Methods for treating vascular stenoses including laser atherectomy and drug delivery via drug-coated balloons

Abstract

A method for treating a stenosis includes providing a laser ablation system including a laser catheter, the laser catheter including a distal end having a plurality of laser emitters; positioning the distal end of the laser catheter within the subject proximate the target vascular portion; delivering laser energy to the laser catheter and emitting the laser energy from the plurality of laser emitters to ablate the stenosis; withdrawing the laser catheter from the subject; providing a balloon system including a drug-coated balloon, the balloon carrying at least one therapeutic agent, the therapeutic agent being a restenosis inhibitor; positioning the balloon within the subject proximate the target vascular portion; expanding the balloon to engage the target vascular portion; delivering the therapeutic agent from the balloon to the target vascular portion; delivering the therapeutic agent from the balloon to the target vascular portion; and withdrawing the balloon from the subject.

Claims

1. A method for treating a target vascular portion of a subject including a stenosis, the method comprising: providing a laser ablation system including a laser catheter, the laser catheter including a distal end having a plurality of laser emitters; positioning the distal end of the laser catheter within the subject proximate the target vascular portion; delivering laser energy to the laser catheter and emitting the laser energy from the plurality of laser emitters to ablate the stenosis, including: emitting the laser energy at a first intensity; emitting the laser energy at a second intensity, the second intensity being different than the first intensity; withdrawing the laser catheter from the subject; providing a balloon system including a drug-coated balloon, the drug-coated balloon carrying at least one therapeutic agent, the at least one therapeutic agent being a restenosis inhibitor; positioning the drug-coated balloon within the subject proximate the target vascular portion; expanding the drug-coated balloon to engage the target vascular portion; delivering the at least one therapeutic agent from the drug-coated balloon to the target vascular portion; and withdrawing the drug-coated balloon from the subject.

2. The method of claim 1, wherein the restenosis inhibitor includes paclitaxel.

3. The method of claim 1, wherein the laser ablation system includes a laser generator, and further comprising delivering the laser energy from the laser generator to the laser catheter.

4. The method of claim 1, wherein the target vascular portion of the subject includes a stent coupled to the stenosis, and wherein emitting the laser energy from the plurality of laser emitters to ablate the stenosis includes emitting the laser energy from the plurality of laser emitters to ablate the stenosis within the stent.

5. The method of claim 1, wherein the second intensity is greater than the first intensity.

6. The method of claim 1, wherein emitting the laser energy from the plurality of laser emitters to ablate the stenosis includes: emitting the laser energy at a first repetition rate; and emitting the laser energy at a second repetition rate, the second repetition rate being different than the first repetition rate.

7. The method of claim 6, wherein the second repetition rate is greater than the first repetition rate.

8. A method for treating a target vascular portion of a subject including a stenosis, the method comprising: providing a laser ablation system including a first laser catheter including a distal end having a first plurality of laser emitters, the first laser catheter having a first external diameter, the laser ablation system further including a second laser catheter including a distal end having a second plurality of laser emitters, the second laser catheter having a second external diameter, the second external diameter being different than the first external diameter; positioning the distal end of the first laser catheter within the subject proximate the target vascular portion; delivering laser energy to the first laser catheter and emitting the laser energy from the first plurality of laser emitters to ablate the stenosis; withdrawing the first laser catheter from the subject; positioning the distal end of the second laser catheter within the subject proximate the target vascular portion; delivering laser energy to the second laser catheter and emitting the laser energy from the second plurality of laser emitters to ablate the stenosis; withdrawing the second laser catheter from the subject; providing a balloon system including a drug-coated balloon, the drug-coated balloon carrying at least one therapeutic agent, the at least one therapeutic agent being a restenosis inhibitor; positioning the drug-coated balloon within the subject proximate the target vascular portion; expanding the drug-coated balloon to engage the target vascular portion; delivering the at least one therapeutic agent from the drug-coated balloon to the target vascular portion; and withdrawing the drug-coated balloon from the subject.

9. The method of claim 8, wherein the second external diameter is greater than the first external diameter.

10. A method for treating a target vascular portion of a subject including a stenosis, the method comprising: providing a laser ablation system including a laser catheter, the laser catheter including a distal end having a plurality of laser emitters; positioning the distal end of the laser catheter within the subject proximate the target vascular portion; delivering laser energy to the laser catheter and emitting the laser energy from the plurality of laser emitters to ablate the stenosis, including: emitting the laser energy at a first repetition rate; emitting the laser energy at a second repetition rate, the second repetition rate being different than the first repetition rate; withdrawing the laser catheter from the subject; providing a balloon system including a drug-coated balloon, the drug-coated balloon carrying at least one therapeutic agent, the at least one therapeutic agent being a restenosis inhibitor; positioning the drug-coated balloon within the subject proximate the target vascular portion; expanding the drug-coated balloon to engage the target vascular portion; delivering the at least one therapeutic agent from the drug-coated balloon to the target vascular portion; and withdrawing the drug-coated balloon from the subject.

11. The method of claim 10, wherein the second repetition rate is greater than the first repetition rate.

12. The method of claim 10, wherein the restenosis inhibitor includes paclitaxel.

13. The method of claim 10, wherein the laser ablation system includes a laser generator, and further comprising delivering the laser energy from the laser generator to the laser catheter.

14. The method of claim 10, wherein the target vascular portion of the subject includes a stent coupled to the stenosis, and wherein emitting the laser energy from the plurality of laser emitters to ablate the stenosis includes emitting the laser energy from the plurality of laser emitters to ablate the stenosis within the stent.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The accompanying drawings are incorporated into and form a part of the specification to illustrate several examples of the present disclosure. These drawings, together with the description, explain the principles of the disclosure. The drawings simply illustrate preferred and alternative examples of how the disclosure can be made and used and are not to be construed as limiting the disclosure to only the illustrated and described examples. Further features and advantages will become apparent from the following, more detailed, description of the various aspects, embodiments, and configurations of the disclosure, as illustrated by the drawings referenced below.

(2) FIG. 1 is a flow diagram of an exemplary method for treating vascular stenoses by using laser atherectomy and drug delivery via drug-coated balloons in accordance with the present disclosure;

(3) FIG. 2 is a perspective view of a distal end of an exemplary embodiment of a laser catheter in accordance with the present disclosure;

(4) FIG. 3 is an elevation view of the distal end of the laser catheter of FIG. 2;

(5) FIG. 4 is a perspective longitudinal section view of the distal end of the laser catheter of FIG. 2;

(6) FIG. 5 is a schematic view of an exemplary embodiment of a laser ablation system in accordance with the present disclosure;

(7) FIG. 6 is a schematic view of an exemplary embodiment of a balloon system in accordance with the present disclosure; a balloon of a balloon catheter of the system is illustrated in an expanded configuration and a distally advanced position relative to a protective sheath;

(8) FIG. 7A is an elevation longitudinal section view of the balloon catheter of FIG. 6 longitudinally offset from a target to be treated; the balloon is in an unexpanded configuration and a proximally retracted position within the protective sheath;

(9) FIG. 7B is an elevation longitudinal section view of the balloon catheter of FIG. 6; the balloon is in a distally advanced position relative to the protective sheath and is longitudinally aligned with the target and radially offset from the target;

(10) FIG. 7C is an elevation longitudinal section view of the balloon catheter of FIG. 6; the balloon is in the distally advanced position relative to the protective sheath and is longitudinally aligned with the target and radially expanded to engage the target;

(11) FIGS. 8A-8F are cross-sectional views of carotid artery segments of a rabbit subjected to treatment by laser ablation and drug-coated balloon systems; and

(12) FIGS. 9A-9F are cross-sectional views of carotid artery segments of a rabbit subjected to treatment by balloon angioplasty and drug-coated balloon systems.

