|Número de publicación||US20080199510 A1|
|Tipo de publicación||Solicitud|
|Número de solicitud||US 12/033,586|
|Fecha de publicación||21 Ago 2008|
|Fecha de presentación||19 Feb 2008|
|Fecha de prioridad||20 Feb 2007|
|También publicado como||CA2678814A1, EP2114301A1, US8980297, US20110022148, US20150142098, WO2008103741A1|
|Número de publicación||033586, 12033586, US 2008/0199510 A1, US 2008/199510 A1, US 20080199510 A1, US 20080199510A1, US 2008199510 A1, US 2008199510A1, US-A1-20080199510, US-A1-2008199510, US2008/0199510A1, US2008/199510A1, US20080199510 A1, US20080199510A1, US2008199510 A1, US2008199510A1|
|Inventores||Patrick H. Ruane, Cameron L. Wilson|
|Cesionario original||Xtent, Inc.|
|Exportar cita||BiBTeX, EndNote, RefMan|
|Citada por (14), Clasificaciones (26), Eventos legales (1)|
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet|
The present application claims the benefit of U.S. Provisional Application No. 60/890,703 (Attorney Docket No. 021629-004500US), filed Feb. 20, 2007, the full disclosure of which is incorporated herein by reference.
1. Field of the Invention
This invention relates generally to medical apparatus and methods, and more specifically to implants and biodegradable implants for use in the vascular system as well as other body lumens and cavities.
The use of implants in body tissue is becoming increasingly important in medical treatment. Examples of implant usage include alteration of tissue in cosmetic or reconstructive procedures such as breast augmentation as well as creation, preservation or closure of lumens, channels or fluid reservoirs (e.g. stenting stenotic lesions, exclusion of aneurysms or embolic coils). Implants are also used as matrices for tissue growth (e.g. orthopedic bone fusion procedures), to control unwanted tissue growth and for delivery of therapeutic agents to tissue. Implants may also be employed to join tissue surfaces together or for isolating or protecting tissue lesions in order to enable or mediate healing. Implants are also used to mediate the rate of substances or energy passing into, out of, or through tissue.
Often, implants are fabricated using various metals and/or polymers. Examples of common metals include stainless steel, titanium, nickel-titanium alloys like Nitinol and polymers such as PTFE (e.g. Teflon®), polyethylene, polyurethane and polyester are often used in implants. A potential disadvantage of these permanent implants is that the implant materials may be harder and stiffer than the surrounding tissues, thus anatomical or physiological mismatch may occur, potentially resulting in tissue damage or causing unwanted biological responses. Some materials may fatigue over time and break which can disrupt the layer of endothelial cells potentially causing thrombosis. Additionally, a permanent implant is not always required. An implant may only be required for a limited time period, therefore the implant often must be surgically explanted when it is no longer needed. To overcome some of these challenges, the use of biodegradable polymeric implants has been proposed. Examples of implantable biodegradable polymers include the aliphatic polyester polylactic acid or polylactide (PLA) and polyglycolide (PGA). PGA was originally proposed for use in suture material in the late 1960's. By the early 1970's PLA was proposed as a suture material including both the optically active poly-L-lactide (PLLA) and the racemic mixture poly-DL-lactide (PDLA). PLLA has also been used in biodegradable stents, as reported by Igaki and Tamai. A co-polymer of PLA and PGA, known as PLGA has also been proposed for use in implants. Another material which has recently been proposed (in the 1980's) for use in sutures and orthopedic implants is polydioxanone. In the mid-1990's implantable drug delivery systems using polyanhydrides were proposed by Langer et al. at the Massachusetts Institute of Technology, and more recently tyrosine derived polyarylate has seen use in hernia repair and companies are developing biodegradable stents composed of materials such as a tyrosine derived polycarbonate, poly(DTE carbonate).
While these newer biodegradable implant materials have overcome some of the challenges of earlier implant materials, other potential drawbacks still exist. For example, it is often desirable to adjust the shape of some implants in situ so that the implant conforms more accurately to the anatomy of the treatment site. However, the biodegradable polymers cannot be plastically deformed, molded or shaped at normal body temperatures since they must be solid at body temperature. The implant must therefore be heated above its glass transition temperature, Tg. Often the glass transition temperature is fairly high, for example PDLLA and PLLA have a Tg approximately 50°-80° C., therefore in situ heating may result in localized tissue damage, thrombosis or patient discomfort. It is well known that adding an impurity to a material will change some of the material's properties such as increasing its boiling point and reducing its freezing point. Therefore, additives may be mixed with the biodegradable polymers to decrease the glass transition temperature, for example 2-10% ε-caprolactone added to 90-98% PLLA can reduce the glass transition temperature down to about 38°-55° C., but a heat source hotter than the glass transition temperature may still be required due to heat transfer inefficiencies or non-uniform heating, therefore, similar complications may still arise.
