Patent Publication Number: US-2012046599-A1

Title: Therapeutic agent delivery system, device and method for localized application of therapeutic substances to a biological conduit

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The invention relates to systems, devices and methods for treating biological conduits, e.g., animal lumens, with localized delivery of therapeutic agents. 
     2. Description of the Related Art 
     A variety of techniques and instruments have been developed for use in the removal or repair of tissue in biological conduits, e.g., without limitation, blood vessels and similar body passageways. A frequent objective of such techniques and instruments is the removal of atherosclerotic plaques in a patient&#39;s arteries. Atherosclerosis is characterized by the buildup of fatty deposits (atheromas) in the intimal layer (under the endothelium) of a patient&#39;s blood vessels. Very often over time, what initially is deposited as relatively soft, cholesterol-rich atheromatous material hardens into a calcified atherosclerotic plaque. Such atheromas restrict the flow of blood, and therefore often are referred to as stenotic lesions or stenoses, the blocking material being referred to as stenotic material. If left untreated, such stenoses can cause angina, hypertension, myocardial infarction, strokes, leg pain and the like. 
     Rotational atherectomy procedures have become a common technique for removing such stenotic material. Such procedures are used most frequently to initiate the opening of calcified lesions in coronary arteries. Most often the rotational atherectomy procedure is not used alone, but is followed by a balloon angioplasty procedure, which, in turn, is very frequently followed by placement of a stent to assist in maintaining patency of the opened artery. For non-calcified lesions, balloon angioplasty most often is used alone to open the artery, and stents often are placed to maintain patency of the opened artery. Studies have shown, however, that a significant percentage of patients who have undergone balloon angioplasty and had a stent placed in an artery experience stent restenosis—i.e., blockage of the stent which most frequently develops over a period of time as a result of excessive growth of scar tissue within the stent. In such situations an atherectomy procedure is the preferred procedure to remove the excessive scar tissue from the stent (balloon angioplasty being not very effective within the stent), thereby restoring the patency of the artery. 
     Several kinds of rotational atherectomy devices have been developed for attempting to remove stenotic material. In one type of device, such as that shown in U.S. Pat. No. 4,990,134 (Auth), a burr covered with an abrasive abrading material such as diamond particles is carried at the distal end of a flexible drive shaft. The burr is rotated at high speeds (typically, e.g., in the range of about 150,000-190,000 rpm) while it is advanced across the stenosis. As the burr is removing stenotic tissue, however, it blocks blood flow. Once the burr has been advanced across the stenosis, the artery will have been opened to a diameter equal to or only slightly larger than the maximum outer diameter of the burr. Frequently more than one size burr must be utilized to open an artery to the desired diameter. 
     U.S. Pat. No. 5,314,438 (Shturman) discloses another atherectomy device having a drive shaft with a section of the drive shaft having an enlarged diameter, at least a segment of this enlarged surface being covered with an abrasive material to define an abrasive segment of the drive shaft. When rotated at high speeds, the abrasive segment is capable of removing stenotic tissue from an artery. Though this atherectomy device possesses certain advantages over the Auth device due to its flexibility, it also is capable only of opening an artery to a diameter about equal to the diameter of the enlarged abrading surface of the drive shaft since the device is not eccentric in nature. 
     U.S. Pat. No. 6,494,890 (Shturman) discloses an atherectomy device having a drive shaft with an enlarged eccentric section, wherein at least a segment of this enlarged section is covered with an abrasive material. When rotated at high speeds, the abrasive segment is capable of removing stenotic tissue from an artery. The device is capable of opening an artery to a diameter that is larger than the resting diameter of the enlarged eccentric section due, in part, to the orbital rotational motion during high speed operation. Since the enlarged eccentric section comprises drive shaft wires that are not bound together, the enlarged eccentric section of the drive shaft may flex during placement within the stenosis or during high speed operation. This flexion allows for a larger diameter opening during high speed operation, but may also provide less control than desired over the diameter of the artery actually abraded. In addition, some stenotic tissue may block the passageway so completely that the Shturman device cannot be placed therethrough. Since Shturman requires that the enlarged eccentric section of the drive shaft be placed within the stenotic tissue to achieve abrasion, it will be less effective in cases where the enlarged eccentric section is prevented from moving into the stenosis. The disclosure of U.S. Pat. No. 6,494,890 is hereby incorporated by reference in its entirety. 
