-103 seeds decay even more quickly, losing half their energy every 17 days so that they are nearly inert after only 3 months. 
     Radioactive brachytherapy seeds may also contain other components. For example, to assist in tracking their proper placement using standard X-ray imaging techniques, such seeds may contain a radiopaque marker. Markers are typically made of high atomic number (i.e., “high Z”) elements or alloys or mixtures containing such elements. Examples of these include platinum, iridium, rhenium, gold, tantalum, lead, bismuth alloys, indium alloys, solder or other alloys with low melting points, tungsten, and silver. Many radiopaque markers are currently being marketed including: platinum/iridium markers (Draximage, Inc. and International Brachytherapy), gold rods (Bebig GmbH), gold/copper alloy markers (North American Scientific), palladium rods (Syncor), tungsten markers (Best Industries), silver rods (Nycomed Amersham), silver spheres (International Isotopes Inc. and Urocor), and silver wire (Implant Sciences Corp.). Other radiopaque markers include polymers impregnated with various substances (see, e.g., U.S. Pat. No. 6,077,880). 
     A number of different U.S. patents disclose technology relating to brachytherapy. For example, U.S. Pat. No. 3,351,049 to Lawrence discloses the use of a low-energy X-ray-emitting interstitial implant as a brachytherapy source. In addition, U.S. Pat. Nos. 4,323,055 to Kubiatowicz; 4,702,228 to Russell; 4,891,165 to Suthanthiran; 5,405,309 to Carden; 5,713,828 to Coniglione; 5,997,463 to Cutrer; 6,066,083 to Slater; and 6,074,337 to Tucker disclose technologies relating to brachytherapy devices. 
     SUMMARY 
     The invention relates to a brachytherapy seed that includes a drug or other therapeutically active substance that can be delivered to a subject upon implantation into the subject through the bore of a brachytherapy implantation needle. Because the brachytherapy seeds of the invention can be sized and shaped to fit through the bore of a brachytherapy implantation needle, they are suitable for use with brachytherapy seed implantation instruments such as an implant needle, a Henschke, Scott, or Mick applicator, or a like device such as a Royal Marsden gold grain gun. A drug or other therapeutically active substance can be included in the seed in addition to, or as an alternative to, a radioisotope. A drug or other therapeutically active substance can also be associated with a biodegradable component so that its rate of release in the implantation site can be controlled according to the rate that the biodegradable substance decomposes at the implantation site. Thus, like conventional radioactive brachytherapy seeds, the seeds within the invention can be precisely implanted in many different target tissues without the need for invasive surgery. And similar to the radiation emitted from conventional brachytherapy seeds, the therapeutically active substance included within a seed of the invention can be delivered in a controlled fashion over a relatively long period of time (e.g., weeks, months, or longer periods). Moreover, because concentrations of the therapeutically active substance will be greater at the implantation site (e.g., the diseased tissue), any potential deleterious effect of the therapeutically active substance on healthy tissue located away from the implantation site will be reduced. 
     Depending on the particular application, the brachytherapy seeds of the present invention offer other advantages. Among these, for example, compared to conventional systemic administration (e.g., oral or intravenous delivery) of therapeutically active substances, the brachytherapy seeds of the invention can provide higher and more consistent concentrations of a therapeutically active substance to a target tissue. They can also eliminate the need for repeated injections as well as circumvent delivery problems such as where a target tissue lacks an intact vascular supply (e.g., a target tissue whose blood flow may be compromised) or is otherwise sequestered from the blood supply (e.g., via the blood-brain barrier of the central nervous system). In some versions of the seeds of the invention that do not contain a radioisotope (e.g., those having only the therapeutically active substance and biodegradable component), after the therapeutically active substance is completely released and the biodegradable component is fully decomposed, no foreign device will remain at the implantation site. 
     Accordingly, the invention features a brachytherapy seed for implantation into a subject including a biocompatible component, a therapeutically active component that includes a non-radioactive drug, and a radiopaque marker. In this seed, the biocompatible component is physically associated with a therapeutically active component and in contact with the radiopaque marker. The invention also features another brachytherapy seed for implantation into a subject. This seed includes a non-metal biocompatible component, a therapeutically active component comprising a radioisotope, and a radiopaque marker, said biocompatible component being (a) physically associated with a therapeutically active component and (b) in contact with said radiopaque marker, wherein said brachytherapy seed has a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge). Brachytherapy seeds of the invention can have a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge). In one version of the invention, the seed is shaped into a cylinder having a diameter of between about 0.5 to 3 millimeters and a length 4 to 10 millimeters, e.g., one wherein the diameter is about 0.8 millimeters and the length is about 4.5 millimeters. 
     In the foregoing seed, the biocompatible component can be biodegradable and include a polymer such as poly(bis(p-carboxyphenoxy) propane anhydride); poly(bis(p-carboxy) methane anhydride); poly(D,L-lactic-coglycolic acid); poly(isobutylcyanoacrylate); a copolymer of poly-carboxyphenoxypropane and sebacic acid; open cell polylactic acid; a co-polymer of a poly-fatty acid dimer and sebacic acid; poly(carboxyphenoxy) hexane; poly-1,4-phenylene dipropionic acid; polyisophthalic acid; polydodecanedioic acid; or other polymers described below. 
     The non-radioactive drug can take the form of stimulating and growth factors; gene vectors; viral vectors; anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents; transforming agents; apoptosis-inducing agents; radiosensitizers; radioprotectants; hormones; enzymes; antibiotics; antiviral agents; mitogens; cytokines; anti-inflammatory agents; immunotoxins; antibodies; or antigens. For example, the non-radioactive can be an anti-neoplastic agent such as paclitaxel, 5-fluorouracil, or cisplatin. It can also be a radiosensitizing agent such as 5-fluorouracil, etanidazole, tirapazamine, BUdR, or IudR. 
     The radiopaque marker can include platinum, iridium, rhenium, gold, tantalum, bismuth, indium, tungsten, silver, or a radiopaque polymer. Radioisotopes for use in the invention can include  125 I and  103 Pd. 
     In another aspect, the invention features a method of making a brachytherapy seed for implantation into a subject. This method includes the steps of: (a) providing a non-metal biocompatible component and a therapeutically active component; (b) physically associating the biocompatible component and the therapeutically active component to form a combination product; and (c) forming the combination product into a seed having a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), or less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge). 