One proposed solution to the challenge of non-uniform heating is to coat the implant with a radiation absorbing material which converts radiation to heat. Exemplary coatings include chromophores like indocyanine green, vital blue, carbon black and methylene blue. The radiation, often ultraviolet or visible light must therefore be supplied in situ from a second device due to the poor penetration of the radiation through the tissue. Additionally, production of sufficient and uniform heat using this technique remains a challenge. Furthermore, the chromophores may degrade into unwanted chemicals that are toxic to the body. Therefore, there exists a need for an easier, less toxic and less invasive way to heat implants, including biodegradable polymer implants, to an elevated temperature so that they may be shaped or molded in situ. Furthermore, such techniques should also be able to heat the implant uniformly.
Additionally, while biodegradable implants will degrade over time, it would also be desirable to be able to control the rate of degradation. For example, when an implant is no longer required, it would be desirable to be able to accelerate the degradation rate so that the implant breaks down faster than its normal in situ rate. For this reason, there is also need for a way to control the degradation rate of a biodegradable implant.
2. Description of the Background Art
Prior patents describing nanoshells for converting incident radiation into heat include: U.S. Pat. Nos. 6,344,272; 6,428,811; 6,530,944; 6,645,517; 6,660,381; 6,685,730; 6,699,724; 6,778,316; and 6,852,252. Prior patents describing thermo-mechanically expansion of stents include: U.S. Pat. Nos. 5,670,161; 5,741,323; 6,607,553; 6,736,842. Prior patents describing meltable stents include: U.S. Pat. Nos. 4,690,684 and 4,770,176. Prior patent describing bioerodable polyanhydrides for controlled drug delivery include: U.S. Pat. No. 4,891,225. Prior patents describing tyrosine derived polycarbonate as an implant include: U.S. Pat. Nos. 6,951,053; 7,101,840; and 7,005,454. Prior patents describing biodegradable stents include: U.S. Pat. Nos. 5,733,327; 5,762,625; 5,817,100; 6,045,568; 6,080,177, 6,200,335; 6,413,272; 6,500,204; 6,632,242; RE38,653; RE38,711; 7,066,952; and 7,070,615. The full disclosure of each of these patents is incorporated herein by reference.
The invention generally provides for an implant having a plurality of particles dispersed therein. The particles are adapted to convert incident radiation into heat energy when the particles are irradiated with electromagnetic radiation. The particles are in thermal contact with the implant and therefore the heat generated by the particles raises the temperature of the implant. The increased temperature changes a material property of the implant.
In a first aspect of the present invention, an implant for use in tissue comprises a structure that is adapted for implantation into the tissue and that has a first material property at normal body temperature. The material property is variable at an elevated temperature above normal body temperature. The implant also comprises a plurality of particles that are dispersed in the structure and that are adapted to convert incident radiation into heat energy when the particles are irradiated with electromagnetic radiation. The particles are in thermal contact with the structure and thus exposure of the particles to incident radiation raises the temperature of the structure thereby changing the first material property.
In another aspect of the present invention, an expandable implant for use in tissue comprises a structure that is adapted for implantation into the tissue and that is not plastically deformable at normal body temperature but that is plastically deformable at an elevated temperature above normal body temperature. The implant also has a plurality of particles dispersed in the structure and that are adapted to convert incident radiation into heat energy when irradiated with electromagnetic radiation. The particles are in thermal contact with the structure such that exposure of the particles to the incident radiation raises the temperature of the structure allowing it to be plastically deformed.
In yet another aspect of the present invention, an expandable, biodegradable implant for use in tissue comprises a biodegradable structure that is adapted for implantation into the tissue and that degrades at a first rate when implanted in the tissue at normal body temperature. The implant also comprises a plurality of particles that are dispersed in the structure with the particles adapted to convert incident radiation into heat energy when they are irradiated with electromagnetic radiation. The particles are in thermal contact with the structure such that exposure of the particles to the incident radiation raises the temperature of the structure thereby increasing the degradation rate of the structure relative to the first rate.
