Patent Grant
9561023
Healthy leg veins contain valves that allow blood to move in one direction from the lower limbs toward the heart. These valves open when blood is flowing toward the heart, and close to prevent venous reflux, or the backward flow of blood. When veins weaken and become enlarged, their valves cannot close properly, which leads to venous reflux and impaired drainage of venous blood from the legs. Venous reflux is most common in the superficial veins. The largest superficial vein is the great saphenous vein, which runs from the top of the foot to the groin, where it originates at a deep vein.
Factors that contribute to venous reflux disease include female gender, heredity, obesity, lack of physical activity, multiple pregnancies, age, past history of blood clots in the legs and professions that involve long periods of standing. According to population studies, the prevalence of visible tortuous varicose veins, a common indicator of venous reflux disease, is up to 15% for adult men and 25% for adult women. A clinical registry of over 1,000 patients shows that the average age of patients treated for venous reflux is 48 and over 75% of the patients are women.
In men, the testicular blood vessels originate in the abdomen and course down through the inguinal canal as part of the spermatic cord on their way to the testis, where they form a network of small veins known as the pampiniform plexus. Upward flow of blood in the veins is ensured by small one-way valves that prevent backflow. Defective valves or venous compression by nearby structures can cause dilation and tortuosity of the pampiniform plexus. This may result in a varicocele, or abnormal enlargement of the veins in the scrotum. Like varicose veins, the presence of a varicocele is a common indicator of venous reflux.
Venous reflux can be classified as either asymptomatic or symptomatic, depending on the degree of severity. Symptomatic venous reflux disease is a more advanced stage of the disease and can have a profound impact on the patient's quality of life. People with symptomatic venous reflux disease may seek treatment due to a combination of symptoms and signs, which may include leg pain and swelling; painful varicose veins; skin changes such as discoloration or inflammation; the presence of a palpable, abnormal mass along the spermatic cord; and open skin ulcers.
A primary goal of treating symptomatic venous reflux is to eliminate the reflux at its source, such as, for example, the great saphenous vein. If a diseased vein is either closed or removed, blood can automatically reroute into other veins without any known negative consequences to the patient.
The current non-invasive methods for treatment of reflux in the greater saphenous vein include radiofrequency (RF) ablation, laser endothermal ablation, and sclerotherapy, including foam sclerotherapy. Radiofrequency ablation and laser ablation require tumescent anesthesia which produce both bruising and pain along the inner thigh and upper inner calf for several weeks, and both can have side effects of burns and nerve damage. Radiofrequency ablation and laser ablation also require capital purchases of a radiofrequency device or laser box, often at costs of more than $50,000, in addition to expensive disposal mechanisms. While foam sclerotherapy is relatively non-invasive, it has a high rate of recurrence and potential side effects. All of the methods require wearing compression stockings for 2-4 weeks.
For those treatments which involve careful placement of a catheter at a particular intravenous treatment site, a reliable means for visualizing the instruments is needed. Ultrasound is a common method for device visualization in the medical device industry. Ultrasound works by emitting sound waves and analyzing the waves that are reflected and returned to the ultrasound sensing device. Despite its popularity, ultrasound visualization often provides inadequate resolution for careful intravenous placement of a catheter for the treatment of venous reflux disease, and improved echogenic catheters and methods of use are needed.
Disclosed herein is a medical device for use under ultrasound visualization. In one embodiment, the device comprises an elongate shaft comprising an outer surface and an inner surface defining an inner lumen, the inner lumen having an open proximal end and an open distal end, a plurality of microlumens having proximal ends and distal ends, embedded within the elongate shaft. The microlumens are arranged between the inner surface and outer surface of the elongate shaft, and they each have closed proximal and distal ends and are configured to contain a gas within to increase the visibility of the device under ultrasound imaging.
According to another embodiment, the device comprises an elongate shaft comprising an outer surface and an inner surface defining an inner lumen, and one or more microwells within the elongate shaft, each microwell having a cross-sectional dimension configured such that gas enters the microwell but surface tension prevents liquid from entering the microwell. The microwells are configured to contain gas within them to increase the visibility of the device under ultrasound imaging.
In yet another embodiment, the medical device comprises an elongate shaft comprising an outer surface and an inner surface defining an inner lumen, wherein the elongate shaft comprises expanded polytetrafluoroethylene containing enclosed gas pockets to increase the visibility of the device under ultrasound imaging.
Disclosed herein are systems, methods and devices for the minimally invasive treatment of varicose veins and other medical conditions. When used herein with respect to the device, proximal can refer to toward the access insertion site into a blood vessel, while distal refers to away from the access insertion site and in the direction of the patient. In the treatment as applied to the greater saphenous vein, proximal may mean cephalad, or towards the head, while distal refers to the caudal direction. In some embodiments an occlusive device is deployed to block the saphenous vein just distal to the Superficial Femoral Vein Junction (SFJ) and create a flattened shape so the vein can be treated further using either a substance to alter the vein such that blood flow is prevented therein, such as sclerosing solution or medical adhesive. In some embodiments, complete vein closure is the desired clinical result of all treatments to mitigate the effects of venous hypertension caused by retrograde venous flow. The occlusion device and medical adhesive can be delivered through a catheter utilizing a “single stick” method. This approach is designed to produce less pain and fewer skin injections than used in current treatment approaches, as well as to mitigate or eliminate the need for patients to wear uncomfortable compression stockings after treatment.
Vein-Collapsing Methods
Methods to treat venous insufficiency are now described, in which the vein is compressed at least partially along the treatment zone. Doing so can better ensure that the vein is partially or fully collapsed as opposed to merely occluded, depending on the desired clinical result. Not to be limited by theory, collapsing the vein may place two or more luminal surfaces of endothelial cells into opposing contact with each other, stimulating fibrous tissue proliferation and resulting in improved long-term closure of the vein with a lower risk of recanalization and vein re-opening. In some embodiments, a deployment catheter is percutaneously introduced into a vein at an access site, and translumenally distally advanced across a treatment zone within a vein. External compression is applied to collapse the vein distally of the deployment catheter. Then the distal end of the catheter advances to the very beginning of the occluded vein at the proximal side of the occlusion to minimize the “trapped” blood between the catheter and the occluded vein. After a bolus of plug forming media is expressed from the distal end of the catheter, the occlusion at the end of the catheter forces the vein-occluding substance to flow retrograde (proximally) toward the catheter insertion point into the vein and reduce the distal flow force and mixing with blood within the vessel. This method also allows the vein-occluding media to replace any existing blood “trapped” between the catheter and the occluded vein and forms an occlusive plug within the vein while minimizing mixing with the blood. This reduction in mixing can be advantageous in certain embodiments because it can increase the bonding strength between the vein-occluding media and the vein. External compression distally to the treatment zone optionally may be removed, or may remain throughout all or a portion of the procedure. External compression can also occur around the area of the vein where the plug forming media is expressed in order to collapse the vein as noted above. The catheter is thereafter proximally retracted while dispensing a vein occluding substance, either continuously or via discrete boluses spaced apart from the initial bolus at regular or irregular intervals across the treatment zone. External compression can continue proximally where the vein occluding substance is being dispensed in order to ensure collapse of the vein as noted above. The catheter is thereafter withdrawn, and the access site closed using conventional techniques. The method is described in greater detail below.
The vein closure system can enter the vein such as the greater saphenous or lesser saphenous vein or other vessel using fluoroscopy, ultrasound, or other guidance means. A micro-catheter system can be placed over a wire for introduction of an outer catheter or introduction sheath into the vein. In some embodiments, the vein is entered as distal as possible or as clinically relevant in the abnormal vein. In some embodiments, the closure method comprises advancement of an introducing sheath and/or dilator over a guide wire to the sapheno-femoral junction below the anterior-inferior epigastric vein, which in some embodiments, can be approximately 1.5 to 2.5 cm from the sapheno-femoral junction. Following placement of the sheath to this level and optional verification with ultrasound, an inner catheter is introduced through the sheath and is luer-locked or otherwise secured to the sheath to maintain a fixed position with the tip extending approximately 5 cm from the end of the sheath.