     Another method of the invention is a method of making a brachytherapy seed for implantation into a subject. This method includes the steps of: (a) providing a biocompatible component, a therapeutically active component comprising a non-radioactive drug, and a radiopaque marker; (b) physically associating the biocompatible component, the therapeutically active component, and the radiopaque marker to form a combination product; and (c) forming the combination product into a seed having a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), or less than about 0.84 millimeters (18 gauge), or less than about 0.56 millimeters (24 gauge). 
     Yet another method within the invention is a method of making a brachytherapy seed for implantation into a subject. This method includes the steps of (a) providing a biocompatible component, a therapeutically active component comprising a drug, and a sealed container housing a radioisotope; and (b) physically associating the biocompatible component, the therapeutically active component, and the container into a seed such wherein the biocompatible component and the therapeutically active component at least partially coat the container and the seed has a size and shape suitable for passing through the bore of a needle having an interior diameter of less than about 2.7 millimeters (10 gauge), less than about 1.4 millimeters (15 gauge), or less than about 0.84 millimeters (18 gauge). 
     In the foregoing methods, the biocompatible component can be biodegradable and include a polymer such as poly(bis(p-carboxyphenoxy) propane anhydride); poly(bis(p-carboxy) methane anhydride); poly(D,L-lactic-coglycolic acid); poly(isobutylcyanoacrylate); a copolymer of poly-carboxyphenoxypropane and sebacic acid; open cell polylactic acid; a co-polymer of a poly-fatty acid dimer and sebacic acid; poly(carboxyphenoxy) hexane; poly-1,4-phenylene dipropionic acid; polyisophthalic acid; polydodecanedioic acid; or other polymers described below. The drug can take the form of stimulating and growth factors; gene vectors; viral vectors; anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents; transforming agents; apoptosis-inducing agents; radiosensitizers; radioprotectants; hormones; enzymes; antibiotics; antiviral agents; mitogens; cytokines; anti-inflammatory agents; immunotoxins; antibodies; or antigens. For example, the drug can be an anti-neoplastic agent such as paclitaxel, 5-fluorouracil, or cisplatin. It can also be a radiosensitizing agent such as 5-fluorouracil, etanidazole, tirapazamine, BUdR, or IUdR. 
     The radiopaque marker can include platinum, iridium, rhenium, gold, tantalum, bismuth, indium, tungsten, silver, or a radiopaque polymer. Radioisotopes for use in the invention can include  125 I and  103 Pd. The radioisotope can be contained within a non-radioactive biodegradable component to, e.g., prevent radioactive contamination of a user or an operating room prior to implantation of the seed in a patient. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by, reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the invention will be apparent from the following detailed description, and from the claims. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention is pointed out with particularity in the appended claims. The above and further advantages of this invention may be better understood by referring to the following description taken in conjunction with the accompanying drawings, in which: 
         FIG. 1  is a schematic side view of a cylindrically shaped brachytherapy seed of the invention. 
         FIG. 2  is a schematic side view of a hollow tube-shaped brachytherapy seed of the invention. 
         FIGS. 3A-3G  are schematic side views of several versions of brachytherapy seeds within the invention that include a radiopaque marker. 
         FIG. 4A  is a schematic view of a brachytherapy seed of the invention having a sealed container housing a radioisotope partially coated by a therapeutically active component and a biocompatible component. 
         FIG. 4B  is a cross-sectional view of a brachytherapy seed of the invention having a sealed container housing a radioisotope completely coated by a therapeutically active component and a biocompatible component. 
         FIG. 5A  is a schematic view of a flaccid chain of several brachytherapy seeds conjoined with several spacer elements. 
         FIG. 5B  is a schematic view of a rigid chain of several brachytherapy seeds conjoined with several spacer elements. 
     
    
    
     DETAILED DESCRIPTION 
     The invention encompasses compositions and methods relating to implantable brachytherapy seeds including a biocompatible component associated with a therapeutically active substance. Referring to the drawings there are illustrated various different embodiments of the brachytherapy seeds of the invention. In  FIG. 1 , there is shown a brachytherapy seed  10  composed of a biocompatible component  12  associated with a therapeutically active component  14  (schematically shown as small circles or spheres). As illustrated, the therapeutically active component  14  is present as a plurality of small particles dispersed throughout a matrix consisting of the biocompatible component  12 . The mixture of the components  12  and  14  is formed into the cylindrically shaped brachytherapy seed  10 . 
     The brachytherapy seed  10  shown in  FIG. 1  has a size and shape suitable for passing through the bore of a brachytherapy implantation needle. Although the bore can be any size compatible with brachytherapy methods, in order to minimize damage to tissue, the bore preferably has an interior diameter of between about 0.01 and 10 mm (e.g., 0.009, 0.01, 0.02, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 4, 5, 6, 7, 8, 9, 10, or 11 mm). For use with 10 gauge or less brachytherapy implantation needles, seed  10  has a size and shape that can pass through a bore having a diameter of less than about 2.7 millimeters (i.e., the interior diameter of a standard 10 gauge brachytherapy implantation needle). For smaller needles such as 15 and 18 gauge needles, seed  10  has a size and shape that can pass through bores having an interior diameter of less than about 1.4 millimeters (e.g., 1.40, 1.39, 1.38, 1.37, 1.36, 1.35, or 1.34 mm) or less than about 0.84 millimeters (e.g., 0.86, 0.85, 0.84, 0.83, 0.82, 0.81, 0.80 mm), respectively. 
     Although there is no lower limit as to how small any dimension of seed  10  can be, in many applications, those that are not able to pass through bores smaller than 0.3 mm are preferred. For example, in many applications where it is desirable for the implanted brachytherapy seeds to maintain their orientation in the tissue, the seed  10  should be large enough to stayed lodged at the site of implantation in the desired orientation for a relatively long period, larger seeds are preferred. In some cases, the selection of materials for use in the seed  10  will affect its size. For instance, in versions of the seed  10  where the biocompatible component  12  is a stainless steel or titanium capsule, the walls of the capsule may need to be greater than a certain minimum size in order to maintain the structural integrity of the seed  10 . In addition, in some applications, the seed  10  should also be large enough to carry a sufficient amount of the therapeutically active component  14  to be therapeutically active (i.e., a therapeutically effective amount or an amount that exerts a desired medically beneficial effect). In order facilitate the passage of seed  10  through the bore of a needle while preventing jamming of the brachytherapy implantation needle bore (e.g., caused by clumping of several seeds), it is also preferred that the diameter of seed  10  be just slightly less than the diameter of the bore of the needle (e.g., 0.5-5% less). 