DETAILED DESCRIPTION

(13) Methods according to the present disclosure generally relate to treating vascular stenoses (for example, scar tissue, plaque build-up, calcium deposits and other types of undesirable lesion) by using laser atherectomy and drug delivery via drug-coated balloons. It is believed that such methods may be more effective for treating stenoses and preventing restenosis than methods that include balloon angioplasty and drug delivery via drug-coated balloons.

(14) FIG. 1 is a flow diagram 100 of an exemplary method for treating vascular stenoses by using laser atherectomy and drug delivery via drug-coated balloons in accordance with the present disclosure. Generally, the method may be performed under fluoroscopy to provide images of the vasculature and positions of medical devices in the vasculature. The method begins at block 102 by providing a laser ablation system. Generally and in some embodiments, the laser ablation system includes a laser catheter that is inserted into and transmits laser energy to a target portion of the vasculature to ablate a stenosis. In some embodiments, the laser ablation system also includes a laser generator that delivers laser energy to the laser catheter.

(15) Examples of laser catheters in accordance with the present disclosure include those available from The Spectranetics Corporation of Colorado Springs, Colo. under the tradenames ELCA and Turbo-Elite. Further examples of laser catheters in accordance with the present disclosure include those disclosed in U.S. Pat. Nos. 5,267,993, 5,383,199, and co-pending application U.S. patent application Ser. No. 13/804,812, the entireties of which are incorporated by reference herein for all purposes. Each of the above laser catheters is typically used for coronary intervention or catheterization such as recanalizing occluded arteries, changing lesion morphology, and facilitating stent placement. The working (distal) end of a laser catheter typically has a plurality of laser emitters that emit laser energy and ablate the targeted vascular portion, namely a thrombus within the lumen of the vasculature. The opposite (proximal) end of a laser catheter typically has a fiber optic coupler, which detachably couples to the laser generator.

(16) Referring now to FIGS. 2-4, a distal end of an exemplary embodiment of a laser catheter 200 in accordance with the present disclosure is illustrated. The laser catheter 200 may (as depicted in FIGS. 2-4) or may not include a lumen 202. If a lumen 202 is included in the laser catheter 200, a clinician may slide the laser catheter over a guidewire (not illustrated) through lumen 202. In some embodiments, however, the catheter 200 may have a separate guidewire lumen (not illustrated) located between an inner band 204 and an outer jacket 206. Incorporation of such a guidewire lumen is generally known to one of ordinary skill in the art, and all such guidewire lumens are within the knowledge of one skilled in the art are considered within the scope of the present disclosure.

(17) The proximal end (not illustrated) of the catheter 200 is attached to a coupler (not illustrated) and includes the outer jacket 206, an inner band, and a plurality of laser transmitters (for example, optical fibers 210) similar to the configuration and orientation of the laser emitters depicted in FIGS. 2-4. The distal end of the catheter 200 includes a tapered outer band 208, which is attached to the distal end of the outer jacket 206, a plurality of laser emitters (for example, exposed ends of the optical fibers 210), and the inner band 204, which creates an orifice that provides an entrance to the guidewire lumen 202. The energy emitted by the optical fibers 210 cuts, separates, and/or ablates the scar tissue, plaque build-up, calcium deposits and other types of undesirable lesion or bodily material within the subject's vascular system in a pattern substantially similar to that of the cross sectional configuration of the optical fibers 210.

(18) As the energy emitted by the optical fibers 210 contacts the undesirable bodily material within the subject's vascular system, it separates and cuts such material in a generally concentric configuration. In other words, one of ordinary skill in the art may refer to this technique as coring. If the bodily material that is cut is substantially solid, it will appear as generally cylindrically looking core or plug. Although FIGS. 2-4 illustrate the optical fibers 210 in a generally concentric configuration, those skilled in the art will appreciate that there are numerous other ways and configurations in which to arrange a plurality of optical fibers 210. Additionally, although these two figures illustrate an outer jacket 206 and an inner band 204, those of skill in the art will appreciate that distinct components need not be used, and the optical fibers may be encapsulated within a single sleeve having a lumen. Accordingly, FIGS. 2-4 are not intended to represent the only way that a laser catheter may be configured and constructed, and all such configurations and constructions are within the knowledge of one skilled in the art are considered within the scope of the present disclosure.

(19) In some embodiments, a laser ablation system may include multiple laser catheters 200 of different sizes (for example, external diameters) or structural configurations.

(20) Examples of laser generators in accordance with the present disclosure include those available from The Spectranetics Corporation under the tradename CVX-300. Further examples of laser generators in accordance with the present disclosure include those disclosed in U.S. Pat. Nos. 5,267,993, 5,383,199, and co-pending application U.S. patent application Ser. No. 13/804,812, the entireties of which are incorporated by reference herein for all purposes. Each of the above laser generators includes a fiber optic coupler for detachably coupling to a laser catheter, such as one or more of the laser catheters described herein, to deliver laser energy to a desired target (for example, a portion of the vasculature including a stenosis formed by scar tissue, plaque build-up, calcium deposits and/or other types of undesirable lesion) via the laser catheter. As such, the above laser generators facilitate coronary intervention or catheterization such as recanalizing occluded arteries, changing lesion morphology, and facilitating stent placement.

(21) In some embodiments, the laser ablation system is configured to emit laser energy at wavelengths of between 300 nanometers to 350 nanometers, at pulse durations between 100 nanoseconds to 150 nanoseconds, and/or at frequencies between 1 pulse per second to 250 pulses per second. In some cases, the laser ablation system is configured to emit laser energy at wavelengths of about 308 nanometers (that is, within 5 percent of 308 nanometers), at pulse durations between 120 nanoseconds and 140 nanoseconds, and/or at frequencies between 25 pulses per second to 80 pulses per second.

(22) Referring now to FIG. 5, an exemplary embodiment of a laser ablation system 500 in accordance with the present disclosure is illustrated. The laser ablation system 500 includes a laser catheter 502, such as any of the laser catheters described herein, that detachably couples to and receives laser energy from a laser generator 504. The laser generator 504 includes a housing 506 that is supported by a plurality of wheels 508. The housing 506 houses a laser 510 and a controller 512. The housing 506 further includes a door 514 that provides access to a storage compartment.

(23) A switch unit 516 (for example, a foot switch) may be stored in the storage compartment when not in use. The switch unit 516 may be actuated by an operator (for example, a clinician) to cause the laser 510 to generate laser energy. The switch unit 516 is coupled to the housing 506 via a tether 518. In some embodiments, the tether 518 may include power and/or communication cables (not illustrated) that facilitate power transmission and/or communication between the controller 512 and the switch unit 516. In other embodiments, the tether 518 may lack power and communication cables, and the controller 512 and the switch unit 516 may communicate via wireless signals.

(24) The laser generator 504 further includes a control panel 520 carried on the housing 506. Via the control panel 520 an operator (for example, a clinician) is able to activate and control the operation of the laser 510 through the controller 512. Specifically, the controller 512 controls the operation of the laser 510 based on an indication of the state of the switch unit 516 (that is, actuated or not actuated). In addition, via the control panel 520 the operator may be able to modify operating parameters of the laser 510 through the controller 512.

