Patent Publication Number: US-8119184-B2

Title: Method of making a variable surface area stent

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of application Ser. No. 10/819,776, filed Apr. 6, 2004, now U.S. Pat. No. 7,674,493, which is a divisional of application Ser. No. 09/834,012, filed Apr. 12, 2001, now U.S. Pat. No. 6,764,505, the entire disclosure and contents of both applications are incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to intravascular implants. In particular, the present invention relates to stent devices to deliver therapeutic agents such as radioisotopes or drugs. 
     BACKGROUND OF THE PRIOR ART 
     In the last several years, minimally invasive surgical procedures have become increasingly common. Minimally invasive procedures such as percutaneous transluminal coronary angioplasty (PTCA) are widely utilized. A PTCA procedure involves the insertion of an angioplasty balloon at the distal end of a catheter to the site of a stenotic lesion. Prior to treatment, the stenotic lesion is bulky and at least partially blocking the coronary artery at issue. Once advanced, the balloon is inflated compressing the stenosis and widening the lumen in order to allow an efficient flow of blood through the lumen. 
     Following PTCA and other stenotic treatment procedures, a significant number of patients may experience restenosis or other vascular blockage problems. These problems are prone to arise at the site of the former stenosis. 
     In order to help avoid restenosis and other similar problems, a stent may be implanted into the vessel at the site of the former stenosis with a stent delivery catheter. A stent is a tubular structure which is delivered to the site of the former stenosis or lesion and compressed against vessel walls thereat, again with a balloon. The structure of the stent promotes maintenance of an open vessel lumen. The stent can be implanted in conjunction with the angioplasty. 
     In addition to stent implantation, radiotherapy and drug delivery treatments have been developed and applied to the site of the former stenosis following angioplasty. Generally such treatments can aid in the healing process and significantly reduce the risk of restenosis and other similar problems. 
     In some cases, stent implantation may be combined with drug delivery or radiotherapy. For example, a stent may be drug loaded or radioactive. A stent with a therapeutic agent may be delivered to the physician about the stent delivery catheter (and with a removable shield if the stent is radioactive). 
     However, delivery of a therapeutic treatment throughout the site of the former stenosis is problematic. The level of uniformity in the delivery of a therapeutic agent to the injured area is dependent upon the particular stent configuration. For example, in the case a radioactive stent, the radioactive stent may have hot spots and cold spots of uneven levels of radioactivity. This is because the stent is made up of struts having radioactivity and window cells having no physical structure or radioactivity (or drug in the case of a drug delivery stent). Therefore, therapeutic agent throughout a particular stent configuration is dependent upon the strut and window cell distribution throughout that stent. Therefore, therapeutic variability results. 
     For example, in the case of a radioactive stent, if about 20 Grays (Gy) of radiation, as measured from 1 mm of tissue depth, are to be delivered to a vessel portion to be treated, a wide range of radiation delivery will actually occur. That is, due to the radioactive stent configuration, a non-uniform delivery, ranging from about 5 Gy to about 25 Gy is more likely delivered to the vessel portion to be treated. Due to limitations of the prior art a range of at least about 20 Gy will be delivered by a radioactive stent throughout the vessel portion to be treated in the given example. As a result, certain portions of the vessel will receive significantly more or significantly less radiation than intended. Such a variability in delivery could lead to underdose failing to reduce the risk of restenosis in certain portions of the vessel, or overdose potentially causing further vascular injury to other portions of the vessel. This variability results regardless of the therapeutic agent to be delivered. 
     Additionally, certain therapeutic agents are delivered to avoid a phenomenon known as “edge restenosis”. Edge restenosis is prone to occur near stent ends. 