     For use with the needles used in many conventional brachytherapy seed implantation devices, brachytherapy seeds shaped into a cylinder (or rod) having a diameter of between about 0.8 to 3 millimeters (e.g., 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, or 3.1 mm) and a length of between about 4 to 10 millimeters (e.g., 3.9, 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6 or 6.1 mm) are preferred. Because many conventional brachytherapy seed applicators make use of brachytherapy implantation needles about 17 to 18 gauge in size, cylindrically shaped brachytherapy seeds having a diameter of between about 0.8 and 1.1 mm (e.g, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1, 1.01, 1.02, 1.03, 1.04, 1.05, 1.06, 1.07, 1.08, 1.09, 1.1, and 1.11 mm) and a length greater than the diameter (e.g., 2-10 mm) are preferred for use with such applicators. In particular, because many conventional brachytherapy seed applicators are designed to accept conventional radioactive brachytherapy seeds that have a diameter of about 0.8 millimeters and a length of about 4.5 millimeters, brachytherapy seeds within the invention of similar size are especially preferred. 
     Brachytherapy seeds within the invention are also not limited to those being cylindrical in shape (e.g., seed  10  shown in  FIG. 1 ), but rather can be any shape suitable for passing through the bore of a needle. For example, in many cases, seeds within the invention can be cuboid, spheroid, ovoid, ellipsoid, irregularly shaped, etc. The ends of the seeds can be rounded, squared, tapered, conical, convex, concave, scalloped, angular, or otherwise-shaped. The brachytherapy seeds within the invention can be solid as shown in  FIG. 1 , but can also have one or more cavities or pores (e.g., to increase the surface area of the seed exposed to the target tissue). As one example, as illustrated in  FIG. 2 , a brachytherapy seed  10  of the invention is shaped into a hollow tube  18  having a cylindrical cavity  20 . In preferred versions of seed  10 , cylindrical cavity  20  is sized to accept and envelop a standard-sized brachytherapy seed (e.g., one having a diameter of about 0.8 mm and a length of about 4.5 mm). For use, the seed  10  can be placed over the standard-sized brachytherapy seed, and introduced into the bore of a needle (sized to accept the enveloped seed) for implantation into a target tissue. The seed  10  shown in  FIG. 2  can also be used alone without being placed over a standard-sized brachytherapy seed, e.g., to increase the surface area exposed in the site of implantation. Hollow tube  18  can have any wall thickness or length suitable for wholly or partially enveloping a standard-sized brachytherapy seed and passing through the bore of a needle. Preferably it has a wall thickness between about 0.01 and 0.1 mm (e.g., 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1 mm) and a length of between about 1 to 4.5 mm (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 mm). 
     Referring again to  FIGS. 1 and 2 , biocompatible component  12  can be composed of any material suitable for implantation in a target tissue in an animal subject (e.g., a mammal such as a human patient) that can be associated with therapeutically active component  14  such that all or part of the therapeutically active component  14  will be delivered to the target tissue when the brachytherapy seed  10  is introduced into the implantation site. A number of materials suitable for use a component  12  are known. See, e.g., Biomaterials Engineering and Devices: Human Applications: Fundamentals and Vascular and Carrier Applications, Donald L. Wise et al. (eds), Humana Press, 2000; Biomaterials Science: An Introduction to Materials in Medicine, Buddy D. Ratner et al. (eds.), Academic Press, 1997; and Biomaterials and Bioengineering Handbook, Donald L. Wise, Marcel Dekker, 2000. In the invention, for ease of use, ease of manufacture, and for therapeutic advantages, it is preferred that the biocompatible component  12  be a biocompatible components (i.e., made of a substance other than titanium or stainless steel). 
     As a representative example, the biocompatible component  12  can be a biodegradable polymer that can act as a carrier for the therapeutically active component  14 . Numerous such polymers are known including, e.g., polyorthoesters, polyanhydrides, polylactides (PLA), polyglycolides (PGA), and poly(lactide-co-glycolides) (PLGA). Other suitable biodegradable polymers include: polylactic acid, polyglycolic acid, poly L-lactide-co-glycolide, polydioxanone, poly glycolide-co-trimethylene carbonate, poly ethylene carbonate, polyiminocarbonates, polyhydroxybutyrate, polyester-amides, and polyamino acids. More specific examples of suitable biodegradable polymers include: poly[bis(p-carboxyphenoxy) propane anhydride] (PCPP); poly[bis(p-carboxy) methane anhydride (PCPM); Resomer® [Poly(D,L-lactic-coglycolic acid) (PLAGA)]; poly(isobutylcyanoacrylate) (PIBCA); Biodel®, a copolymer of poly-carboxyphenoxypropane and sebacic acid (PCPP:SA); OPLA® (open cell polylactic acid); poly-fatty acid dimer and sebacic acid [P(FAD-SA)]; poly(carboxyphenoxy) hexane (PCPH); poly-1,4-phenylene dipropionic acid (PPDP); polyisophthalic acid [P(Iph-SA)]; and polydodecanedioic acid (PDD). Other polymers suitable for use as component  12  include: polyamido-amines (PAA), poly-2-hydroxy ethyl methacrylate, poly N-vinyl pyrrolidone, polymethyl methacrylate, polyvinyl alcohol, polyacrylic acid, polyacrylamide, polyethylene-co-vinyl acetate, polyethylene glycol, polymethacrylic acid, and those described in U.S. Pat. Nos. 3,625,214; 3,867,519; 4,093,709; 4,391,797; and 4,767,628. 