(25) Returning now to FIG. 1, the method continues at block 104 by positioning the laser ablation system in an appropriate position for treating the target. In some embodiments, positioning the laser system in an appropriate position includes positioning the distal end of a laser catheter within the vasculature of a subject proximate a target to be treated. In some embodiments, positioning the distal end of the laser catheter within the vasculature of the subject proximate the target includes positioning a guidewire in the vasculature of the subject, crossing a stenosis at the target with the guidewire, and advancing the laser catheter along the guidewire such that the distal end of the laser catheter is proximate the target.

(26) The method continues at block 106 by activating the laser ablation system to deliver laser energy to and thereby treat the target. In some embodiments, activating the laser ablation system to deliver laser energy includes activating the laser generator to deliver laser energy to the laser catheter and emitting the laser energy from the distal end of the laser catheter to deliver laser energy to and thereby ablate a stenosis at the target. In some embodiments and as described above, the laser energy emitted from the laser catheter may separate and cut the thrombus in a generally concentric configuration (that is, core the tissue) depending on the configuration of the optical fibers carried by the laser catheter. In some embodiments, emitting the laser energy from the distal end of the laser catheter to ablate the stenosis includes varying the intensity of the emitted laser energy. In some embodiments, emitting the laser energy from the distal end of the laser catheter to ablate the stenosis includes varying the repetition rate of the emitted laser energy.

(27) The method continues at block 108 by withdrawing the laser ablation system from the subject. In some embodiments, withdrawing the laser ablation system from the subject includes removing the laser catheter from the vasculature of the subject.

(28) In some embodiments, the method may include employing multiple laser catheters having different sizes or configurations. For example, the method may include uncoupling a first laser catheter (for example, a laser catheter having a first size) from the laser generator, coupling a second laser catheter (for example, a laser catheter having a second size, the second size being different than the first size) to the laser generator, positioning the distal end of the second laser catheter within the vasculature of a subject proximate the target, and emitting laser energy from the distal end of the second laser catheter to deliver laser energy to and thereby ablate the stenosis at the target.

(29) At block 110, the method continues by providing a balloon system. Generally and in some embodiments, the balloon system includes a drug-coated balloon (DCB) catheter, which is described in more detail below. The DCB catheter is inserted into and delivers one or more therapeutic agents to the vasculature of a subject. In some embodiments, the balloon system also includes an inflation fluid source that delivers an inflation fluid to the DCB catheter to cause the balloon of the DCB catheter to inflate or expand and, in some embodiments, deliver the therapeutic agent(s) to the vasculature.

(30) Examples of DCB catheters in accordance with the present disclosure include those available from Lutonix, Inc. of New Hope, Minn. under the tradename Lutonix, such as the Lutonix 014 catheter, and those available from Medtronic of Minneapolis, Minn., such as the IN.PACT Admiral catheter. Further examples of DCB catheters, therapeutic agents, and balloon coatings including therapeutic agents in accordance with the present disclosure include those disclosed in U.S. Pat. Nos. 8,114,429; 8,128,951; 8,257,304; 8,257,722; 8,491,925; 8,563,023; 8,673,332; 8,734,825, 8,740,841; 9,011,896; U.S. Pat. Apps. 62/098,242; Ser. Nos. 13/628,608; 13/707,401; 11/411,635; 60/680,450; 13/310,320; 12/712,134; 12/558,420; 12/210,344; 14/149,862; 13/560,538; 13/926,515; 61/665,758; 13/628,627; 13/975,209; 13/975,220; 13/975,228; 14/032,336; 14/162,900; 14/254,160; 14/731,715; the entireties of which are incorporated by reference herein for all purposes.

(31) Referring now to FIG. 6, an exemplary embodiment of a balloon system 600 in accordance with the present disclosure is illustrated. The balloon system 600 includes a DCB catheter 602 that receives inflation fluid from an inflation fluid source 604. The DCB catheter 602 includes a tubular element 606 that carries a drug-coated expandable element or balloon 608. The tubular element 606 includes an inflation lumen (not illustrated) that receives inflation fluid from the inflation fluid source 604 and delivers the inflation fluid to the balloon 608 to inflate the balloon 608. In some embodiments, the tubular element 606 also includes a guidewire lumen (not illustrated) for receiving a guidewire (not illustrated) to guide the DCB catheter 602 to the target.

(32) The balloon 608 carries a coating 610 that includes one or more therapeutic agents. Therapeutic agents in accordance with the present disclosure can be chosen based upon functional characteristics, including, but not necessarily limited to, the ability to inhibit restenosis, mitosis or cellular proliferation. For example, a therapeutic agent can be a taxane, including paclitaxel, docetaxel, protaxel, DHA-paclitaxel, PG-paclitaxel, docosahexaenoic acid (DHA), or any combinations or derivatives thereof capable of inhibiting mitosis or cellular proliferation. In some cases, the presence of a mitotic inhibitor prevents restenosis that may occur in the absence of the inhibitor. Other examples of therapeutic agents include rapamycin (for example, sirolimus) or a derivative of rapamycin (for example, everolimus), or any combinations or derivatives thereof. Additionally or alternatively, specific inhibitors of neovascularization such as thalidomide, statins such as atorvastatin, cerivastatin, fluvastatin, or anti-inflammatory drugs like corticoids or lipophilic derivatives of corticoids such as betamethasone diproprionate or dexa-methasone-21-palmitate are examples of oxitherapeutic agents that can be used in accordance with the present disclosure. In some cases, the therapeutic agent is stable against oxidative degradation, or oxidation in sensitive. Various therapeutic agents may be applied or combined if different pharmacological actions are required or efficacy or tolerance is to be improved.

(33) Coatings in accordance with the present disclosure include a therapeutic agent dispersed throughout a polymer matrix. The polymer coating may include additional components such as a plasticizer and/or wax. The therapeutic agent can be either water-soluble or water-insoluble. The polymer matrix may be complexed with iodine, or non-covalently bound iodine may be dispersed throughout the polymer matrix. In some embodiments, the polymer matrix is a non-ionic thermoplastic polymer or co-polymer. In some embodiments, the amphiphilic polymer is hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), methyl cellulose, hydroxypropyl methylcellulose, or co-polymers of N-vinylpyrrolidone with other reactive double bond containing monomers such as styrene, acrylic acid, vinyl acetate or vinyl caprolactam. PVP and HPC exhibit higher solubility rates in aqueous solvents than PEG. Molecular weight of the polymers may also factor into solubility rates. In some embodiments, the PEG has as molecular weight of 1.5 KD to 50 KD. Co-polymers can be block or random.

(34) Coatings in accordance with the present disclosure include an amphiphilic polymer coating that includes one or more therapeutic agents and one or more amphiphilic polymers or co-polymers. The amphiphilic polymer coating may include additional components such as a plasticizer and/or wax. The therapeutic agent can be either water-soluble or water-insoluble. Hydration of the amphiphilic polymer coating occurs immediately when exposed to aqueous fluids, such as blood in vivo, causing the amphiphilic polymer coating to dissolve and the therapeutic agent to release into tissue of the vasculature of the subject. Thus, the amphiphilic polymer coating is bioerodable in the sense that it is removable by bodily fluids, and non-durable. In some embodiments, the amphiphilic polymer or co-polymer is a non-ionic thermoplastic polymer or co-polymer. In some embodiments, the amphiphilic polymer is hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), methyl cellulose, hydroxypropyl methylcellulose, or co-polymers of N-vinylpyrrolidone with other reactive double bond containing monomers such as styrene, acrylic acid, vinyl acetate or vinyl caprolactam. PVP and HPC exhibit higher solubility rates in aqueous solvents than PEG. Molecular weight of the polymers may also factor into solubility rates. In some embodiments, the PEG has as molecular weight of 1.5 KD to 50 KD. In some embodiments, the coating includes paclitaxel in PEG complexed with iodine in a polymer matrix, or non-covalently bound iodine may be dispersed throughout the polymer matrix. The PEG has a number average molecular weight, Mn, of about 8 KD. The amphiphilic polymer may also be a poly(hydroxyethyl methacrylic) acid, also known as poly(HEMA). In some embodiments, the poly(HEMA) has a number average molecular weight, Mn, below approximately 8 KD. In some embodiments, the poly(HEMA) has a number average molecular weight, Mn, of approximately 7 KD. In some embodiments, the amphiphilic polymer may be a co-polymer of HEMA with a monomer such as glycidyl methacrylate (GMA) or acrylic acid. Co-polymers can be block or random.