The degradation rate of an implant may also be controlled by using an additional reagent such as a catalyst or enzyme. The reagent is adapted to react with the structure so as to increase the structure's degradation rate relative to the first rate at normal body temperature. Often, the reagent is dispersed in a carrier such as a microsphere along with particles such as nanoshells. The microsphere, which may be a hydrogel, is distributed in the implant structure and exposure of the particles to incident radiation raises the temperature of the carrier or microsphere, thereby releasing the reagent.
Often the structure is biodegradable and is composed of a polymer or copolymer, either synthetic or natural, that is not plastically expandable at normal body temperature but is thermo-mechanically expandable at an elevated temperature above normal body temperature. The structure is often composed of one or more of the following materials including, polyhydroxyalkanoates, polyalphahydroxy acids, polysaccharides, proteins, hydrogels, lignin, shellac, natural rubber, polyanhydrides, polyamide esters, polyvinyl esters, polyvinyl alcohols, polyalkylene esters, polyethylene oxide, polyvinylpyrrolidone, polyethylene maleic anhydride and poly(glycerol-sibacate). The structure may also comprise poly-L-lactide, poly-ε-caprolactone or a biological fluid in the solid state such as blood plasma. The material property may be the biodegradation rate of the structure, viscosity or the property may be the ability of the structure to be plastically expanded.
Sometimes the structure may be a stent which may be tubular and that is radially expandable at the elevated temperature. The stent may comprise a tube having a sidewall and the sidewall may define a plurality of openings therein. Sometimes the structure may also have a therapeutic agent that is adapted to be released therefrom. The therapeutic agent may be an anti-restenosis agent or it may be at least one of the following, including antibiotics, thrombolytics, anti-thrombotics, anti-inflammatories, cytotoxic agents, anti-proliferative agents, vasodilators, gene therapy agents, radioactive agents, immunosuppressants, chemotherapeutics, endothelial cell attractors, endothelial cell promoters, stem cells and combinations thereof. Sometimes the structure may be adapted to be implanted into a breast or it may be used to deliver a drug to the tissue. The structure may also be used to exclude aneurysms or it may be an orthopedic implant.
The particles may comprise nanoparticles or nanoshells and often the particles have a non-conducting core layer such as silicon dioxide, with a first thickness and a conducting outer shell layer, such as gold, adjacent to the core layer with a second thickness. The ratio of the first thickness to the second thickness defines a maximum wavelength of electromagnetic radiation converted by the particles into heat. Sometimes the particles are substantially spherical. Often the elevated temperature is in the range from about 38° C. to about 60° C. and the electromagnetic radiation often is ultraviolet, visible, near infrared or infrared light.
In another aspect of the present invention, a method of controlling a material property of an implant comprises the steps of providing an implant having a plurality of particles dispersed therein. The implant has a first material property when implanted in tissue at normal body temperature and the material property is variable at an elevated temperature above normal body temperature. Exposing the implant to electromagnetic radiation results in the incident radiation being converted into heat energy thus raising the temperature of the implant above normal body temperature and thereby changing the material property relative to the first material property.
In yet another aspect of the present invention, a method of delivering an expandable implant to a treatment site in a body comprises providing an implant having a plurality of particles dispersed therein and positioning the implant at the treatment site. Positioning may include advancing a catheter through a body lumen with the implant disposed on the catheter. Exposing the implant to electromagnetic radiation allows the particles to convert the incident radiation into heat energy. The heat energy raises the implant temperature above its glass transition temperature such that the implant may be plastically deformed so as to change its shape. Expanding the implant may include expanding a balloon.
In another aspect of the present invention, a method of controlling the degradation rate of an implant comprises providing a biodegradable implant having a plurality of particles dispersed therein. The implant degrades at a first rate when implanted in tissue at normal body temperature. Exposing the implant to electromagnetic radiation allows the particles to convert the incident radiation into heat energy which raises the temperature of the implant above normal body temperature. The elevated temperature changes the biodegradation rate of the implant relative to the first rate. Exposing the implant may include irradiating a carrier such as a microsphere, dispersed in the implant and containing a reagent and particles. The carrier heats up and releases the reagent when irradiated and the reagent reacts with the implant to degrade it. The reagent may be an enzyme or catalyst.
The method may also comprise discontinuing exposure of the implant to the electromagnetic radiation in order to allow the implant to cool down so that it returns to body temperature so that the implant is substantially undeformable plastically at body temperature. The method may also include monitoring the temperature of implant. Exposing the implant to electromagnetic radiation may include exposing the implant from outside the body or from within the body. Sometimes a catheter may be used to deliver the radiation to the implant. The radiation may be delivered for a fixed duration of time, continuously for a defined period or over periodic intervals until a desired temperature obtained in the implant.