     U.S. Pat No. 5,681,336 (Clement) provides an eccentric tissue removing burr with a coating of abrasive particles secured to a portion of its outer surface by a suitable binding material. This construction is limited, however because, as Clement explains at Col. 3, lines 53-55, that the asymmetrical burr is rotated at “lower speeds than are used with high speed ablation devices, to compensate for heat or imbalance.” That is, given both the size and mass of the solid burr, it is infeasible to rotate the burr at the high speeds used during atherectomy procedures, i.e., 20,000-200,000 rpm. Essentially, the center of mass offset from the rotational axis of the drive shaft would result in development of significant centrifugal force, exerting too much pressure on the wall of the artery and creating too much heat and excessively large particles. 
     Another method of treatment of occluded vessels may include the use of stents. Stents may be placed at the site of a stenosis and expanded to widen the vessel, remaining in position as a vessel implant. 
     No matter the technique used to open an occluded conduit, e.g., blood vessel, and restore normal fluid flow therethrough, one problem remains: restenosis. A certain percentage of the treated conduits and vessels will reocclude (restenose) after a period of time; occurring in as many as 30-40% of the cases. When restenosis does occur, the original procedure may be repeated or an alternative method may be used to reestablish fluid, e.g., blood, flow. 
     The relevant commonality shared by each of the above treatment methods is that each one results in some trauma to the conduit wall. Restenosis occurs for a variety of reasons; each involving trauma. Small clots may form on the arterial wall. Small tears in the wall expose the blood to foreign material and proteins which are highly thrombogenic. Resulting clots may grow gradually and may even contain growth hormones released by platelets within the clot. Moreover, growth hormones released by other cells, e.g., macrophages, may cause smooth muscle cells and fibroblasts in the affected region to multiply in an abnormal fashion. There may be an injury in the conduit wall due to the above methods that results in inflammation which may result in the growth of new tissue. 
     It is known that certain therapeutic substances may have a positive effect on prevention and/or inhibition of restenosis. Several difficulties present themselves in the application of these substances to the affected region in a therapeutic dose. For example, the region in need of treatment is very small and localized. Fluid, e.g., blood, flow in the conduit is continuous, resulting in a flow boundary along the wall which must be disrupted so that the therapeutic substances may reach the localized region of interest within a dose range considered therapeutic. The art fails to adequately provide a mechanism for breaking through this flow boundary to target the region of interest; electing instead generally to place the therapeutic substance into the general flow of the conduit, either by intravenous means or intra-lumen infusion, at a dose that is much higher than therapeutic since the majority of the therapeutic substance will simply flow downstream and either be absorbed systemically or eliminated as waste. For example, intravenous medications are delivered systemically by vein, or regionally, e.g., through intra-lumen infusion without targeting the subject region. Such unnecessary systemic exposure results with unknown and unnecessary adverse results in regions, tissue, and/or organs that are distant from the region of interest. Clearly, systemic delivery and exposure is not well suited to treatment of diseases or conditions having a single intra-lumen region of interest. 
     The potential utility of localized application of a therapeutic dose of therapeutic substances is not limited to treatment of coronary arteries. Beyond coronary artery delivery, other sites of atherosclerosis, e.g., renal, iliac, femoral, distal leg and carotid arteries, as well as saphenous vein grafts, synthetic grafts and arterio-venous shunts used for hemodialysis would be appropriate biological conduits for a localized therapeutic substance delivery method and mechanism. Nor is the potential utility limited to blood vessels; any biological conduit having a region of interest amenable to treatment may benefit from such a treatment method and mechanism. 
     The present invention overcomes these deficiencies. 