(35) Coatings in accordance with the present disclosure may include a therapeutic agent combined with various adjuvants and excipients to enhance efficacy or delivery of the therapeutic agents. For example, the therapeutic agents can be combined with lipophilic antioxidant such as nordihydroguaiaretic acid, resveratrol, propyl gallate, hydroxytoluene, butylated hydroxyanisole, and ascorbyl palmitate to enhance the adhesion of the therapeutic to the balloon 608. In some embodiments, the combination of a therapeutic agent such as paclitaxel and a lipophilic antioxidant such as nordihydroguaiaretic acid can be applied to the balloon 608 without the need for additional polymers.

(36) Coatings in accordance with the present disclosure may be applied to balloons by using a variety of processes. For example, coatings may be applied to balloons using similar processes to the following Examples regarding coating of PET and Nylon 12 coupons. Solution percentages provided are by weight.

Example 1

(37) One (1.0) grams of a 7.5 percent solution of 60 K Dalton HPC in ethanol is mixed with 0.15 grams of 1 percent solution of propylene glycol (plasticizer) in acetone, 0.075 grams paclitaxel and 0.08 grams n-butanol. The mixture is heated in a water bath to dissolve the paclitaxel; a clear solution results. When dip coated (single dip) on PET coupons at a dip speed of about 10 inches/minute, and dried at room temperature, there results a slightly milky dry coating. About 3 cm.sup.2 of coupon surface is coated per coupon. The average coating density determined by gravimetric analysis is 6 g/mm.sup.2 and the implied paclitaxel density is 3 g/mm.sup.2. The dry coating is sufficiently ductile to withstand a 180 degree bend without cracking or delaminating. A coupon coated as above is immersed in 3 ml of 37 degrees C. water for 3 minutes with agitation, after which the coupon is removed and the turbid suspension diluted with 9 ml dimethyl sulfoxide (DMSO) to produce a clear solution. Quantitative UV analysis at 260 nm and 280 nm vs. a standard curve shows an 88 percent recovery. This result demonstrates the rapid dissolution of the amphiphilic polymer coating and drug release in vitro. The in vivo milieu is expected to present serum proteins with a surfactant effect, which will increase the dissolution rate of the drug and coating polymer in vivo.

Example 2

(38) 0.075 grams paclitaxel is mixed with 0.9 grams of a 20 percent povidone-iodine solution in 2-propanol, 0.06 grams of a 10 percent propylene glycol solution in 2-propanol and 0.04 grams acetone. When dip coated (single dip) on a PET coupon at a dip speed of 10 inches/min, and dried at room temperature, there results a clear amber dry coating. About 2.5 g/mm.sup.2 of paclitaxel is deposited. The above coupon is immersed in 1.5 ml of 37 degrees C. water for 30 seconds. All of the coating dissolves in the water, and the solution is totally transparent amber, and not turbid as in Example 1.

Example 3

(39) An identical formula to Example 2 is made, however noniodinated PVP is employed instead of povidone-iodine of the same molecular weight (40 K Dalton). When dip coated (single dip) on a PET coupon at a dip speed of 10 inches/min, and dried at room temperature, there results a clear water white dry coating. About 2.5 g/mm.sup.2 of paclitaxel is deposited. This coupon is immersed in 1.5 ml of 37 degrees C. water for 30 seconds. All of the coating polymer dissolves in the water, and the solution shows a suspension of needle crystals. This suspension becomes more turbid after 24 hours, while the above amber solution from Example 2 remains transparent. This demonstrates that the povidone-iodine changes the aqueous solubility of paclitaxel.

Example 4

(40) 0.1 grams rapamycin (available from LC Laboratories of Woburn, Mass.) is dissolved in 0.08 grams of a 10 percent propylene glycol solution in 2-propanol and 0.053 grams acetone at 40 degrees C. The solution is cooled to room temperature, then added to 1.2 grams of a 20 percent solution of povidone-iodine in 2-propanol. The formula is dip coated (single dip) on a Nylon 12 coupon, and dried at room temperature for 30 minutes. The coupon is immersed in 1 ml of 37 degrees C. water for one minute. All of the coating dissolves in the water, and the solution is clear amber.

Example 5

(41) An identical formula to Example 4 is made, however noniodinated C-30 PVP is employed instead of povidone-iodine. The formula is dip coated (single dip) on a Nylon 12 coupon, and dried at room temperature for 30 minutes. The coupon is immersed in 1 ml of 37 degrees C. water for one minute. All of the coating dissolves in the water, and the solution is turbid due to the water-insoluble rapamycin.

Example 6

(42) 0.1 grams everolimus (available from LC Laboratories) is dissolved in 0.08 grams of a 10 percent propylene glycol solution in 2-propanol and 0.053 grams acetone at 40 degrees C. The solution is cooled to room temperature, then added to 1.2 grams of a 20 percent solution of povidone-iodine in 2-propanol. The formula is dip coated (single dip) on a Nylon 12 coupon, and dried at room temperature for 30 minutes. The above coupon is immersed in 1 ml of 37 degrees C. water for one minute. All of the coating dissolves in the water, and the solution is clear amber.

Example 7

(43) An identical formula to Example 6 is made, however noniodinated C-30 PVP is employed instead of povidone-iodine. The formula is dip coated (single dip) on a Nylon 12 coupon, and dried at room temperature for 30 minutes. The above coupon is immersed in 1 ml of 37 degrees C. water for one minute. All of the coating dissolves in the water, and the solution is turbid due to the water-insoluble everolimus.

(44) Light scattering experiments at 600 nm and 700 nm were performed comparing the drug (paclitaxel, rapamycin and everolimus) and polymer eluted water solutions of Examples 2, 4 and 6 (containing povidone-iodine) with Examples 3, 5 and 7 (containing non-iodinated PVP). The results illustrated in Table I below provide a quite unexpected increase in solubility of paclitaxel, rapamycin and everolimus in the povidoneiodine eluted water solutions of Examples 2, 4 and 6 compared to the non-iodinated PVP eluted water solution of Examples 3, 5 and 7. Consequently, and quite unexpectedly this suggests that the iodine complexed PVP polymer may assist in tissue uptake of the non-aqueous soluble therapeutic agents in vivo.

