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|Número de publicación
|Tipo de publicación
|Número de solicitud
|Fecha de publicación
|25 Mar 2004
|Fecha de presentación
|24 Sep 2002
|Fecha de prioridad
|24 Sep 2002
|También publicado como
|Número de publicación
|Maria Palasis
|Cesionario original
|Maria Palasis
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|BiBTeX, EndNote, RefMan
|Citas de patentes (5), Citada por (70), Clasificaciones (25), Eventos legales (4)
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet
[0001] The present invention relates to catheters which may be inserted into body lumens for delivery of biologically active agents. More particularly, the invention relates to catheters having inflatable balloons for occluding body lumens and delivering therapeutic, biologically active agents to a portion of the occluded body lumen.
[0002] Atherosclerotic disease can cause the build-up of plaque deposits in a localized portion of an arterial vessel. As the deposition increases, the inner diameter of the vessel becomes smaller (stenosis occurs) and impedes blood flow through the vessel. This reduction in blood throughput is harmful to the body and must be corrected. One method of correcting this arterial stenosis is to perform angioplasty using a balloon catheter, which involves inserting a catheter having at least a dilatation balloon into the stenotic area of the artery, inflating this balloon and expanding the inner diameter of the plaque-ridden segment of the artery.
[0003] An alternative variation of the above angioplasty method employs a catheter having two spaced-apart occlusion balloons whereby one of the balloons is a dilatation balloon used to expand the plaque-affected segment of the artery. Catheters having double occlusion balloons are disclosed, for example, in U.S. Pat. Nos. 5,836,967 and 5,279,546. After an initial expansion of the stenotic segment of the artery, the dilatation balloon is deflated and the catheter is manipulated and positioned such that the affected segment of the artery is between the two balloons. The two balloons are simultaneously pressurized and inflated, forming an enclosed, sealed space wherein the affected portion of the artery is contained within this space. In other words an occluded portion in the artery or lumen is formed. The catheter portion between the two balloons has a hole or plurality of holes for delivery of biologically active agents therethrough to variously treat the affected arterial segment. Thus, unlike a catheter having only a single balloon, the double-balloon catheter advantageously allows isolation of the affected segment and permits subsequent targeted application of beneficial agents to the affected arterial segment.
[0004] The double balloons thus function to seal off or occlude a section of the vessel apart from performing a dilatation function to expand the opening of a plaque-ridden, stenotic area of the vessel. During this occlusion step, the surfaces of the balloons contact healthy vessel tissue. Pressurizing and inflating the balloons to contact healthy endothelial or endoluminal tissue can cause injury to such tissue. The first kind of injury arises from abrading and compressing the surface cells of the inner vessel wall, which may lead to denuding of the surface, when the occlusion balloons are inflated. Denuding of the vessel wall may initiate the restenosis process. Another kind of injury, disruption of the internal elastic lamina, may be sustained because of the pressures that may be needed to provide a seal between the occlusion balloons and the vessel surfaces; this injury may result in distension of the vessel wall. Thus, certain balloon pressures may also cause injury to healthy vessel wall.
[0005] Hence, a comparative disadvantage of using a double-balloon catheter for delivery of biologically active agents is that the balloons must contact healthy portions of the inner wall of the vessel being treated, unlike a catheter with only a single dilatation balloon which generally only touches the plaque-covered vessel wall in their dilatation function of opening the stenotic segment. A double-balloon catheter, however, contacts not only the plaque-ridden part of the vessel during the dilatation step, but also touches at least two healthy, unaffected areas of the vessel during the occlusion step when both balloons are inflated. Accordingly, there exists a need for an improved double-balloon catheter that minimizes the denuding of healthy endothelial or endoluminal tissue due to abrasion and compression by the occlusion balloons when they are inflated.
[0006] The present invention applies to a catheter having two or more occlusion balloons wherein the balloons are spaced apart, and the balloons are simultaneously inflated to form a sealed space in a portion of a body lumen or an occluded portion in the body lumen. An object of the present invention is to provide a balloon catheter that reduces abrasion-type damage to healthy endothelial or endoluminal tissue.
[0007] Yet another object of the invention is to provide a double-balloon catheter having at least two balloons dispensing biologically active agents in the targeted area of the occluded portion of the body lumen situated between the occlusion balloons. Such balloons may provide superior sealing, can concurrently permit the use of comparatively lower balloon inflation pressures. The advantage of using lower pressures to achieve sufficient sealing is that the distension of the lumen wall may be reduced when the occlusion balloons are inflated.
[0008] Another object of the present invention is to provide a method to seal a targeted space within the body lumen which is to be treated with a biologically active agent, while facilitating more effective sealing and less injury to the endothelial or endoluminal wall. Moreover, by dispensing the biologically active agent in a targeted area that is effectively sealed, the present invention provides a more efficient and economical method of dispensing the biologically active agents and treating a body lumen.
[0009] The present invention provides in one aspect, a balloon catheter for occluding two ends of a portion of a body lumen and treating the occluded portion. The catheter comprises at least two balloons each having an exterior surface and a catheter segment connectively placed between the balloons. A coating comprising a hydrogel polymer is applied to the exterior surface of each of the occlusion balloons. The presence of such hydrogel on the occlusion balloons reduces the damage to the endothelial tissue of the body lumen that contacts the balloon upon expansion. The balloons are capable of being inflated and deflated within the body lumen, and when both balloons are inflated, form a substantially closed space within the occluded portion of the body lumen by forming a seal between the balloon surface and inner wall surface of the body lumen. The catheter segment is capable of delivering a biologically active agent to the occluded portion of the body lumen.
[0010] Embodiments of the balloon catheter may incorporate one or more of the following features. The delivery of the biologically active agent may be conducted using a plurality of holes or ports extending through the catheter wall of the catheter segment connecting the balloons. The holes or ports fluidly connect an inner lumen of the catheter segment and its exterior. The holes or ports are located between the balloons, and permit the biologically active agent to pass through from the inner catheter lumen to the exterior of the catheter segment. Other methods of delivering biologically active agents may also be employed with this multi-balloon catheter so long as the material is delivered between the balloons. The balloons can be made of an expandable material or a material that is substantially non-expandable, although the balloons are inflatable in either case.
[0011] The biologically active agents that can be used may have various effects. For example, it may be an anti-inflammatory drug which reduces body reaction to tissue injury, or it may be an anti-proliferative agent which is capable of blocking smooth muscle cell proliferation, in particular, as a reaction to tissue injury or irritation. The biologically active agents used may be dispensed through holes or ports in the catheter wall.
[0012] The exterior of both balloons are coated with a coating comprising a hydrogel polymer, which is preferably tenaciously adhering on the balloon surface. This coating can be variously manufactured to have different thicknesses in its dry and hydrated states. The hydrogel polymer may be selected from poly-carboxylic acids, celluosic polymers, gelatin polyvinyl-pyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, and polyethylene oxides. The hydrogel coating may be substantially free of a biologically active agent.
[0013] In another aspect of the invention, the coating comprising a hydrogel polymer over the exterior of the balloons may be loaded with a biologically active agent within the hydrogel matrix. The coating over the balloons may be used to deliver biologically active agents to proactively treat the healthy, inner lining of the body lumen that contacts the coating. Suitable biologically active agents should be capable of being incorporated into a hydrogel matrix which can leach or elute out on when pressure is applied to the hydrogel coating the balloon surfaces. It will be appreciated that the hydrogel coating of a multi-balloon catheter may optionally contain a biologically active agent to treat the contact area of healthy endothelial lumen tissue. This is a separate treatment modality, distinct from the treatment modality wherein the biologically active agent is delivered from within the catheter to treat the plaque-affected segment of the lumen that is contained in the space formed by inflation of the balloons or occluded portion of the body lumen.
[0014] In yet another aspect, a three-balloon catheter is provided, where the two outer balloons can be occlusion balloons and the middle balloon can be a dilatation or occlusion balloon. The two outer occlusion balloons can have a coating of hydrogel which is generally free of any therapeutic, biologically active agents since they contact only healthy vessel tissue. The middle, dilatation or occlusion balloon can be coated with a hydrogel which may be loaded with a biologically active agent to treat the target site of the vessel.