     BRIEF SUMMARY OF THE INVENTION 
     The invention provides a system, device and method for localized application of therapeutic substances within a biological conduit after the lumen wall has been scored by an eccentric scoring head. One embodiment comprises radial scoring with the eccentric scoring head, with a therapeutic agent coated balloon inflated distal to the scoring and dragged proximally through the scoring. Another embodiment comprises inflation of two anchor balloons on either side of scoring with subsequent inflation of a therapeutic agent coated balloon therebetween which causes the distance between anchor balloons to increase, thus stretching the scoring crevices while applying the agent therein with subsequent closure of crevices on deflation of anchor and application balloons. Another embodiment comprises an inflated anchor balloon with a threaded scoring device wherein the scoring members are coated with agent and rotation of the threaded device enables travel in the proximal direction away from anchor balloon. 
     In this manner, application of at least one therapeutic dose of the therapeutic substance(s) at the affected region is achieved, while minimizing unwanted systemic exposure and the accompanying undesirable side effects. As a consequence, the need to administer super-therapeutic doses is eliminated. 
     The figures and the detailed description which follow more particularly exemplify these and other embodiments of the invention. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The invention may be more completely understood in consideration of the following detailed description of various embodiments of the invention in connection with the accompanying drawings, which are as follows. 
         FIG. 1  is a perspective view of one embodiment of a therapeutic agent delivery system comprising an eccentric abrading head of a rotational atherectomy device of the invention; 
         FIG. 2  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 3  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 4  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 5  is a cutaway cross-sectional view of the indicated portion from  FIGS. 3 and 4 ; 
         FIG. 6  is a perspective view of one embodiment of a therapeutic agent delivery system comprising an eccentric abrading head of a rotational atherectomy device of the invention; 
         FIG. 7  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 8  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 9  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 10  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 11  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 12  is a partial cutaway cross-sectional view of one embodiment of the invention; 
         FIG. 13  is a perspective view of one embodiment of a therapeutic agent delivery system comprising an eccentric abrading head of a rotational atherectomy device of the invention; and 
         FIG. 14  is a partial cutaway cross-sectional view of one embodiment of the invention. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION, INCLUDING THE BEST MODE 
     While the invention is amenable to various modifications and alternative forms, specifics thereof are shown by way of example in the drawings and described in detail herein. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention. 
     For the purposes of the present invention, the following terms and definitions apply: 
     “Bodily disorder” refers to any condition that adversely affects the function of the body. 
     The term “treatment” includes prevention, reduction, delay, stabilization, and/or elimination of a bodily disorder, e.g., a vascular disorder. In certain embodiments, treatment comprises repairing damage cause by the bodily, e.g., vascular, disorder and/or intervention of same, including but not limited to mechanical intervention. 
     A “therapeutic agent” comprises any substance capable of exerting an effect including, but not limited to therapeutic, prophylactic or diagnostic. Thus, therapeutic agents may comprise anti-inflammatories, anti-infectives, analgesics, anti-proliferatives, and the like including but not limited to antirestenosis drugs. Therapeutic agent further comprises mammalian stem cells. Therapeutic agent as used herein further includes other drugs, genetic materials and biological materials. The genetic materials mean DNA or RNA, including, without limitation, of DNA/RNA encoding a useful protein, intended to be inserted into a human body including viral vectors and non-viral vectors. Viral vectors include adenoviruses, gutted adenoviruses, adeno-associated virus, retroviruses, alpha virus, lentiviruses, herpes simplex virus, ex vivo modified cells (e.g., stem cells, fibroblasts, myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytes, macrophage), replication competent viruses, and hybrid vectors. Non-viral vectors include artificial chromosomes and mini-chromosomes, plasmid DNA vectors, cationic polymers, graft copolymers, neutral polymers PVP, SP1017, lipids or lipoplexes, nanoparticles and microparticles with and without targeting sequences such as the protein transduction domain (PTD). 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 .alpha. and .beta., platelet derived endothelial growth factor, platelet derived growth factor, tumor necrosis factor .alpha., hepatocyte growth factor and insulin like growth factor), transcription factors, proteinkinases, CD inhibitors, thymidine kinase, and bone morphogenic proteins. These dimeric proteins can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. 