In accordance with
As shown in
When the inner catheter is in position and verified with ultrasound to be in the appropriate position below the sapheno-femoral junction, compression at the sapheno-femoral junction is performed and small amounts of vein occluding substances, including liquid adhesives such as glues including cyanoacrylates, or any substances described elsewhere herein or known in the art, are injected into the vein. The vein can then be collapsed using compression, such as external compression to assist in coapting the vein and adhering the internal walls of the vein to the vein-occluding substance in a solid, permanent bond. In some embodiments, an additional compression device can be provided in addition to the ultrasound transducer or probe (either proximally or distally) to assist in collapsing the vein. In some embodiments, the compression device can be a sequential compression device configured to apply compressive pressure from a compressor against the patient's limb through a flexible pressurized sleeve. The compression can be configured to deliver uniform compression along its length, distal-to-proximal compression in a peristaltic wave or other modes depending on the desired clinical result. In some embodiments, the compressive device could be configured to deliver a pressure of at least about 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, or more mm Hg, or between about 30-150 or 50-100 mm Hg in some embodiments. In some embodiments, an external device delivering energy to create a controlled vasospasm of the vein is used. The energy could be, for example, electrical stimulation, cryotherapy, infrared, visible, or UV light, microwave, RF energy, ultrasound energy, magnetic energy, thermal energy, or a combination of the energy sources.
In accordance with
In some embodiments, each bolus of media can have a volume of between 0.01 to 3 cc of a vein-occluding substance (e.g., cyanoacrylate compound), such as between 0.01 cc to 1 cc of a vein-occluding substance. The rate of injection can be controlled manually, or by a mechanical and/or electronic controller configured to release a predetermined volume of vein-occluding substance at a specified flow rate. While in some embodiments the injection rate can be relatively constant throughout the procedure in some embodiments, in other embodiments, the injection rate can be variable, releasing periodic boluses of vein-occluding substance at specified time and/or distance intervals. In some embodiments, the injection rate is between 0.002 cc/sec and 6 cc/sec, such as between about 0.02 cc/sec and 0.2 cc/sec. Controlling the volume and flow rate of the bolus of media to levels described herein advantageously prevents unnecessary overflow or undertreatment of the media within the vein. In some embodiments, an injector is provided that is configured to precisely deliver a predetermined volume of media, such as between about 0.05 mL and 0.5 mL, or between about 0.1 mL and 0.2 mL, into the vein when a physician actuates a control, such as a button, switch, dial, or foot pedal, for example. In some embodiments, the injector includes a safety feature, such as an electronic lockout that prevents unintended multiple bolus injections of glue within a specified period of time, such as, for example, requires that bolus injections be spaced apart by at least about 0.5, 1, 2, 3, 4, 5 seconds, or more.
In accordance with
In accordance with
Once the vein-occluding substance 502 is injected into the second site of the vessel 400, a compression element e.g., the hand 640, can once again be used to assist in collapse of the portion of the vessel 400, as shown in
The application of the ultrasound probe and/or additional compression device can be repeated at multiple locations along the greater saphenous vein, as shown in
While the methods above have been described with the intention of occluding the great saphenous vein, a wide variety of other veins, arteries, lymphatics, or other body lumens, natural or artificial can be occluded as well using systems and devices as disclosed herein. Furthermore, a variety of conditions can be treated with the systems, devices, and methods disclosed herein, for example, venous insufficiency/varicose veins of the upper and/or lower extremities, esophageal varices, gastric varices, hemorrhoidal varices, venous lakes, Klippel-Trenanay syndrome, telangiectasias, aneurysms, arterio-venous malformations, embolization of tumors or bleeding vessels, lymphedema, vascular and non-vascular fistulas, closure of fallopian tubes for sterilization, etc.
In some embodiments, the vein-occluding substance can be injected into the vein using an automated process in order to minimize undesired over-injection or under-injection of the vein-occluding substance, injection at undesired intervals or injection of undesired bolus sizes. For example, the outer catheter member of the catheter can be made easily compressible (e.g., with a thin wall). The column strength needed for catheter placement can thus be supplied predominantly with the inner tube. Once the inner catheter has been withdrawn from the vein, the remaining outer catheter is filled with the vein-occluding substance. The proximal end of the outer catheter just distally of the luer lock, manifold, or other coupling to the vein-occluding substance injector can carry a compression element such as a clamp, parallel rollers, or a slideable element with the catheter extending transversely between two portions of the slideable element. Actuating the compression element will radially compress the outer catheter. An operator can then hold the clamp in place while the catheter is pulled proximally through the clamp. The clamp thus slides, rolls, or otherwise moves along the tube, while the catheter is compressed to precisely express the volume of the catheter as a function of the distance the catheter is withdrawn proximally from the vein.
After withdrawal of the inner catheter, a vein-occluding substance such as described above can be injected through the outer catheter into the vein 400 proximal to the deployed occlusion device. As illustrated in
A method of occluding a vein utilizing a vein-occluding substance as an occluding member according to some embodiments will now be described in further detail. First, a catheter can be deployed to a desired location in a tubular structure such as a vein as illustrated and described in connection with
The vein-occluding substance serving as an occluder 500 can be, for example, a larger-volume bolus of a vein-occluding substance compared to a volume of vein-occluding substance injected more proximally over a specified period of time and/or length of vein, of which specific ranges are described above. The initial bolus can be at least about 0.1 cc, 0.25 cc, 0.5 cc, 0.75 cc, 1 cc, 1.5 cc, or more in some embodiments, or between about 0.05 mL and about 0.9 mL, between about 0.05 mL and about 0.5 mL, or between about 0.1 mL and about 0.2 mL in other embodiments The initial bolus can be at least about 10%, 25%, 50%, 75%, 100%, 150%, 200%, or more greater than a volume of vein-occluding substance injected more proximally over a similar length of vein.
In addition to, or instead of a large bolus volume of vein-occluding substance as described above, a second vein-occluding substance with different properties than a first vein-occluding substance used to treat the vein more proximally can also be used as an occluder. The second vein occluding substance is deployed first, to form the distal vein block. The first vein occluding substance is then dispensed along the length of the treatment site as the catheter is proximally retracted.
The second vein-occluding substance can be, for example, a glue or other occlusive medium that expands to a greater volume, hardens more rapidly, and/or has a shorter polymerization time relative to the first vein-occluding substance. In some embodiments, the second vein-occluding substance can be partially or completely bioresorbable. If multiple different vein-occluding substances are used, the catheter can be configured to have two or more lumens to accommodate delivery of the different vein-occluding substances. Alternatively the first and second occluding substances can be deployed sequentially via a common lumen.
When the vein-occluding substance serving as a distal occluder hardens such that a plug 500 is formed to completely prevent blood flow distally as shown in
Thus, in accordance with one implementation of the present invention, a deployment catheter 200 is percutaneously introduced into a vein at an access site, and translumenally distally advanced across a treatment zone within a vein. External compression, such as manual compression, is applied to collapse the vein distally of the deployment catheter and create a first occlusion. A bolus of plug forming media is expressed from the distal end of the catheter against a proximal side of the first occlusion, to form an occlusive plug 500 within the vein. External compression optionally may be removed, or may remain throughout the procedure. The catheter 200 is thereafter proximally retracted while dispensing a vein occluding substance 502 across the treatment zone, either continuously as a long stream, or intermittently at spaced apart intervals, where a second occlusion in the vein can be created, spaced apart from the first occlusion, and then a second bolus of media is introduced against the proximal side of the second occlusion External compression may be applied proximally, anywhere along the length of the vein, to ensure complete filling of the vein with the vein occluding substance 502. In some embodiments, a second, third, or more boluses of plug-forming media are progressively released into the vein more proximally at desired intervals, and external compression can be applied just distal to the point in which the catheter releases the plug forming media as described above. The catheter 200 is thereafter withdrawn, and the access site closed using conventional techniques.
In some embodiments, an occlusion in a vein can be created as described herein. A deployment catheter having a distal opening and side wall is provided. The distal end of the deployment catheter can be positioned within the vein at the desired location. Media can then be introduced through the distal opening in a volume sufficient to advance proximally around the catheter between the sidewall of the catheter and the wall of the vein. In some embodiments, the volume sufficient to advance proximally around the catheter between the sidewall of the catheter and the wall of the vein is at least about 0.05 mL, 0.1 mL, 0.2 mL, 0.3 mL, 0.5 mL, 0.7 mL, 0.8 mL, 1 mL, 1.5 mL, 2 mL, 3 mL, or more.
The distal plug 500 may be formed by a bolus of the same material as used for the vein occluding substance 502. Alternatively, the distal plug 500 may be formed from a material that polymerizes more rapidly than vein occluding substance 502, or solidifies through a mechanism other than polymerization to form an occlusive plug. Plug 500 may alternatively be formed by a self-expanding preformed material, such as a foam or woven or non-woven fiber based material, which may be displaced distally from the catheter such as by distally advancing a push wire, or utilizing the pressure of vein occluding substance 502. The self-expanding foam or other plug material 500 may be a bioabsorbable material, so that no long term implant is left behind in the body.