(45) TABLE-US-00001 TABLE I Optical density measurements Therapeutic Wave- Optical Solubility Example Agent length Polymer Density Increase 2 paclitaxel 600 nm PVP-iodinated 0.120 2.99 3 paclitaxel 600 nm PVP (ton-iodinated) 0.359 4 rapamycin 600 nm PVP-iodinated 0.079 3.10 5 rapamycin 600 nm PVP (non-iodinated) 0.245 6 everolimus 600 nm PVP-iodinaied 0.068 2.38 7 everolimus 600 nm PVP (non-iodinated) 0.162 2 paclitaxel 700 nm PVP-iodinated 0.089 3.19 3 paclitaxel 700 nm PVP (non-iodinated) 0.284 4 rapamycin 700 nm PVP-iodinated 0.056 3.66 5 rapamycin 700 nm PVP (non-iodinated) 0.205 6 everolimus 700 nm PVP-iodinated 0.051 2.66 7 everolimus 700 nm PVP (non-iodinated) 0.136

Example 8

(46) 0.2 grams of iodine (Sigma-Aldrich) was added to 10 grams of methanol and dissolved with heat and agitation. 4.29 grams of PEG (4 K Daltons, Fluka) was then added, and dissolved with mild heat and agitation. 0.20 grams of paclitaxel was added to 1.66 grams of the above PEG-iodine solution. Mild heat and agitation were used to dissolve the paclitaxel. A Nylon 12 coupon was coated with the formulation and dried for about 1 hour. The coupon was then soaked in 1.5 ml bovine serum at 37 degrees C. for 3 minutes. 200 micro-liters of the serum sample was tested for optical density at 600 and 700 nm on a plate reader.

Example 9

(47) An identical formula to Example 8 is made without iodine as a counter example. A Nylon 12 coupon was coated with the formulation and dried for about 1 hour. The coupon was then soaked in 1.5 ml bovine serum at 37 degrees C. for 3 minutes. 200 micro-liters of the serum sample was tested for optical density at 600 and 700 nm on a plate reader.

(48) Light scattering experiments at 600 nm and 700 nm were performed comparing the drug (paclitaxel) and polymer eluted bovine serum solutions of Example 8 (iodinated PEG) with Example 9 (non-iodinated PEG). The results illustrated in Table II below provide a quite unexpected increase in solubility of paclitaxel in the PEG eluted bovine serum solution of Example 8 compared to the non-iodinated PEG eluted bovine serum solution of Example 9. Consequently, and quite unexpectedly this suggests that the iodine complexed PEG polymer may assist in tissue uptake of the non-aqueous soluble therapeutic agents in vivo.

(49) TABLE-US-00002 TABLE II Optical density measure Merits Therapeutic Wave- Optical Solubility Example Agent length Polymer Density Increase Serum 600 nm 0.099 blank 8 paclitaxel 600 nm poly-4KD- 0.109 1.13 iodinated 9 paclitaxel 600 nm poly-4KD- 0.123 (non-iodinated) Serum 700 nm 0.062 blank 8 paclitaxel 700 nm poly-4KD- 0.069 1.26 iodinated 9 paclitaxel 700 nm poly-4KD- 0.087 (non-iodinated)

Example 10

(50) A morphaline based initiator (ME-Br) was synthesized according to the following procedure. 18 ml 4-(2-hydroxy-ethyl) morpholine was dissolved in 200 ml toluene. 21.2 ml triethylamine (dried over Na2S04) was added. The mixture was cooled in an ice bath. With stirring, 18.36 ml 2-bromoisobutyryl bromide was added dropwise over 30 minutes. The mixture was stirred in a cooling bath for an additional hour and then room temperature for 40 hours. The precipitated triethylarnmonium salt was filtered off and washed with 50 ml toluene. The solvent was rotoevaporated from the combined solution. The product, a brownish oil, was analyzed by NMR and was found to be highly pure. It was used without further purification. A 10 KD polymer was synthesized according to the following ATRP procedure utilizing the ME-Br initiator. 4.076 grams of the above ME-Br initiator was loaded in a 100 ml round bottomed flask, equipped with a stir bar. A solution of 0.0280 grams tris[(2-pyridyl)methyl]amine (TPMA), 0.0215 CuBr2 and 0.0795 grams azobisisobutyronitrile (AIBN) in 100 ml ethanol was prepared and added. To this solution, 100 ml HEMA was added, the flask was capped, cooled in an ice bath and purged with nitrogen for 2 hours. The reaction was then carried out at 60 degrees C. for 3 hours. 30 percent conversion was achieved. The polymer was precipitated in ether, washed with ether and dried. Molecular weight by GPC was 10,000 grams per mole. The 10 KD material was found to be water insoluble.

Example 11

(51) A morphaline based initiator (ME-Br) was synthesized according to the procedure described in Example 10. A 7 KD polymer was synthesized according to the following procedure. 12.24 grams of the above ME-Br initiator was loaded in a 100 ml round bottomed flask, equipped with a stir bar. A solution of 0.0280 grams tris[(2-pyridyl)methyl]amine (TPMA), 0.0215 CuBr2 and 0.0795 grams azobisisobutyronitrile (AIBN) in 100 ml ethanol was prepared and added. To this solution, 100 ml HEMA was added, the flask was capped, cooled in an ice bath and purged with nitrogen for 2 hours. The reaction was then carried out at 60 degrees C. for 2 hours. 32 percent conversion was achieved. The polymer was precipitated in ether, washed with ether, re-dissolved in methanol, re-precipitated in ether and dried. Molecular weight by GPC was 7,000 grams per mole. The 7 KD material was found to have water solubility.

Example 12

(52) A 30 percent solution of 7 KD poly(HEMA) in 2-propanol was prepared in accordance with the procedures of Example 11. To 0.79 grams of this solution was added: 0.12 grams of 10 percent propylene glycol in 2-propanol, 0.06 grams acetone and 0.1 grams paclitaxel. Gentle heating was used to form a clear solution. This paclitaxel containing solution was used to dip coat onto Nylon 12 coupons. The coupons were dried at room temperature. The resultant coating was clear and free of obvious phase separation.

Example 13

(53) A 30 percent solution of 7 KD poly(HEMA) in 2-propanol was prepared in accordance with the procedures of Example 11 with the addition of iodine at a level of 7 percent iodine based on poly(HEMA). A clear amber solution resulted. To 0.79 grams of this solution was added: 0.12 grams of 10 percent propylene glycol in 2-propanol, 0.06 grams acetone and 0.1 grams paclitaxel. Gentle heating was used to form an amber solution. This paclitaxel containing solution was used to dip coat onto Nylon 12 coupons. The coupons were dried at room temperature. The resultant coating was clear amber and free of obvious phase separation.

(54) The coupons from Examples 12 and 13 were then immersed and agitated in 1.5 ml of adult bovine serum at 37 degrees C. for 3 minutes. Subsequent gravimetric analysis showed that 90 percent of both coatings were removed by this process. 200 micro-liters of the serum samples were tested for optical density at 600 and 700 nm on a plate reader. The results are provided in Table III below, show an increase in solubility of paclitaxel in the iodinated poly(HEMA) eluted bovine serum solution of Example 13 compared to the non-iodinated poly(HEMA) eluted bovine serum solution of Example 12. Consequently, this suggests that iodine enhances the solubility of hydrophobic materials contained in the coating when in contact with biological systems. The data in Table III also indicates that poly(HEMA) synthesized using the ATRP initiator (ME-Br) forms a fully amphiphilic coating that achieves water solubility, and consequent rapid release of the drug; that poly(HEMA) is capable of complexing with iodine, resulting in improved solubility of a substantially water-insoluble, hydrophobic drug such as paclitaxel; that poly(HEMA) synthesized using the ATRP initiator (ME-Br) is useful as a medical device coating for rapid release of drug agents into tissue; and the addition of iodine to poly(HEMA) may enhance solubility and tissue uptake of a substantially water insoluble, hydrophobic drug such as paclitaxel.