     Even though a stent is structurally configured to maintain the patency of a vessel lumen, edge restenosis is prone to occur with the use of radioactive stents. Edge restenosis involves the formation of vascular overgrowths in vascular areas immediately adjacent radioactive stent ends, generally within about 2 mm of each radioactive stent end. Edge restenosis is a result of delivery of a sub-threshold level of radiation to the vascular areas immediately adjacent the radioactive stent ends. These vascular areas are near or within the site of the former stenosis. They include vasculature likely to be diseased, or subjected to a recent trauma such as angioplasty. When a sub-threshold level of radiation, between about 2 Grays and about 10 Grays, as measured at 1 mm of tissue depth, reaches such vulnerable vascular areas, stenotic overgrowths may actually be stimulated. These overgrowths result in narrowed vessel portions near stent ends giving an appearance of a candy wrapper crimped around the ends of the stent. Thus, this effect is often referred to as the “candy wrapper” effect. 
     The occurrence of the candy wrapper effect is likely when a radioactive stent is used. This is because the intensity of radiation decreases as the source of the radiation, the radioactive stent, terminates at its ends leading to a drop of in radiation levels at vessel portions adjacent its ends. Thus, a sub-threshold radiation delivery is likely to occur near the radioactive stent ends. 
     As indicated, heretofore, the level of therapeutic uniformity or focus any particular stent has been able to deliver has been dependent upon that stent&#39;s configuration with respect to strut and window cell distribution. However, a stent structure (i.e. strut layout) which physically promotes maintenance of an open vessel lumen may be of a particular configuration which is not necessarily best suited for a more uniform delivery of a therapeutic agent. Additionally, this stent configuration may fail to avoid an unintended “candy wrapper” effect in which portions of the vessel adjacent the stent become narrowed. 
     SUMMARY OF THE INVENTION 
     An embodiment of the present invention provides a stent having a variable stent surface area per unit length. The variable stent surface area is used to accommodate a therapeutic agent. 
     Another embodiment of the present invention provides for a stent having an end and a variable stent surface area per unit length to accommodate a therapeutic agent. A decreased level of therapeutic agent in provided at the end. 
     An embodiment of the present invention provides for a stent having an end and a variable stent surface area per unit length to accommodate a therapeutic agent. An increased level of therapeutic agent in provided at the end. 
     In an embodiment of the invention a method of vessel treatment utilizing a stent with a variable stent surface area is provided. A therapeutic agent is disposed on the stent surface area to provide a patterned distribution of the therapeutic agent. 
     In another embodiment of the invention a method of stent manufacture is provided where indentations are cut into a surface of a stent. A therapeutic agent is disposed on the surface of the stent. 
     In another embodiment of the invention a method of stent manufacture is provided where struts of the stent are cut of increased thickness to provide a variable stent surface area. Therapeutic agent is disposed on the variable stent surface area. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a side view of an embodiment of a stent of the present invention. 
         FIG. 2  is a pictorial view of an embodiment of a stent of the present invention implanted within a vessel of a patient. 
         FIG. 3  is an enlarged view of an embodiment of a strut of the stent of  FIG. 2 . 
         FIG. 4  is an enlarged view of an embodiment of a strut of the stent of  FIG. 2 . 
         FIG. 5  is a cross sectional view of an embodiment of a strut taken along the line  5 - 5  of  FIG. 4 . 
         FIG. 6  is a chart depicting an embodiment of a dose delivery profile of the present invention. 
         FIG. 7  is a representation of an embodiment of a source profile of the invention. 
         FIG. 8  is a chart depicting an embodiment of a dose delivery profile of the present invention. 
         FIG. 9  is a representation of an embodiment of a source profile of the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The following description makes reference to numerous specific details in order to provide a thorough understanding of the present invention. However, each and every specific detail need not be employed to practice the present invention. Additionally, well-known details, such as particular materials or methods, have not been described in order to avoid obscuring the present invention. 
     Referring to  FIG. 1  an embodiment of a stent  100  of the present invention is shown. The stent  100  is formed of struts  180 , which provide physical structure, and open spaces, referred to as window cells  190 . The struts  180  are formed from stainless steel or other materials which are generally biocompatible. For purposes of illustration, the struts  180  shown have a cylindrical shape longitudinally. However, in alternate embodiments non-cylindrical strut  180  shapes are used. As discussed further herein the struts  180  provide a variable surface area to the stent  100 . 