[0015] In a further aspect of the invention, the entire exterior surface of the catheter as well as the balloons may be coated with a hydrogel for ease of manufacture.
[0016] In yet another aspect of the invention, a method is provided for treating a body lumen using a multi-balloon catheter that maintains the integrity of the endothelial cells of the body lumen, the method comprising: inserting a catheter having at least two spaced-apart balloons into the body lumen, wherein the balloons are coated with a coating comprising a hydrogel polymer; inflating both balloons to contact the endothelial or cells of the inner wall of the body lumen; forming a substantially closed space between the balloons within the body lumen; and providing a biologically active agent into the closed space to treat a portion of the body lumen.
[0017] The present invention will be explained with reference to the following drawings.
[0018]FIG. 1 is a perspective view of an embodiment of a double-balloon catheter with both balloons inflated;
[0019]FIG. 2 is a cross-sectional view of the catheter of FIG. 1 showing the inner channels at section A-A of FIG. 1;
[0020]FIG. 3 is longitudinal cross-sectional view of a catheter of the present invention inserted within a stenotic blood vessel with both balloons inflated, this embodiment shows the hydrogel coating on the occlusion and dilatation balloons and also the plaque on the vessel inner wall; and
[0021]FIG. 4 shows an embodiment of a catheter having a plurality of balloons.
[0022]FIG. 1 shows an exemplary embodiment of the catheter assembly having two spaced-apart balloons, the occlusion balloon 40 and dilatation/occlusion balloon 50. The outer catheter 10 is configured with two lumina (not shown). The two balloons may be made of an expandable material or a substantially non-expandable material such as polyurethanes. In either case, the balloons are inflatable and thus capable of pushing against the inner wall of the body vessel once they are inserted. The catheter has a distal orifice 90, a metal marker 120 to enable x-ray identification of the location of the dilatation/occlusion balloon, and a catheter segment 20 that connects the two balloons. Extending through the orifice 90, a guidewire 34 has a stop plug 170 which can be used to cap the orifice 90. A coating comprising a hydrogel polymer (not shown) is applied to the exterior surface of balloons 40 and 50. A plurality of ports or holes 70 extend through the wall of the catheter segment 20 which permits a biologically active agent to pass from an inner lumen in the catheter segment 20 to the exterior of the catheter segment 20 and thereby target treatment to the section of the body lumen between the two balloons or the occluded portion of the body lumen. Also shown in FIG. 1 are a number of Y connectors, 140 and 160 with side ports 130 and 150, respectively. Connections 100 and 110 are inputs connected to balloons 40 and 50, respectively, for supplying a pressurizing medium.
[0023] The catheter shown in FIG. 1 is only one example of a catheter suitable for the present invention. Other catheter designs can also be employed in this invention. The skilled artisan is aware of such additional suitable catheter designs.
[0024]FIG. 2 shows an exemplary embodiment of a cross-sectional view of the catheter of FIG. 1 at section A-A. The outer catheter is shown with two lumens 35 and 33. An inner catheter stem 31 is shown inserted into lumen 33 and this stem 31 has two lumens 30 and 32. This view shows that four different lumens can be used to provide independent pressure control to occlusion balloon 40 and dilatation /occlusion balloon 50, to deliver a biologically active agent through the holes 70, and to receive the guidewire 34. The outer catheter 10 is configured with two lumina. The lumen 35 serves to supply the pressurizing medium to the occlusion balloon 40 while the lumen 33 permits a biologically active agent to be delivered to a targeted vessel portion. The lumen 30 serves to supply the pressurizing medium to dilatation/occlusion balloon 50 while lumen 32 can be used to receive guidewire 34. It should be noted that this is only one of many embodiments that can be used to independently control the inflation and deflation of the two balloons as well as to provide a separate fluid channel for the biologically active agents to travel and exit from the holes or plurality of holes 70. Generally, there should be at least three separate channels within the catheter to service the two balloons and to deliver the biologically active agents through the catheter holes 70.
[0025]FIG. 3 shows, in accordance with the present invention, a longitudinal cross-sectional view of a catheter of the present invention that has been inserted within a blood vessel 80 with both balloons 40 and 50 inflated. This embodiment shows the coating comprising a hydrogel polymer 60 over the exterior surface of the occlusion and dilatation/occlusion balloons and also the plaque 180 on the vessel inner wall. FIG. 3 shows the subsequent position of the two balloons following the step in which the plaque-lined vessel has been previously dilated by inflating the dilatation/occlusion balloon 50 at the site of the plaque 180. After the expansion of the plaque site, the catheter is moved to re-position the two balloons such that the target area of the vessel having the plaque 180 on the vessel wall 80 is between the occlusion balloon 40 and dilatation/occlusion balloon 50.
[0026] In operation, the double-balloon catheter described in FIGS. 1-3 is advanced into a body lumen such as an arterial vessel until the dilatation/occlusion balloon 50 is precisely located at the stenotic site, while the location of the balloon 50 is monitored by x-ray with the aid of a metal marker 120 attached to the inner stem 31 within the dilatation/occulsion 50 balloon. By supplying a pressurizing medium via the connection 110 the dilatation balloon 50 can be inflated, dilating the stenotic, plaque-coated site of the lumen. Once this dilatation action has been completed, the pressurizing medium is drained from the dilatation balloon 50 and the catheter is advanced into the body lumen beyond the plaque-coated site until the dilatation balloon 50 is downstream, while the occlusion balloon 40 remains located in a portion upstream of the treated segment of the body lumen. Then, a pressurizing medium is supplied to the two balloons via the connections 100 and 110 so that both balloons are inflated to isolate the plaque-coated segment of the body lumen and form an occluded portion of the body lumen. The balloons are internally pressurized to between about 1 to 10 atmospheres and preferably between about 1 to 6 atmospheres to provide a seal between the hydrogel coated surface of each balloon and the healthy, endothelial tissue of the body lumen wall. In this inflated state, the two balloons form a substantially fluid-tight, enclosed space which contains the segment of body lumen wall to be treated. A biologically active agent can be delivered into this occluded portion of the body lumen from the holes 70 while the balloons 40 and 50 remain inflated. The biologically active agent can be delivered via the connection 150 of the Y connector 160 into the occluded portion of the body lumen between the two balloons 40 and 50. After delivery of the biologically active agent for a period of seconds to 10 minutes, the excess fluid can be drawn out from the occluded portion of the body lumen through the ports 70 and into the inner stem 20 of the inner catheter and via the guidewire lumen 32. It is also possible to deliver the biologically active agent via the guidewire lumen 32 of the inner catheter and to drain the biologically active agent via the lumen 33 in the outer catheter.
[0027] With this embodiment, throughout the duration of treatment, the guidewire 34 must be retracted in the guidewire lumen 32 sufficiently so that occlusion element 170 abuts the orifice 90 to cap it. Once the orifice is sealed, the guidewire lumen 32 can be employed as the lumen for supply and removal of the biologically active agent.
[0028] After the biologically active agent is allowed to react with the target plaque and endothelial tissue of the body lumen upon which the plaque is deposited, and after the excess biologically active agent has been drawn off from the occluded portion of the body lumen formed by the two inflated balloons, the pressurizing medium is drawn off from the two balloons to deflate them. With the treatment procedure thus completed, the catheter assembly is removed from the body lumen.
[0029] When plaque build-up is the cause of stenosis, the catheter having a balloon with a dual dilatation/occlusion function, as shown in FIG. 1, can be used. Many other treatments, however, do not require a balloon having a dilatation function. Instead, two occlusion balloons can be inflated to seal a vessel portion, wherein a biologically active agent may be delivered into this sealed portion. For example, preventing the recurrence of arterial thrombus in a vessel may be accomplished by isolating the affected portion of the vessel and delivering a biologically active agent, such as an anti-proliferative or anti-thrombogenic into the isolated portion. Because the balloons function only to occlude a vessel and touch healthy vessel wall which are especially susceptible to de-nuding, a catheter having two hydrogel-coated balloons which are generally free of any biologically active agents, in accordance with the present invention, can be used to substantially reduce the potential for vessel damage. Additionally, the balloons may be further optimized to reduce potential abrasion to the healthy tissue by being made more compliant than a typical dilatation balloon.