     Therapeutic agents further includes cells that 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. Cells within the definition of therapeutic agents herein further 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. 
     Therapeutic agent also includes non-genetic substances, such as: anti-thrombogenic agents such as heparin, heparin derivatives, and urokinase; anti-proliferative agents such as enoxaprin, angiopeptin, or monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid, amlodipine and doxazosin; anti-inflammatory agents such as glucocorticoids, betamethasone, dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, and mesalamine; antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, methotrexate, azathioprine, adriamycin and mutamycin; endostatin, angiostatin and thymidine kinase inhibitors, taxol and its analogs or derivatives; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; anti-coagulants such as heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin anticodies, anti-platelet receptor antibodies, aspirin, dipyridamole, protamine, hirudin, prostaglandin inhibitors, platelet inhibitors and tick antiplatelet peptides; vascular cell growth promotors such as growth factors, Vascular Endothelial Growth Factors, growth factor receptors, transcriptional activators, and translational promotors; 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; cholesterol-lowering agents; vasodilating agents; and agents which interfere with endogenous vasoactive mechanisms; anti-oxidants, such as probucol; antibiotic agents, such as penicillin, cefoxitin, oxacillin, tobranycin angiogenic substances, such as acidic and basic fibrobrast growth factors, estrogen including estradiol (E2), estriol (E3) and 17-Beta Estradiol; and drugs for heart failure, such as digoxin, beta-blockers, angiotensin-converting enzyme, inhibitors including captopril and enalopril. The biologically active material can be used with (a) biologically non-active material(s) including a solvent, a carrier or an excipient, such as sucrose acetate isobutyrate, ethanol, n-methyl pymolidone, dimethyl sulfoxide, benzyl benxoate and benzyl acetate. 
     Further, “therapeutic agent” includes, in particular in a preferred therapeutic method of the present invention comprising the administration of at least one therapeutic agent to a procedurally traumatized, e.g., by an angioplasty or atherectomy procedure, mammalian vessel to inhibit restenosis. Preferably, the therapeutic agent is a cytoskeletal inhibitor or a smooth muscle inhibitor, including, for example, taxol and functional analogs, equivalents or derivatives thereof such as taxotere, paclitaxel, abraxane TM, coroxane TM or a cytochalasin, such as cytochalasin B, cytochalasin C, cytochalasin A, cytochalasin D, or analogs or derivatives thereof. 
     Additional specific examples of “therapeutic agents” that may be applied to a bodily lumen using various embodiments of the present invention comprise, without limitation:
     L-Arginine;   Adipose Cells;   Genetically altered cells, e.g., seeding of autologous endothelial cells transfected with the beta-galactosidase gene upon an injured arterial surface;   Erythromycin;   Penicillin:   Heparin;   Aspirin;   Hydrocortisone;   Dexamethasone;   Forskolin;   GP IIb-IIIa inhibitors;   Cyclohexane;   Rho Kinsase Inhibitors;   Rapamycin;   Histamine;   Nitroglycerin;   Vitamin E;   Vitamin C;   Stem Cells;   Growth Hormones;   Hirudin;   Hirulog;   Argatroban;   Vapirprost;   Prostacyclin;   Dextran;   Erythropoietin;   Endothelial Growth Factor;   Epidermal Growth Factor;   Core Binding Factor A;   Vascular Endothelial Growth Factor;   Fibroblast Growth Factors;   Thrombin;   Thrombin inhibitor; and   Glucosamine, among many other therapeutic substances.   

     The therapeutic agent delivery system of the present invention can be used to apply the therapeutic agent to any surface of a body lumen where a catheter can be inserted. Such body lumen includes, inter alia, blood vessels, urinary tract, coronary vasculature, esophagus, trachea, colon, and biliary tract. 
