The invention relates to embolization, as well as related particles, compositions and methods.
Therapeutic vascular occlusions (embolizations) are used to prevent or treat pathological conditions in situ. Compositions including embolic particles are used for occluding vessels in a variety of medical applications. Delivery of embolic particles through a catheter is dependent on size uniformity, density and compressibility of the embolic particles.
The invention relates to embolization, as well as related particles, compositions and methods.
In one aspect, the invention features a substantially spherical porous silica particle having a diameter of from about 100 microns to about 3000 microns.
In another aspect, the invention features a composition that includes a carrier fluid that contains a plurality of substantially spherical porous silica particles. At least some of the plurality of substantially spherical silica particles have a diameter of from about 100 microns to about 3000 microns; and
In a further aspect, the invention features a method that includes administering to a subject a therapeutically effective amount of a composition including a plurality of substantially spherical silica particles in a carrier fluid. At least some of the plurality of substantially spherical silica particles having a diameter of from about 100 microns to about 3000 microns.
Embodiments can include one or more of the following.
In some embodiments, the carrier fluid includes a saline solution.
In certain embodiments, the carrier fluid includes a contrast agent.
In some embodiments, at least some of the substantially spherical porous silica particles have a diameter of at most about 1500 microns.
In certain embodiments, for at least some of the substantially spherical porous silica particles, pores in the substantially spherical porous silica particles have a diameter of from about 20 nanometers to about 90 nanometers.
In some embodiments, for at least some of the substantially spherical porous silica particles, a pore volume of the substantially spherical silica particles is from about 0.4 ml/g to about 1.6 ml/g.
In certain embodiments, the particles can have a pore volume distribution such that about 70% or more of the pore volume of the particles is made up of pores having pore diameters which have a tolerance of about 10 nm or less on the mean pore diameter.
In some embodiments, the particles exhibit a loss of attrition resistance of about 0.1% by weight or less.
In certain embodiments, at least some of the plurality of substantially spherical porous silica particles include one or more therapeutic agents, one or more ferromagnetic materials, one or more MRI visible materials and/or one or more radiopaque materials.
In some embodiments, the plurality of substantially spherical porous silica particles are sterilized.
In some embodiments, the composition is administered to the subject by percutaneous injection.
In certain embodiments, the composition is administered to the subject by a catheter.
In some embodiments, the composition is used to treat a cancer condition. The cancer condition can be, for example, ovarian cancer, colorectal cancer, thyroid cancer, gastrointestinal cancer, breast cancer, prostate cancer and/or lung cancer. Treating the cancer condition can include at least partially occluding a lumen in the subject that provides nutrients to a site of the cancer condition with at least some of the plurality of particles.
In certain embodiments, the method includes at least partially occluding a lumen in the subject with at least some of a plurality of particles.
Embodiments may include one or more of the following advantages.
In some embodiments, the silica particles can be substantially biologically inert and non-degradable in the body.
In certain embodiments, the particles can have, and can maintain after implantation, a highly uniform diameter, geometry, pore volume, and pore size.
In general, the particle diameter, geometry, pore volume and pore diameter can be selected based on a desired application. As an example, in some embodiments (e.g., for embolic applications), the particles may have a spherical geometry with a particle diameter of about 3000 microns or less (e.g., about 1500 microns or less) and a relatively large pore volume, to enhance the suspendability of the particles in a delivery medium such as a contrast agent, and a relatively small pore size to enhance surface uniformity, robustness and abrasion resistance. As another example, in certain embodiments (e.g., for a therapeutic agent delivery applications), pore volume can be selected to contain a desired therapeutic agent volume, and pore size can be selected to produce a desired time release, based on diffusion of therapeutic agent from the pores.
In some embodiments, the particles can be made targetable by incorporation of a magnetic material.
In certain embodiments, the particles can be highly incompressible and exhibit a high crushing strength such that they can withstand contact and delivery through a syringe, catheter or the like, as well as, withstand internal body fluid pressure without fracturing.
Features and advantages are in the description, drawings, and claims.
Like reference symbols in the various drawings indicate like elements.
Referring to
In general, embolic compositions can be used in, for example, neural, pulmonary, and/or AAA (abdominal aortic aneurysm) applications. The compositions can be used in the treatment of, for example, fibroids, tumors, internal bleeding, arteriovenous malformations (AVMs), and/or hypervascular tumors. The compositions can be used as, for example, fillers for aneurysm sacs, AAA sac (Type II endoleaks), 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 (subserosal type), inside the uterine cavity (submucosal type), between the layers of broad ligament supporting the uterus (interligamentous type), attached to another organ (parasitic type), or on a mushroom-like stalk (pedunculated type). Internal bleeding includes gastrointestinal, urinary, renal and varicose bleeding. AVMs 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 particles can be used to prophylactically treat a condition.
The magnitude of a dose of an embolic composition can vary based on the nature, location and severity of the condition to be treated, as well as the route of administration. A physician treating the condition, disease or disorder can determine an effective amount of embolic composition. An effective amount of embolic composition refers to the amount sufficient to result in amelioration of symptoms or a prolongation of survival of the subject. The embolic compositions can be administered as pharmaceutically acceptable compositions to a subject in any therapeutically acceptable dosage, including those administered to a subject intravenously, subcutaneously, percutaneously, intratrachealy, intramuscularly, intramucosaly, intracutaneously, intra-articularly, orally or parenterally.