Proximal retraction of the deployment catheter 200 may be accomplished in either a steady, continuous fashion, or in an intermittent, stepped manner. Similarly, extrusion of vein occluding substance 502 may be accomplished in a continuous manner as the catheter 200 is proximally retracted. Alternatively, vein occluding substance 502 may be dispensed in a plurality of bolus ejections along the length of the treatment zone, spaced apart by a predetermined or clinically determined distance. Spacing between adjacent injected volumes of vein occluding substance 502 may be at least about 0.5 cm, at least about 1 cm, at least about 2 cm, and, in some implementations, at least about 4 cm. This procedure minimizes the total volume of injected vein occluding substance 502, while providing a plurality of distinct bonding points along the length of the treatment zone.
Also disclosed herein is a method of obliterating a hollow structure, such as a vein, including the steps of reducing an interior cross-sectional area of the hollow structure near the obliterating site by applying a pressure to an exterior of the hollow structure; and placing a catheter in the hollow structure and advancing it to the obliterating site, where the obliterating site is next to the reduced cross-sectional area. A medical adhesive can then be injected at the obliterating site. The interior cross-sectional area of the medical adhesive at the obliterating site can then be reduced by compressing an exterior of the hollow structure to form an occlusion in the hollow structure. Compression can be achieved, for example, via an imaging probe such as an ultrasound transducer, manual pressure, or a harness. The medical adhesive can then solidify, forming an occlusion in the hollow structure. The method can also include the step of identifying an obliterating site prior to reducing an interior cross-sectional area of the hollow structure. In some embodiments, the catheter is removed from the obliterating site before compression.
With any of the methods and devices described herein, a wide variety of vein-occluding substances can be used. In some embodiments, the substance can include an adhesive such as cyanoacrylate, e.g., 2-octyl cyanoacrylate, and/or a sclerosing agent such as hypertonic saline, sodium tetradecyl sulfate, chromated glycerol, tetracycline, talc, bleomycin, or polydocanol. In some embodiments, a cyanoacrylate can be an aliphatic 2-cyanoacrylate ester such as an alkyl, cycloalkyl, alkenyl or alkoxyalkyl 2-cyanoacrylate ester. The alkyl group may have from 1 to 16 carbon atoms in some embodiments, and can be a C1-C8 alkyl ester or a C1-C4 alkyl ester. Some possible esters include the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, cyclohexyl, heptyl, octyl, 2-methoxyethyl and 2-ethoxyethyl esters of cyanoacrylic acid. Other adhesives that can be used include a biological glue such as a bovine serum albumin-gluteraldehyde combination (e.g., BIOGLUE, Cryolife, Atlanta, Ga.), PVA, Biogard, collagen, fibrinogen, fibronectin, vitronectin, laminin, thrombin, gelatin, mixtures thereof, or other biocompatible adhesives. In some embodiments, a foam generated from, for example, one or more of the above components can be used to enhance ablation and closure of the vein. The viscosity and air bubble mixture can also be controlled while taking into account the desired clinical result.
In one embodiment, the chosen adhesive will not produce a significant thermal effect or significant local tissue abnormal effect, but rather produces an initial vessel co-aption/adhesion which will withstand physiological venous pressures within the immediate post-procedure period. Since the adhesive will not produce a significant thermal reaction, no tumescent anesthesia is needed. In some embodiments, the chosen adhesive induces an inflammatory reaction which scars. The inflammatory reaction can be followed by permanent closure of the abnormal greater or less saphenous vein. In some embodiments, the chosen adhesive is hardened after the first few moments (e.g., seconds or minutes) of application and therefore, compression stockings may not be required. With the chosen adhesive, there can be minimal or no danger to surrounding nerves or tissue. While the amount of chosen adhesive delivered to a target site in a vessel will vary depending on the size of the vessel itself, in some embodiments, the amount of adhesive or other vein-occluding substance delivered in a single injection can be between about 0.05 mL and about 0.9 mL, between about 0.05 mL and about 0.5 mL, or between about 0.1 mL and about 0.2 mL in other embodiments. In some embodiments, the amount delivered in a single injection could be more than about 0.4 mL, 0.6 mL, 0.8 mL, 0.9 mL, 1 mL, or more. In some embodiments, the amount delivered in a single injection could be less than about 0.8 mL, 0.6 mL, 0.4 mL, 0.3 mL, 0.2 mL, 0.1 mL, 0.05 mL, or less.
In some embodiments, the cyanoacrylate preparation will contain any additives necessary to impart the desired properties to the preparation as viscosity, color, X-ray opacity, etc. Certain examples of additives such as thickening agents and polymerization inhibitors are discussed further below.
In some embodiments, the chosen adhesive can also be mixed with a thickening agent, including various cyanoacrylate polymers, cyanoacrylate oligomers and biocompatible polymers. The biocompatible polymers can include, for example, PLA, PLLA, PGA, PCL, PDLLA, PLDGA, PMMA, PET, nylon, PE, PP, or PEEK, and in some embodiments, the biocompatible polymers are soluble in a cyanoacrylate monomer. In some embodiments, the thickening agent can comprise glucose, sugar, starch or hydrogel. In some embodiments, the thickening agent can also comprise various particulates, ranging in size between about 0.001 microns to 100 microns. The particulates can be provided in dry solid form and can disperse throughout a liquid adhesive to thicken the adhesive prior to use. In some embodiments, the particulate comprises any of the biocompatible polymers above, such as PLA, PLLA, PGA, PCL, PDLLA, PLDGA, PMMA, PET, nylon, PE, PP, CAB and PEEK, while in other embodiments, the particulate comprises a silica material with or without an acrylic polymer. The thickening agent can assist in providing a suitable viscosity for the adhesive as it flows through the catheter to a target site.
In some embodiments, the chosen adhesive can also be mixed with one or more polymerization inhibitors, which could be, for example, an anionic or a free-radical polymerization inhibitor. Anionic polymerization inhibitors can include soluble acidic gases such as sulfur dioxide, or a biocompatible acid including, but not limited to, acetic acid, sulfuric acid, sulfonic acid, hydrochloric acid, phosphoric acid, carboxylic acid, nitric acid, or combinations thereof. In some embodiments, the acid can be from 0.01% to about 10% by weight, such as between about 0.01% and 1% by weight. Free-radical polymerization inhibitors include hydroquinone, t-butyl catechol, hydroxyanisole, butylated hydroxyanisole and butylated hydroxytoluene. The addition of one or more polymerization inhibitors such as a biocompatible acid helps to change the curing rate of the adhesive to prevent the adhesive from sticking prematurely to the catheter and prevent premature curing of the adhesive prior to binding to the vein wall. In some embodiments, the acid helps to delay the curing and/or polymerization of the adhesive to prevent the glue from sticking to sections of the catheter.
One skilled in the art will appreciate that multiple compositions of adhesive mixtures can be used in accordance with the embodiments described herein. In one embodiment, a composition of adhesive comprises from about 0.01 to about 50.0 weight percent of cyanoacrylate polymer, from about 0.01 to about 50.0 weight percent of a thickening agent selected from the group consisting of cyanoacrylate polymer, cyanoacrylate oligomer and biocompatible polymers, and from about 0.01 to about 10.0 weight percent of a biocompatible acid.
In some embodiments, the adhesive can also include a therapeutic agent such as an anti-inflammatory agent, an anti-infective agent, an anesthetic, a pro-inflammatory agent, a cell proliferative agent, or combinations thereof.
In some embodiments, the medical adhesives, such as the cyanoacrylate adhesives, can have select properties. In some embodiments, the medical adhesives can have a setting time of between about 5 to 60 seconds. The medical adhesives can also have a viscosity of between about 40 to 3000 cp. In some embodiments, the viscosity could be at least about 500 cp, at least about 1,000 cp, at least about 1,500 cp, at least about 2,000 cp, at least about 2,500 cp, or more. In some embodiments, the viscosity could be no more than about 2,000 cp, no more than about 1,500 cp, no more than about 1,000 cp, no more than about 500 cp, no more than about 300 cp, or less. One skilled in the art will appreciate that the type of adhesive is not limited to these particular characteristics, and that other adhesives having different properties may also be applicable.