     Referring to  FIG. 2  an embodiment of a stent  200  of the present invention is shown within a vessel  2  near the site of a former stenosis  3  to maintain the patency of the vessel lumen  7 . The stent  200  of  FIG. 2  is equipped with struts  280  which have variability in surface area, in terms of a change in surface area per unit length, as described further below. For each strut  280  portion, a surface area (γ) is provided which is given by the equation: γ=2 πrlh r , where r is a radius (r) of the strut  280  portion, l is a length (l) of the strut  280  for the portion of the strut  280  being examined, and h r  is the roughness factor (h r ) of the strut  280  portion. 
     Referring to  FIGS. 3 and 4 , strut types  220 ,  230  of  FIG. 2  are shown enlarged. The radius (r) (or r 1  and r 2 ) and a given length (l) are shown (see also  FIG. 5  showing a radius (r 2 ) of a cross-section of a strut). The strut surface area (γ) includes a loading surface  340 . The loading surface  340  portion of the surface area (γ) is that portion of the surface area (γ), generally facing outward (i.e. toward vessel  2  as shown in  FIG. 1 ), that accommodates therapeutic agent. As the overall surface area (γ) increases or decreases, so does the loading surface  340 . Therefore, if strut surface area (γ) varies throughout a given length (l), as it does in the embodiment shown, then the dose amount for a given length (l) (i.e. the dose concentration (δ)) will vary throughout that same length (l). Given the equation: γ=2 πrlh r , it can be seen that if the variables r or h r  of the equation fluctuate in value, for the same given length (l), as is the case in the shown embodiment, then so too will the surface area (γ) of the strut type  220 ,  230  within the given length (l). 
     Referring to  FIGS. 2 and 3 , in order to vary surface area (γ) of the stent  200 , certain roughened strut  220  types are provided with a surface pattern. The roughened struts  220  are those in which the variable h r , referred to above, has changed in value throughout a given length (l). Or, in other words, γ′=2 πrlΔh r . For example, where an entirely smooth surface strut is provided (not shown), the roughness factor (h r ) is 1.0, having no effect on the surface area (γ) of the smooth surface strut. However, if the roughness factor (h r ) is greater than 1.0, the surface area (γ) will correspondingly increase as shown in the present embodiment. Therefore, the dose concentration (δ) of therapeutic agent deliverable to the vessel  2  is increased in corresponding portions of the strut  280  where (h r ) is greater than 1.0. 
     As shown in  FIG. 3 , an embodiment of a roughened strut  220  is provided of a given length (l). Moving from a first portion  360  of the given length (l) to a second portion  300 , the roughness factor (h r ) changes as indicated by the change in roughness over that same length (l). That is, increased roughness, as indicated by the granular appearing texture of the loading surface  340 , is provided near first portion  360 . Alternatively, the value of the roughness factor (h r ) decreases and approaches a value of 1.0 near second portion  300  as shown by the smoother appearance of the loading surface  340  near second portion  300 . Therefore, a roughened strut  220 , as in the embodiment shown, provides one manner of varying surface area (γ) throughout a given length (l), and thus provides a variation in dose concentration (δ) throughout that same length (l). 
     Referring to  FIGS. 2 and 3 , in order to increase the roughness factor (h r ) chemical, plasma, laser, mechanical or alternate methods of etching are used in embodiments of the invention. For example, in one embodiment the stent  200  is dry etched by sand blasting or plasma etched with argon in order to increase roughness. 
     Another embodiment focuses the increased roughness factor (h r ) at particular struts  280  by a lithography technique of coating the stent  200  with a protective polymer such as ethylene vinyl alcohol. The stent  200  is then selectively treated with a solvent, such as dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), or dimethyl acetamide (DMAc), in strut  280  areas to remove portions of the protective polymer. For example, in one embodiment, a stent end  250  is dipped into the solvent to remove protective polymer from portions of the struts  280  nearer the stent end  250 . By removing the protective polymer, these portions of the stent  200  are susceptible to increased roughening following application of an etching process to an exterior of the stent. Thus, once the stent  200  is etched, an increased roughness factor (h r ) is present at the stent end  250 . However, in an alternate embodiment increasing roughness interior of the stent 1 is avoided in order to promote a flow of blood through the stent. 