[0030] In accordance with the present invention, isolation of a vessel may be accomplished with another embodiment of the invention wherein a catheter has three balloons, each coated with hydrogel. A three balloon catheter can occlude two different sections of a target vessel simultaneously or at different times. Each balloon would be accessible through an independent catheter channel, and a separate channel or channels would be used to deliver the biological agent from the holes 70 in the catheter segments 20 between the balloons. A catheter having more than three balloons is also possible, restricted only by the complexity of needing additional channels within the catheter, and the physical limitations thereon.
[0031]FIG. 4 shows one embodiment of a three-balloon catheter 200, wherein the middle balloon 250 may be used to dilate the stenotic (lesion) portion of the vessel and the outer balloons 240, which contact only healthy vessel tissue and thus coated with hydrogel, can serve as the occlusion balloons for isolating the treatment portion of the vessel. The expandability of the middle 250 and outer balloons 240 can be chosen to optimize their respective functions. Because balloon abrasion to a vessel lesion is less of a concern than abrasion to healthy tissue, the dilatation balloon may be designed to be less expandable than an occlusion balloon and employ higher pressures (up to 20 atms).
[0032] In operation the middle, dilatation balloon 250 may be inflated to dilate the stenotic area of the vessel. The middle, dilatation balloon 250 is deflated. Then the two, outer occlusion balloons 240 may be inflated to isolate the treatment portion of the vessel and a biologically active agent, e.g., cells or viral vectors may be delivered via the catheter into the enclosed space to treat the vessel wall.
[0033] In an alternative gene delivery embodiment, a three-balloon catheter 200 is used to apply the viral vector (or other agent) present in the coating on the middle balloon 250 (not necessarily a dilatation). When the middle balloon 250 is inflated, a therapeutic viral vector (or other agent) can be delivered via a diffusion process to the vessel wall. The two outer balloons 240 are inflated during this gene transfer process in order to provide vessel isolation. Optionally, in another embodiment of the method, in accordance with the present invention, another separate, biologically active agent can be delivered via holes 70 in the catheter in addition to the gene transfer procedure.
[0034] In another embodiment of the catheter of the present invention, the two outer balloons may be placed around a dispatch catheter. The dispatch catheter has a coil frame which permits delivery of biologically active agents, while the two outer balloons provide isolation of the vessel portion being treated.
[0035] There are a number of preferred variations of the present invention of the balloon catheters with hydrogel coating as provided in FIGS. 1-4. The first variation has an apparatus for delivering a biologically active agent situated between two spaced-apart, hydrogel coated balloons, but, morever, provides an additional treatment functionality in that the hydrogel is a matrix containing a biologically active agent that is delivered to the vessel wall when pressure is applied to the hydrogel coating on the balloon. Another variation builds on the above first or second variation. In this embodiment, the hydrogel coats not only the balloons, but also coats the entire catheter. This latter embodiment may be advantageous because it may be easier and less costly to manufacture. The hydrogel coating disposed over the surface of the balloons and, optionally, over the remaining surface of the catheter may or may not contain eluting biologically active agents.
[0036] Thus, the present invention provides a method for treating a body lumen using a multi-balloon catheter that maintains the integrity of the endothelial cells of the inner wall of the body lumen. The method comprises: (a) inserting a catheter having at least two balloons into the body lumen, wherein the balloons are coated with a coating comprising a hydrogel polymer; (b) inflating both balloons to contact the endothelial cells of the inner wall of the body lumen; (c) forming a substantially closed space between the balloons within the body lumen; and (d) providing a biologically active agent into the closed space.
[0037] The last step may be accomplished in various ways. However, a preferred means is to deliver the biologically active agent through a channel or inner lumen in the catheter segment connecting the two balloons. The inner catheter lumen is fluidly connected to holes 70 or ports extending through the walls of the catheter segment 20 which is connectively between the two spaced-apart balloons. The holes 70 permit the biologically active agent to pass through or be ejected from an inner catheter lumen to the exterior of the catheter segment 20.
[0038] An important element of the method is the use of hydrogel coated balloons to contact healthy endothelial cells in the body lumen during the occlusion step. There are several advantages provided by using hydrogel coated balloons. The hydrogel, which may be described alternatively as a foam, provides a cushioning interface between the balloon and the healthy body lumen cell lining. The cushioning can reduce the abrasion of the cells and consequent de-nuding of the body lumen when the balloons are inflated. Additionally, the hydrogel may help to create an effective sealant between the balloon and the body lumen, which may enable a reduction in pressure needed to inflate the balloons. Less pressure may reduce distension of the body lumen and thereby potentially reduce damage and irritation to the contact areas of the body lumen. In sum, the injury to the body lumen at the contact areas can be reduced.
[0039] The presence of the coating comprising a hydrogel polymer over the surface of balloons is, thus, a key element to the multi-balloon catheter of the present invention. The hydrogel polymer may be a cross-linked polymer material formed from the combination of a colloid and water. Preferably, the hydrogel is tenaciously adhering to the balloon surface, so that the hydrogel does not separate when the balloon is inflated within a body lumen. Cross-linking can reduce solubility and produce a jelly-like polymer that is characterized by the ability to swell and absorb a substantial amount of the drug, usually in aqueous solution form. The hydrogel coating is preferably hydrophilic, water swellable, and lubricious (i.e., having low coefficient of friction). Preferred hydrogels are polyacrylic acid and polymers available as HYDROPLUS® (Boston Scientific Corporation). Some other examples of materials from which hydrogels may be manufactured include poly-carboxylic acids, celluosic polymers, gelatin polyvinyl-pyrrolidone, maleic anhydride polymers, polyamides, polyvinyl alcohols, and polyethylene oxides. Additional details concerning materials for making hydrogels are provided in U.S. Pat. Nos. 5,304,121, and 5,954,706, both issued to Sahatjian, and U.S. Pat. Nos. 5,674,192, and 5,843,049 issued to Sahatjian et. al.
[0040] In particular U.S. Pat. No. 5,304,121, Example 1, provides one method of producing hydrogel coated balloon using a "dipping" process. The surface of the balloon (polyethlene) of an angiographic catheter is prepared by wiping down with clean cloth. The balloon has an O.D. (outer diameter) of about 3.5 mm (inflated). The balloon is coated with a solution of 4,4 diphenylmethane diisocyanate (MDI) in methylethylketone for 30 minutes. After drying in an air oven at 85° C. for 30 minutes, the balloon is dipped in a 1.7% solution of poly(acrylic acid) homopolymer having a molecular weight of about 3,000,000 in dimethylformamide (DMF) and tertiarybutyl alchohol. After drying at about 85 ° C. for 30 minutes, a smooth coating is obtained. The balloon is oven dried for 8 hours at 50° C. One function of the drying steps is to remove solvent from the coating. The surface of the balloon becomes instantly lubricious upon exposure to water. The polyisocynanate solution is at a concentration of about 0.5 to 10% by weight. The poly (carboxyl acid) to polyisocyanate molar ratio is generally about 1:1. The formation of the hydrogel is further described in U.S. Pat. No. 5,091,205.
[0041] In addition to the above "dipping" process, there are other methods for providing a hydrogel coating over a balloon including "spraying" the coating onto the balloon. While the "dipping" method is described above as an example, the present invention is not limited to the particular manufacturing method in which the hydrogel is applied to the balloon, and, indeed, is inclusive of all forms of making the hydrogel coated balloon.
[0042] In general, when dried, the hydrogel coating should be greater than about 0.5microns in thickness and preferably in the range of about 1.0 to 10.0 micrometers in thickness. The hydrogel coating thickness can swell by about a factor of 6 to 10 or even more when the hydrogel is hydrated. More preferably, the thickness of the hydrated coating is about 10 to about 55 microns in the swelled, uncompressed state.