An embolic composition can be prepared in calibrated concentrations of the particles for ease of delivery by the physician. Suspensions of the particles in saline solution can be prepared to remain stable (e.g., to not precipitate) over a duration of time. A suspension of the particles can be stable, for example, for from about one minute to about 20 minutes (e.g. from about one minute to about ten minutes, from about two minutes to about seven minutes, from about three minutes to about six minutes). The concentration of particles can be determined by adjusting the weight ratio of the particles to the physiological solution. If the weight ratio of the particles is too small, then too much liquid could be injected into a blood vessel, possibly allowing the particles to stray into lateral vessels. In some embodiments, the physiological solution can contain from about 0.01 weight percent to about 15 weight percent of the particles. A composition can include a mixture of particles, such as particles including one type of surface preferential material and particles including another, different, type of surface preferential material.
In some embodiments, among the particles delivered to a subject in an embolic composition, the majority (e.g., about 50 percent or more, about 60 percent or more, about 70 percent or more, about 80 percent or more, about 90 percent or more) of the particles have a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less; about 1,200 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; about 900 microns or more; about 1,200 microns or more; about 1,500 microns or more; about 2,000 microns or more; about 2,500 microns or more).
In certain embodiments, the particles delivered to a subject in an embolic composition have a mean diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less; about 1,200 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; about 900 microns or more; about 1,200 microns or more; about 1,500 microns or more; about 2,000 microns or more; about 2,500 microns or more). Exemplary ranges for the mean diameter of particles delivered to a subject include from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about 300 microns to about 500 microns; from about 500 microns to about 700 microns; and from about 900 microns to about 1,200 microns. In general, the particles delivered to a subject in an embolic composition have a mean diameter in approximately the middle of the range of the diameters of the individual particles, and a variance of about 20 percent or less (e.g. about 15 percent or less, about ten percent or less).
In some embodiments, the mean size of the particles delivered to a subject in an embolic composition can vary depending upon the particular condition to be treated. As an example, in embodiments in which the particles in an embolic composition are used to treat a liver tumor, the particles delivered to the subject can have a mean diameter of about 500 microns or less (e.g., from about 100 microns to about 300 microns; from about 300 microns to about 500 microns). As another example, in embodiments in which the particles in an embolic composition are used to treat a uterine fibroid, the particles delivered to the subject in an embolic composition can have a mean diameter of about 1,200 microns or less (e.g., from about 500 microns to about 700 microns; from about 700 microns to about 900 microns; from about 900 microns to about 1,200 microns).
In general, particle 111 is substantially spherical. For example, in some embodiments, particle 111 can have a sphericity of about 0.8 or more (e.g., about 0.85 or more, about 0.9 or more, about 0.95 or more, about 0.97 or more). The sphericity of a particle can be determined using a Beckman Coulter RapidVUE Image Analyzer version 2.06 (Beckman Coulter, Miami, Fla.). Briefly, the RapidVUE takes an image of continuous-tone (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=√(4A/π); Dp=P/π; A=pixel area; P=pixel perimeter), is a value from zero to one, with one representing a perfect circle.
In certain embodiments, particle 111 has a diameter of about 3,000 microns or less (e.g., about 2,500 microns or less; about 2,000 microns or less; about 1,500 microns or less; about 1,200 microns or less; about 900 microns or less; about 700 microns or less; about 500 microns or less; about 400 microns or less; about 300 microns or less; about 100 microns or less) and/or about ten microns or more (e.g., about 100 microns or more; about 300 microns or more; about 400 microns or more; about 500 microns or more; about 700 microns or more; about 900 microns or more; about 1,200 microns or more; about 1,500 microns or more; about 2,000 microns or more; about 2,500 microns or more). Exemplary ranges for the diameter of particle 111 include from about 100 microns to about 500 microns; from about 100 microns to about 300 microns; from about 300 microns to about 500 microns; from about 500 microns to about 700 microns; and from about 900 microns to about 1,200 microns.
In some embodiments, particle 111 has a substantially uniform pore structure. In certain embodiments, particle 111 has non-uniform pore structure.
In certain embodiments, pores 112 can interconnect throughout particle 111. In some embodiments, pores 112 do not interconnect throughout particle 111.
In some embodiments, the diameters of pores 112 in particle 111 are about 20 nanometers or more (e.g., about 30 nanometers or more, about 40 nanometers or more) and/or about 90 nanometers or less (e.g., about 80 nanometers or less, about 70 nanometers or less, about 60 nanometers or less).
In general, the density of particle 111 (e.g., as measured in grams of material per unit volume) is such that it can be readily suspended in a carrier fluid (e.g., a pharmaceutically acceptable carrier, such as a saline solution, a contrast solution, or a mixture thereof) and remain suspended during delivery (e.g., to form a composition, such as an embolization composition). In some embodiments, the density of particle 111 is from about 1.1 grams per cubic centimeter to about 1.4 grams per cubic centimeter. As an example, for suspension in a saline-contrast solution, the density of particle 111 can be from about 1.2 grams per cubic centimeter to about 1.3 grams per cubic centimeter.
In some embodiments, particle 111 can have a high pore diameter and/or a high pore volume uniformity. For example, particle 111 can have a pore diameter distribution such that about 70% or more of the pore volume is made up pores having pore diameters which have a tolerance of not more than 10 nanometers on the mean pore diameter. Pore volume and diameter can be measured by mercury porosimetry.