     The invention is not limited to the use of any particular substance for use as the biocompatible component  12 . Rather certain substances will be preferred for certain applications while others will be preferred for other applications. A skilled artisan can select the particular composition of the component  12  that is most suited for a given application. For example, where the seed  10  is intended to be used to slowly deliver the therapeutically active component  14  when implanted in a target tissue, a biocompatible and biodegradable material made up of a chemical composition of a polymer known to degrade at a desired rate when placed under conditions similar to those encountered in the implantation site can be selected for use as component  12 . Various characteristics of such biodegradable components are described, e.g., in Biomaterials Engineering and Devices: Human Applications: Fundamentals and Vascular and Carrier Applications; Biomaterials Science: An Introduction to Materials in Medicine; and Biomaterials&#39; and Bioengineering Handbook, supra. For example, by selecting an appropriate material for use as the biocompatible component  12  of the brachytherapy seed  10 , the duration of release of the therapeutically active component  14  from seed  10  can be varied from less than about an hour to more than about several months (e.g., 10 min., 30 min., 1 h., 2 h., 3 h., 6 h., 12 h., 1 day, 2 days, 3 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, or 3 years). Biocompatible component  12  is not limited to being biodegradable. For example, in some cases, component  12  can also be made of a non-biodegradable material such as stainless steel or titanium. In this case, biocompatible component  12  can be coated or otherwise associated with therapeutically active component  14 , such that component  14  will be delivered to a target tissue into which seed  10  is implanted. For instance, component  12  might take the form of a porous stainless steel or titanium cylinder having a plurality of pores through its outer surface, such pores being filled with or otherwise in communication with the component  14  such that the component  14  can diffuse from the seed  10  into the environment surrounding the seed  10 . (e.g., a target tissue). 
     Compositions with unknown or incompletely investigated characteristics might also be used as biocompatible component  12 . These can be tested for suitability in a given application by conventional clinical testing. For example, a test composition can be fashioned into a brachytherapy seed and implanted in a laboratory animal in a selected target tissue. The effects of the implanted compositions on the animal can then be monitored over a period of time. Those that prove to be biocompatible (e.g., not causing an undesired response such as calcification or an allergic response) and have a desired rate of degradation and delivery of a therapeutically active component (if included in the test seed) can thus be identified. 
     Therapeutically active component  14  is a material that can (a) be implanted in a target tissue of an animal subject (e.g., a mammal such as a human patient) to exert an effect on the animal&#39;s physiology, and (b) be associated with the biocompatible component  12  in the brachytherapy seed  10 . Myriad different substances can be used as the therapeutically active component  14 . See, e.g., Physician&#39;s Desk Reference, The Merck Index, and USP DI® 2000 published by U.S. Pharmacopeia. For example, the therapeutically active component  14  can include a small molecule drug (e.g., a non-peptide or non-nucleic acid-based molecule with a molecular weight generally less than 5 kDa) such as a chemical with known anti-cancer properties. It can also include a biologic such as a polypeptide (e.g., an antibody or a cytokine) or nucleic acid (e.g., an expression vector). Further examples drugs that can be included in therapeutically active component  14  include without limitation: stimulating and growth factors; gene vectors; viral vectors; anti-angiogenesis agents; cytostatic, cytotoxic, and cytocidal agents; transforming agents; apoptosis-inducing agents; radiosensitizers; radioprotectants; hormones; enzymes; antibiotics; antiviral agents; mitogens; cytokines (e.g., tumor necrosis factor-alpha); anti-inflammatory agents; immunotoxins; antibodies; and antigens. 
     Therapeutically active component  14  is not, however, limited to any of the above-listed compositions or uses. Rather a skilled artisan can select a particular composition of use as the therapeutically active component  14  depending on the application that the brachtherapy seed  10  is intended to be used for. For example, where the seed  10  is intended to be used as a primary treatment for prostate cancer, the therapeutically active substance  14  can include a anti-neoplastic drug such as paclitaxel (taxol), cisplatin, or 5-fluorouracil; or a hormone such as leuprolide. As another example, where the seed  10  is intended to be used as an adjuvant to radiation treatment for prostate cancer, the therapeutically active substance  14  can include a radio-sensitizing agent such as tirapazamine, BUdR, IUdR, or etanidazole. Because brachytherapy seed  10  allows in situ drug delivery to a tissue, the therapeutically active substance  14  might in some cases include a drug that is usually considered too toxic to treat a given condition if given systemically, e.g., tirapazamine or camptotbecin. 
     As indicated in the above description of the brachytherapy seed  10  shown in  FIGS. 1 and 2 , the biocompatible component  12  is associated with the therapeutically active component  14 . As used herein, when referring to the biocompatible component  12  and the therapeutically active component  14 , the phrase “associated with” means physically contacting. Thus, in the seed  10 , the association of the biocompatible component  12  with the therapeutically active component  14  can take many forms. For example, the biocompatible component  12  and the therapeutically active component  14  can be combined into a mixture as shown in  FIGS. 1 and 2 . This mixture can have a uniform or non-uniform distribution of components  12  and  14 . 
     The brachytherapy seed  10  shown in  FIG. 1  is an example of a uniform mixture of components  12  and  14 . The brachytherapy seed  10  of this example can be made by simply mixing together the biocompatible component  12  and the therapeutically active component  14  to form a combination product and then forming the product into the desired size and shape, e.g., using a mold. 
     Although the brachytherapy seeds shown in  FIGS. 1 and 2  include mixture of discrete particles dispersed through a matrix consisting of the therapeutically active component  14 , in other versions of brachytherapy seed  10 , components  12  and  14  are combined in a single particle or in a larger mass without discrete particles (e.g., a pellet the size and shape of brachytherapy seed  10 ). For example, biocompatible component  12  and therapeutically active component  14  can be dissolved into a liquid and then dried or cured to form microspheres or a larger pellet made up of a homogeneous distribution of both components  12  and  14 . (see, e.g., Ramirez et al., J. Microencapsulation 16:105, 1999). Microspheres can be of any size suitable for use in the invention. For example, they can have a diameter of about 1 to 1000 microns (e.g., 10-100 microns, 100-200 microns, 200-300 microns, 300-400 microns, 400-500 microns, 500-600 microns, 600-700 microns, 700-800 microns, 800-900 microns, 900-1000 microns). The skilled artisan can select the desired size according to the properties desired and particular properties of the microsphere constituents. In one variation of this, the microspheres are also made to include magnetic elements. The microspheres can then be molded or compressed together into the desired shape and sized of brachytherapy seed  10 . The larger pellet can likewise be sculpted, extruded, molded or compressed into the desired shape and size of brachytherapy seed  10 . Alternatively, the liquid mixture of components  12  and  14  can be poured into a mold defining the shape and size of brachytherapy seed  10 , and then cured in the mold. Brachytherapy seeds having components  12  and  14  combined in a single particle or in a larger mass (rather than discrete particles of each) are advantageous for delivering the therapeutically active component  14  into a target tissue over longer time periods. 