(55) TABLE-US-00003 TABLE III Optical density measure Merits Ex- Therapeutic Wave- Optical Solubility ample Agent length Polymer Density Increase Serum 600 nm 0.144 blank 11 paclitaxel 600 nm poly(HEMA)- 0.150 1.09 7KD-iodinated 10 paclitaxel 600 nm poly(HEMA)- 7 KD 0.163 (non-iodinated) Serum 700 nm 0.102 blank 11 paclitaxel 700 nm poly(HEMA)- 0.107 1.10 7KD-iodinated 10 paclitaxel 700 nm poly(HEMA)- 7 KD 0.118 (non-iodinated)

(56) In some embodiments, the DCB catheter 620 further includes a protective sheath 612 that is translatable relative to the tubular element 606 and the balloon 608. The protective sheath 612 initially surrounds the unexpanded balloon 608 to prevent the coating 610 from prematurely dissolving when the DCB catheter 620 is inserted into the vasculature of the subject.

(57) Returning now to FIG. 1 and referring also to FIGS. 7A-7C, the method continues at block 112 by positioning the balloon system in an appropriate position for delivering the therapeutic agent(s) to the vasculature of the subject. In some embodiments, positioning the balloon system in an appropriate position includes (1) as illustrated in FIG. 7A, positioning the DCB catheter 602 in the vasculature 700 of the subject such that the catheter 602 is longitudinally offset (that is, offset in a longitudinal direction of the catheter 602) from the target 702 to be treated (for example, the portion of the vasculature that previously included the stenosis treated by the laser ablation system or that includes any remnants of the stenosis treated by the laser ablation system); the balloon 608 may be in an unexpanded configuration and a proximally retracted position within the protective sheath 612; (2) as illustrated in FIG. 7B, translating the balloon 608 to a distally advanced position relative to the protective sheath 612 such that the balloon 608 is longitudinally aligned with the target 702 and radially offset (that is, offset in a radial direction of the catheter 602) from the target 702; and (3) as illustrated in FIG. 7C, expanding the balloon 608 in the radial direction to contact the target 702. In some embodiments, the inflation fluid source 604 delivers inflation fluid to the balloon 608 to expand the balloon 608. At block 614, the balloon 608 delivers the therapeutic agent(s) to the target 702. In some embodiments, the balloon 608 delivers the therapeutic agent(s) to the target 702 by the balloon 608 contacting the blood of the subject, thereby dissolving the coating 610, and/or expanding the balloon 608 to contact the target 702.

(58) In some embodiments, the coating 610 includes a therapeutic agent that is a restenosis inhibitor (such as paclitaxel) to inhibit restenosis at the target. In some embodiments and if the target includes any remnants of the stenosis treated by the laser ablation system, expanding the balloon 608 may also facilitate angioplasty at the target.

(59) The method concludes at block 116 by withdrawing the balloon system from the subject. In some embodiments, withdrawing the balloon system from the subject includes removing the DCB catheter 602 from the vasculature 700 of the subject.

(60) Animal Study I.

(61) An in-stent restenosis model in the carotid artery of hypercholesterolemic rabbits was established to create chronic total occlusion for assessment of laser ablation with adjunct treatment with a drug-coated balloon system.

(62) The animals (rabbits) were fed a 1 percent high cholesterol diet with subsequent 3F Fogarty injury and bare metal stent implantation after seven days. The atherogenic high cholesterol feed was continued until day 28 at which time the diet was switched to 0.025 percent cholesterol for the remaining in-life-period. An intra-luminal bovine thrombin injection within the restenotic stented arterial segment was performed at 62 days after initiation of the high cholesterol diet) to create total occlusion. Surviving animals 30 days later underwent: i) laser ablation and treatment with a drug-coated balloon (DCB) or ii) balloon angioplasty (PTCA) and DCB, and were then studied/terminated at 28-day follow-up.

(63) Materials and Methods

(64) Animals Treated with Laser Ablation and Drug-Coated Balloon Systems

(65) Laser ablation of carotid stents with occlusive lesions was performed using a CVX-300-P Excimer Laser System [Spectranetics, Colorado Springs, Colo.] followed by drug-coated balloon treatment for animals 1-4 as described below. Anti-platelet therapy (aspirin 40 mg PO) was administered for the remainder of the study, which was a 28-days period following laser ablation. Heparin (150 IU/kg) was given during the catheterization procedure.

(66) Animal 1

(67) The animal was treated under fluoroscopy to provide images of the vasculature and positions of medical devices in the vasculature. The stenosis was crossed with a guidewire. The stenosis partially occluded the vasculature, and pre-treatment optical coherence tomography (OCT) was used to provide images of the vasculature and the stenosis. A 0.9 mm diameter Turbo-Elite laser catheter was then used as follows: (1) one laser ablation pass through the stent to a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (2) laser ablation at a position proximal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (3) one laser ablation pass in the stent at a fluence of 60 mJ/mm.sup.2 and a repetition rate of 80 Hz; (4) laser ablation at a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (5) laser ablation at a position proximal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; and (6) one laser ablation pass in the stent at a fluence of 60 mJ/mm.sup.2 and a repetition rate of 80 Hz.
A 1.4 mm diameter Turbo-Elite laser catheter was then used as follows: (1) one laser ablation pass from a position proximal to the stent, through the stent, and to a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (2) laser ablation at a position proximal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; and (3) two laser ablation passes in the stent at a fluence of 50 mJ/mm.sup.2 and a repetition rate of 50 Hz.
OCT was then used to provide images of the vasculature. A 3.015 mm Lutonix 014 balloon catheter was then inflated in the stent at a pressure of 6 atm for 60 seconds.

(68) Animal 2

(69) The animal was treated under fluoroscopy to provide images of the vasculature and positions of medical devices in the vasculature. The stenosis was crossed with a guidewire. The stenosis partially occluded the vasculature, and pre-treatment OCT was used to provide images of the vasculature and the stenosis. A 0.9 mm diameter Turbo-Elite laser catheter was then used as follows: (1) one laser ablation pass from a position proximal to the stent, through the stent, and to a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; and (2) one laser ablation pass in the stent at a fluence of 60 mJ/mm.sup.2 and a repetition rate of 80 Hz.
A 1.4 mm diameter Turbo-Elite laser catheter was then used as follows: (1) one laser ablation pass from a position proximal to the stent, through the stent, and to a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; and (2) one laser ablation pass in the stent at a fluence of 50 mJ/mm.sup.2 and a repetition rate of 50 Hz. OCT was then used to provide images of the vasculature. A 3.015 mm Lutonix 014 balloon catheter was then inflated in the stent at a pressure of 6 atm for 60 seconds.

(70) Animal 3

(71) The animal was treated under fluoroscopy to provide images of the vasculature and positions of medical devices in the vasculature. The stenosis was crossed with a guidewire. The stenosis partially occluded the vasculature, and pre-treatment OCT was used to provide images of the vasculature and the stenosis. A 0.9 mm diameter Turbo-Elite laser catheter was then used as follows: (1) two laser ablation passes from a position proximal to the stent and through the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; and (2) one laser ablation pass in the stent at a fluence of 60 mJ/mm.sup.2 and a repetition rate of 80 Hz.
A 1.4 mm diameter Turbo-Elite laser catheter was then used as follows: (1) two laser ablation passes in the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (2) one laser ablation pass in the stent at a fluence of 50 mJ/mm.sup.2 and a repetition rate of 50 Hz; (3) laser ablation at a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (4) one laser ablation pass in the stent at a fluence of 50 mJ/mm.sup.2 and a repetition rate of 50 Hz; and (5) one laser ablation pass in the stent at a fluence of 60 mJ/mm.sup.2 and a repetition rate of 80 Hz.
0.5 mL of lidocaine and 0.25 mL of nitroglycerine was then administered to the vasculature. OCT was then used to provide images of the vasculature. A 3.015 mm Lutonix 014 balloon catheter was then inflated in the stent at a pressure of 6 atm for 60 seconds. 0.5 mL of lidocaine and 0.25 mL of nitroglycerine was then administered to the vasculature.