     The roughened strut  220  embodiment shown is viewed in light of its positioning in the stent  200 . It can be seen that the roughened strut  220  is found near stent end  250 . The roughened strut  220  includes a loading surface  340  which has been roughened as discussed above. The degree of roughening increases moving toward the first portion  360  (nearer the stent end  250 ) of the roughened strut  220 . Alternatively, the loading surface  340  becomes smoother moving toward a second portion  300  (nearer the stent body  251 ). That is, in view of the stent  200  as a whole, additional surface area (γ), and thus, increased radioactivity upon activation, is found near the stent end  250  due to the roughened strut  220  patterning provided. 
     Referring to  FIGS. 2 and 4 , in order to vary surface area (γ) of the stent  200 , certain struts  280  are formed as increased thickness struts  230 . The increased thickness struts  230  are those in which the radius (r), referred to above, has changed in value throughout a given length (l). Or, in other words, γ″=2 πΔrlh r . 
     As shown in  FIG. 4 , an embodiment of an increased thickness strut  230  is provided of a given length (l). Moving from a first strut portion  450  of the given length (l) to a second strut portion  400 , we see that the radius (Δr) changes as indicated by the change in radius size from r 1  to r 2  respectively, with r 2  indicating an increased radius (i.e. Δr) from that of r 1 . Therefore, an increased thickness strut  230  provides an alternate manner of varying surface area (γ) throughout a given length (l), and thus allowing for a variable dose concentration (δ) throughout that same length (l). This pattern of surface area (γ) along the given length (l) holds true even in non-linear strut portions  425 . 
     As shown with reference to positioning within the stent  200 , the increased thickness strut  230  is shown near opposite stent end  260  of  FIG. 1 . As a result, increased surface area (γ) and thus, increased radioactivity upon activation, is provided near opposite stent end  260 . 
     In a method of manufacturing the stent  200 , including struts  280 , the stent  200  is laser cut from, for example, a stainless steel tube. The laser cutting process is run according to an automated process to form a particular stent configuration. In order to increase or vary a radius (r) in portions of particular struts  280 , the automated process is programmed to cut a strut  280  of increasing radius (r), for example, near opposite stent end  260 . In this manner, an increased thickness strut  230  is provided. 
     Referring to  FIGS. 4 and 5 , a cross section taken from the line  5 - 5  of  FIG. 4  is shown as  FIG. 5 . In addition to a greater amount of loading surface  340  generally, the increased thickness strut  230  of  FIG. 4  includes increased size indentations  435 . As shown in the embodiment of  FIG. 5 , the increased size indentations  435  have been cut into the loading surface  340  with a laser during manufacture to provide additional loading surface  340  at the interior of the increased size indentations  435  by providing additional interior surface with the increased size indentations  435 . 
     Each indentation may increase surface area by about threefold per unit area. Where the depth L is increased, surface area provided by the indentation is increased. Increased size indentations may have a depth L of about one half of the increased thickness strut  230  at the location of the indentation. Increased size indentations  435 , have a depth L beyond about 60-80 microns, and are provided as thickness increases (as shown toward the opposite strut end  400  of  FIG. 4 ). The increased size indentations  435  provide a volume as well as increased surface area (γ). In the embodiment shown, the indentations  435  are of a truncated cone shape. However, in other embodiments, other shapes are used. For example, in one embodiment of the invention, the indentations  435  are of a dimpled shape 
     Referring to all of  FIGS. 2-5 , the surface area (γ) discussed in relation to the above embodiments is increased by the use of particular increased size indentations  435 , an increased thickness strut  230 , and a roughened strut  220 . However, all of these features, alone and in any combination, are used in other embodiments to increase surface area (γ) in particular stent  200  portions and provide particularly configured and focused loading surfaces  340  for accommodating therapeutic agents. Once a particular stent  200  configuration of increased surface area (γ) is chosen and provided, it is activated with therapeutic agent, accommodated at the loading surface  340 . 