In additional embodiments, a vein closure system is described that does not require capital purchases for a radiofrequency device or laser box. Simple and non-invasive methods of using the vein closure system are provided, and in some embodiments, the methods do not require application of a tumescent anesthesia or wearing compression stockings. The acceptance by and demand from patients of the vein closure system described herein will be much higher over existing devices and techniques.
In some embodiments, the closure system comprises at least two major components. One is a vein closure device which precisely delivers an adhesive to the abnormal saphenous vein under ultrasound guidance. The other component is a unique intravascular adhesive which allows for co-aptation and closure of the abnormal saphenous vein in a flattened, closed position. In other embodiments, the closure system comprises three major components. The first is a vein closure device which precisely delivers an adhesive to the abnormal saphenous vein under ultrasound guidance. The second is a unique intravascular adhesive which allows for co-aptation and closure of the saphenous vein just distal to the Superficial Femoral Vein Junction, such as within about 5 cm, 4 cm, 3 cm, 2 cm, 1 cm, or less in a flattened, closed position. The third is a solution that can have adhesive and/or sclerosing properties which allows for co-aptation and closure of the rest of the saphenous vein to alter the vein such that blood flow is prevented therein.
The Vein Closure Device
In some embodiments, the vein closure device which delivers the vein-occluding substance, e.g., an embolic adhesive, comprises three components. The first component is an outer catheter or introducer sheath that allows for placement under precise ultrasound guidance into the saphenous vein from as low a position as possible in the greater saphenous vein or lesser saphenous vein. The vein closure device is also configured for precise distal tip placement into the vein to be occluded. In some embodiments, the sheath is available in multiple size ranges and includes ID of 3 fr-7 fr and a length from 25 cm to 100 cm depending on the placement site. In some embodiments, the sheath is echogenic under ultrasound observation and therefore can be precisely placed below the sapheno-femoral junction. The sheath can have multiple graduations, as well as measurement markings that indicate increments along the sheath, such as 0.2, 1, 2, or 5 cm increments. The graduations and markings assist in providing precise, monitored pull-back motions along the saphenous vein. In some embodiments, a dilator is positioned within the introducer sheath to aid in positioning the device at the treatment site. The dilator may have comparatively greater stiffness than the introducer sheath. Upon advancement to the desired treatment site, the dilator may be removed, followed by advancement of the introduction or inner catheter through the introducer sheath. In some embodiments, the dilator is echogenic under ultrasound observation which may aid in precise placement below the sapheno-femoral junction.
The second portion of the vein closure system is an introduction or inner catheter for the vein-occluding substance or adhesive. The inner catheter can be multiple sizes, such as from 3 fr-7 fr and include lengths of between about 25 cm to 100 cm to match the introduction sheath size ranges. In some embodiments, the inner catheter can be longer than the introduction sheath to allow the inner catheter to extend from a distal end of the introduction sheath. In one embodiment, both the inner catheter and the introducer sheath are made of materials such as PTFE, ePTFE, PFA, FEP, or similar polymeric materials that will provide for negligible (if any) adhesion to the vein-occluding substance. In some embodiments, the inner catheter has an echogenic tip that assists in advancement through the introducer sheath. The inner catheter can be attached to the introducer sheath, such as by luer lock or other locking mechanism. The inner catheter protrudes from the introduction sheath at its distal end approximately 0.5-10 cm. and is visible under ultrasound due to its echogenic tip. The inner catheter is used for precise delivery of a vein-occluding substance into the vein for co-apting and occluding the vein into a flattened configuration. In some embodiments, the outer catheter and/or inner catheter can be coupled to or extend from a syringe designed to dispense a vein-occluding substance.
Also disclosed herein is a medical device that can include one, two, or more echogenic characteristics for enhanced visualization. For example, one or more of the outer catheter, the dilator, and the inner catheter may be echogenic in certain embodiments, providing for improved visualization under ultrasound. Since sound waves are reflected at junctions of differentiated density, the greater the density difference, the brighter the junction appears on an ultrasound visualization monitor. Since ultrasound waves do not pass easily through gases and are mostly reflected, the presence of gas in the path of ultrasound waves provides for improved visualization. In certain embodiments, to provide a high degree of visualization, the introducer sheath, dilator, and/or the catheter may include a high degree of density differentiation by using gas, such as air. This reflection of ultrasound waves provides a means to visualize the location and allow ease of placement of devices within soft tissue.
Most ultrasound visualization of medical devices involves using metals (such as platinum marker bands or metal wire woven extrusions) or the addition of powders (such as barium sulfate) to extrusions to create density differences between the device and the surrounding tissues. Using a gas, rather than a metal or powder, to create the density differences provides several distinct advantages in certain situations. First, gas can be orders of magnitude less expensive than other ultrasound visualization materials of the same given volume. Even relatively inexpensive metals, such as stainless steel, cannot compete with the low cost of a gas, such as air. Second, gas does not need to be processed into a particular shape; it takes the form of whatever void it is filling. Hence it is more pliable and retains much less embodied energy. This improves the ease of manufacture as well as the final flexibility of the catheter. Third, the density disparity between the gas and the object holding and/or the surrounding tissue is typically greater than that of other visualization methods, thereby allowing the device to reflect more ultrasound waves and providing a clearer or brighter image. Improved ultrasound imaging may facilitate more accurate placement of the device to the desired treatment spot, such as within the greater saphenous vein or other vessels as described herein. Ultrasound can also be advantageous in not carrying the radiation concerns inherent in, for example, fluoroscopy. This gas/solid boundary can be created in any number of ways. Some non-limiting examples follow.
In one embodiment, microlumens containing trapped gas may be formed within the sidewall of the catheter. With reference to
Embedding the microlumens 606 within the catheter wall 602 ensures that they do not interfere with the operation of the catheter or hinder its intravascular mobility. Any raised edge or protruding portion on the outer surface of catheter 600 could potentially increase the likelihood of the catheter being caught or even causing injury to the vasculature during advancement to the treatment site, or during retraction therefrom. Similarly, any protrusion into the inner lumen 604 would potentially inhibit the flow of adhesive or the passage of an inner catheter therethrough. Since embedding the microlumens 606 within the wall 602 maintains both a smooth outer surface and a smooth inner surface, these potential problems may advantageously be avoided.
In certain embodiments, the catheter 600 may include one microlumen 606. Other embodiments may include two, three, four, five, six, or more microlumens embedded within the catheter wall 602. According to some embodiments, the microlumens may run parallel or substantially parallel to the main inner lumen 604 and/or the catheter sidewall 602. In other embodiments, the microlumens may be oriented in another configuration. For instance, the microlumens may spiral helically around the catheter 600, or may form a zig-zag pattern along its length. Other configurations are also possible.
As shown in
The use of a gas/solid boundary may also be combined with other techniques for improving ultrasound visibility. For instance, as shown in
In some embodiments, the length of the metal wire 608 varies from one microlumen to the next. For instance, a first microlumen may contain a metal wire 608 of a first length. A second microlumen may contain a metal wire 608 of a second length longer than the first length. A third microlumen may contain another metal wire 608 that is longer than the second, and so forth. In certain embodiments, the lengths of the metal wires may be offset from one another by a uniform amount. For instance, a one metal wire may extend the full length of the catheter, while the next metal wire terminates 1 cm short of the distal tip. Another metal wire may terminate 2 cm short of the distal tip, and so forth. The arrangement of several metal wires of subsequently shorter lengths may advantageously provide a means for determining more precisely the location of the catheter within the body. This configuration may aid in determining the position of the catheter within the body.
With reference to
With continuing reference to
In another embodiment, a gas/solid boundary may be provided via small holes in a direction either normal or oblique to the longitudinal axis of the catheter. The apertures form microwells that are large enough to hold gas within, but small enough to prevent fluids from entering the hole due to surface tension. As such, a meniscus 612 naturally forms at the boundary of gas and liquid at the surface of the microwell 610. The gas trapped within each microwell provides for increased ultrasound visibility. In exemplary embodiments, the microwells are configured such that gas is retained therein when the catheter is submerged within whole blood. For example, the microwells may be dimensioned so that surface tensions between about 30×10−3 N/m and 80×10−3 N/m, or about 50×10−3 N/m and 64×10−3 N/m prevent liquids from entering the microwells. With reference to
The microwells 610 may be arranged radially in a regular pattern. For instance, the microwells 610 may be spaced equally radially around the catheter 600. Alternatively, the microwells 610 may be arranged in clusters or irregularly radially around the catheter 600. In addition to the radial orientation, the longitudinal spacing of the microwells may be varied. For instance, the microwells may be oriented in groups arranged circumferentially and spaced apart longitudinally by equal distances. In this configuration, each ring of microwells surrounds the catheter at a given location, and is spaced apart from the longitudinally adjacent ring of microwells by a particular distance. In certain embodiments, the longitudinal distance between adjacent rings of microwells may vary to provide location identification.