       FIG. 1  illustrates one embodiment  100  of a scoring and seeding high-speed rotational atherectomy system of the present invention, elements of which are utilized in various embodiments of the present invention. The device includes a handle portion  10 , an elongated, flexible drive shaft  20  having an eccentric scoring head  28  and inflatable balloon  30 , inflatable balloon coated  30  with at least one therapeutic agent  37  and disposed proximal to eccentric scoring head  28 , and an elongated catheter  13  extending distally from the handle portion  10 . The drive shaft  20  is constructed from helically coiled wire as is known in the art and the eccentric scoring head  28  and coated inflatable balloon  30  are fixedly attached thereto. The catheter  13  has a lumen L within which the drive shaft  20 , eccentric scoring head  28  and deflated coated inflatable balloon  30  are slidably disposed and further comprises a distal end. 
     The handle  10  desirably contains a turbine (or similar rotational drive mechanism) for rotating the drive shaft  20  at high speeds. The handle  10  typically may be connected to a power source, such as compressed air delivered through a tube  16 . A pair of fiber optic cables  25 , alternatively a single fiber optic cable may be used, may also be provided for monitoring the speed of rotation of the turbine and drive shaft  20 . Details regarding such handles and associated instrumentation are well known in the industry. The handle  10  also desirably includes a control knob  11  for advancing and retracting the turbine and drive shaft  20  with respect to the catheter  13  and the body of the handle. 
     Turning now to  FIGS. 2 and 3 , the scoring head  28  may comprise at least one scoring element  32  on the external surface(s) of the eccentric scoring head  28  to facilitate scoring of the vessel wall V during high-speed rotation, i.e., 20,000 to 200,000 rpm. Each scoring element  32  comprises a length L, the magnitude of which is a key element to determining the depth of scoring that occurs in operation. 
     Additional variations of the eccentric scoring head  28  are possible, including an arrangement whereby the wire turns of the drive shaft are enlarged on one side of the drive shaft but not the opposing side, creating an offset of the center of mass C from the axis of rotation A. This arrangement is disclosed within U.S. Pat. No. 6,494,890 to Shturman, the entire contents of which is hereby incorporated herein by reference. The significant part of the eccentric scoring head  28  of the present invention and its various embodiments is that eccentricity is created, i.e., that the center of mass C of the eccentric scoring head  28  is offset from the axis of rotation A of the drive shaft  20 . Such eccentricity drives an orbital pattern of rotation for the eccentric scoring head  28  as will be discussed further and which is a significant element of the various embodiments of the present invention. 
     Accordingly, it should be understood that, as used herein, the word “eccentric” is defined and used herein to refer to either a difference in location between the geometric center of the enlarged abrading head  28  and the rotational axis A of the drive shaft  20 , or to a difference in location between the center of mass C of the enlarged abrading head  28  and the rotational axis A of the drive shaft  20 . Either such difference, at the proper rotational speeds, will enable the eccentric enlarged abrading head  28  to score walls of vessels having a diameter substantially greater than the nominal, resting diameter of the eccentric scoring head  28 . Moreover, for an eccentric scoring head  28  having a shape that is not a regular geometric shape, the concept of “geometric center” can be approximated by locating the mid-point of the longest chord which is drawn through the rotational axis A of the drive shaft  20  and connects two points on a perimeter of a transverse cross-section taken at a position where the perimeter of the eccentric scoring head  28  has its maximum length. 
     The eccentric scoring head  28  and the scoring elements  32  of the therapeutic agent delivery device of the invention may be constructed of stainless steel, tungsten, titanium or similar material. The eccentric scoring head  28  may be a single piece unitary construction or, alternatively, may be an assembly of two or more abrading head components fitted and fixed together to achieve the objects of the present invention. 
     As described and illustrated in incorporated reference U.S. Pat. No. 6,494,890, the eccentric scoring head of the present invention comprises a generally spiral orbital path during high-speed rotation and, will create radial scoring throughout the entire circumference of the inner vessel lumen. 