In certain embodiments, particle 111 can exhibit good resistance to abrasion. For example, a particle can exhibit no detectable loss in attrition resistance. In some embodiments, the loss of attrition of particle 111, as measured using a standard attrition test according to the Peter Spence method, is about 0.1 weight percent or less (e.g., about 0.05 weight percent or less).
In some embodiments, particle 111 can exhibit high crush strength.
Characterization of silica particles is disclosed, for example, in U.S. Pat. No. 4,640,807 and European Patent No. 067459, both of which are hereby incorporated by reference.
In some embodiments, particle 111 can include one or more therapeutic agents (e.g., drugs). The therapeutic agent can be in and/or on particle 111. For example, pores 112 of particle 111 can include a therapeutic agent.
Therapeutic agents include agents that are negatively charged, positively charged, amphoteric, or neutral. Therapeutic agents can be, for example, materials that are biologically active to treat physiological conditions; pharmaceutically active compounds; gene therapies; nucleic acids with and without carrier vectors; oligonucleotides; gene/vector systems; DNA chimeras; compacting agents (e.g., DNA compacting agents); viruses; polymers; hyaluronic acid; proteins (e.g., enzymes such as ribozymes); cells (of human origin, from an animal source, or genetically engineered); stem cells; immunologic species; nonsteroidal anti-inflammatory medications; oral contraceptives; progestins; gonadotrophin-releasing hormone agonists; chemotherapeutic agents; and radioactive species (e.g., radioisotopes, radioactive molecules). Non-limiting examples of therapeutic agents include anti-thrombogenic agents; antioxidants; angiogenic and anti-angiogenic agents and factors; anti-proliferative agents (e.g., agents capable of blocking smooth muscle cell proliferation); anti-inflammatory agents; calcium entry blockers; antineoplastic/antiproliferative/anti-mitotic agents (e.g., paclitaxel, doxorubicin, cisplatin); antimicrobials; anesthetic agents; anti-coagulants; vascular cell growth promoters; vascular cell growth inhibitors; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogenous vasoactive mechanisms; and survival genes which protect against cell death. Therapeutic agents are described, for example, in co-pending U.S. patent application Ser. No. 10/615,276, filed on Jul. 8, 2003, and entitled “Agent Delivery Particle”, which is incorporated herein by reference.
Referring to
The particle diameter, pore diameter and volume and/or uniformity can be controlled to produce particles optimized for a particular application. For example, for a therapeutic delivery application, particle diameter and pore volume can be selected to contain a desired amount of therapeutic agent. The pore diameter can be selected to elute the therapeutic agent into the body based on diffusion processes at a desired rate. A composition including a mixture of particles having known percentages of particles with different particle diameters, pore diameter and pore volume can be prepared to produce a desired dosage profile. Particles of different diameters and pore characteristics can also include different therapeutic agents. The therapeutic agent delivery particles can be implanted into a lumen, e.g., a vascular lumen by catheterization, e.g., as embolic particles, or injected into soft tissue adjacent a cancerous tumor or other lesion.
While certain embodiments have been described, the invention is not so limited.
As an example, in some embodiments a particle can be coated (e.g., with a bioabsorbable material, such as sodium alginate). The coating can contain, for example, one or more therapeutic agents. In some cases, the coating can be, for example, a degradable and/or bioabsorbable polymer which erodes when the particle is administered. The coating can assist in controlling the rate at which therapeutic agent is released from the particle (e.g., from the surface preferential material). For example, the coating can be in the form of a porous membrane. The coating can delay an initial burst of therapeutic agent release. The coating can be applied by dipping or spraying the particle. The erodible polymer can be a polysaccharide (such as an alginate) or a polysaccharide derivative. In some embodiments, the coating can be an inorganic, ionic salt. Other erodible coatings include water soluble polymers (such as polyvinyl alcohol, e.g., that has not been cross-linked), biodegradable poly DL-lactide-poly ethylene glycol (PELA), hydrogels (e.g., polyacrylic acid, haluronic acid, gelatin, carboxymethyl cellulose), polyethylene glycols (PEG), chitosan, polyesters (e.g., polycaprolactones), and poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids). The coating can include therapeutic agent or can be substantially free of therapeutic agent. The therapeutic agent in the coating can be the same as or different from an agent on a surface layer of the particle. A polymer coating, e.g. an erodible coating, can be applied to the particle surface in cases in which a high concentration of therapeutic agent has not been applied to the particle surface. Coatings are described, for example, in U.S. patent application Ser. No. 10/615,276, filed on Jul. 8, 2003, and entitled “Agent Delivery Particle”, which is incorporated herein by reference.
As an additional example, in some embodiments one or more particles is/are substantially nonspherical. In some embodiments, particles can be shaped (e.g., molded, compressed, punched, and/or agglomerated with other particles) at different points in the particle manufacturing process. Shaped particles are described, for example, in Bourne et al., U.S. Published Patent Application No. US 2003/0203985 A1, which is incorporated herein by reference.
As a further example, in some embodiments the 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, percutaneously, laparoscopically, 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 sphincteric deficiency (ISD), vesicoureteral reflux, gastroesophageal reflux disease (GERD), and/or vocal cord paralysis (e.g., to restore glottic competence in cases of paralytic dysphonia). 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 (e.g., 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 al., U.S. Published Patent Application No. US 2003/0233150 A1, which is incorporated herein by reference.