(72) Animal 4

(73) The animal was treated under fluoroscopy to provide images of the vasculature and positions of medical devices in the vasculature. The stenosis was crossed with a guidewire by using a 0.014 inch guidewire-compatible Quick-Cross Capture guidewire retriever. The stenosis partially occluded the vasculature, and pre-treatment OCT was used to provide images of the vasculature and the stenosis. 0.5 mL of lidocaine and 0.25 mL of nitroglycerine was then administered to the vasculature. A 0.9 mm diameter Turbo-Elite laser catheter was then used as follows: (1) laser ablation at a position proximal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (2) one laser ablation pass in the stent at a fluence of 50 mJ/mm.sup.2 and a repetition rate of 50 Hz; (3) laser ablation at a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; (4) one laser ablation pass from a position proximal to the stent, through the stent, and to a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; and (5) one laser ablation pass in the stent at a fluence of 60 mJ/mm.sup.2 and a repetition rate of 80 Hz.
The laser catheter contacted the stent, and an angioplasty balloon catheter was employed to urge the stent to expand toward the wall of the vasculature. Specifically, a 2.020 mm Maverick.sup.2 Monorail balloon catheter (available from Boston Scientific Corporation) was inflated at the proximal end of the stent at a pressure of 8 atm for 60 seconds. A 1.4 mm diameter Turbo-Elite laser catheter was then used as follows: (1) two laser ablation from a position proximal to the stent, through the stent, and to a position distal to the stent at a fluence of 30 mJ/mm.sup.2 and a repetition rate of 30 Hz; and (2) one laser ablation pass in the stent at a fluence of 50 mJ/mm.sup.2 and a repetition rate of 50 Hz.
0.5 mL of lidocaine and 0.25 mL of nitroglycerine was then administered to the vasculature. The 1.4 mm diameter Turbo-Elite laser catheter was then used as follows: (1) one laser ablation pass in the stent at a fluence of 50 mJ/mm.sup.2 and a repetition rate of 50 Hz; and (2) one laser ablation pass in the stent at a fluence of 60 mJ/mm.sup.2 and a repetition rate of 80 Hz.
0.5 mL of lidocaine and 0.25 mL of nitroglycerine was then administered to the vasculature. The 2.020 mm Maverick.sup.2 Monorail balloon catheter was used as follows: (1) inflation at a position distal to the stent at a pressure of 6 atm for 60 seconds; (2) inflation in the stent at a pressure of 9 atm for 60 seconds; (3) inflation at a position proximal to the stent at a pressure of 8 atm for 60 seconds; (4) inflation at a position proximal to the position in (3) at a pressure of 8 atm for 60 seconds; (5) inflation at the position in (3) at a pressure of 9 atm for 60 seconds; and (6) inflation in the stent at a pressure of 9 atm for 60 seconds.
OCT was then used to provide images of the vasculature. A 3.015 mm Lutonix 014 balloon catheter was then used as follows: (1) inflation in the stent at a pressure of 6 atm for 60 seconds; and (2) inflation at the proximal end of the stent at a pressure of 1 atm for 60 seconds.

(74) Animals Treated with Balloon Angioplasty and Drug-Coated Balloon Systems

(75) Balloon angioplasty of carotid stents with occlusive lesions was performed followed by drug-coated balloon treatment for animals 5 and 6 as described below. Anti-platelet therapy (aspirin 40 mg PO) was administered for the remainder of the study. Heparin (150 IU/kg) was given during the catheterization procedure.

(76) Animal 5

(77) The animal was treated under fluoroscopy to provide images of the vasculature and positions of medical devices in the vasculature. The stenosis was crossed with a guidewire. The stenosis fully occluded the vasculature, and pre-treatment OCT was not used. A 2.520 mm Maverick.sup.2 Monorail balloon catheter was used as follows: (1) inflation in the stent at a pressure of 6 atm for 60 seconds; and (2) inflation at a position proximal to the stent at a pressure of 6 atm for 60 seconds.
A dissection proximal to the stent was revealed by fluoroscopy. Subsequent short inflations of the Maverick.sup.2 Monorail balloon catheter were performed along proximal branch to improve flow. The dissection was still present. A 3.015 mm Lutonix 014 balloon catheter was then inflated in the stent at a pressure of 6 atm for 60 seconds.

(78) Animal 6

(79) The animal was treated under fluoroscopy to provide images of the vasculature and positions of medical devices in the vasculature. The stenosis was crossed with a guidewire by using a 0.014 inch guidewire-compatible Quick-Cross Capture guidewire retriever. The stenosis fully occluded the vasculature, and pre-treatment OCT was not used. 0.5 mL of lidocaine and 0.25 mL of nitroglycerine was then administered to the vasculature. A 2.520 mm Maverick.sup.2 Monorail balloon catheter was used as follows: (1) two inflations at a position distal to the stent at a pressure of 6 atm for 60 seconds; (2) two inflations at a distal portion of the stent at a pressure of 6 atm for 60 seconds; (3) two inflations at an intermediate portion of the stent at a pressure of 6 atm for 60 seconds; (4) two inflations at a proximal portion of the stent at a pressure of 6 atm for 60 seconds; and (5) two inflations at a position proximal to the stent at a pressure of 6 atm for 60 seconds.
A 3.015 mm Lutonix 014 balloon catheter was then inflated in the stent at a pressure of 6 atm for 60 seconds.

(80) Results

(81) At the scheduled termination, the stented carotid was found patent in animals 1, 2, and 3, while persistent occlusions were noted for animals 4, 5, and 6. Carotid artery segments with stents were dehydrated in a graded series of ethanol and embedded in methylmethacrylate (MMA) resin. After polymerization, two to three millimeter length segments were sawed from the proximal, middle and distal portions of each stent. Histologic sections at 6-micron thickness were then prepared using a rotary microtome, mounted on charged glass slides, and stained with hematoxylin and eosin and Movat Pentachrome (connective tissue stain). Adjacent proximal and distal section segments to the stent were embedded in paraffin, sectioned at four to five microns, and stained with hematoxylin and eosin and Movat's Pentachrome. All sections were examined by light microscopy for the presence of inflammation, thrombus and neointimal formation and vessel wall injury.

(82) FIGS. 8A-8F are views of carotid artery segments of Animal 3. FIGS. 9A-9F are views of carotid artery segments of Animal 6.

(83) Histologic sections were analyzed with an NIST traceable calibrated microscope system (IP Lab software, Rockville, Md.). The cross-sectional areas (external elastic lamina [EEL], internal elastic lamina [IEL], and lumen) of a proximal, mid and distal stented section per segment were measured. Neointimal thickness was measured as the distance from the inner (abluminal) surface of each scaffold strut to the luminal border. Area measurements were used to calculate vessel layer areas with the following formulas:
Medial Area=EEL AreaIEL Area
Neointimal Area=IEL AreaLumen Area
% Stenosis=[1(Lumen Area/IEL Area)]*100

(84) Variables were first checked for normal distribution using Shapiro Wilk test then separated into variables with normal and non-parametric distribution. Mean values with standard deviation were derived from normally distributed parameters while non-parametric data were described as median with 25 percent and 75 percent quartiles. In the event of normal distribution, variables were compared using Student's t test or ANOVA with appropriate post hoc corrections for multiple comparisons, when applicable. Wilcoxon rank sum test was used when non-parametric data were compared. A value of p0.05 was considered statistically significant.