     Although not wishing to be constrained to any particular theory of operation, applicants believe that offsetting the center of mass from the axis of rotation A produces an “orbital” movement of the eccentric scoring head  28 , the diameter of the “orbit” being controllable by varying, inter alia, the rotational speed of the drive shaft  20 . Applicants have empirically demonstrated that by varying the rotational speed of the drive shaft  20  one can control the centrifugal force urging the eccentric scoring head  28  against the surface of the stenosis. The centrifugal force can be determined according to the formula: 
         F   c   =mΔx (π n/ 30) 2  
 
     where F c  is the centrifugal force, m is the mass of the eccentric scoring head  28 , Δx is the distance between the center of mass of the eccentric scoring head  28  and the rotational axis A of the drive shaft  20 , and n is the rotational speed in revolutions per minute (rpm). Controlling this force F c , together with the length L of the individual scoring elements  32  provides control over the depth of scoring in the vessel wall. 
     Returning to  FIGS. 2 and 3 , the drive shaft  20  in  FIG. 2  is illustrated as extended distally out of catheter  13  lumen to the point that the eccentric scoring head  28  is exposed to the vessel lumen and high-speed rotation of the drive shaft  20  and eccentric scoring head  28  has occurred. Thus, scoring  34  is created in a radial pattern around the circumference of the inner wall of the vessel lumen. The depth of scoring is, as discussed above, controlled by (1) the length L of the scoring elements  32 ; and (2) by controlling the centrifugal force of the eccentric scoring head  28  during high-speed rotation. At this point in the procedure, inflatable balloon  30  is still retained in a deflated state within the catheter  13  lumen. 
       FIG. 3  illustrates the drive shaft  20  further extended distally out of the lumen of catheter  13 , wherein the eccentric scoring head  28  is disposed distal to the scoring  34  and the inflated coated balloon  30  is shown proximal the scoring  34 . No rotation of the drive shaft is occurring while the balloon  30  is inflated. The drive shaft  20  is then advanced distally to scrape the coating comprising at least one therapeutic agent  37  from the balloon and into the radial scoring  34 . Translation of the coated balloon, proximally and/or distally across the radial scoring  34  will pull the scoring  34  open, exposing each newly created crevice  36  in the vessel wall during the scoring procedure, smearing the at least one therapeutic agent  37  into the exposed crevice  36  which then closes as the balloon passes the crevice  36  and scoring  34 . This arrangement is illustrated in close up in  FIG. 5 , with scoring  34  shown and crevices  36  filled at least partially with at least one therapeutic agent  37 , wherein the crevices  36  are closed as the inflated balloon has passed the scoring  34 . 
     An alternate embodiment is provided in  FIG. 4 , wherein the inflatable balloon  30 , coated with at least one therapeutic agent  37  is slidably disposed in a deflated state within the lumen of drive shaft  20 . A wire  38  operatively connects the proximal end of balloon  30  with the handle  10  where an operator may translate the balloon  30  proximally or distally as well as inflate balloon  30  when translated out of the lumen of drive shaft  20 . As illustrated, radial scoring  34  is achieved with the high-speed scoring element  28  as described in connection with  FIGS. 2 and 3 . The deflated but inflatable coated balloon  30  now may be translated distally out of the lumen of the drive shaft  20 , where it is inflated at a point distal to the scoring  34 . The operator then pulls the wire  38  to translate the inflated coated balloon  30  proximally across the scoring  34 , thereby opening the scoring and allowing the therapeutic agent(s)  37  to smear or deposit within the crevices  36  of the scoring  34 . 
       FIG. 6  illustrates a therapeutic delivery system  200  comprising a handle portion  10 , an elongated, flexible catheter  13  comprising a lumen therethrough, wherein non-rotatable inflating sheath  40  is slidingly translatably disposed. Sheath  40  comprises a lumen therethrough, within which is slidably and rotatably disposed flexible drive shaft  20 , drive shaft  20  having eccentric scoring head  28  attached thereto.  13  Inflating balloon assembly  42  is deflated and slidably disposed within lumen of catheter  13  in  FIG. 7 . The drive shaft  20  is constructed from helically coiled wire as is known in the art and the eccentric scoring head  28  is fixedly attached thereto. 