As another example, the particles can include (e.g., encapsulate) diagnostic agent(s) such as a radiopaque material, an MRI-visible material, a ferromagnetic material, and/or an ultrasound contrast agent. For example, a silica particle can encapsulate a ferromagnetic material so that the position of the particle in a lumen can be manipulated with a magnetic field. The magnetic field can be created outside the subject or inside the subject (e.g., via a magnetic catheter). In some embodiments, a ferromagnetic material can be incorporated into silica particles by adding the magnetic material to the silica hydrosol mix (step 300,
As yet another example, in certain embodiments, a particle can include one or more therapeutic agents (e.g., in the pores of the particle) and one or more diagnostic agents (e.g., one or more ferromagnetic materials encapsulated in the silica). In certain embodiments, a therapeutic agent can be conjugated with a diagnostic agent. Including both therapeutic agent(s) and diagnostic agent(s) in a particle can enhance the ability to deliver the therapeutic agent in a targeted way.
As a further example, in some embodiments a particle contains materials in addition to silica. For example, in some embodiments, the particle can include one or more polymeric materials (e.g., matrix polymeric materials). Examples of polymeric materials include polyvinyl alcohols, polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates, carboxymethyl celluloses, hydroxyethyl celluloses, substituted celluloses, polyacrylamides, polyethylene glycols, polyamides, polyureas, polyurethanes, polyesters, polyethers, polystyrenes, polysaccharides, polylactic acids, polyethylenes, polymethylmethacrylates, polycaprolactones, polyglycolic acids, poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids), and copolymers or mixtures thereof. In some embodiments, the polymer can be substantially formed of a highly water insoluble, high molecular weight polymer. An example of such a polymer is a high molecular weight polyvinyl alcohol (PVA) that has been acetalized. A polymer can be substantially pure intrachain 1,3-acetalized PVA and substantially free of animal derived residue such as collagen. Examples of particles containing such materials are disclosed in U.S. patent application Ser. No. 10/637,130, filed Aug. 8, 2003, and entitled “Embolization”, which is hereby incorporated by reference.
As an additional example, in some embodiments, a particle can be shaped, such as described, for example, in U.S. patent application Ser. No. 10/700,970, filed on Nov. 4, 2003, and entitled “Embolization”, and U.S. patent application Ser. No. 10/700,403 filed on Nov. 4, 2003, and entitled “Embolization”, both of which are incorporated herein by reference.
As another example, in some embodiments a particle can be formed with no pores and/or no cavities.
Other embodiments are in the claims.
Number | Name | Date | Kind |
---|---|---|---|
2275154 | Merrill et al. | Mar 1942 | A |
2609347 | Wilson | Sep 1952 | A |
3663470 | Nishimura et al. | May 1972 | A |
3737398 | Yamaguchi | Jun 1973 | A |
3957933 | Egli et al. | May 1976 | A |
4025686 | Zion | May 1977 | A |
4034759 | Haerr | Jul 1977 | A |
4055377 | Erickson et al. | Oct 1977 | A |
4076640 | Forgensi et al. | Feb 1978 | A |
4094848 | Naito | Jun 1978 | A |
4096230 | Haerr | Jun 1978 | A |
4098728 | Rosenblatt | Jul 1978 | A |
4110529 | Stoy | Aug 1978 | A |
4159719 | Haerr | Jul 1979 | A |
4191672 | Salome et al. | Mar 1980 | A |
4198318 | Stowell et al. | Apr 1980 | A |
4243794 | White et al. | Jan 1981 | A |
4246208 | Dundas | Jan 1981 | A |
4266030 | Tschang et al. | May 1981 | A |
4268495 | Muxfeldt et al. | May 1981 | A |
4271281 | Kelley et al. | Jun 1981 | A |
4402319 | Handa et al. | Sep 1983 | A |
4413070 | Rembaum | Nov 1983 | A |
4427794 | Lange et al. | Jan 1984 | A |