[0043] In one embodiment, the hydrogel can be loaded with a biologically active agent that is released when in contact with fluid or when inflation pressure is applied. This provides a way for further deactivating the body's inflammatory and cell proliferation responses caused by irritation when the balloon contacts the healthy cell lining in the body lumen. Here, the treatment is directed not to the body lumen that is plaque-affected, but to the healthy part of the body lumen that is especially susceptible to injury when a foreign object such as a catheter balloon abrades or compresses the body lumen cell lining or distends the body lumen. Also, the hydrogel composition and biologically active agent may be chosen for the purpose of a particular rate-of-release response characteristic, this being dependent on the hydrogel's degree of cross-linking, charge, structure, thickness, or sensitivity to compression, and the agent's solubility, particle size and charge. For example, the response characteristic of the hydrogel coating may be designed such that an application of compressive pressure urges delivery of the biologically active agent in about 10 minutes or less, with 10 minutes representing the outward duration a balloon catheter should be inside an arterial vessel.
[0044] One example of an embodiment in which the hydrogel includes a biologically active agent is the use of heparin with the hydrogel. Heparin is absorbed into the coating without complexing and is freely released therefrom. Such hydrogel-drug combination can deliver about half of the drug solution in response to pressures used for balloon angioplasty. In other particular embodiments, the hydrogel polymer includes acid groups and incorporates the biologically active agent which is anionic in nature and is bound by electrostatic attraction to cations in the coating, such as an ammonium cation.
[0045] With respect to suitable biologically active agents that are intended to be delivered through a catheter channel, the agent should be easily dispensed through small holes or ports in the catheter segment joining the balloons. These biologically active agents are, in general, placed into an aqueous solution. Various biologically active agents may be delivered including, anti-inflammatory drugs, such as heparin or heparin derivatives, Ppack (dextro-phenylalanine proline argine chloromethylketone), enoxaprin, hirudin, or aspirin (acetylsalicylic acid) or an anti-proliferative agent, such as heparin (which has antiproliferative properties), enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation. Dosages applied to the body lumen tissue, for example, of heparin are in the range of 10-30 mg of heparin solution containing 200-1000 units of sodium heparin.
[0046] Other examples of biologically active agents include thrombolytic agents, such as the enzyme, urokinase, which can be used to remove existing arterial thrombus. The term "biologically active material" encompasses therapeutic agents, such as drugs, and also genetic materials and biological materials. The genetic materials mean DNA or RNA, including, without limitation, of DNA/RNA encoding a useful protein stated below, anti-sense DNA/RNA, intended to be inserted into a human body including viral vectors and non-viral vectors. Examples of DNA suitable for the present invention include DNA encoding
[0047] anti-sense RNA
[0048] tRNA or rRNA to replace defective or deficient endogenous molecules
[0049] angiogenic factors including growth factors, such as acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor and insulin like growth factor
[0050] cell ccle inhibitors including CD inhibitors
[0051] thymidine kinase ("TK") and other agents useful for interfering with cell proliferation, and
[0052] the family of bone morphogenic proteins ("BMP's") as explained below. Viral vectors include adenoviruses, gutted adenoviruses, adeno-associated virus, retroviruses, alpha virus (Semliki Forest, Sindbis, etc.), lentiviruses, herpes simplex virus, ex vivo modified cells (e.g., stem cells, fibroblasts, myoblasts, satellite cells, pericytes, cardiomyocytes, sketetal myocytes, macrophage), replication competent viruses (e.g., ONYX-015), and hybrid vectors. Non-viral vectors include artificial chromosomes and mini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic polymers (e.g., polyethyleneimine, polyethyleneimine (PEI)) graft copolymers (e.g., polyether-PEI and polyethylene oxide-PEI), neutral polymers PVP, SP 1017 (SUPRATEK), lipids or lipoplexes, nanoparticles and microparticles with and without targeting sequences such as the protein transduction domain (PTD).
[0053] The biological materials include cells, yeasts, bacteria, proteins, peptides, cytokines and hormones. Examples for peptides and proteins include growth factors (FGF, FGF-1, FGF-2, VEGF, Endotherial Mitogenic Growth Factors, and epidermal growth factors, transforming growth factor α and β, platelet derived endothelial growth factor, platelet derived growth factor, tumor necrosis factor α, hepatocyte growth factor and insulin like growth factor), transcription factors, proteinkinases, CD inhibitors, thymidine kinase, and bone morphogenic proteins (BMP's), such as BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7(OP-1), BMP-8. BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14 , BMP-15, and BMP-16. Currently preferred BMP's are BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7. Alternatively or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the "hedgehog" proteins, or the DNA's encoding them. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Cells can be of human origin (autologous or allogeneic) or from an animal source (xenogeneic), genetically engineered, if desired, to deliver proteins of interest at the transplant site. The delivery media can be formulated as needed to maintain cell function and viability. Cells include whole bone marrow, bone marrow derived mono-nuclear cells, progenitor cells (e.g., endothelial progentitor cells) stem cells (e.g., mesenchymal, hematopoietic, neuronal), pluripotent stem cells, fibroblasts, macrophage, and satellite cells.
[0054] Biologically active material also includes non-genetic therapeutic agents, such as:
[0055] anti-thrombogenic agents such as heparin, heparin derivatives, urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone);
[0056] anti-proliferative agents such as enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid, amlodipine and doxazosin;
[0057] anti-inflammatory agents such as glucocorticoids, betamethasone, dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, and mesalamine;
[0058] immunosuppressants such as sirolimus (RAPAMYCIN), tacrolimus, everolimus and dexamethasone,
[0059] antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, halofuginone, adriamycin, actinomycin and mutamycin; endostatin, angiostatin and thymidine kinase inhibitors, and its analogs or derivatives;
[0060] anesthetic agents such as lidocaine, bupivacaine, and ropivacaine;
[0061] anti-coagulants such as D-Phe-Pro-Arg chloromethyl keton, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin anticodies, anti-platelet receptor antibodies, aspirin (aspirin is also classified as an analgesic, antipyretic and anti-inflammatory drug), dipyridamole, protamine, hirudin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides;
[0062] vascular cell growth promotors such as growth factors, Vascular Endothelial Growth Factors (FEGF, all types including VEGF-2), growth factor receptors, transcriptional activators, and translational promotors;
[0063] vascular cell growth inhibitors such as antiproliferative agents, growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin;
[0064] cholesterol-lowering agents; vasodilating agents; and agents which interfere with endogenous vasoactive mechanisms;
[0065] anti-oxidants, such as probucol;
[0066] antibiotic agents, such as penicillin, cefoxitin, oxacillin, tobranycin
[0067] angiogenic substances, such as acidic and basic fibrobrast growth factors, estrogen including estradiol (E2), estriol (E3) and 17-Beta Estradiol; and
[0068] drugs for heart failure, such as digoxin, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors including captopril and enalopril.
[0069] Also, the biologically active materials of the present invention include nitric oxide adducts, which prevent and/or treat adverse effects associated with use of a medical device in a patient, such as restenosis and damaged blood vessel surface. Typical nitric oxide adducts include nitroglycerin, sodium nitroprusside, S-nitroso-proteins, S-nitroso-thiols, long carbon-chain lipophilic S-nitrosothiols, S-nitrosodithiols, iron-nitrosyl compounds, thionitrates, thionitrites, sydnonimines, furoxans, organic nitrates, and nitrosated amino acids, preferably mono-or poly-nitrosylated proteins, particularly polynitrosated albumin or polymers or aggregates thereof. The albumin is preferably human or bovine, including humanized bovine serum albumin. Such nitric oxide adducts are disclosed in U.S. Pat. No. 6,087,479 to Stamler et al. which is incorporated herein by reference.
[0070] A biologically active material may be encapsulated in micro-capsules by the known methods. Still other biologically active agents can be therapeutic genes which may be carried in viral vectors such as recombinant, nuclear-specific adenoviral β-galactosidase. The delivered genes may be used to treat vascular proliferative disease by increasing gene expression in vascular tissue.