These and other embodiments are described in further detail in the following description related to the appended drawing figures.
Nanoshells have a unique ability to interact with specific wavelengths of electromagnetic radiation and effectively convert the incident radiation into heat energy. By adjusting the relative core and shell thicknesses, and choice of materials, nanoshells can be fabricated that will react with or scatter light at any wavelength across much of the ultraviolet, visible and infrared range of the electromagnetic spectrum. The nanoshell may therefore be tuned to specific wavelengths of electromagnetic radiation and the conversion of incident radiation to heat energy can be optimized.
Nanoshells are well described in the scientific and patent literature. Other aspects of nanoshells such as manufacturing methods, materials and principles of operation are described in U.S. Pat. Nos. 6,428,811; 6,530,944; 6,645,517; 6,660,381; 6,685,730; 6,699,724; 6,778,316; and 6,852,252, the entire contents of which have previously been incorporated herein by reference.
Because nanoshells are efficient at converting incident radiation into heat, they may be dispersed in implants and light or other forms of electromagnetic radiation may be used to heat up the implant. Furthermore, since a nanoshell may be tuned to certain wavelengths, a nanoshell that preferentially interacts with light at near infrared wavelengths between approximately 700 and approximately 2500 nm is desirable, and more preferably between about 800 nm and 1200 nm, since this range of wavelengths is transmitted through tissue with very little absorption and therefore relatively little attenuation. Thus the majority of the light is delivered to the nanoparticles, converted into heat and transferred to the implant in which the nanoparticles are dispersed. This makes external access to an implanted device possible and heating of the tissue surrounding the implant is substantially avoided. One particular source of near infrared light, a Nd:YAG laser emits light at a wavelength of 1064 nm and hence is ideal for irradiating an implant from outside the body. Additionally, in the case of a biodegradable implant, as the implant breaks down the nanoshells are released into surrounding tissue. Due to their small size, the nanoshells are easily purged by body systems such as the kidneys. Nanoshells therefore present a unique way of allowing an implant to be heated from outside the body with minimal biocompatibility issues.
In many of the embodiments described herein, near infrared light is used to irradiate the nanoparticles and generate heat. However, it should be obvious to one of ordinary skill in the art that many wavelengths of electromagnetic radiation may also be used, including a magnetic field. The nanoparticles may be magnetically responsive so that they produce heat upon exposure to a magnetic field. Examples of magnetically responsive materials include iron oxides, magnetite (Fe3O4) and maghemite (γ-Fe3O3).
It should also be noted that the embodiment of
A number of other stent geometries are applicable and have been reported in the scientific and patent literature. Other stent geometries include, but are not limited to those disclosed in the following U.S. patents, the full disclosures of which are incorporated herein by reference: U.S. Pat. Nos. 6,315,794; 5,980,552; 5,836,964; 5,527,354; 5,421,955; 4,886,062; and 4,776,337.
Referring back to
Referring now to
Having multiple stents allows the physician operator to select the number of stents to deliver and thus customization of stent length is possible, as disclosed in U.S. Patent Publication Nos. 2006/0282150 and 2007/0027521, the entire contents of which are incorporated herein by reference. Additionally, other customizable-length stent delivery systems have been proposed for delivering multiple stent segments and these may also be used to deliver one or more stents 502. Prior publications describing catheters for delivering multiple segmented stents include: U.S. Pat. Nos. 7,309,350; 7,326,236; 7,137,993; and 7,182,779; U.S. Patent Publication Nos. 2005/0038505; 2004/0186551; and 2003/0135266. Prior related U.S. patent applications, Publications and Provisionals include Ser. Nos. 2006/0282150; 2006/0282147; 2007/0179587; 2007/0067012; 60/784,309; and 11/462,951. The full disclosures of each of these patents and applications are incorporated herein by reference.
Stent delivery catheter 500 is then slidably advanced over the guidewire GW into the vessel V so that stent 502 traverses the lesion L. Optional radiopaque markers (not illustrated) may be placed on the catheter shaft 504 in order to facilitate visualization of the delivery catheter under fluoroscopy. Once the delivery catheter has been properly positioned in the vessel, the stent 502 may be heated up to facilitate its expansion.
Radiation is applied until the temperature of stent 502 is above its glass transition temperature, Tg, which is approximately 40°-60° C. in this exemplary embodiment. The exposure time is dependent upon many factors, including but not limited to, area of radiation coverage, wavelength and intensity of the radiation, type and mass of the implant material and nanoshell concentration. Therefore, exposure time could range from a few seconds to a few hours, and more preferably from about 10 seconds to about an hour. Longer exposure times are not desirable due to patient inconvenience.