     In other embodiments of seed  10 , components  12  and  14  are not necessarily homogeneously mixed in the seed  10 . Rather they can be positioned in different areas of the seed  10 . For example, components  12  and  14  can separately be fashioned into discrete sections, strips; coils, tubes, etc. The discrete sections, strips, coils, tubes, etc. of the component  12  can then be combined (e.g., by molding together, adhering, structurally interlocking, etc.) with the discrete sections, strips, coils, tubes, etc. of the component  14  to form the seed  10 . In another embodiment, the seed  10  shown in  FIG. 2  can be modified by filling the cylindrical cavity  20  with a hydrogel (e.g., hydrogels from Alkermes, Cambridge, Mass.) including a therapeutically active substance, and capping off the ends of the hollow tube  18 . 
     Many different therapeutically active substances have been associated with biocompatible materials for use in drug delivery systems apart from brachytherapy seeds. These include, for example, adriamycin (Moritera et al., Invest. Ophthal. Vis. Sci. 33:3125-30, 1992); bupivicaine (Park et al., J. Controlled Release 52:179-189, 1998); camptothecin (Weingart et al., Int. J. Cancer 62:1-5, 1995); carboplatin (Chen et at, Drug Delivery 4:301-11, 1997); carmustine (Brem et at, J. Neurosurg 74:441-6, 1991; and U.S. Pat. Nos. 4,789,724 and 5,179,189); cefazolin (Park et al., J. Controlled Rel. 52:179-10, 1998); cisplatin (Yapp et al., UROBP 39:497-504, 1997); cortisone (Tamargo et at, J. Neurooncol. 9:131-8, 1990); cyclosporine (Sanchez et al., Drug Delivery 2:21-8, 1995); daunorubicin (Dash et at, J. Pharmacol. Tox, Meth. 40:1-12, 1999); dexamethasone (Reinhard et al., J. Contr. Rel. 16:331-340, 1991); dopamine (During et at, Ann. Neural. 25:351-6, 1989); etanidazole (Yapp et al., Radiotherapy Oncol. 53:77-84, 1999); 5-fluorouracil (Menei et at, Cancer 86:325-30, 1999); fluconazole (Miyamoto et al., Curr. Eye Res. 16:930-5, 1997); 4-hydroxycyclophosphamide (Judy et al., J. Neurosurg. 82:481-6, 1995); ganciclovir (Kunou et al., J. Controlled Rel. 37:143-150, 1995); gentamicin (Laurentin et al., J. Orthopaed. Res. 11:256-62, 1993); heparin (Tamargo et al., J. Neurooncol. 9:131-8, 1990); interleukin-12 (Kuriakose et al., Head &amp; Neck 22:57-63, 2000); naproxen (Conforti et al., J. Pharm. Pharmacal. 48:468-73, 1996); nerve growth factor (Camerata et al., Neurosurgery 30:313-19, 1992); retroviral vector producer cells to transfer a cytotoxic gene product (Beer et al., Adv. Drug Deliver. Rev. 27:59-66, 1997); taxol (Park et al., J. Controlled Rel. 52:179-189, 1998; and Harper, E et al., Clin. Cancer Res., 5:4242-4248, 1999); tetanus toxoid (Alonso et al., Vaccine 12:299-306, 1994); tetracaine hydrochloride (Ramirez et al., J. Microencap. 16:105-15, 1999); tirapazamine (Yuan et al., Radiation Oncol. Investig. 7:218-30, 1999); thyrotropin-releasing hormone (Kubek et al., Brain Res. 809:189-97, 1998); and vaccines (Chattaraj et al., J. Controlled Rel. 58:223-32, 1999). Other therapeutically active substances that can be combined with a biocompatible component include: anesthetics, angiogenesis inhibitors (e.g., Lau D. H. et al., Cancer Biother. Radiopharm. 14:31-6,1999), antibiotics (e.g., Bahk J. Y. et al., J. Urol. 163:1560-4, 2000; and Miyamoto H. et al., Current Eye Research 16:930-5, 1997), antibodies (e.g., Gomez S. M. et al., Biotechnol. Prog, 15:238-44, 1999), anticoagulants (e.g., Tamargo R. J. et al., J. Neurooncol. 9:131-138, 1990), antigens (e.g., Machluf M. et al., J. Pharm. Sci. 89:1550-57, 2000), anti-inflammatory agents (e.g., Reinhard C. S. et al., J. Controlled Release 16:331-40, 1991; and Tamargo R. J. et al., J. Neurosurg. 74: 956-61, 1991), antivirals, apoptosis-inhibiting agents (e.g., Macias D. et al., Anat. Embryol. (Berl) 193:533-41, 1996), cytokines (e.g., Edelman E. R. et al., Biomaterials 12:619-26, 1991), cytotoxic agents (e.g., Brem H. et al., J. Neurosurg. 80:283-90, 1994; Brem H. et al., J. Neurosurg. 80:283-90, 1994; Brem H. et al., Lancet 345:1008-12, 1995; Ewend M. G. et al., Cancer Res. 56:5217-23, 1996; Fung L. K. et al., Cancer Res. 58:672-85, 1998; Grossman S. et al., J. Neurosurg. 76:640-47, 1992; Kong Q. et al., J. Surgical Oncology 69:76-82, 1998; Shikani A. H. et al., Laryngoscope 110:907-17, 2000; Straw R. C. et al., J. Orthop. Res. 12:871-7, 1994; Tamargo R. J. et al., Cancer Research 53:329-33, 1993; Valtonen S. et al., Neurosurgery 41:44-9, 1997; Walter K. A. et al., Cancer Research 54:2207-12, 1994; Yapp D. T. T. et al., IJROBP 39:497-504, 1997; Yapp D. T. T. et al., Anti-Cancer Drugs 9:791-796, 1998; Yapp D. T. T. et al., IJROBP 42:413-20, 1998; and Yoshida M. et al., Biomaterials 10:16-22, 1989), enzymes (e.g., Park T. G. et al., J. Control Release 55:181-91, 1998), gene vectors (e.g., Hao T. et al., J. Control Release 69:249-59, 2000; and Maheshwari A. et al., Mol. Ther. 2:121-30, 2000), hormones (e.g., Rosa G. D. et al., J. Control Release 69:283-95, 2000), immunosuppressants (e.g., Sanchez A. et al., Drug Delivery 2:21-8, 1995), mitogens (e.g., Ertl B. et al., J. Drug Target 8:173-84, 2000), neurotransmitters (e.g., During M. J. et al., Ann Neurology 25:351-6, 1989), radioprotectants (e.g., Monig H. et al., Strahlenther Onkol. 166:235-41, 1990), radiosensitizers (e.g., Williams J. A. et al., IJROBP 42:631-39, 1998; and Cardinale R. M. et al., Radiat. Oncol. Invest. 6:63-70, 1998), stimulating and growth factors, transforming agents (e.g., Hong L. et al., Tissue Eng. 6:331-40, 2000), and viral vectors. 