In some embodiments, the microwells may have identical sizes. In other embodiments, the cross-sectional dimensions may vary, as may the depth.
In still another embodiment, a gas/solid boundary may be formed via enclosed gas pockets, whether random or otherwise, within the wall of the catheter 600. For instance, as shown in
The enclosed gas pockets may be formed within any suitable material within the catheter. For instance, in some embodiments, a polymer containing gas-filled microspheres may be used to manufacture the catheter. In other embodiments, gas or foaming agents may be injected into a polymer, such as polyurethane, to form a polymeric layer with enclosed gas pockets. Chemical foaming agents that could be added to the plastics material include azocarbonomides, dinitrosopentmethelyene-tetramine, benzenephonohydrazine, 4,4 oxybis(benzenephonohydrazine), NN1dimethyl-NN.sup.1dinitrosoterephthalamide, azoisobutyronitrile, sodium bicarbonate, terephthalazide or trihydrazinatrazine. Another way of forming the gas pockets would be by incorporating a liquid into the plastics melt which volatizes during the melt process. Alternatively, solid powdered dry ice (carbon dioxide) could be incorporated into the melt so that the particles of dry ice become gas pockets during the forming process. It could be possible to use other solids which undergo sublimation in this way. The gas pockets could be formed directly as a result of chemical reaction during polymerisation and or alternatively during cross-linking. The gas pockets could be formed mechanically by whipping the plastics in a liquid form, such as in the manner used to form latex foam. Alternatively, small particles of a soluble material could be added to the plastics melt and subsequently dissolved away.
A protective sheath may surround a polymer with enclosed gas pockets to define the catheter, or in other embodiments no such sheath is required.
The gas pockets in some embodiments extend in a continuous or discontinuous region along the length of the device. The gas pockets may have a dimension, such as a width of between 0.1 μm to 300 μm, between 1 μm and 50 μm, or between 5 μm and 10 μm. In some embodiments, the width of the gas pockets are 0.1 μm, 5 μm, 10 μm, 50 μm, 300 μm, or more. In other embodiments, the width of the gas pockets are 300 μm, 50 μm, 10 μm, 5 μm, 0.1 μm, or less. In certain embodiments, the enclosed gas pockets are distributed uniformly along the length of the device. In other embodiments, the enclosed gas pockets may be patterned, irregularly distributed, or otherwise within the device.
In each of these aforementioned non-limiting examples, the inclusion of gas regions within the catheter provides for multiple gas/solid boundary regions. As discussed above, each of these boundaries allows for improved ultrasound visibility. With greater visibility and heightened resolution, the location of the catheter within the body may be accurately determined. In particular, the use of such an echogenic catheter may advantageously facilitate precise placement below the sapheno-femoral junction for use in the treatment of venous reflux, such as for injection of an adhesive composition at one, two, or more locations within the vein for example.
Glue Gun and Adapter
The third portion of the vein closure system is the glue gun or other adhesive introducing device that attaches to the inner catheter. In some embodiments, the adhesive introducing device is a manual liquid dispenser gun that can dispense an adhesive into a vessel with control and accuracy. One such dispenser gun is disclosed in U.S. Pat. No. 6,260,737 to Gruendeman et al., which is incorporated by reference herein in its entirety. Other embodiments of the glue gun are discussed in more detail below.
Additional embodiments are provided that are directed to a vein-occluding substance dispenser adapter, such as a glue gun, and associated components. In some embodiments, a glue gun is provided that is mateably attachable to a dispensing catheter or syringe by an adapter. The adapter can advantageously convert, for example, a conventional industrial glue gun for medical use, such as described herein while being properly sterilized as well.
The glue gun 2 includes a handle 31 and a pull trigger 12. The pull trigger 12 is used in connection with internal mechanisms of the glue gun 2 (shown in
The plunger 3 comprises a solid rail-like segment that extends from outside the body of the glue gun 2 and through the internal body of the glue gun 2. The plunger 3 includes teeth that work in conjunction with a spring pawl mechanism (shown in
The adapter lock end 4 includes one or more collars or flanges 25 that are receivable into a holding segment of the dispenser gun upon rotation. The adapter lock end 4 is configured such that upon rotation of the adapter 1, the flanges 25 are received in and secured in the holding segment 33. In addition, the adapter lock end 4 includes an opening or slot (shown in
The syringe lock end 5 includes a holding slot 6 for receiving a syringe 36 and an opening 41 through which the plunger 3 can pass. As shown in
The hollow body 7 of the adapter 1 is designed to receive the syringe plunger 3 as it moves transversely substantially along a longitudinal axis of the hollow body 7 during injection. In some embodiments, the length of the hollow body 7 of the adapter is between 2 and 5 inches. The hollow body can be circular, elliptical or any other shape suitable for receiving the plunger 3. The diameter of the hollow body 7 can be, in some embodiments, between 0.5 and 1.1 inches.
As shown in
To limit the effect of the spring mechanism 15 and restrict the forward displacement of the plunger teeth 16, the spring mechanism 15 is accompanied by a stopper 11. The stopper 11 serves as a physical barrier to the movement of the spring mechanism, thereby providing for greater control over dispensation of the glue or adhesive.
The embodiments of the glue gun system described in
Deployable Occlusion Device
Embodiments are now described that relate to components of a venous occlusion system comprising a deployable occlusion device.
Transformation of the occlusion device may be accomplished in any of a variety of ways, such as by releasing a restraint on a frame which is biased in the direction of the enlarged configuration. Alternatively, the occlusion device may be transformed to the enlarged configuration under active force, such as by axial shortening to achieve radial expansion. As a further alternative, occlusion devices for use with the system of the present invention may include detachable inflatable balloons, open cell or closed cell foam, sponge, embolic coil meshes having either a randomized or predetermined pattern, or other structures depending upon the desired clinical performance. The occlusion device may be provided with one or two or more tissue anchors or barbs, for engaging the vessel wall, or other anti-migration surface features such as a roughened or adhesive surface, and/or enhanced surface area for contact with the vessel wall in a manner sufficient to inhibit migration.
The frame 102 may have a wide variety of wall patterns depending on the desired clinical result, or have a continuous sidewall in some embodiments. In the illustrated embodiment, the wall pattern comprises a generally sinusoidal framework including a plurality of proximally facing apexes 112 and distal apexes 110 interconnected by a plurality of struts 114. This can be clearly seen, for example, in
The frame portion 102 can be made of a metal, such as stainless steel, or a shape memory material such as, for example, nitinol or elgiloy. However, in some embodiments, the frame portion 102 may be made of a shape memory polymer or biodegradable material, such as, for example, poly(alpha-hydroxy acid) such as poly-L-lactide (PLLA); poly-D-lactide (PDLA), polyglycolide (PGA), polydioxanone, polycaprolactone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, poly(hydroxybutyrate), polyanhydride, polyphosphoester, poly(amino-acids), or related copolymers. In some embodiments, the frame portion 102 can be laser-cut out of a tube. If the frame portion 102 is biodegradable, it can be configured to fully degrade over a period of time depending on the desired clinical result and the properties of the vein-occluding substance (e.g., hardening or polymerization time of a glue), such as, for example, less than about 1 year, 6 months, 3 months, 1 month, 2 weeks, 1 week, 3 days, 1 day, 12 hours, 6 hours, 3 hours, or less.
The barrier portion 104 can be sized, shaped, and attached to the frame 102 in a variety of ways such that when deployed in an expanded configuration in the blood vessel, the occlusion device 100 prevents blood flow through the vessel. In some embodiments, the barrier 104 is coupled to the frame 102 via sutures, adhesives, clips, or other form of attachment. The barrier 104 may be made of any appropriate biocompatible material suitable for occluding a vessel, such as a mesh. In some embodiments, the barrier 104 may be made of nitinol, elgiloy, Dacron®, Gore-Tex®, nylon, TFE, PTFE, ePTFE, peritoneum, subintestinal submucosa or other synthetic or biological membrane. Further materials that can be used for both the frame 102 and barrier 106 portions can be found, for example, in U.S. Patent Pub. No. 2007/0292472 A1 to Paul et al., which is hereby incorporated by reference in its entirety.