4428869 | Munteanu et al. | Jan 1984 | A |
4429062 | Pasztor et al. | Jan 1984 | A |
4442843 | Rasor et al. | Apr 1984 | A |
4444961 | Timm | Apr 1984 | A |
4452773 | Molday | Jun 1984 | A |
4456693 | Welsh | Jun 1984 | A |
4459145 | Elsholz | Jul 1984 | A |
4472552 | Blouin | Sep 1984 | A |
4477255 | Pasztor et al. | Oct 1984 | A |
4492720 | Moiser | Jan 1985 | A |
4515906 | Friesen et al. | May 1985 | A |
4522953 | Barby et al. | Jun 1985 | A |
4542178 | Zimmermann et al. | Sep 1985 | A |
4551132 | Pasztor et al. | Nov 1985 | A |
4551436 | Johnson et al. | Nov 1985 | A |
4573967 | Hargrove et al. | Mar 1986 | A |
4622362 | Rembaum | Nov 1986 | A |
4623706 | Timm et al. | Nov 1986 | A |
4640807 | Afghan et al. | Feb 1987 | A |
4657756 | Rasor et al. | Apr 1987 | A |
4661137 | Garnier et al. | Apr 1987 | A |
4663358 | Hyon et al. | May 1987 | A |
4671954 | Goldberg et al. | Jun 1987 | A |
4674480 | Lemelson | Jun 1987 | A |
4675113 | Graves et al. | Jun 1987 | A |
4678710 | Sakimoto et al. | Jul 1987 | A |
4678814 | Rembaum | Jul 1987 | A |
4680320 | Uku et al. | Jul 1987 | A |
4681119 | Rasor et al. | Jul 1987 | A |
4695466 | Morishita et al. | Sep 1987 | A |
4713076 | Draenert | Dec 1987 | A |
4742086 | Masamizu et al. | May 1988 | A |
4743507 | Franses et al. | May 1988 | A |
4772635 | Mitschker et al. | Sep 1988 | A |
4782097 | Jain et al. | Nov 1988 | A |
4789501 | Day et al. | Dec 1988 | A |
4793980 | Torobin | Dec 1988 | A |
4795741 | Leshchiner et al. | Jan 1989 | A |
4801458 | Hidaka et al. | Jan 1989 | A |
4804366 | Zdeb et al. | Feb 1989 | A |
4819637 | Dormandy, Jr. et al. | Apr 1989 | A |
4822535 | Ekman et al. | Apr 1989 | A |
4833237 | Kawamura et al. | May 1989 | A |
4850978 | Dudar et al. | Jul 1989 | A |
4859711 | Jain et al. | Aug 1989 | A |
4863972 | Itagaki et al. | Sep 1989 | A |
4897255 | Fritzberg et al. | Jan 1990 | A |
4929400 | Rembaum et al. | May 1990 | A |
4933372 | Feibush et al. | Jun 1990 | A |
4946899 | Kennedy et al. | Aug 1990 | A |
4954399 | Tani et al. | Sep 1990 | A |
4981625 | Rhim et al. | Jan 1991 | A |
4990340 | Hidaka et al. | Feb 1991 | A |
4999188 | Sololdovnik et al. | Mar 1991 | A |
5007940 | Berg | Apr 1991 | A |
5011677 | Day et al. | Apr 1991 | A |
H915 | Gibbs | May 1991 | H |
5015423 | Eguchi et al. | May 1991 | A |
5032117 | Motta | Jul 1991 | A |
5034324 | Shinozaki et al. | Jul 1991 | A |
5047438 | Feibush et al. | Sep 1991 | A |
5079274 | Schneider et al. | Jan 1992 | A |
5091205 | Fan | Feb 1992 | A |
5106903 | Vanderhoff et al. | Apr 1992 | A |
5114421 | Polak | May 1992 | A |
5116387 | Berg | May 1992 | A |
5120349 | Stewart et al. | Jun 1992 | A |
5125892 | Drudik | Jun 1992 | A |
5147631 | Glajch et al. | Sep 1992 | A |
5147937 | Frazza et al. | Sep 1992 | A |
5149543 | Cohen et al. | Sep 1992 | A |
5158573 | Berg | Oct 1992 | A |
5171214 | Kolber et al. | Dec 1992 | A |
5171217 | March et al. | Dec 1992 | A |
5181921 | Makita et al. | Jan 1993 | A |
5190760 | Baker | Mar 1993 | A |
5190766 | Ishihara | Mar 1993 | A |
5192301 | Kamiya et al. | Mar 1993 | A |
5202352 | Okada et al. | Apr 1993 | A |
5216096 | Hattori et al. | Jun 1993 | A |
5253991 | Yokota et al. | Oct 1993 | A |
5260002 | Wang | Nov 1993 | A |
5262176 | Palmacci et al. | Nov 1993 | A |
5263992 | Guire | Nov 1993 | A |
5288763 | Li et al. | Feb 1994 | A |
5292814 | Bayer et al. | Mar 1994 | A |
5302369 | Day et al. | Apr 1994 | A |
5314974 | Ito et al. | May 1994 | A |
5316774 | Eury et al. | May 1994 | A |
RE34640 | Kennedy et al. | Jun 1994 | E |
5320639 | Rudnick | Jun 1994 | A |
5328936 | Leifholtz et al. | Jul 1994 | A |
5336263 | Ersek et al. | Aug 1994 | A |
5344452 | Lemperle | Sep 1994 | A |
5344867 | Morgan et al. | Sep 1994 | A |
5354290 | Gross | Oct 1994 | A |
5369133 | Ihm et al. | Nov 1994 | A |
5369163 | Chiou et al. | Nov 1994 | A |