     The handle  10  desirably contains a turbine (or similar rotational drive mechanism) for rotating the drive shaft  20  at high speeds. The handle  10  typically may be connected to a power source, such as compressed air delivered through a tube  16 . A pair of fiber optic cables  25 , alternatively a single fiber optic cable may be used, may also be provided for monitoring the speed of rotation of the turbine and drive shaft  20 . Details regarding such handles and associated instrumentation are well known in the industry. The handle  10  also desirably includes a control knob  11  for advancing and retracting the turbine and drive shaft  20  and may also control axial translation of sheath  40  with respect to the catheter  13  and the body of the handle. 
       FIGS. 7-10  illustrate the therapeutic delivery system  200  inserted into vessel V, wherein a non-rotatable inflating sheath  40 , translatably disposed within the lumen of catheter  13 , is distally translated beyond the distal end of the catheter  13 . Sheath  40  comprises a lumen, within which the drive shaft  20  is rotatably and slidably disposed. Drive shaft  20  is illustrated as distally translated out of catheter  13 , and distally out of the lumen of sheath  40 , thereby exposing eccentric scoring head  28  with scoring elements  32  disposed thereon as described supra to the vessel lumen. Non-rotatable inflating sheath  40  comprises an inflating balloon assembly  42 , comprising a distal anchor balloon  44 , a proximal anchor balloon  46 , with a coated balloon  48  disposed therebetween, the coated balloon  48  comprising a coating of at least one therapeutic agent  49 . Distal anchor and proximal anchor balloons  44 ,  46  and coated balloon  48  are deflated until the eccentric scoring head  28  completes its scoring operation, creating crevices  36  in the vessel wall V. 
     As illustrated in  FIGS. 7-10 , the distal and proximal anchor balloons  44 ,  46  are positioned generally distally and proximally to the crevices  36 , with the coated balloon  48  disposed therebetween, so that inflation of the coated balloon will engage the scoring  34  created by eccentric scoring head  28 . The distal and proximal anchor balloons  44 ,  46  are first inflated and compressed against the vessel walls V and, as shown in  FIG. 7 , establishing a first distance D 1  therebetween. The coated balloon  48  is then inflated to compression against the proximal and distal balloons  46 ,  44  as well as the vessel wall V comprising crevices  36 . This inflation compression pushes the proximal balloon  46  further proximally and the distal balloon  44  further distally, establishing a second distance D 2 , wherein D 2  is greater than D 1 . Thus, the crevices  36  are axially stretched open, allowing the coated balloon  48  to pressure its coating of therapeutic agent(s)  49  therein, filling at least partially the stretched open crevices  36 . Then, deflation of the coated balloon  48  relaxes the stretched crevices  36 , effectively closing the crevices  36  as the distance between the proximal and distal anchor balloons  46 ,  44  returns to D 1 . The proximal and distal anchor balloons  46 ,  44  are then deflated and the system removed. The proximal and distal anchor balloons  46 ,  44  and coated balloon  48  are inflated with inflation medium as is well known in the art. 
     Turning now to  FIGS. 11 and 12 , illustrates one embodiment  100  of a scoring and seeding high-speed rotational atherectomy system  300  of the present invention, elements of which are utilized in various embodiments of the present invention. The device includes a handle portion  10 , an elongated catheter  13  extending distally from the handle portion  10  and having a lumen therethrough, an elongated, flexible drive shaft  20  slidably and rotatably disposed with lumen of catheter  13 , the drive shaft  20  comprising a scoring assembly  50  on its distal end. The drive shaft  20  is constructed from helically coiled wire as is known in the art. 
     The handle  10  desirably contains a turbine (or similar rotational drive mechanism) for rotating the drive shaft  20  at high speeds. The handle  10  typically may be connected to a power source, such as compressed air delivered through a tube  16 . A pair of fiber optic cables  25 , alternatively a single fiber optic cable may be used, may also be provided for monitoring the speed of rotation of the turbine and drive shaft  20 . Details regarding such handles and associated instrumentation are well known in the industry. The handle  10  also desirably includes a control knob  11  for advancing and retracting the turbine and drive shaft  20  with respect to the catheter  13  and the body of the handle. 