While the above occlusion device 100 is described as having a frame portion 102 and a barrier portion 104, various other occlusion devices to prevent blood flow through the vessel lumen are also within the scope of the invention, such as plugs, sponges, coils, adhesives, prothrombotic agents, and the like.
In the embodiment illustrated in
Occlusion device 100 as shown is releasably attached to a detach mechanism 120 that allows for retraction and repositioning of the occluder member prior to deployment. The detach mechanism 120 can be any of a wide variety of mechanisms to provide releasable detachment, for example, mechanical, chemical, or electrolytic detachment. Some examples of mechanical detach mechanisms include a snare, suture loop, clip and the like. The proximal end of the catheter preferably includes a luer lock or similar mechanism for coupling to a syringe or other injector for inserting a vein-occluding substance into the vein.
In some embodiments, after the occlusion device is deployed, a vein-occluding material such as a sclerosing agent is injected into the vein. The purpose of the vein-occluding material can be to partially or completely destroy the endothelial cells lining the venous lumen, expose the subendothelial collagen fibers within the vein, and ultimately form a fibrous cord. After the lining of the vein is damaged the vein can be forced closed by the use of compression stocking worn by the patients. Over time the damaged vein scars upon itself creating a completely closed vein. Endothelial damage is preferably as complete as possible, because otherwise, thrombus will form and layer endoluminally. The presence of a deployed occlusion device 100 advantageously prevents distal embolization of the vein-occlusion substance distally past the occlusion device 100. Any vein-occluding material can be used depending on the desired clinical result.
A wide variety of vein-occluding substances can be used. In some embodiments, the substance can include an adhesive such as cyanoacrylate, e.g., 2-octyl cyanoacrylate, and/or a sclerosing agent such as hypertonic saline, sodium tetradecyl sulfate, chromated glycerol, tetracycline, talc, bleomycin, or polydocanol. Other adhesives that can be used include a biological glue such as a bovine serum albumin-gluteraldehyde combination (e.g., BIOGLUE, Cryolife, Atlanta, Ga.). In some embodiments, a foam generated from, for example, one or more of the above components can be used to enhance ablation and closure of the vein. The viscosity and air bubble mixture can also be controlled taking into account the desired clinical result. Ultrasound or other imaging modalities such as, for example, fluoroscopy, CT, or MRI can be used to observe and control distribution of the vein-occlusion substance. In some embodiments, foam or other micro-bubbles within the vein-occlusion substance can also serve as ultrasonic contrast. Further examples of agents, methods, and devices for vein closure that can be used as well are described, for example, in U.S. Pat. No. 4,039,665 to Foley, U.S. Pat. No. 5,676,962 to Garrido et al., U.S. Pat. No. 6,572,873 to Osman et al., U.S. Pat. No. 6,726,674 to Leu, U.S. Pat. No. 7,314,466 to Lary et al., and U.S. Patent Pub. No. 2003/0206864 A1 to Mangin, all of which are hereby incorporated by reference in their entireties. In some embodiments, the invention can be practiced using a cyanoacrylate based echogenic adhesive, visible under conventional ultrasound.
Using the systems and methods described herein provides little to no risk of injury to surrounding nerves or tissue, because the length of the treated vessel can be clearly identified without unnecessary overtreatment. This is in contrast to many other procedures which require, for example, that a catheter is placed superior to nerves which may be juxtaposed to the saphenous vein.
The vein closure system allows for a simple treatment for veins, such as abnormal refluxing varicose veins. The vein closure system includes the delivery system and the unique intravascular adhesive. The procedure is less invasive, less painful, more effective and easier to recover from compared to existing treatments.
Although this application has been disclosed in the context of certain embodiments and examples, it will be understood by those skilled in the art that the present application extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the application and obvious modifications and equivalents thereof. Additionally, the skilled artisan will recognize that any of the above-described methods can be carried out using any appropriate apparatus. Further, the disclosure herein of any particular feature in connection with an embodiment can be used in all other disclosed embodiments set forth herein. Thus, it is intended that the scope of the present application herein disclosed should not be limited by the particular disclosed embodiments described above.
This application claims the benefit under 35 U.S.C. §120 as a continuation of U.S. patent application Ser. No. 13/730,258 filed Dec. 28, 2012, which claims the benefit under 35 U.S.C. §120 as a continuation of U.S. patent application Ser. No. 13/553,542 filed on Jul. 19, 2012, which claims priority under 35 U.S.C. §119(e) to U.S. Provisional App. No. 61/510,001 filed on Jul. 20, 2011. U.S. patent application Ser. No. 13/730,258, filed Dec. 28, 2012, also claims the benefit under 35 U.S.C. §120 as a continuation-in-part application of U.S. patent application Ser. No. 12/710,318, filed on Feb. 22, 2010, now U.S. Pat. No. 8,475,492, issued on Jul. 2, 2013, which claims priority under 35 U.S.C. §119(e) to U.S. Provisional App. Nos. 61/154,322 filed on Feb. 20, 2009 and 61/285,926 filed on Dec. 11, 2009. Each of these applications is hereby incorporated by reference in its entirety.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3699127 | O'Sullivan et al. | Oct 1972 | A |
| 3834394 | Hunter et al. | Sep 1974 | A |
| 4038345 | O'Sullivan et al. | Jul 1977 | A |
| 4039665 | Foley | Aug 1977 | A |
| 4085757 | Pevsner | Apr 1978 | A |
| 4102945 | Gleave | Jul 1978 | A |
| 4125494 | Schoenberg et al. | Nov 1978 | A |
| 4213461 | Pevsner | Jul 1980 | A |
| 4268495 | Muxfeldt et al. | May 1981 | A |
| 4582061 | Fry | Apr 1986 | A |
| RE32348 | Pevsner | Feb 1987 | E |
| 4705517 | DiPisa, Jr. | Nov 1987 | A |
| 4805628 | Fry et al. | Feb 1989 | A |
| 4994069 | Ritchart | Feb 1991 | A |
| 4997861 | Hechenberger et al. | Mar 1991 | A |
| 5022399 | Biegeleisen | Jun 1991 | A |
| 5034456 | Katsumura et al. | Jul 1991 | A |
| 5269762 | Armbruster et al. | Dec 1993 | A |
| 5327891 | Rammler | Jul 1994 | A |
| 5382261 | Palmaz | Jan 1995 | A |
| 5383466 | Partika | Jan 1995 | A |
| 5456693 | Conston et al. | Oct 1995 | A |
| 5480935 | Greff et al. | Jan 1996 | A |
| 5520653 | Reilly et al. | May 1996 | A |