5382260 | Dormandy, Jr. et al. | Jan 1995 | A |
5384124 | Courteille et al. | Jan 1995 | A |
5397303 | Sancoff et al. | Mar 1995 | A |
5398851 | Sancoff et al. | Mar 1995 | A |
5403870 | Gross | Apr 1995 | A |
5417982 | Modi | May 1995 | A |
5431174 | Knute | Jul 1995 | A |
5435645 | Faccioli et al. | Jul 1995 | A |
5443495 | Buscemi et al. | Aug 1995 | A |
5456693 | Conston et al. | Oct 1995 | A |
5468801 | Antonelli et al. | Nov 1995 | A |
5469854 | Unger et al. | Nov 1995 | A |
5476472 | Dormandy, Jr. et al. | Dec 1995 | A |
5484584 | Wallace et al. | Jan 1996 | A |
5490984 | Freed | Feb 1996 | A |
5494682 | Cohen et al. | Feb 1996 | A |
5494940 | Unger et al. | Feb 1996 | A |
5512604 | Demopolis | Apr 1996 | A |
5514090 | Kriesel et al. | May 1996 | A |
5514347 | Ohashi et al. | May 1996 | A |
5525334 | Ito et al. | Jun 1996 | A |
5534589 | Hager et al. | Jul 1996 | A |
5541031 | Yamashita et al. | Jul 1996 | A |
5542935 | Unger et al. | Aug 1996 | A |
5553741 | Sancoff et al. | Sep 1996 | A |
5556391 | Cercone et al. | Sep 1996 | A |
5556610 | Yan et al. | Sep 1996 | A |
5558255 | Sancoff et al. | Sep 1996 | A |
5558822 | Gitman et al. | Sep 1996 | A |
5558856 | Klaveness et al. | Sep 1996 | A |
5559266 | Klaveness et al. | Sep 1996 | A |
5567415 | Porter | Oct 1996 | A |
5569193 | Hofstetter et al. | Oct 1996 | A |
5569449 | Klaveness et al. | Oct 1996 | A |
5569468 | Modi | Oct 1996 | A |
5571182 | Ersek et al. | Nov 1996 | A |
5580575 | Unger et al. | Dec 1996 | A |
5583162 | Li et al. | Dec 1996 | A |
5585112 | Unger et al. | Dec 1996 | A |
5595821 | Hager et al. | Jan 1997 | A |
5622657 | Takada et al. | Apr 1997 | A |
5624685 | Takahashi et al. | Apr 1997 | A |
5635215 | Boschetti et al. | Jun 1997 | A |
5637087 | O'Neil et al. | Jun 1997 | A |
5639710 | Lo et al. | Jun 1997 | A |
5648095 | Illum et al. | Jul 1997 | A |
5648100 | Boschetti et al. | Jul 1997 | A |
5650116 | Thompson | Jul 1997 | A |
5651990 | Takada et al. | Jul 1997 | A |
5653922 | Li et al. | Aug 1997 | A |
5657756 | Vrba | Aug 1997 | A |
5681576 | Henry | Oct 1997 | A |
5695480 | Evans et al. | Dec 1997 | A |
5695740 | Porter | Dec 1997 | A |
5698271 | Liberti et al. | Dec 1997 | A |
5701899 | Porter | Dec 1997 | A |
5715824 | Unger et al. | Feb 1998 | A |
5716981 | Hunter et al. | Feb 1998 | A |
5718884 | Klaveness et al. | Feb 1998 | A |
5723269 | Akagi et al. | Mar 1998 | A |
5725534 | Rasmussen | Mar 1998 | A |
5733925 | Kunz et al. | Mar 1998 | A |
5741331 | Pinchuk | Apr 1998 | A |
5746734 | Dormandy, Jr. et al. | May 1998 | A |
5752974 | Rhee et al. | May 1998 | A |
5756127 | Grisoni et al. | May 1998 | A |
5760097 | Li et al. | Jun 1998 | A |
5766147 | Sancoff et al. | Jun 1998 | A |
5770222 | Unger et al. | Jun 1998 | A |
5779668 | Grabenkort | Jul 1998 | A |
5785642 | Wallace et al. | Jul 1998 | A |
5785682 | Grabenkort | Jul 1998 | A |
5792478 | Lawin et al. | Aug 1998 | A |
5795562 | Klaveness et al. | Aug 1998 | A |
5797953 | Tekulve | Aug 1998 | A |
5807323 | Kriesel et al. | Sep 1998 | A |
5813411 | Van Bladel et al. | Sep 1998 | A |
5823198 | Jones et al. | Oct 1998 | A |
5827502 | Klaveness et al. | Oct 1998 | A |
5827531 | Morrison et al. | Oct 1998 | A |
5830178 | Jones et al. | Nov 1998 | A |
5833361 | Funk | Nov 1998 | A |
5840387 | Berlowitz-Tarrant et al. | Nov 1998 | A |
5846518 | Yan et al. | Dec 1998 | A |
5853752 | Unger et al. | Dec 1998 | A |
5855615 | Bley et al. | Jan 1999 | A |
5863957 | Li et al. | Jan 1999 | A |
5876372 | Grabenkort et al. | Mar 1999 | A |
5877224 | Brocchini et al. | Mar 1999 | A |
5885216 | Evans, III et al. | Mar 1999 | A |
5885547 | Gray | Mar 1999 | A |
5888546 | Ji et al. | Mar 1999 | A |
5888930 | Smith et al. | Mar 1999 | A |
5891155 | Irie | Apr 1999 | A |
5894022 | Ji et al. | Apr 1999 | A |
5895398 | Wensel et al. | Apr 1999 | A |
5895411 | Irie | Apr 1999 | A |