     Scoring assembly  50  comprises a distal inflatable anchor balloon  52  having a proximal end which is fixedly attached to a threaded segment  53 . Threaded segment  53  comprises threads thereon and a distal stop  56 . Scoring assembly  50  further comprises an inflatable scorer and seeder  54  fixedly attached to the distal end of rotatable drive shaft  20 . Inflatable scorer and seeder  54  comprising scoring elements  36  as described supra, with at least one therapeutic agent coated thereon. Alternatively, a reservoir may be provided within scorer and seeder containing therapeutic agent, wherein the scoring elements  36  also comprise a lumen therethrough which is in fluid communication with the scoring element lumen. Still more alternatively, the scoring element  36  may comprise a pre-filled lumen, filled with therapeutic agent. The inflatable scorer and seeder  54  further comprises a threaded distal port  58 , within which threaded segment  53  of distal inflatable anchor balloon  52  is threadingly disposed. 
     In operation, catheter  13 , together with drive shaft  20  disposed in lumen of catheter  13 , is positioned within patient&#39;s lumen adjacent, preferably distally, to the region desired to be scored and seeded. The drive shaft  20  is translated axially and distally until the scoring assembly  50  reached the region of interest. The anchor balloon  52  is then inflated with inflation media using an inflation device as is well known in the art. Inflation of anchor balloon  52  compresses balloon  52  against the lumen wall, fixing balloon  52  in place and preventing rotation thereof. Then, the operator inflates the inflatable scorer and seeder  54  and actuates the drive shaft  20 , causing it to rotate. As this rotation progresses, several things occur. The scoring elements  36  begin to score the lumen wall V and in the various embodiments, the therapeutic agent(s) is deposited within the scoring. Rotation of the drive shaft  20  results in concurrent rotation of the inflatable scorer and seeder  54 , in particular counterclockwise rotation of inflatable scorer and seeder  54  results in proximal threaded movement of the scorer and seeder  54  as the threaded distal port  58  engages the threads of threaded segment  53 . As this proximal threading movement occurs, the scoring elements  36  also score proximally in the vessel wall V, leaving the therapeutic agent(s) within the scoring. The rotation of scorer and seeder  54  may progress until the distal stop  56  is encountered, which stops the proximal threaded translational movement of scorer and seeder  54 . The anchor balloon  52  and the scorer and seeder  54  are deflated, withdrawn proximally into lumen of catheter  13  and removed from the patient&#39;s lumen. 
     With reference now to  FIGS. 13 and 14 , a catheter  13  is provided with a lumen therein, catheter  13  is inserted to the region of interest in the vessel. A slicer  62  is disposed within lumen of catheter  13  in a first retracted position. At least one, but preferably two or more, fins  64  are provided on the body of slider  62  as illustrated. The fins  64  are, in the slicer&#39;s first retracted position, retracted to allow axial translation within lumen of catheter  13 . A wire  60  is attached to the proximal end of slicer  62 , whereby proximal and/or distal translation of slicer  62  is achieved. Once the catheter  13  is positioned in the vessel, the operator translates the slicer  62  out of the lumen of the catheter  13 , whereby slicer  62  achieves automatically its second, expanded position as in  FIG. 12 . In this second, expanded position, fins  64 , automatically expand, slicing into the vessel wall V. Fins  64  may be coated with at least one therapeutic agent  65 , so that frictional contact with the vessel wall V during slicing into wall V will release some of the at least one therapeutic agent  65  into wall V. Proximally translation of slicer in its second, expanded position by pulling on wire  60  will cause the coated fins  64  to slice proximally through the vessel wall V, leaving a coating of the at least one therapeutic agent therein. Once the slicer  62  reaches the lumen of the catheter, it is forced into the first, retracted position as it translates proximally therein for removal from the vessel along with catheter  13 . 
     The present invention should not be considered limited to the particular examples described above, but rather should be understood to cover all aspects of the invention. Various modifications, equivalent processes, as well as numerous structures to which the present invention may be applicable will be readily apparent to those of skill in the art to which the present invention is directed upon review of the present specification.