| 5536490 | Klaveness et al. | Jul 1996 | A |
| 5656036 | Palmaz | Aug 1997 | A |
| 5665817 | Greff et al. | Sep 1997 | A |
| 5667767 | Greff et al. | Sep 1997 | A |
| 5676962 | Gamido et al. | Oct 1997 | A |
| 5733294 | Farber et al. | Mar 1998 | A |
| 5814016 | Valley et al. | Sep 1998 | A |
| 5830178 | Greff et al. | Nov 1998 | A |
| 5830222 | Makower | Nov 1998 | A |
| 5851508 | Greff et al. | Dec 1998 | A |
| 5868703 | Bertolero et al. | Feb 1999 | A |
| 5874044 | Kotzev | Feb 1999 | A |
| 5981621 | Clark et al. | Nov 1999 | A |
| 6013053 | Bower et al. | Jan 2000 | A |
| 6053870 | Fulton, III | Apr 2000 | A |
| 6106806 | Klaveness et al. | Aug 2000 | A |
| 6136326 | Kotzev | Oct 2000 | A |
| 6143352 | Clark et al. | Nov 2000 | A |
| 6143805 | Hickey et al. | Nov 2000 | A |
| 6190353 | Makower et al. | Feb 2001 | B1 |
| 6191202 | Greff et al. | Feb 2001 | B1 |
| 6260737 | Gruendeman | Jul 2001 | B1 |
| 6322548 | Payne et al. | Nov 2001 | B1 |
| 6323275 | Takahashi et al. | Nov 2001 | B2 |
| 6412639 | Hickey | Jul 2002 | B1 |
| 6433096 | Hickey et al. | Aug 2002 | B1 |
| 6443941 | Slepian et al. | Sep 2002 | B1 |
| 6565840 | Clark et al. | May 2003 | B1 |
| 6572873 | Osman et al. | Jun 2003 | B1 |
| 6579311 | Makower | Jun 2003 | B1 |
| 6579916 | Askill et al. | Jun 2003 | B1 |
| 6602241 | Makower et al. | Aug 2003 | B2 |
| 6607512 | Oliver et al. | Aug 2003 | B2 |
| 6616675 | Evard et al. | Sep 2003 | B1 |
| 6638293 | Makower et al. | Oct 2003 | B1 |
| 6655386 | Makower et al. | Dec 2003 | B1 |
| 6695787 | Hogendijk et al. | Feb 2004 | B2 |
| 6699928 | Cobbley et al. | Mar 2004 | B2 |
| 6723052 | Mills | Apr 2004 | B2 |
| 6726674 | Leu | Apr 2004 | B2 |
| 6743858 | Hickey et al. | Jun 2004 | B2 |
| 7077836 | Lary et al. | Jul 2006 | B2 |
| 7083634 | Shalaby | Aug 2006 | B2 |
| 7094216 | Trombley, III et al. | Aug 2006 | B2 |
| 7134438 | Makower et al. | Nov 2006 | B2 |
| 7201758 | Farmache | Apr 2007 | B2 |
| 7229413 | Violante et al. | Jun 2007 | B2 |
| 7235052 | Kellar et al. | Jun 2007 | B2 |
| 7258669 | Russell | Aug 2007 | B2 |
| 7303571 | Makower et al. | Dec 2007 | B2 |
| 7314466 | Lary et al. | Jan 2008 | B2 |
| 7351426 | Shalaby et al. | Apr 2008 | B2 |
| 7371345 | Stewart et al. | May 2008 | B2 |
| 7402320 | Mirizzi et al. | Jul 2008 | B2 |
| 7648527 | Agnew | Jan 2010 | B2 |
| 7687053 | Porter | Mar 2010 | B2 |
| 7772306 | Blacklock et al. | Aug 2010 | B2 |
| 7875017 | Sabbah | Jan 2011 | B2 |
| 7932305 | Badejo et al. | Apr 2011 | B2 |
| 8029560 | Bates et al. | Oct 2011 | B2 |
| 8092390 | Field | Jan 2012 | B2 |
| 8110144 | Morales | Feb 2012 | B2 |
| 8173722 | Baiker et al. | May 2012 | B2 |
| 8192731 | Misiak et al. | Jun 2012 | B2 |
| 8198344 | Zhang et al. | Jun 2012 | B2 |
| 8287687 | Schueneman et al. | Oct 2012 | B1 |
| 8293838 | Zhang et al. | Oct 2012 | B2 |
| 8313533 | Goldmann | Nov 2012 | B2 |
| 8398596 | Field | Mar 2013 | B2 |
| 8419711 | Sabbah | Apr 2013 | B2 |
| 8475492 | Raabe et al. | Jul 2013 | B2 |
| 8491881 | Salamone et al. | Jul 2013 | B2 |
| 8518104 | Bates et al. | Aug 2013 | B2 |
| 8541495 | Ishizaki et al. | Sep 2013 | B2 |
| 8617079 | Mitchell | Dec 2013 | B2 |
| 8808620 | Chu et al. | Aug 2014 | B1 |
| 8845614 | Raabe et al. | Sep 2014 | B2 |
| 20020177772 | Altman | Nov 2002 | A1 |
| 20020188195 | Mills | Dec 2002 | A1 |
| 20030012735 | Unger et al. | Jan 2003 | A1 |
| 20030050531 | Field | Mar 2003 | A1 |
| 20030065266 | Russell | Apr 2003 | A1 |
| 20030186005 | Rivera et al. | Oct 2003 | A1 |
| 20030202956 | Clark et al. | Oct 2003 | A1 |
| 20030206864 | Mangin | Nov 2003 | A1 |
| 20040068190 | Cespedes | Apr 2004 | A1 |
| 20040073238 | Makower | Apr 2004 | A1 |
| 20040098030 | Makower et al. | May 2004 | A1 |
| 20040193055 | Field et al. | Sep 2004 | A1 |
| 20040230119 | Brustad et al. | Nov 2004 | A1 |
| 20050113798 | Slater | May 2005 | A1 |
| 20050137575 | Thompson et al. | Jun 2005 | A1 |
| 20050273074 | Lewis | Dec 2005 | A1 |
| 20060030808 | Kennedy | Feb 2006 | A1 |
| 20060052822 | Mirizzi et al. | Mar 2006 | A1 |
| 20060052823 | Mirizzi et al. | Mar 2006 | A1 |
| 20060062687 | Morales | Mar 2006 | A1 |
| 20060195134 | Crittenden | Aug 2006 | A1 |
| 20060276743 | MacMahon et al. | Dec 2006 | A1 |
| 20070021730 | Flaherty et al. | Jan 2007 | A1 |
| 20070078207 | Jonn et al. | Apr 2007 | A1 |
| 20070208417 | Agnew | Sep 2007 | A1 |
| 20070248486 | Morales | Oct 2007 | A1 |
| 20070255140 | Violante et al. | Nov 2007 | A1 |
| 20070265370 | Anitua Aldecoa | Nov 2007 | A1 |
| 20070292472 | Paul et al. | Dec 2007 | A1 |
| 20080021139 | Blacklock et al. | Jan 2008 | A1 |
| 20080039548 | Zavatsky et al. | Feb 2008 | A1 |
| 20080045996 | Makower et al. | Feb 2008 | A1 |
| 20080103456 | Johnson et al. | May 2008 | A1 |
| 20080103564 | Burkinshaw et al. | May 2008 | A1 |
| 20080154136 | Webler | Jun 2008 | A1 |
| 20080241249 | Quintero et al. | Oct 2008 | A1 |
| 20080269720 | Sabbah | Oct 2008 | A1 |
| 20080311323 | Morales | Dec 2008 | A1 |
| 20090054773 | Shizuka | Feb 2009 | A1 |
| 20090131938 | Khatri et al. | May 2009 | A1 |
| 20090257976 | Kerber et al. | Oct 2009 | A1 |
| 20090264769 | Sadaka | Oct 2009 | A1 |
| 20100144895 | Porter | Jun 2010 | A1 |
| 20100213096 | Morales | Aug 2010 | A1 |
| 20100217306 | Raabe et al. | Aug 2010 | A1 |
| 20100217313 | Raabe et al. | Aug 2010 | A1 |
| 20100239505 | Reichl et al. | Sep 2010 | A1 |
| 20110060277 | Lilley | Mar 2011 | A1 |
| 20110098564 | Larson et al. | Apr 2011 | A1 |
| 20110172488 | Field | Jul 2011 | A1 |
| 20110178399 | Del Corso | Jul 2011 | A1 |
| 20110224538 | Linares | Sep 2011 | A1 |
| 20110224723 | Lee et al. | Sep 2011 | A1 |
| 20110251318 | Ishizaki et al. | Oct 2011 | A1 |
| 20110269870 | Cohn et al. | Nov 2011 | A1 |
| 20120027821 | Shirotake et al. | Feb 2012 | A1 |
| 20120064027 | Shalaby | Mar 2012 | A1 |
| 20120109191 | Marano, Jr. et al. | May 2012 | A1 |
| 20120128903 | Morales | May 2012 | A1 |
| 20130011589 | Morales | Jan 2013 | A1 |
| 20130052152 | Keplinger | Feb 2013 | A1 |
| 20130072907 | Lichty, II et al. | Mar 2013 | A1 |
| 20130085384 | Field | Apr 2013 | A1 |
| 20130095262 | Morales | Apr 2013 | A2 |
| 20130116633 | Lichty, II et al. | May 2013 | A1 |
| 20130144159 | Field et al. | Jun 2013 | A1 |
| 20130150712 | Field | Jun 2013 | A1 |
| 20130156824 | Keplinger | Jun 2013 | A1 |
| 20130204232 | Wieser et al. | Aug 2013 | A1 |
| 20130211182 | Sabbah et al. | Aug 2013 | A1 |
| 20130225640 | Kim | Aug 2013 | A1 |
| 20130267942 | Fulton et al. | Oct 2013 | A1 |
| 20130281835 | Field et al. | Oct 2013 | A1 |
| 20130303654 | Salamone et al. | Nov 2013 | A1 |
| 20150018867 | Raabe et al. | Jan 2015 | A1 |
| Number | Date | Country |
|---|---|---|
| 2735942 | Oct 2005 | CN |
| 201101549 | Aug 2008 | CN |
| 0567186 | Oct 1993 | EP |
| 1 230 313 | Aug 2002 | EP |
| 1 206 291 | Oct 2005 | EP |
| 2 162139 | Mar 2010 | EP |
| 2 303 342 | Apr 2011 | EP |