5899877 | Leibitzki et al. | May 1999 | A |
5902832 | Van Bladel et al. | May 1999 | A |
5902834 | Porrvik | May 1999 | A |
5922025 | Hubbard | Jul 1999 | A |
5922304 | Unger | Jul 1999 | A |
5928626 | Klaveness et al. | Jul 1999 | A |
5935553 | Unger et al. | Aug 1999 | A |
5951160 | Ronk | Sep 1999 | A |
5957848 | Sutton et al. | Sep 1999 | A |
5959073 | Schlameus et al. | Sep 1999 | A |
6003566 | Thibault et al. | Dec 1999 | A |
6015546 | Sutton et al. | Jan 2000 | A |
6027472 | Kriesel et al. | Feb 2000 | A |
6028066 | Unger | Feb 2000 | A |
6047861 | Vidal et al. | Apr 2000 | A |
6048908 | Kitagawa | Apr 2000 | A |
6051247 | Hench et al. | Apr 2000 | A |
6056721 | Shulze | May 2000 | A |
6056844 | Guiles et al. | May 2000 | A |
6059766 | Greff | May 2000 | A |
6063068 | Fowles et al. | May 2000 | A |
6071495 | Unger et al. | Jun 2000 | A |
6071497 | Steiner et al. | Jun 2000 | A |
6073759 | Lamborne et al. | Jun 2000 | A |
6090925 | Woiszwillo et al. | Jul 2000 | A |
6096344 | Liu et al. | Aug 2000 | A |
6099064 | Lund | Aug 2000 | A |
6099864 | Morrison et al. | Aug 2000 | A |
6100306 | Li et al. | Aug 2000 | A |
6139963 | Fujii et al. | Oct 2000 | A |
6149623 | Reynolds | Nov 2000 | A |
6160084 | Langer et al. | Dec 2000 | A |
6162377 | Ghosh et al. | Dec 2000 | A |
6165193 | Greene, Jr. et al. | Dec 2000 | A |
6179817 | Zhong | Jan 2001 | B1 |
6191193 | Lee et al. | Feb 2001 | B1 |
6214331 | Vanderhoff et al. | Apr 2001 | B1 |
6214384 | Pallado et al. | Apr 2001 | B1 |
6224630 | Bao et al. | May 2001 | B1 |
6224794 | Amsden et al. | May 2001 | B1 |
6235224 | Mathiowitz et al. | May 2001 | B1 |
6238403 | Greene, Jr. et al. | May 2001 | B1 |
6245090 | Gilson et al. | Jun 2001 | B1 |
6251661 | Urabe et al. | Jun 2001 | B1 |
6258338 | Gray | Jul 2001 | B1 |
6261585 | Sefton et al. | Jul 2001 | B1 |
6264861 | Tavernier et al. | Jul 2001 | B1 |
6267154 | Felicelli et al. | Jul 2001 | B1 |
6268053 | Woiszwillo et al. | Jul 2001 | B1 |
6277392 | Klein | Aug 2001 | B1 |
6280457 | Wallace et al. | Aug 2001 | B1 |
6291605 | Freeman et al. | Sep 2001 | B1 |
6296604 | Garibaldi et al. | Oct 2001 | B1 |
6296622 | Kurz et al. | Oct 2001 | B1 |
6296632 | Luscher et al. | Oct 2001 | B1 |
6306418 | Bley | Oct 2001 | B1 |
6306419 | Vachon et al. | Oct 2001 | B1 |
6306425 | Tice et al. | Oct 2001 | B1 |
6306427 | Annonier et al. | Oct 2001 | B1 |
6312407 | Zadno-Azizi et al. | Nov 2001 | B1 |
6312942 | Plüss-Wenzinger et al. | Nov 2001 | B1 |
6315709 | Garibaldi et al. | Nov 2001 | B1 |
6335384 | Evans et al. | Jan 2002 | B1 |
6344182 | Sutton et al. | Feb 2002 | B1 |
6355275 | Klein | Mar 2002 | B1 |
6368658 | Schwarz et al. | Apr 2002 | B1 |
6379373 | Sawhney et al. | Apr 2002 | B1 |
6388043 | Langer et al. | May 2002 | B1 |
6394965 | Klein | May 2002 | B1 |
6423332 | Huxel et al. | Jul 2002 | B1 |
6432437 | Hubbard | Aug 2002 | B1 |
6436112 | Wensel et al. | Aug 2002 | B2 |
6443941 | Slepian et al. | Sep 2002 | B1 |
6458296 | Heinzen et al. | Oct 2002 | B1 |
6468493 | Chevallier et al. | Oct 2002 | B1 |
6476069 | Krall et al. | Nov 2002 | B2 |
6482324 | Kirkland et al. | Nov 2002 | B2 |
6495155 | Tice et al. | Dec 2002 | B1 |
6544503 | Vanderhoff et al. | Apr 2003 | B1 |
6544544 | Hunter et al. | Apr 2003 | B2 |
6545097 | Pinchuk et al. | Apr 2003 | B2 |
6575896 | Silverman et al. | Jun 2003 | B2 |
6602261 | Greene, Jr. et al. | Aug 2003 | B2 |
6602524 | Batich et al. | Aug 2003 | B2 |
6605111 | Bose et al. | Aug 2003 | B2 |
6629947 | Sahatjian et al. | Oct 2003 | B1 |
6632531 | Blankenship | Oct 2003 | B2 |
6652883 | Goupil et al. | Nov 2003 | B2 |
6680046 | Boschetti | Jan 2004 | B1 |
6699222 | Jones et al. | Mar 2004 | B1 |
7591993 | Boschetti | Sep 2009 | B2 |
20010001835 | Greene, Jr. et al. | May 2001 | A1 |
20010016210 | Mathiowitz et al. | Aug 2001 | A1 |
20010036451 | Goupil et al. | Nov 2001 | A1 |