[0071] Delivery of genes to a treatment site can be accomplished in several ways. The genes may be delivered as a viral solution through holes or ports in a double-balloon catheter wall after isolation of the vessel. Another method of delivering the gene to the site is by applying a gene vector to a balloon's hydrogel surface and then transferring the genes to vessel wall tissue by inflating the balloon. This balloon can be prepared, for example, with a viral solution of 25μl of a 1.7×1011 PFU/ml adenoviral β-galactosidase stock solution which can be applied over the surface of a hydrogel-coated, catheter balloon. This particular method of gene transfer is described in "Analysis of Adenoviral Transport Mechanisms in the Vessel Wall and Optimization of Gene Transfer Using Local Delivery Genes" by Palasis et al., Human Gene Therapy, 11:237-246, Jan. 20, 2000.
[0072] The following experimental studies have been performed and illustrate the advantages of using a hydrogel coated balloon to contact healthy endothelium as compared to a non-coated balloon. The experimental protocol was in compliance with the Guide for Care and Use of Laboratory Animals (NIH publication no. 86-23, 1985). New Zealand White Rabbits were anesthetized with ketamine (10 mg/kg) and acepromazine (0.2 mg/kg) after premedication with xylazine (2 mg/kg). The bilateral external iliac arteries were used for all experiments. A balloon of a catheter having no hydrogel coating was inflated to about 6 atm, resulting in a balloon diameter of about 3 mm inside one iliac and then deflated after 2 or 30 minutes elapsed. A balloon of a catheter coated with three layers of a high molecular weight polyacrylic acid polymer, i.e., hydrogel, was inserted into the contralateral iliac and then inflated to about 6 atm then deflated after 2 or 30 minutes. Three days after this transduction, the animals were anesthetized and the iliac arteries were harvested. The harvested vessels were fixed in paraformaldehyde for 10 minutes and washed in phosphate buffered solution post-fixation. The vessels were later cut open longitudinally. Cross-sectional specimens were embedded in paraffin, sectioned into 5 micrometer sections, and counterstained with hematoxylin and eosin. Slides were observed using light microscopy. An examination of the vessel specimens treated with the hydrogel coated balloon showed very little or no visible damage to the endothelium whereas, the vessel specimen treated with the uncoated balloon evidenced noticeable damage to the endothelial wall. Thus, the hydrogel coating over the balloon clearly prevented subsequent damage to healthy vessel endothelium when a balloon was dilated against the endothelium.
[0073] It is to be understood that, while various embodiments of the invention have been described, the foregoing are intended only as exemplary embodiments and that other embodiments may be within the spirit and scope of the present invention. It is further understood that other advantages, modifications and embodiments may be within the scope of the present invention as defined by the appended claims. Furthermore, the references mentioned herein are incorporated herein by reference.
|Patente citada
|Fecha de presentación
|Fecha de publicación
|4 May 1936
|28 Mar 1939
|American Box Board Co
|Título no disponible
|Título no disponible
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|Título no disponible
|Patente citante
|Fecha de presentación
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|22 Jun 2005
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|Mcclain James B
|Drug/polymer composite materials and methods of making the same
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|17 Mar 2010
|23 Sep 2010
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|5 Ago 2013
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|Endovascular multi-balloon cathethers with optical diffuser for treatment of vascular stenoses
|Clasificación de EE.UU.
|604/101.01, 604/102.01
|Clasificación internacional
|Clasificación cooperativa
|Clasificación europea
|24 Sep 2002
Owner name: SCIMED LIFE SYSTEMS, INC., MINNESOTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PALASIS, MARIA;REEL/FRAME:013707/0626
Effective date: 20020905
Owner name: SCIMED LIFE SYSTEMS, INC., MINNESOTA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:PALASIS, MARIA;REEL/FRAME:013326/0701
Effective date: 20020905
|6 Nov 2006
Owner name: BOSTON SCIENTIFIC SCIMED, INC.,MINNESOTA
Free format text: CHANGE OF NAME;ASSIGNOR:SCIMED LIFE SYSTEMS, INC.;REEL/FRAME:018505/0868
Effective date: 20050101
|20 Nov 2009
|Fee payment
Year of fee payment: 4
|13 Nov 2013
|Fee payment
Year of fee payment: 8


text:
THE CAPE | Pilot & Tarot (Jan. 9) *Spoilers!*
View Single Post
January 23 2011, 04:51 AM
Star Wolf
Rear Admiral
Location: ciudad de Los Angeles
Re: THE CAPE | Pilot & Tarot (Jan. 9) *Spoilers!*
Temis the Vorta wrote:
Just because it's based on a comic book doesn't mean we need to settle for crap. Low standards is what doomed
Seriously wasn't
an attempt to put "super" characters into a real world like the Wild Card series of novels or
what was the name of the 90s comic book company? I don't see
The Cape
as trying to be a "real" guy with some skill or supernatural gift living in "our world' but rather a comic book world
I'm not crazy! All I Really Need to Know I learned by Watching The Wire
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subset: commoncrawl


text:
Tonight: Mostly clear. Low around 49. Northwest wind around 6 mph becoming calm in the evening.
Wednesday: Partly sunny. High near 80. Light and variable ... More
A father's communication
By David De Rurange/KTVL.com
WHITE CITY, Ore. -- Preventing gang activity starts in the home. Just ask Jesus Sevilla. He's a White City father doing what he can to keep his teenage son away from gangs. One of those things was attending a gang awareness meeting.
At the meeting, the Oregon National Guard showed families self-defense. It's one of topics, Jesus learned for his family. He said the gang influence is spreading all around him.
Medford Police Officer Ian McDonald spoke about his exclusive relationship with Teddy Sanchez., a local teen who died as a result of gang relations.
"One day he gets confronted by somebody who we still believe is a rival was Sureno affiliated or rival, that came up to him and said, 'you still bangin'? What's up?'" McDonald said. "And he said, 'no no, I don't do that, I'm a family man now. If you are a gang member and you gave it up, good on ya. I care. Police care.Your parents care. You know who doesn't care? Rival gang members. You still got it. He still had the tattoo on his face. The person who confronted him pulled out a knife and stabbed him in the chest. Teddy Sanchez died at age 18."
Weeks after the gang awareness meeting, Jesus brought his 15-year-old son Luis to speak with News 10 during a work break. In the 13 years Jesus has lived in White City, he says he's seen the gang problem get worse. Luis said many of his friends are in gangs. Yet, Luis maintains his 4.0 GPA -- and his distance from gang affiliation.
"I always see some people who start doing bad stuff, like joining gangs. He told me that if I wanted to do good in life I should keep on studying. I trust him." Luis said.
Luis' dad said he guides his family with trust, friendship and open communication.
"My children talk about everything with me and my wife. In reality, that makes me feel good, because there's a lot of communication." Jesus said.
Whether it's with a mentor or a parent, Jesus said a child needs a channel of clear communication, instead of miscommunication, like what happened in the Teddy Sanchez gang-related murder.
Business News
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text:
Originally Posted by wclavey
It also removes scratches that may be in the glass of your contact printing frame. When I first started contact printing my 4x5 negaitves, I was using the ceiling light in my small 1/2 bathroom as my light source and used the diffusion screens I described above to control the amount of light. But then I switched to a 7 watt light source about 3 feet above the toilet seat top and eliminated the diffusion screens ... and started getting scratches in all my prints... surprisingly all in the same place, yet I couldn't find any scratches on the negatives. Thats when it dawned on me that the diffusion screen layers on top of the frame were eliminating the scratches in the glass.
True. I had an old contact frame with scratches and pits that caused similar problems. A diffusion screen directly over the frame would send light under the scratches and minimize or eliminate them. Instead, I just had a new piece of regular glass cut, it was something like $3 bucks. As long as your springs are strong you shouldn't have problems with regular glass, but I have heard of some persons in humid areas where newton rings are more prevalent using a lightly frosted glass that still lets them see the neg. I wonder if that awful no glare framing glass would do the same thing? I would have trouble with a diffusion over the frame, as then I couldn't see to dodge and burn.
Last edited by JBrunner; 10-15-2007 at 10:29 PM. Click to view previous post history.
That's just, like, my opinion, man...