| 2 303 343 | Apr 2011 | EP |
| H067440 | Jan 1994 | JP |
| 2000290600 | Oct 2000 | JP |
| 2006-523471 | Oct 2006 | JP |
| WO 8606738 | Nov 1986 | WO |
| WO 9640347 | Dec 1996 | WO |
| WO 2004071612 | Aug 2004 | WO |
| WO 2010033406 | Mar 2010 | WO |
| WO 2013013080 | Jan 2013 | WO |
| Entry |
|---|
| “Bacillus Atrophaeus Spores,” Autoclave Testing Service, Inc. www.autoclavesporetesting.com-Bacillus—Atrophaeus—Spores.htm, Jul. 6, 2010, webpage copy from Internet Archive Wayback Machine: https:--archive.org-web-, 3 pp. |
| “Biological Indicators and Inoculated Carriers,” NAMSA—Medical Device Testing Laboratory and Contract Research Organization, www.namsa.com-products-biological.com, Jul. 30, 2010, webpage copy from Internet Archive Wayback Machine: https:--archive.orq-web-, 2 pp. |
| “Dry Heat Sterilizers,” Autoclave Testing Service, Inc., www.autoclavesporetesting.com-dry—heat—sterilization.com, Jul. 4, 2010, webpage copy from Internet Archive Wayback Machine: https:--archive.org-web-, 3 pp. |
| “Monitoring the Effectiveness of the Sterilization Process,” Sterile Processing University 2007, www.spdceus.com-monitoring—sterilization—process.com, Nov. 28, 2010, webpage copy from Internet Archive Wayback Machine: https:--archive.org-web-, 6 pp. |
| “Process Validation: Moist Heat Sterilization for Pharmaceuticals,” Health Canada, Health Products and Food Branch Inspectorate, www.hc-sc.gc.ca-dhp-mps-compli-conform-gmp-bpf-validation-mhsp-schpp—tc-tm-eng.php, Mar. 1, 2001, 20 pp. |
| “Steps of Dry-Heat Sterilization,” Engender Health www.engenderhealth.org-ip-instrum-inm11.com, Aug. 13, 2010, webpage copy from Internet Archive Wayback Machine: https:--archive.org-web-, 2 pp. |
| “Sterility Assurance for Industry & Healthcare,” Raven Labs Products and services, Mesa Laboratories, Inc., www.mesalabs.com-products-services-raven-labs.com, Jul. 30, 2010, webpage copy from Internet Archive Wayback Machine: https:--archive.org-web-, 4 pp. |
| “Sterilization —An Overview,” Pacific BioLabs, 2004 PowerPoint presentation, www.pacificbiolabs.com-tech—downloads.asp, Sep. 26, 2010, copy from Internet Archive Wayback Machine: https:--archive.org-web-, 37 pp. |
| “Validating Heat Sterilization,” Pacific BioLabs, 2007 PowerPoint presentation, www.pacificbiolabs.com-tech—downloads.asp, Sep. 26, 2010, copy from Internet Archive Wayback Machine: https:--archive.orq-web-, 38 pp. |
| Case et al., “Dry Heat Sterilization and Depyrogenation Validation and Monitoring,” Agalloco et al. ed., Validation of Pharmaceutical Processes, Informa Healthcare USA, Inc., Sep. 2007, pp. 223-240. |
| Chieppo et al., “Sterilization: Dry Heat,” Swarbrick, ed., Encyclopedia of Pharmaceutical Technology, 3rd Ed., vol. 6, Informa Healthcare USA, Inc., Chapter 252, Oct. 2006, pp. 3512-3518. |
| Darmady et al., “Sterilization by Dry Heat,” J. Clin. Path., vol. 14, 1961, pp. 38-44, lecture given on Feb. 2, 1960. |
| Gillis et al., “Understanding Biological Indicator Grow-Out Times,” Pharmaceutical Technology, vol. 34(1), Jan. 2010, 9 pp. |
| Joslyn, “Sterilization by Heat,” Block, ed., Disinfection, Sterilization, and Preservation, 5th Ed. Lippincott Williams & Wilkins, Chapter 36, Jan. 2001, pp. 695-728. |
| Merritt, “Sterilization Process for a Medical Adhesive,” Senior Project submitted in partial fulfillment for Bachelor of Science in Manufacturing Engineering, California Polytechnic State University, San Luis Obispo, Jul. 11, 2011, pp. 1-45. |
| Pistolesi, “Sterilization: Moist Heat,” Swarbrick, ed., Encyclopedia of Pharmaceutical Technology, 3rd Ed., vol. 6, Informa Healthcare USA, Inc., Chapter 252, Oct. 2006, pp. 3529-3539. |
| Sasaki et al., “Evaluation of High-Temperature and Short-Time Sterilization of Injection Ampules By Microwave Heating,” Abstract, PDA Journal of Pharmaceutical Science and Technology, vol. 52(1), Jan./Feb. 1998, 1 pp. |
| Sasaki et al., “Microwave Continuous Sterilization of Injection Ampoules,” Abstract, PDA Journal of Pharmaceutical Science and Technology, vol. 50(3), May-Jun. 1996, 4 pp. |
| Sasaki et al., “Validation of a Microwave Sterilizer for Injection Ampules,” PDA Journal of Pharmaceutical Science and Technology, vol. 53, Mar.-Apr. 1999, pp. 60-69. |
| Solanki et al., “Microwave Technology—A Potential Tool in Pharmaceutical Science,” International Journal of PharmTech Research, vol. 2(3), Jul.-Sep. 2010, pp. 1754-1761. |
| Tietjen et al., “Sterilization,” Infection Prevention Guidelines for Healthcare Facilities with Limited Resources, Chapter 11, 1992, JHPIEGO Corporation, 2003, www.reproline.jhu.edu-english-4morerh-4ip-Ip manual-11Sterilization.pdf, 14 pp. |
| International Search Report from International Patent Application No. PCT/US2010/024820, mailed May 11, 2010, 2 pp. |
| Written Opinion from International Patent Application No. PCT/US2010/024820, mailed May 11, 2010, 5 pp. |
| International Search Report and Written Opinion from International Patent Application No. PCT/US12/47460, mailed Dec. 21, 2012, 12 pp. |
| International Preliminary Report on Patentability from Counterpart International Patent Application No. PCT/US2012/047460, mailed Jan. 21, 2014, 7 pp. |
| U.S. Appl. No. 13/470,200, by Jack Chu, filed May 11, 2012. |
| U.S. Appl. No. 13/842,722, by Choi et al., filed Mar. 15, 2013. |
| U.S. Appl. No. 14/323,926, by Don Crawford, filed Jul. 3, 2014. |
| U.S. Appl. No. 14/453,493, by Carlos Morales, filed Aug. 6, 2014. |
| Prosecution History from U.S. Appl. No. 12/710,318, dated Aug. 13, 2012 through Mar. 15, 2013, 25 pp. |
| Prosecution History from U.S. Appl. No. 13/553,542, dated Apr. 24, 2014 through Jan. 13, 2015, 20 pp. |
| Prosecution History from U.S. Appl. No. 13/730,258 dated Aug. 14, 2013 through Apr. 25, 2014, 40 pp. |
| Office Action from U.S. Appl. No. 13/553,542, dated Aug. 31, 2015, 9 pp. |
| Office Action from U.S. Appl. No. 13/553,542, dated Mar. 9, 2016, 11 pp. |
| Prosecution History from U.S. Pat. No. 8,475,492, dated Aug. 13, 2012 through Mar. 15, 2013, 41 pp. |
| Prosecution History from U.S. Appl. No. 13/553,542, dated Apr. 24, 2014 through Nov. 30, 2015, 60 pp. |
| Prosecution History from U.S. Pat. No. 8,845,614, dated Apr. 23, 2013 through Apr. 25, 2014, 79 pp. |
| Final Office Action from U.S. Appl. No. 13/553,542, dated Sep. 8, 2016, 12 pp. |
| Response to Final Office Action dated Sep. 8, 2016, from U.S. Appl. No. 13/553,542, filed Nov. 7, 2016, 15 pp. |
| Number | Date | Country | |
|---|---|---|---|
| 20150018867 A1 | Jan 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61154322 | Feb 2009 | US | |
| 61285926 | Dec 2009 | US | |
| 61510001 | Jul 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13730258 | Dec 2012 | US |
| Child | 14473596 | US | |
| Parent | 13553542 | Jul 2012 | US |
| Child | 13730258 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12710318 | Feb 2010 | US |
| Child | 13730258 | US |