     In an embodiment of the invention, where the therapeutic agent to be provided includes radioactive isotopes, plasma ion implantation of the isotopes into the loading surface  340  is used for activation. Embodiments of the invention employ Plasma and Ion Beam Assisted Deposition for loading. Plasma ion implantation results in radioactive ions being implanted below the loading surface  340  of the stent  200 . By implanting ions below the loading surface  340 , a radioactive layer is formed which is shielded from a biological environment when the stent  200  is later inserted into a patient. Plasma ion implantation involves loading the stent  200  into an isolation chamber where a plasma of radioactive ions is generated. The plasma is provided by providing a liquid or gas which includes a stable precursor to the ion type to be used. Radio Frequency (RF) or microwave power are coupled to the isolation chamber to transform the mixture into a plasma state within the chamber. Negative voltage energy pulses are then applied to the treatment stent  1  to cause implantation of ions below the loading surface  40 . In various embodiments, ions such as Phosphorous (P 32 ), Rhenium (Re 188 ), Yttrium (Y 90 ), Palladium (Pd 103 ), Iodine (I 125 ), and Ruthenium (Ru 106 ) are loaded above and below the loading surface  340  in this manner. 
     In other embodiments, where the therapeutic agent to be provided includes bioactive drugs, alternate methods of loading onto the loading surface  340  are used. For example, a dip coating, spray, or centrifugation process is used. The dip coating process involves submerging the stent  200  in a solvent having an anti-coagulant or other drug solution. Heparin or heparin coating substances such as Duraflo®, available from Baxter International, Inc., are used as part of the drug solution. 
     The stent  200  is then placed into a centrifugation chamber and spun to direct the first solution to particular portions of the stent  200 . The stent  200  is then dried and submerged in a second drug solution. This second drug solution also contains radioactive ions as additional therapeutic agent. 
     Mechanical rinsing of the stent  200  is used to remove any excess of the drug solution. Centrifugation of the stent  200  is then repeated to remove excess drug solution. 
     In one embodiment, where a volume is provided by increased size indentations  435 , drug solution is deposited therein as a result of such methods of loading described above. In other embodiments, such methods of loading are repeated to add bioactive elutable drugs or even a separate anti-coagulant barrier to encase drug solution on the loading surface  340 . The barrier is added by dipping, centrifugation and plasma deposition as indicated, or alternately by spraying or plasma polymerization. 
     The variability in surface area provided by any combination of the above referenced features accommodating a therapeutic agent allows delivery of therapeutic agent in a manner not limited solely to strut  280  and window cell  290  distribution. As a result, stent  200  embodiments are provided which increase therapeutic agent focus in particular areas of the stent  200 . 
     In an embodiment of the invention, increased surface area is provided in areas of the stent  200  known to deliver an under-dose of therapeutic agent. Alternatively in another embodiment, less surface area is present in areas known to deliver an overdose of therapeutic agent. These surface area configurations are used to help avoid irregularities or significant variation in delivery of therapeutic agent. 
     Additionally, in an embodiment of the invention, increased surface area struts  280  are developed to focus an increased amount of therapeutic agent near stent ends  250 ,  260 . This embodiment helps avoid delivery of sub-threshold levels of radiation to portions of a vessel immediately adjacent stent ends  250 ,  260  (i.e. to avoid delivery of between about 2 and about 10 Grays, as measured at 1 mm of tissue depth to the vessel  2  in this area). Likewise, another similar embodiment helps provide other therapeutic agents to help combat edge restenosis in this manner. Alternatively, variability in surface area can be used to minimize delivery of a radioactive therapeutic agent near stent ends  250 ,  260  in order to avoid sub-threshold radiation delivery and edge restenosis. 
       FIGS. 6-9  show the results of making use of particular variable surface area stent embodiments having unique focuses of therapeutic agent distribution. The results are shown with respect to dose delivery and source profiles. 