text:
|Project Name
|Price (USD)
|Project Name
|Price (USD)
|PHP Zend Framework Developer (part-time)
|We are looking for an experienced PHP Zend Framework Developer who will continue to work on our existing...3 months and based on results can extend to full-time or longer period. Only serious bidders please.
|PHP, AJAX, Zend, MySQL
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|Sep 7, 2011Ended
|Zend Framework Developer
|Looking for a PHP/MySQL developer with experience using the Zend Framework for possible daily and weekly...individual or small company located in the western part of the US.
|PHP, MySQL
|Dec 27, 2011
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|Zend Framework Developer
|We are developing in Zend Framework and need a PHP developer proficient in Zend to added CSS and Jquery...great communication skills, strong work ethic and time management skills as this could lead to a longer
|PHP, Javascript, Linux, CSS, Zend
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|Full-time PHP Developer with Zend Framework Experience wanted!
|...com, looking for an experienced developer to join our team full-time. Our current operations extend to...database. Our application is written using Zend Framework 1. You will be joining an ambitious team and...freelancers. Please do not apply if you work as part of a team or work with an agency. Thank you.
|PHP, Software Testing, Zend, MySQL, jQuery / Prototype
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|362470 Part-Time Zend Framework Dev.
|...a proffessional web developer myself and I look for a person I can delegate part of my work to. First...First of all, I'm looking for Zend Framework developers, but a good knowledge of HTML,CSS,Javascript,AJAX...This is a part-time position 20hours/week. I need this to be 4 hours/day at the negotiated time and a programmer
|PHP, Javascript, AJAX, SQL, Anything Goes, HTML
|Oct 28, 2009
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|Zend/PHP 5 Developer
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|Java, AJAX
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|Full Time PHP Zend Framework / Jquery Developer
|Software Developer & Digital Marketing Agency is a company registered in 2005 and activating in the online/new...---- We are looking for a SENIOR DEVELOPER to work as a full time programmer with our team. ------...-------------------------------------- PHP, Zend Framework, JQuery, JavaScript, CSS, HTML5, MYSQL.
|PHP, Zend, MySQL, HTML5, jQuery / Prototype
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|Dedicated PHP(Zend Framework) developer
|We are lookig for Zend developer, who will continue development of a financial-accounting web application...application. YOU MUST: -have GREAT Zend Framework experience with PHP/MySQL -can modify existing code -document...-have knowledge in accounting OUR OFFER: - full time position without any end date, since the project
|PHP, Javascript, CSS, Software Architecture, Software Testing, Website Testing, MySQL, HTML, Website Management, Web Hosting
|Aug 30, 2012
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|PHP/ Zend Framework Developer Needed
|Need an experienced PHP/ Zend framework/ MYSQL developer. Individuals need to be able to work at least...between PST time 8am-7pm. The other hours can be worked not in the Pacific Standard time slot of 8am-7pm...individuals with Extensive knowledge of PHP, Zend framework, and Mysql .Must have decent English skills
|PHP, Project Management, Engineering, Software Architecture, Software Testing, MySQL, Amazon Web Services
|Jan 3, 2011
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|Zend 2 Framework & Multiple API Developer
|...venture online, and we need someone who can put their time and their personal style into creating our customer...that will have libraries that work with the ZEND Framework. Skill Requirements: You Must have Good Experience...Experience with • API interaction • PHP (MVC and ZEND) • HTML5 (Responsive) • CSS3 (Responsive) •
|PHP, Zend
|Jul 15, 2014
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|PHP Zend Framework Updates
|We have a site currently developed in PHP Zend Framework that is e-commerce based. There are 2 issues...checking the part they mentioned below and I went directly to ups.com and chose the "Calculate time and cost"
|PHP, Software Architecture, eCommerce, MySQL
|May 19, 2012
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|Zend Framework
|PHP developer with knowledge of Zend framework.
|Jul 13, 2015
|Jul 13, 2015Ended
|Full Time Developer Zend Framework MVC
|PHP, CMS, Zend, HTML5
|Jun 8, 2011
|Jun 8, 2011Ended
|Full Time Zend Developer
|Arts & Crafts, Anything Goes
|Apr 12, 2011
|Apr 12, 2011Ended
|PHP Developer - Zend framework
|...need a developer to maintain and improve my current site. Needs to be proficient on the Zend framework...framework. About 1000 lines of PHP so far.
|PHP, Linux, Software Architecture, Software Testing, Website Testing, MySQL, Website Management, Web Hosting
|Aug 16, 2012
|Aug 16, 2012Ended
|PHP Zend framework developer
|Dear Freelancer, I am a developer based in europe with a lot of onging projects and projects that...together with me!! Skills: - Programming Zend framework (Most Import) - Jquery skills - Cross browser...skills) - HTML/php - Create Wordpress templates **Dont reply if you don't have Zend framework experience
|PHP, Website Design, Graphic Design, Zend, HTML
|Apr 12, 2012
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|PHP Developer with Zend Framework Experience wanted for world domination!
|...com, looking for an experienced developer to come on board full-time. We have just signed a huge contract...next couple of years. It is a very exciting time to be a part of Cleoo! We currently operate in the UK...database. Our application is written using Zend Framework 1. You will be joining a forward-thinking team
|PHP, Software Testing, Zend, MySQL, jQuery / Prototype
|Apr 28, 2014
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|Changelog with Zend Framework
|...manage the changelog. - Developer logs into the web application - Developer sees all the products assigned...assigned to him - Developer can create a new release entry - Function to update/modify the release log...release entry 2. Front End The front end is the part that is visible to the public. It should offer the
|PHP, Data Processing
|Apr 18, 2009
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|PHP Zend developer
|Job: develop the back-end with PHP Zend framework for a webapplication with the following modules: ...is only a back-end part to develop. Requirements: - Start today - Zend framework experience - Jquery
|PHP, Zend, HTML, jQuery / Prototype
|Sep 12, 2012
|Sep 12, 2012Ended
|Zend developer
|Hi, I need some one is good in php framework and also having exposure in facebook. I have to finish...good and can be available during day time (Indian standard time, which is GMT +5:30) Thanks Sheo
|PHP, Zend, MySQL
|Apr 11, 2014
|Apr 11, 2014Ended


text:
Top Definition
The theory that the warthogs are the ones who are really running things.
I think warthogism is crazy!
by keyscul January 28, 2013
Type your email address below to get our free Urban Word of the Day every morning!
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text:
Grapevine has it that Sonakshi Sinha and Aditya Roy Kapur have replaced Alia Bhatt and Varun Dhawan respectively, for the remake of Mani Ratnam's Tamil blockbuster 'OK Kanmani' to be directed by Saad Ali. A couple of months ago, it was reported that the 'Student of The Year' actors would b
NOW SHOWING: Vikram talks about 'Raavan'
Catch the Tamil actor talk about his experience working with Mani Ratnam
mani ratnam
With reports doing the round that ace filmmaker Mani Ratman was admitted to a hospital in Delhi for cardiac attack, his wife Suhasini clears the weather surrounding Ratnam's health woes report and said that all is well with Mani Sir. He is doing absolutely fine. "All is well with Mani sir
Eminent filmmaker Mani Ratnam's illness and subsequent hospitalization turns out to be a rumor. He had actually visited the Delhi hospital for a long pending master health check-up, while on a holiday with his wife in the national capital, it was confirmed. "A master health checkup was lon


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Queen Creek Olive MillMarch 18, 2014Restaurant • Queen Creek, United States
This place is great for breakfast!! Plenty of room to sit outside when the weather is nice.
This place is great for breakfast!! Plenty of room to sit outside when the weather is nice.
24/7. Fresh salsa made daily. I think this is one of the better ones in the valley.
I would have liked to have seen cheaper lunch specials; however, their portion size does not disappoint. All fish was fresh and tasty!
Word around the campfire is Amanda makes the best Bloody Marys you've ever had!!
This place is solid. Great work at a fair price. I've been here quite a few times and am very happy with them.
The food is fresh, healthy and awesome! Tina is about the nicest lady you could meet. To say the prices are fair is an understatement!!