     The foregoing combination products (i.e., at least one biocompatible component mixed with at least one therapeutically active component) can be used in the brachytherapy seeds of the invention by forming them into a size and shape suitable for passing through the bore of a needle such as one in a conventional brachytherapy seed implantation device. 
     Referring now to  FIGS. 3A-F , in others embodiments of the invention, a brachytherapy seed  10  includes a biocompatible component  12  associated with a therapeutically active component  14 , and a radiopaque marker  30  attached to the biocompatible component  12  and/or the therapeutically active component  14 . Radiopaque marker  30  allows for the position of brachytherapy seed  10  to be determined using standard X-ray imaging techniques (e.g., fluoroscopy) after seed  10  has been implanted in a target tissue. Proper positioning of seed  10 - and spacing of a plurality of brachytherapy seeds in a given target tissue is important for ensuring that the therapeutically active component  14  is delivered adequately to the site of the disease in the target tissue. 
     Radiopaque marker  30  can be made of any substance that can be detected by conventional X-ray imaging techniques. See, e.g., Fundamentals of Diagnostic Radiology, 2d edition, William E. Brant and Clyde A. Helms (eds.), Lippincott, Williams and Wilkins, 1999; Physical Principles of Medical Imaging, 2d ed., Perry Jr. Sprawls, Medical Physic Publishing, 1995; Elements of Modern X-ray Physics, Jens Als-Nielsen and Des McMorrow, Wiley &amp; Sons, 2001; X-ray and Neutron Reflectivity Principles and Applications, J. Daillant et al., Springer-Verlag, 1999; Methods of X-ray and Neutron Scattering in Polymer Science, Ryoong-Joon J. Roe, Oxford University Press, 2000; and Principles of Radiographic Imaging: An Art &amp; A Science, Richard R. Carlton, Delmar Publishers, 2000. Many such substances that can be used as marker  30  are known including, most notably; high atomic number (i.e., “high Z”) elements or alloys or mixtures containing such elements. Examples of these include platinum, iridium, rhenium, gold, tantalum, bismuth alloys, indium alloys, solder or other alloys, tungsten and silver. Many currently used radiopaque markers that might be adapted for use in the invention include platinum/iridium markers from Draximage, Inc.; and International Brachytherapy; gold rods from Bebig GmbH; gold/copper alloy markers from North American Scientific, palladium rods from Syncor; tungsten markers from Best Industries; silver rods from Nycomed Amersham; silver spheres from International Isotopes Inc, and Urocor, and silver wire from Implant Sciences Corp. Other radiopaque markers include polymers impregnated with various substances (see, e.g., U.S. Pat. Nos. 6,077,880; 6,077,880; and 5,746,998). Radiopaque polymers useful in the invention are described in European Patent Application 894, 503 filed May 8, 1997; European Patent Application 1,016,423 filed Dec. 29, 1999; and published PCT application WO 9605872 filed Aug. 21, 1995. Those radiopaque polymers that are biodegradable are preferred in applications where it is desired to have the implant degrade over time in the implantation site. 
     As indicated above, radiopaque marker  30  is attached to seed  10  via the biocompatible component  12  and/or the therapeutically active component  14 . The exact manner in which radiopaque marker  30  is attached to seed  10  can is not critical so long as (a) the seed  10  can be passed through the bore of a brachytherapy implantation needle and (b) the attachment allows the position of seed  10  to be readily detected by X-ray imaging. A description of some different examples of how marker  30  can be associated with seed is presented in  FIGS. 3A-F . In the embodiment shown in  FIG. 3A , the radiopaque marker  30  in the form of a ribbon, filament, strip, thread, or wire is placed in the center and along the length of cylindrical seed  10 . In  FIG. 313 , the radiopaque marker  30  takes the form of two end caps placed at both ends of cylindrical seed  10 . In the embodiment illustrated in  FIG. 3C , the radiopaque marker  30  is a coil made of a radiopaque substance running through the length of cylindrical seed  10  as shown. In  FIG. 3D , the radiopaque marker  30  takes the form of two beads or pellets placed at two locations along cylindrical seed  10 . In the embodiment shown in  FIG. 3E , the radiopaque marker  30  takes the form of two bands or rings placed at two locations along the outer surface of cylindrical seed  10 . In the seed  10  shown in  FIG. 3F , the radiopaque marker  30  takes the form of a mesh formed into cylindrical shape. In the seed  10  shown in  FIG. 3G , the radiopaque marker  30  is dispersed throughout the seed in a stippled pattern. 