Stent 502 is fabricated from a material having a glass transition temperature above normal body temperature. Therefore, stent 502 is solid at or below normal body temperature. Normal body temperature is approximately 37° C., therefore the stent 502 material is selected to have a Tg slightly higher than 37° C., yet not so high that the temperature required to heat the stent above Tg results in tissue damage.
Once the temperature of stent 502 is raised above the glass transition temperature, it's viscosity decreases, permitting stent 502 to be plastically deformed. In
Referring now to
Nanoshells may also be used to control the degradation rate of a biodegradable implant.
Some examples of other biodegradable materials include polyesters such as polyhydroxyalkanoates (PHA) and polyalphahydroxy acids (AHA). Exemplary PHAs include, but are not limited to polymers of 3-hydroxypropionate, 3-hydroxybutyrate, 3-hydroxyvalerate, 3-hydroxycaproate, 3-hydroxyheptanoate, 3-hydroxyoctanoate, 3-hydroxynonanoate, 3-hydroxydecanoate, 3-hydroxyundecanoate, 3-hydroxydodecanoate, 4-hydroxybutyrate and 5-hydroxyvalerate. Examples of AHAs include, but are not limited to various forms of polylactide or polylactic acid including PLA, PLLA or PDLLA, polyglycolic acid and polyglycolide, poly(lactic-co-glycolic acid), poly(lactide-co-glycolide), poly(ε-caprolactone) and polydioxanone. Polysaccharides including starch, glycogen, cellulose and chitin may also be used as a biodegradable material. It is also feasible that proteins such as zein, resilin, collagen, gelatin, casein, silk or wool could be used as a biodegradable implant material. Still other materials such as hydrogels including poly(hydroxyethyl methylacrylate), polyethylene glycol, poly(N-isopropylacrylamide), poly(N-vinyl-2-pyrrolidone), cellulose polyvinyl alcohol, silicone hydrogels, polyacrylamides, and polyacrylic acid are potential biodegradable implant materials. Other potential biodegradable materials include lignin, shellac, natural rubber, polyanhydrides, polyamide esters, polyvinyl esters, polyvinyl alcohol, polyalkylene esters, polyethylene oxide, polyvinylpyrrolidone, polyethylene maleic anhydride and poly(glycerol-sibacate). Still another potential biodegradable material include the polyphosphazenes developed by Harry R. Allcock at Pennsylvania State University.
As stent 602 temperature increases, naturally occurring chemical reactions between the body and the stent 602 are accelerated, thereby increasing the rate at which stent 602 breaks down. In
In alternative embodiments, a microsphere containing nanoshells and a chemical reagent may be dispersed in the implant and used to accelerate biodegradation even more than previously described.
As the microsphere 700 is irradiated and heats up, it expands and releases the reagent E into the implant material. The reagent begins to chemically react with the implant material, breaking it down, thus accelerating the in situ biodegradation rate. Additional information on methods of use, materials and principles of operation of controlled drug delivery systems are reported in the scientific and patent literature including U.S. Pat. Nos. 6,645,517 (West et al.) and 4,891,225 (Langer et al.), the entire contents of which are incorporated herein by reference. In other embodiments, an implant having different layers of degradable materials could be independently degraded by selectively releasing various reagents E from the microsphere 700 at different temperatures. The various layers could be bioeroded away at the same time during a single treatment session, or the layers may be selectively bioeroded away with multiple exposures to electromagnetic radiation at different times.
While the exemplary embodiments have been described in some details for clarity of understanding and by way of example, a variety of additional modifications, adaptations and changes may be clear to those of skill in the art. Hence, the scope of the present invention is limited solely by the appended claims.
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|Clasificación de EE.UU.||424/426, 623/1.19, 623/8, 623/1.38, 623/23.75|
|Clasificación internacional||A61F2/82, A61F2/02, A61F2/12|
|Clasificación cooperativa||A61F2250/0004, A61L31/148, A61L31/128, A61F2250/0012, A61L27/54, A61F2/28, A61L27/44, A61F2/82, G21K5/02, A61L2430/04, A61L31/16, A61F2/025, A61L27/58, A61F2210/0004, A61F2250/0067, A61F2/12|
|Clasificación europea||A61F2/12, A61F2/82|
|1 May 2008||AS||Assignment|
Owner name: XTENT, INC., CALIFORNIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RUANE, PATRICK H.;WILSON, CAMERON L.;REEL/FRAME:020887/0499
Effective date: 20080430