Someone should talk to the store owner about giving the mayor a free cigar every time he comes in!!
The hotdogs at the pool are great!! The kids loved them and so did the adults.


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Palo Alto, California - inneractive is excited to announce that it has positioned itself as the first ever ad mediation platform for rich media mobile advertising on a global scale. With many mobile advertising solutions competing to produce significant revenue for developers, the answer lies with rich media advertising.
However, just like the many ad networks out there, developers are finding it increasingly difficult to choose one rich media provider for its mobile advertising efforts, especially with the need to integrate multiple SDKs. inneractive is taking what it has accomplished in the space of traditional mobile advertising and reproducing it in the world of rich media.
inneractive will be partnering with all the rich media providers so developers do not have to choose one over the other, and with one HTML5-based SDK, developers will get access to all rich media campaigns across all the different providers.
The inneractive rich media platform supports all the market standards such as ORMMA (Open Rich Media Mobile Ad Delivery), VAST (Video Ad Serving Technology), IAB (Interactive Advertising Bureau), and other proprietary Javascript APIs.
Rich media mobile advertising includes interactive interstitials, expandable and float-overs, HTML5, 3D, and full blown video, all from within a mobile app. Such campaigns have proven to produce significantly higher CTR due to an increased interactive nature.
In addition, many developers have not yet adopted the mobile advertising revenue model for their apps out of fear that integrated ads would negatively influence the user experience of the app. In general, inneractive puts UX at the top of its priorities and implements a very careful ad placement strategy.
With rich media, the UX of a mobile app is not only affected negatively, it is actually enhanced. Given inneractive'
Finally, rich media mobile advertising is CPM-based and can reach numbers as high as $20 eCPM and more. These are numbers that traditional display advertising was never able to achieve and the interactive nature of rich media ads is the drive behind these increased numbers.
inneractive is now looking to expand its rich media partnerships and is calling on all rich media providers to join some of the biggest names in mobile advertising that have already begun the integration process with inneractive.
Roy Timor-Rousso, VP marketing of inneractive says "inneractive is already partnering with some of the biggest names in mobile advertising with over 100 ad partners and is now building its different partnerships in the world of rich media mobile advertising."
About inneractive
inneractive is the industry's premier mobile ad mediation provider with over 100 ad networks and local agencies available at the click of a button.
With inneractive, mobile developers know they are getting the highest performance and widest global coverage, while not compromising on personal and high quality customer care. inneractive is on the side of the developer!
inneractive offers the most advanced real time optimization platform for mobile advertising campaigns that ensures developers are maximizing in app revenue and not leaving any money on the table. inneractive only makes money when the developer makes more!


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June/July at Coin Perdu.
June and July went by so quickly, I am still wondering where I was..I fell and broke my leg 2 weeks ago, so my moving about is somewhat restricted, especially here in the barn and on the rugged terrain of Coin Perdu. The crutches drive me nuts, but they are my best friends at the moment. At least my biceps are now something to look at. I'm not doing a lot of cooking, if any and it is only the most easiest of cooking – a handful of tomatoes from the potager on the plate with the salt and pepper pots beside it. A bowl of peaches. Half a chicken done by mon chéri on the barbecue. A tub of ice cream. A slab of Lindt fleur de sel chocolate.Lots of water to prevent the leg from swelling. More chocolate and ice cream. Macarons. Don't you think I am a good girl for eating so healthy?
WARNING: This is a fairly long post! I am also adding my Facebook page if you would like to follow and my instagram account as well as Lindiwe, our german shepherddog's account.
- Facebook page: Café des artistes
- Instagram: Ronellesatelier
- Lindiwe's instagram: shepherddog_lindiwe
In the meantime, the garden is running out from under my hands. Our summer has been very hot up to now and very dry and the garden is showing signs of fatigue without water and my loving care. It is big holiday time and France has come to its summer standstill. No one is available for helping in the garden. But it was nonetheless so beautiful before the drought took over and I thought I'd share it with you, since I can't really show you my plate of tomatoes with salt and pepper or half a chicken on my plate…even though it was as goo..ood!
June/July 2015 it started off lush and green in May, everything was flowering beautifully, newly planted lavenders santolinas…
..even when the pool was being built, it looked…OK
iceberg roses, feverfew,, salvia nemerosas to name but a few
On the terrace with Partia, purple oxalys, herbs..
..My beloved olde world flower, the hollyhocks, a lost sunflower that sprouted from the birds' winterseeds and even dried roses..
..new additions to the family are the two babygees, who mon chéri calls Hansie & Grietjie, some cute chicks and Lindiwe, our german sheperd dog, who has her own instagram account, should you be interested in following!
And of course hours spent around the table..our favorite pastime, you could say.
à bientôt
"Un oeuf cocotte" for Easter.
Easter is coming up pretty fast and everybody is munching on Easter chocolate. So are we. But one can't live on chocolate alone. An egg every now and then will help. An "oeuf cocotte". It is easy to make with many variations to suit each taste an ddesire.
- Preheat the oven to 200°C. (39°F, gas 6)
- Butter 4 ramekins(with volume of 125 ml or 1/2 cup) liberally with butter. Sprinkle with salt and pepper and place some shredded spinach on the bottom.
- Spoon 1 heaped TBS of créme fraîche onto the spinach and spread it evenly over the spinach.
- Break open 1 egg into a little bowl and and slide onto the créme fraîche in each ramekin without breaking the egg yolk.
- Drizzle a little cream over the egg yolk to protect it during cooking.
- Place in a deep ovenproof dish, fill with boiling water up to half the height of the ramekins and bake at 200°C for 9 minutes for a runny yolk. The egg white should just be coagulated and don't worry if there is still a little transparent egg white left…while standing the eggs will still continue cooking a bit.
- Remove from the oven and sprinkle with salt and pepper, some fried bacon pieces and chopped chives. Serve immediately with toasted bread fingers to dip into the eggs.
Pincée de fleur de sel:
- Use any nice containers for the eggs as long as they are ovenproof. Glass looks especially nice with the layers of egg and cream showing through the sides.
- Place bacon pieces or asparagus tips, frozen creamed spinach, mushrooms, strips of ham… and place at the bottom before filled with créme fraîche. the list is endless.
- Use small brioche buns instead of ramekins and steady them in muffin pans, fill with eggs and bake…especially popular with children.
- Infuse cream with saffron, or other spices/herbs of your choice, bring cream to a boil and simmer a few minutes to reduce and use instead of créme fraîche.
I am not one for a lot of Easter decoration. But I love having spring flowers in my house and the chickns provide me with a moutain of eggs, which I use simply in bowls to add an Easter flavor.
..Eggs from the poulaillier, rosemary and terracotta in which the eggs end up when stolen from the poullaillier…a winning combination for me..
..For a little playfulness – an empty egg carton filled with shredded wooden strips colour green, the egg shells used for the recipe filled with water and holding spring flowers and herbs, some eggs and tiny quail eggs..
..tulips in hotelsilver, my ink drawing book, a feather pen, feathers from the poullaillier and …some eggs!..
..last, but not least..Lindt Easter chocolates, Raffaello and Ferrerro Rocher..
Tomato and orange soup with scallops….and a visit from Jack Frost.
Tomato velouté is my most favorite soup. Since childhood I loved my mother's creamed tomato soup. In summer it is gazpacho and in winter a velvety soup.
The recipe is so easy…I can only say what I used and then it is up to your own taste. Taste and taste and taste again. Unlike for a summer gazpacho, I don't use fresh tomatoes for the soup. They are bland and tasteless. I use good quality Italian canned tomatoes which make a rich flavorful soup. It would be perfect if you have bottled your own tomatoes in summer.
La recette:
- A large can of tomatoes make about 2 to 3 large helping(2 of those helpings are mine…). Add to a saucepan with a bouquet garni, the juice and grated zest of 1 orange, 1 TBSP of sherry(Jerez) vinegar and 2 cubes of sugar. Rinse the can with 1 cup of vegetable stock and add to the soup.
- Simmer over medium heat for about 30 minutes.