     A particularly preferred embodiment of a brachytherapy seeds having a radiopaque marker is one in which the radiopaque markers is a polymer. In one version of this embodiment, such radiopaque polymers are combined with a biocompatible component and a therapeutically active component to form a brachytherapy seed that can be visualized by X-ray imaging. Alternatively, the radiopaque polymer can serve as the biocompatible component. As one example of the former, microspheres made of a radiopaque polymer are co-mingled with microspheres containing a biocompatible component and microspheres containing (e.g., encapsulating) a therapeutically active component (or microspheres containing both a biocompatible component and a therapeutically active component). The co-mingled microspheres are then molded into a radiopaque brachytherapy seed. As another example, the radiopaque polymer, the biocompatible component, and the therapeutically active component can be mixed together into a liquid, and the liquid can be cured to form a solid pellet that can be sculpted, molded, compressed, or otherwise made into the size and shape of a brachytherapy seed. An advantage of preparing a radiopaque brachytherapy seed in this manner is that, after implantation, the entire seed can be visualized by X-ray imaging rather than only a portion of a seed (e.g., as occurs with seeds utilizing conventional markers). 
     Referring now to  FIGS. 4A and 4  B, in another aspect of the invention, a brachytherapy seed  10  includes a biocompatible component  12  associated with a therapeutically active component  14 , and a sealed container  40  housing a radioisotope  42 . Sealed container  40  is at least partially coated (e.g., partially coated in the version shown in  FIG. 4A , and completely coated in the version shown in  FIG. 4B ) by the biocompatible component  12  and/or the therapeutically active component  14 . Sealed container  40  is similar in some respects to those employed in conventional radioactive brachytherapy seeds (e.g., those lacking a biocompatible component  12  associated with a therapeutically active component  14 ). Thus to prevent leaching of radioisotope  42  after seed  10  is implanted into a target tissue, sealed container  40  is made of a non-biodegradable substance such as titanium or stainless steel. Further, radioisotope  42  is hermetically sealed within container  40 . 
     The exact shape of sealed container  40  is not critical as long as it can be at least partially coated with component  12  and/or  14  to form a brachytherapy seed that can fit through the bore of a brachytherapy implantation needle. It can thus vary in shape from cylindrical (as shown in  FIG. 4 ), cuboid, spheroid, ovoid, ellipsoid, irregularly shaped, etc. Of more importance is the size of sealed container  40 . Because the brachytherapy seed  10  containing both the sealed container  40  and the biocompatible component  12  and/or therapeutically active component  14  must fit through the bore of a brachytherapy implantation needle, container  40  must be smaller than the overall size of seed  10 . In the example shown in  FIG. 4B , sealed container  40  is a cylindrical canister placed down the center of the length of the rod-shaped seed  10  in a coaxial fashion. Thus, where the seed  10  has a diameter of about 0.8 mm and a length of about 4.5 mm, sealed container will have a diameter less than 0.8 mm (e.g., 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, or 0.75 mm) and a length less than 4.5 mm (e.g., 1, 1.5, 2, 2.5, 3, 3.5, or 4 mm). And rather than having only a single sealed container  40  included within brachytherapy seed  10 , there can be two or more such containers (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) housing the radioisotope  42 . 
     The therapeutically active agent  14  in seed  10  including the sealed container  40  can be any of those agents described above. Preferably, however, the agent  14  is selected to provide a synergistic effect when used in combination with the radioisotope  42  to treat a particular diseased tissue. For example, in this preferred embodiment, agent  14  can be a radiosensitizing agent such as 5-FU, etanidazole, tirapazamine, BUdR, and/or IUdR. Various combinations of substances are known to be more effective when used in combination than when used alone. See, e.g, Brem et al., J. Neurosurg. 80:283-290, 1994; Ewend et al., Cancer Res. 56:5217-5223, 1996; Cardinale, Radiation Oncol. Investig. 6:63-70, 1998; Yapp et al., Radiotherapy and Oncol. 53:77-84, 1999; Yapp, IJROBP 39:497-504, 1997; Yuan et al., Radiation Oncol. Investig. 7:218-230, 1999; and Menei et al., Cancer 86:325-330, 1999. 
     Radioisotope  42  can be any substance that emits electromagnetic radiation (e.g., gamma-rays or X-rays), beta-particles or alpha-particles and is suitable for use in brachytherapy seed  10 . Examples of such substances include those that decay principally by electron capture followed by X-ray emission such as palladium-103 and iodine-125; isotopes that decay by the emission of beta-particles such as gold-198, gold-199, yttrium-90, and phosphorus-32; isotopes that decay with the emission of both beta-particles and gamma-rays such as iridium-192; and isotopes that decay with the emission of alpha-particles such as americium-241. Also useful is gadolinium-157, e.g, for use in boron-neutron capture therapy, and californium-252, rhenium-188, samarium-153, indium-111, ytterbium-169, and holmium-166. For the treatment of prostate cancer, palladium-103 and iodine-125 are preferred as these have been the subject of much clinical investigation for the treatment of the disease. The amount of radioactivity of radioisotope  42  can vary widely. For example, when using palladium-103 or iodine-125, an exemplary amount to treat prostate cancer is respectively about 1.5 mCi and 0.33 mCi per seed if about 50-150 seeds are used at the time of implantation. In other applications the radioactivity per seed can range from about 0.01 mCi to May 1, 2001 about 100 mCi. 
     In one embodiment, radioisotope  42  can be mixed with and then configured into microspheres, or it can be encapsulated by the biocompatible component to form microspheres. The radioactive microspheres can be molded or otherwise sized and shaped into a brachytherapy seed suitable for implantation via a brachytherapy implantation device. In one version of this embodiment, the biocompatible component is biodegradable such that the radioisotope contained by this component is gradually released from the seed. Alternatively, the biocompatible component and radioisotope can be mixed together and configured as an amorphous pellet having the size and shape of a brachytherapy seed suitable for implantation via a brachytherapy implantation device. 
     In another embodiment of the present invention as illustrated in  FIGS. 5A and 5B , a plurality of brachytherapy seeds  10  may be conjoined into a chain  50  using a plurality of spacers  52  to connect the plurality of seeds  10 . In the embodiments shown in  FIGS. 5A and 5B , a spacer  52  is used to connect two adjacent seeds  10 . Spacer  52  can have any size suitable for use with brachytherapy seed  10 . And where a plurality of spacers are used in one chain  50 , the length of each spacer  52  can be the same or different from the other spacers  52 . For many applications the length of spacer  52  will vary from between about 0.5 mm to about 50 mm (e.g., 0.4, 0.5, 1, 2, 3, 4, 5, 5.5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 51 mm). In many cases, it is important to minimize the bunching or straying of seeds  10  to avoid over- or under-dosing of the target tissue by the therapeutically active component  14  and/or radioisotope  42 . Thus, the length of spacer  52  should be selected accordingly. 