     For example,  FIG. 6  depicts a chart indicating the distribution of therapeutic agent, in the form of radioisotopes, with respect to dose delivery for an embodiment of the invention. The x-axis, labeled “Vessel Length”, includes the stent length  601  along with the treatment portion  620  of a vessel. The y-axis, labeled “Dose Delivery (Gy)”, indicates the amount of radiation absorbed in Grays (Gy) throughout a vessel  2  such as that of  FIG. 1  (as measured from 1 mm of vessel depth). 
     Similarly,  FIG. 7  represents a source profile of a stent  700  according to the therapeutic distribution indicated in the embodiment of  FIG. 6 . The profile includes an extension of radioactivity  730  significantly beyond stent ends  750 ,  760  (i.e. hot ends) to help avoid edge restenosis. Also, a uniform field of radioactivity  755  throughout the stent body  751  is provided. 
     With reference to the embodiments represented in  FIGS. 6 and 7 , an increased amount of therapeutic agent is provided near stent ends  750 ,  760  due to the increased loading surface provided thereat. Therefore, where the therapeutic agent is radiation, as with the embodiments of  FIGS. 6 and 7 , delivery of a sub-threshold level of radiation is avoided at vessel portions immediately adjacent the stent  700  (i.e. within about 2 mm of the stent longitudinally). 
     Additionally, the stent  700  is configured with increased loading surface directed toward portions of the stent  700  previously responsible for a more uneven distribution of therapeutic agent. In the case of radiation delivery, a more uniform field of radioactivity  755  provides a more consistent delivery of therapeutic agent (i.e. radiation) throughout the stent body  751  of the stent  700 . 
     A prior art distribution of radiation  51  is un-even. That is, the uniform surface area of a prior art stent may deliver a highly variable dose within a stent length  601 . For example, the variable dose can include a maximum dose  91  that is 20 Gy greater than a minimum dose  92  while delivering only an average dose of 20 Gy (with all measurements taken at 1 mm of tissue depth). Alternatively, a more level delivery of radioactivity  650  is provided in embodiments of the invention. Embodiments of the invention can also include peak deliveries of radioactivity  630  to ensure avoidance of sub-threshold delivery  21  in vessel areas of concern, within about 2 mm of the stent longitudinally. 
     Referring to  FIGS. 8 and 9 , and continuing with the example of a radioactive therapeutic agent, a decreased amount of radioactivity (i.e. an early termination of radioactivity  930 ) is provided near stent ends in another embodiment of the invention. This is due to the decreased loading surface provided at the stent ends  950 ,  960  as compared to the remainder of the stent  900 . Delivery of a sub-threshold level of radiation is nevertheless minimized or avoided at portions of a vessel immediately adjacent the stent  900  (i.e. within about 2 mm of the stent ends  950 ,  960 ). That is, any radiation delivered here is below a sub-threshold level to help avoid edge restenosis. 
     Additionally, as with  FIG. 6 , the stent  900  represented by  FIG. 9  has been configured to have increased surface area directed toward portions of a stent  900  that would otherwise be responsible for an uneven distribution of therapeutic agent. A more uniform field of radioactivity  955  provides a more consistent delivery of therapeutic agent (i.e. radiation) throughout a stent body of the stent  900  as seen above the x-axis throughout stent length  860 . 
     Again, by way of comparison, a prior art distribution of radiation  51  is un-even and a sub-threshold level of radiation  21  is delivered by a prior art stent to vessel areas within 2 mm of the stent. Alternatively, a more level delivery of radioactivity  850  is provided in embodiments of the invention. Embodiments of the invention can also include tapered deliveries of radioactivity  830  to ensure avoidance of sub-threshold delivery  21  in vessel areas of concern. 
     Embodiments of the invention described above include a therapeutic stent which is able to provide an overall pattern of therapeutic agent, where the pattern is not determined solely by strut and window cell distribution throughout the stent. Embodiments of the invention also include patterns of therapeutic agent which help avoid edge restenosis while also helping to avoid delivery of a non-uniform level of therapeutic agent throughout the portion of a vessel to be treated. While such exemplary embodiments have been shown and described in the form of particular stents having variable surface area, many changes, modifications, and substitutions may be made without departing from the spirit and scope of this invention.