20010051670 | Goupil et al. | Dec 2001 | A1 |
20020054912 | Kim et al. | May 2002 | A1 |
20020061954 | Davis et al. | May 2002 | A1 |
20020160109 | Yeo et al. | Oct 2002 | A1 |
20020182190 | Naimark et al. | Dec 2002 | A1 |
20020197208 | Ruys et al. | Dec 2002 | A1 |
20030007928 | Gray | Jan 2003 | A1 |
20030032935 | Damiano et al. | Feb 2003 | A1 |
20030108614 | Volkonsky et al. | Jun 2003 | A1 |
20030183962 | Buiser et al. | Oct 2003 | A1 |
20030185895 | Lanphere et al. | Oct 2003 | A1 |
20030185896 | Buiser et al. | Oct 2003 | A1 |
20030187320 | Freyman | Oct 2003 | A1 |
20030194390 | Krall et al. | Oct 2003 | A1 |
20030203985 | Baldwin et al. | Oct 2003 | A1 |
20030206864 | Mangin | Nov 2003 | A1 |
20030215519 | Schwarz et al. | Nov 2003 | A1 |
20030233150 | Bourne et al. | Dec 2003 | A1 |
20040076582 | DiMatteo et al. | Apr 2004 | A1 |
20040091543 | Bell et al. | May 2004 | A1 |
20040092883 | Casey, III et al. | May 2004 | A1 |
20040096662 | Lanphere et al. | May 2004 | A1 |
20040101564 | Rioux et al. | May 2004 | A1 |
20040186377 | Zhong et al. | Sep 2004 | A1 |
20050025800 | Tan | Feb 2005 | A1 |
20050037047 | Song | Feb 2005 | A1 |
20050048859 | Canham et al. | Mar 2005 | A1 |
20050095428 | DiCarlo et al. | May 2005 | A1 |
20050129775 | Lanphere et al. | Jun 2005 | A1 |
20050196449 | Dicarlo et al. | Sep 2005 | A1 |
Number | Date | Country |
---|---|---|
A-7618698 | Oct 1998 | AU |
3834705 | Apr 1990 | DE |
94 14 868.6 | Feb 1995 | DE |
297 24 255 | Oct 2000 | DE |
100 26 620 A 1 | Mar 2002 | DE |
0067459 | Dec 1982 | EP |
0 122 624 | Oct 1984 | EP |
0 123 235 | Oct 1984 | EP |
0243165 | Oct 1987 | EP |
0294206 | Dec 1988 | EP |
0 422 258 | Oct 1989 | EP |
0 402 031 | May 1990 | EP |
0 458 079 | Nov 1991 | EP |
0 458 745 | Nov 1991 | EP |
0 470 569 | Feb 1992 | EP |
0 547 530 | Jun 1993 | EP |
0 600 529 | Dec 1993 | EP |
0 623 012 | Nov 1994 | EP |
0 706 376 | Apr 1996 | EP |
0 730 847 | Sep 1996 | EP |
0 744 940 | Dec 1996 | EP |
0 797 988 | Oct 1997 | EP |
0 067 459 | Mar 1998 | EP |
0 764 047 | Aug 2003 | EP |
0 993 337 | Apr 2004 | EP |
2 096 521 | Mar 1997 | ES |
59-196738 | Nov 1984 | JP |
62-45637 | Feb 1987 | JP |
4-74117 | Mar 1992 | JP |
6-57012 | Mar 1994 | JP |
9-110678 | Apr 1997 | JP |
9-165328 | Jun 1997 | JP |
9-316271 | Dec 1997 | JP |
10-130329 | May 1998 | JP |
2000189511 | Jul 2000 | JP |
2001079011 | Mar 2001 | JP |
2002 017848 | Jan 2002 | JP |
255409 | Feb 1997 | NZ |
517377 | Aug 2003 | NZ |
421658 | Feb 2001 | TW |
WO 9112823 | May 1991 | WO |
WO 9221327 | Dec 1992 | WO |
WO 9300063 | Jan 1993 | WO |
WO 9319702 | Oct 1993 | WO |
WO 9410936 | May 1994 | WO |
WO 9503036 | Feb 1995 | WO |
WO 9522318 | Aug 1995 | WO |
WO 9533553 | Dec 1995 | WO |
WO 9637165 | Nov 1996 | WO |
WO 9639464 | Dec 1996 | WO |
WO 9804616 | Feb 1998 | WO |
WO 9810798 | Mar 1998 | WO |
WO 9826737 | Jun 1998 | WO |
WO 9847532 | Oct 1998 | WO |
WO 9900187 | Jan 1999 | WO |
WO 9912577 | Mar 1999 | WO |
WO 9943380 | Sep 1999 | WO |
WO 9951278 | Oct 1999 | WO |
WO 9957176 | Nov 1999 | WO |
WO 0023054 | Apr 2000 | WO |
WO 0032112 | Jun 2000 | WO |
WO 0040259 | Jul 2000 | WO |
WO 0071196 | Nov 2000 | WO |
WO0066183 | Nov 2000 | WO |
WO 0074633 | Dec 2000 | WO |
WO 0112359 | Feb 2001 | WO |
WO 0166016 | Sep 2001 | WO |
WO 0170291 | Sep 2001 | WO |
WO 0172281 | Oct 2001 | WO |
WO 0176845 | Oct 2001 | WO |
WO 0193920 | Dec 2001 | WO |
WO 0211696 | Feb 2002 | WO |
WO 0234298 | May 2002 | WO |
WO 0234299 | May 2002 | WO |
WO 0234300 | May 2002 | WO |
WO 0243580 | Jun 2002 | WO |
WO 03013552 | Feb 2003 | WO |
WO03016364 | Feb 2003 | WO |
WO 03051451 | Jun 2003 | WO |
WO03082359 | Sep 2003 | WO |
WO2004019999 | Mar 2004 | WO |
WO 2004040972 | May 2004 | WO |
WO 2004073688 | Sep 2004 | WO |
WO2004075989 | Sep 2004 | WO |
Number | Date | Country | |
---|---|---|---|
20050226935 A1 | Oct 2005 | US |