     Spacer  52  can be made of a biocompatible material that can be used to join two brachytherapy seeds. See, e.g., U.S. Pat. No. 6,010,446. The biocompatible material can be either biodegradable or non-biodegradable. For example, spacer  52  can be made of catgut or a like material. Spacers designed for use with conventional radioactive brachytherapy seeds can be used in chain  50 . For example, Ethicon, Inc. (Cincinnati, Ohio) manufactures the PG 910 non-sterile autoclavable spacer for Indigo (Cincinnati, Ohio) that is sold in conjunction with an Express Seed Cartridge. In addition, Medical Device Technologies, Inc. (Gainesville, Fla.) distributes a pre-sterilized 5.5 mm long absorbable pre-cut spacer that is made of collagen (Look® model number 1514b). Materials for use as the spacer  52  are also manufactured by Surgical Specialties Corp. (Reading Pa.). Where spacer  52  is made of a relatively flexible material, the chain  50  can be relatively flaccid as shown in  FIG. 5A . Where spacer  52  is made of an inflexible material, chain  50  will be rigid as shown in  FIG. 5B . 
     In some embodiments of the present invention, the spacer  52  may include a radiopaque substance (e.g., a high Z material or radiopaque polymer described above), so that spacer  52  serves both to facilitate locating an implanted brachytherapy seed by X-ray imaging as well as to physically join together (and/or control the distance between) two or more seeds. 
     Spacer  52  can be connected to seed  10  by any means known. For example, spacer  52  can be connected to seed  10  by direct attachment such as by gluing, crimping, or melting. Spacer  52  can be attached to any portion of the seed  10 . For rod or cylinder-shaped seeds  10 , to facilitate implantation, it is generally preferred that spacer  52  be attached to the ends of the seeds  10  that the ends would be adjacent to one another when the chain  50  is inserted into the barrel of a brachytherapy implantation needle. Spacer  52  and seed  10 , however, need not be physically attached to each other. Rather they can also be associated with each other by placing each with within the lumen of a tube. The tube can be used to load a brachytherapy seed implantation device with a plurality of spacers  52  and seeds  10  in any sequence. For example, the brachytherapy seed implantation device can be loaded with one (or 2, 3, 4, 5, or more) spacer  52  being interposed between every two seeds  10 . Similarly, the brachytherapy seed implantation device can be loaded with one (or 2, 3, 4, 5, or more) seed  10  being interposed between every two spacers  52 . 
     Methods of Making Brachytherapy Seeds 
     Brachytherapy seeds of the invention can be made by first providing a biocompatible component (e.g., a biocompatible component) and a therapeutically active component; then physically associating the two components to form a combination product; and finally forming the combination product into a seed having a size and shape suitable for passing through the bore of a brachytherapy implantation needle (e.g., one having an interior diameter of less than about 2.7 millimeters (10 gauge)). Seeds can be formed into a suitable size and shape by any suitable method, e.g., molding, pressing, extruding, stamping, or chopping. 
     Brachytherapy seeds of the invention that are associated with a radiopaque marker can be made similarly, with the addition of a step of associating the radiopaque marker with the seed. Brachytherapy seeds of the invention that include a sealed container housing a radioisotope can be made by at least partially coating the container with the biocompatible component and therapeutically active component. 
     Method for Administering a Therapeutically Active Component to a Target Tissue in a Subject 
     The brachytherapy seeds of the invention can be fashioned into a size and shape similar or identical to conventional radioactive brachytherapy seeds. Accordingly, the brachytherapy seeds of the invention can be implanted into a target tissue within a subject (e.g., a human patient or a non-human animal) by adapting known methods for implanting conventional radioactive brachytherapy seeds into a tissue. For example, the brachytherapy seeds of the present invention can be implanted using one or more implantation needles; Henschke, Scott, or Mick applicators; or a Royal Marsden gold grain gun (H. J. Hodt et al., British J. Radiology, pp. 419-421, 1952). A number of suitable implantation devices are described in, e.g., U.S. Pat. Nos. 2,269,963; 4,402,308; 5,860,909; and 6,007,474. 
     Pharmacokinetics 
     The brachytherapy seeds of the invention can advantageously be used to selectively deliver a predetermined amount of a therapeutically active substance to a target tissue. For example, when a brachytherapy seed including a therapeutically active substance is implanted in a prostate, the therapeutically active substance will be released from the seed into the tissue surrounding the implantation site. The diffusion or release characteristics of the therapeutically active substance in relation to the target tissue, i.e., the pharmacokinetics of the substance, can be modulated by selecting appropriate biocompatible components included within the seeds, and by varying the concentration of the therapeutically active substance in each seed. 
     In many applications, to treat a given target tissue with a therapeutic agent it is desirable (or even ideal) to fully saturate the target tissue with the therapeutic agent, while avoiding under- or over-dosing the target tissue. This can be achieved by implanting the brachytherapy seeds of the invention into a target tissue using a brachytherapy implantation device so that, e.g., a precise number of seeds can be implanted in precise locations within the target tissue. By previously calculating the rate of diffusion of the therapeutically active substance under experimental conditions (e.g., using tissue from animal models), an appropriate dosage can be delivered to the target tissue. Because use of brachytherapy implantation devices allows the brachytherapy seeds of the invention to be implanted in any number of different desired locations and/or patterns in a tissue, this method is advantageous over methods where a drug or drug impregnated matrix is simply placed on the surface of a tissue or manually inserted into a surgically dissected tissue. 
     Other Embodiments 
     While the above specification contains many specifics, these should not be construed as limitations on the scope of the invention, but rather as examples of preferred embodiments thereof. Many other variations are possible. For example, although the foregoing embodiments describe brachytherapy seeds having a single type of therapeutically active component and/or single type of radioisotope, brachytherapy seeds within the invention can also have a plurality of different therapeutically active agents and/or a plurality of different radioisotopes. Accordingly, the scope of the invention should be determined not by the embodiments illustrated, but by the appended claims and their legal equivalents.