- Leave to cool a little and mix with a hand blender to a creamy soup.
- Remove the bouquet garni and adjust the seasoning…orange juice, vinegar, salt and pepper.
- Fry some scallops only on one side and season with salt and pepper. Remove and keep aside. Deglaze the pan with some freshly squeezed orange juice .
- Serve the soup in warmed soup plates. Place a scallop, cut in half in the soup and drizzle the juice from the pan over the scallops.
- Decorate with a slice of orange and serve immediately.
A visit from Jack Frost.
Mr Jack Frost showed up this morning. Totally unexpected. He just showed up without any call beforehand, without any warning. I actually find that a bit rude, just showing up like that at someone's door and at a very indecent hour in the morning at that! But there he was in all his glory when I opened the door this morning. I couldn't control the shiver that ran instantly through my body. We expected him, but I so hoped he would skip his visit to us this year. Alas…
A very interesting character he is, this Jack Frost. Definitely not someone to take on without gloves. But speak of handsome! He has a disarming charm that cannot be missed, even if he's rather cold and sometimes somewhat foggy and distant. Definitely not a boring character. But as handsome and charming as he is, he has a slippery side that I just don't trust. I always feel unsure of my step around him. I have lost my balance around him before which resulted in me seeing my own butt and bright stars all at the same time. I've learnt my lesson since…don't be fooled by the charisma of Mr Jack Frost!
I sighed heavily on the sight of Jack Frost in front of me, just outside my barn door. Bof OK, he's here, what else could I do but accept his arrival…after all, we are known for our hospitality here at Coin Perdu! So I decided to make the best of it. I dug into my linen closet for extra warm linens and blankets and duvets, all the time thanking the good Lord that this guest only shows up once a year and immensely grateful that he doesn't stay the whole year. Now that would be unbearable!
I wondered how long Mr Frost would stay this time? I didn't dare ask for fear I wouldn't like the answer. In any case, the sun came out and he took the road. I had no idea where he had gone off to or when we would see him again. He is like that, this Mr Frost…always takes off somewhere when the sun shines and returns in the early hours the next morning. Oh well, he's here now for some time. I might as well accept it and make the most of it. I think I'll go make a tomato soup for tonight. Mr Jack Frost will be cold when he gets in. Tomato soup will make him happy
December ambiance 2014…and Apple, date and pear compote.
Apples and spices…only two words necessary to express winter. And the festive season. The markets groan under the weight of all the apples available and we are used to eating varieties picked recently here in our own region. We don't even consider buying imported apples and pears when we can pick and choose between many varieties home grown. Which is exactly what I did to make this festive apple, pear and date compote. You can't get it any easier than this..quick, simple, but so flavorful. It goes to show just once again that you don't need complicated ingredients to get flavour into your dishes. The golden phrase in cooking is always…keep it simple and use quality ingredients.
La recette: Apple, pear and date compote:
- Peel and cut 3 firm pears and 3 firm apples into cubes.
- Place in a saucepan and drizzle liberally with the juice of 1 lemon.Add to the fruit mixture: 6 dates halved and seed removed, 1 vanilla pod with its seed scraped into the mixture, the grated peel of 1 lemon, 1 star anise, 1 bark of cinnamon, 1/2 tsp of Szechuan pepper(crushed in mortar and pestle, a tiny pinch of salt, 1 TBSP of maple syrup and 1tsp of cane sugar.
- Simmer on gentle heat for about 30 minutes or until the fruit is tender, but NOT PUREED. The fruit must still have a slight bite. Strain the compote and remove the cinnamon and star anise. Keep aside.
- Replace the juice on the heat and reduce to syrup.
- Serve the compote in bowls and sprinkle with pomegranate seeds for a fresh crunch. Drizzle with the syrup and serve with a dollop of crème fraîche.
Serves 6 people (dessert)
Pincée de fleur de sel:
- Instead of serving the compote as a dessert, it can be served as an accompaniment to meat like porc or veal.
- As an accompaniment, omit the pomegranate seeds and chop a red onion into small dice. Add some of the meat juices to the onion and compote to make it more suitable for an accompaniment.
- the compote can be served at room temperature or warm.
- Serve with whipped cream or vanilla ice cream instead of créme fraîche.
- It can be prepared a day ahead and reheated at a gentle temperature.
This year has passed by so quickly, totally without my permission. I have the feeling I wasn't even present at times. I am definitely present today, the 1st of December 2014…a day I usually enjoy, because it is the day day we put up our Christmas tree, decorate it, drink vin chaud and listen to our first Christmas carols.
Every year, since Myfrenchkitchen's first December in 2007, I have posted on 1 December showing our Christmas tree for that year. It has just been a delight being able to share it with you these 7 years. Little has changed in these 7 years. From the beginning I had a recipe and then rambled on about some subject with words and images and bored you with my art. the only change is probably that I don't write from Montlouis any more, but from a barn on a farm in the south west of France.
Some years I wrote a lot and some years my presence was few and far between. there were times I even thought of quitting. But My little blog(s) has become such a part of me, I don't think I could let it go. I have many friends who gave it up for Facebook and Instagram, but finishing a post on my blog, still gives me such a big kick, every time.
I hope I can be more present in the near future, but if not, then that will be OK too. I am not going anywhere and I won't desert this baby of 7 years. This is my own little "corner", where I write for myself and for those readers and friends who have walked alongside me all this time. It is still fun.
And so, our Christmas this year is all in white and silver, my favorite colours for the festive season. the dry branch with moss from the garden, a pot filled with sand, candles and tea lights we burn every night for those gone, far away or just simply those we love. Birds are omnipresent on/in our trees. and there they are again this year, perched high on the branches I chose to hang a large brightly coloured painting behind the tree. I love the contrast of the simple tree in white and silver against the abundant colour of the painting. The painting depicts a scene in a church, which is quite fitting too. I wish you all a wonderful month of December. This is not the last you'll see of me for the month, so I greet you as usual:
à la prochaine fois!


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Lewis Burnell
The only game to have distracted Lewis away from MMOG's over the last 15 years was Pokemon Red. Despite that blip, Lewis has worked his way through countless games in the genre in search of something that comes close to his much loved (and long time dead) Neocron. Having written for several gaming networks before Ten Ton Hammer, Lewis likes to think he knows a thing or two about what makes an MMOG and its player-base tick.


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Commercial Property Management
The need for landlords and property investors to generate maximum returns from their assets is increasingly important.
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Key contacts
Nicholas Herward
Executive Director
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Savills Finsbury Circus
+44 (0 ) 207 877 4728


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Regulations (Standards - 29 CFR) - Table of Contents
| Part Number:
| Part Title:
|Approved State Plans for Enforcement of State Standards
| Subpart:
| Subpart Title:
| Standard Number:
| Title:
|Level of Federal enforcement.
| GPO Source:
With Hawaii's agreement and as a result of the Assistant Secretary's reinstatement of Hawaii's initial approval status, Hawaii and Federal OSHA will begin exercising concurrent jurisdiction under section 18(e) of the Act on September 21, 2012.
To provide a workable division of enforcement responsibilities, Hawaii and Federal OSHA have entered into an operational status agreement. Electronic copies of the agreement are available at: http://www.osha.gov/dcsp/osp/stateprogs/hawaii.html
[49 FR 19192, May 4, 1984; 65 FR 36627, June 9, 2000; 76 FR 63190, Oct. 12, 2011; 77 FR 58490, Sept. 21, 2012; 79 FR 8857, Feb. 14, 2014]
Next Standard (1952.315)
|Regulations (Standards - 29 CFR) - Table of Contents
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Crispy Baked Ravioli
Crispy Baked Ravioli
Cost per serving: 44¢
Skip the mozzarella sticks and opt for these baked appetizers instead! This party-perfect appetizer is a treat for guests of all ages.
Prep time: 15 min.
Cook time: 12 min.
Ingredients to Shop For:
• Eggs
• Frozen cheese ravioli
• Marinara sauce
Ingredients You May Already Have:
• Unseasoned bread crumbs
• Salt
See recipe: Crispy Baked Ravioli