(85) A morphometric comparison of the cross-sectional vessel areas and neointimal thickness of animals 1-4 and 5-6 is shown in Tables IV and V, below. The comparison includes vessel meansstandard deviation of all sections of the vessels (proximal, mid, and distal).

(86) TABLE-US-00004 TABLE IV A morphometric comparison of the cross-sectional vessel areas and neointimal thickness of Animals 1-4 and 5-6. A value of p 0.05 was considered to be statistically significant. Lumen Medial LCCA Area Area Animals sections (mm.sup.2) (mm.sup.2) 1-4 n = 12 3.61 0.95 0.09 0.09 5-6 n = 6 2.91 0.58 0.05 0.04 p-value 0.0602 0.1710

(87) TABLE-US-00005 TABLE V A morphometric comparison of the cross- sectional vessel areas and neointimal thickness of Animals 1-4 and 5-6. A value of p 0.05 was considered to be statistically significant. Neointimal Neointimal Stenosis Thickness Animals Area (mm.sup.2) (%) (mm) 1-4 2.36 0.54 40.25 11.52 0.22 0.13 5-6 2.82 0.3 49.50 6.66 0.36 0.06 p-value 0.0360 0.0450 0.0116

(88) As indicated in Table V. above, the neointimal area, the stenosis and the neointimal thickness each had a p-value of less than 0.05, thereby indicating that delivering paclitaxel via a drug-coated balloon catheter after laser revascularization of a chronic total occlusion, in comparison to performing balloon angioplasty followed by delivering paclitaxel via a drug-coated balloon catheter, provides an appreciable therapy in maintaining long-term patency for the treatment of peripheral artery disease.

(89) Lesions treated with balloon angioplasty and drug-coated balloon systems tended to show an absence of endothelium within the stent along with plaque debris consisting mainly of macrophage-derived foam cells, free cholesterol, and platelets/fibrin. Chronic inflammatory cell infiltration was also noted within neointimal tissue. The inhibition of the healing response, evidenced by poor endothelialization, along with the presence of fibrin and inflammatory cells suggests a paclitaxel drug effect within this group.

(90) Lesions treated with laser ablation and drug-coated balloon systems also tended to show poor endothelialization with adherent inflammatory cells over underlying fibrotic tissue, which was often acellular. The lumens showed evidence of surface fibrin and/or aggregated fibrin and inflammation with focal areas of neointimal thinning. Fibrin and inflammatory cell staining was implied as being more prominent than in the balloon angioplasty and drug-coated balloon group, which may indicate a stronger paclitaxel drug effect. The higher percentage of patent lumens found in the laser atherectomy and drug-coated balloon group suggests that laser ablation allows for a greater paclitaxel response, the removal of stenotic material prevents reocclusion of the vessel, or a combination thereof.

(91) Stated another way, the results suggest that using a laser system not only removes stenosis, but it also surprisingly and unexpectedly sensitizes the vessel wall to enhance the ability of the drug delivered by a balloon system to reduce the amount of restenosis in comparison to methods that employ balloon angioplasty and drug-coated balloon systems.

(92) Animal Study II.

(93) A second animal study involved six pigs, which were utilized to evaluate the difference in vascular drug uptake between arteries treated with laser ablation prior to drug-coated balloon treatment and arteries treated with balloon angioplasty and drug-coated balloon without laser ablation treatment. On Day 0, each animal (pig) underwent a denudation and vessel over-stretch procedure in the right and left external femoral arteries in an effort to trigger a stenosis response for lesion creation.

(94) Approximately 21 days later the animals underwent another vessel denudation procedure as well as thrombin injection into the vessel to create the total occlusion. Two days following the second denudation procedures, ultrasound was performed to ensure occlusions were intact. However, none of the thrombin induced occlusions were observed to be in place at follow-up. Thrombin was re-dosed four days later and the vessels ligated to enhance stability of the thrombin induced occlusions. The ligatures were removed immediately prior to the treatment procedures. At Day 35 post the initial treatment, the animals underwent the treatment procedures with laser ablation and drug-coated balloon or balloon angioplasty and drug-coated balloon. On Day 49 the animals were humanely euthanized and sent to necropsy. In necropsy, the animals were grossly examined for abnormalities and the treated vessels were harvested for histological analysis.

(95) The study pathologist was blinded during the evaluation. Upon completion of scoring and evaluation, the pathologist was unblinded by the study director for completion of the report. Semi-quantitative morphological observations were recorded to assess the biological response of vascular tissue to treatment. Differences in scoring parameters between the control and test were considered meaningful based on frequency distribution of the grades within each scoring parameter.

(96) One animal (Animal #1) died prematurely within one day after the treatment procedure and one animal (Animal #2) was terminated early (five days after the treatment procedure) due to health issues.

(97) The following abnormalities were noted at necropsy and histopathologically: In Animal #1, a large hematoma was observed surrounding both treated arteries and the left external femoral (LEF) and right external femoral (REF) arteries had a tear in the vessel wall. These findings were histologically correlated with ruptured internal elastic lamina (IEL), media and external elastic lamina (EEL) structures in these arteries. In Animal #2, there was a mass above the LEF treatment site. The mass was filled with fresh and clotted blood. The REF and LEF arteries had a tear in the vessel wall. These findings were histologically correlated with ruptured IEL, media and EEL structures in these arteries. All of these gross and histopathological abnormalities were considered to be related to the treatment procedure and were present in both treatment groups.

(98) Scheduled Animals

(99) The following findings were noted at necropsy and histopathologically: there was firm white tissue (scar) surrounding the treated vessels/access sites noted at necropsy in all animals. This finding was histologically correlated with the presence of adventitial fibrosis and adventitial inflammation and it was considered to be an expected finding related to the surgical procedure. Sections of the REF artery from Animal #3 and the LEF artery from Animal #4 had occlusive thrombus in the lumen. Thrombus generation likely occurred in the vessels after the treatment procedure due to severe vessel wall injury. These samples were not included in the final analysis.

(100) Endothelial Cell Coverage

(101) Endothelial cell coverage was greater in the control and untreated vessel when compared to the test group. Since paclitaxel can inhibit re-endothelialization, the test group likely had greater paclitaxel uptake or exposure to the lumen surface than the control group.

(102) Luminal Thrombus

(103) There was thrombus present in nine of ten ( 9/10) test group sections examined and in two of ten ( 2/10) control sections. Thrombus ranged from minimal to marked. The thrombi in the test group tended to be larger when compared to the control group.

(104) Neointimal Hyperplasia and Maturity

(105) In the test group, some sections had low-maturity neointima. In contrast, in the control group, the neointima was more mature. These differences may be due to greater paclitaxel uptake or greater exposure of the lumen surface to paclitaxel within the test group.

(106) Inflammation

(107) The amount of inflammation in the test group was greater when compared to the control group or untreated vessel. This finding may be due to greater paclitaxel uptake or exposure to paclitaxel in the test group.

(108) Fibrin

(109) The amount of fibrin in the test group was greater when compared to the control group or untreated vessel. This finding was likely due to a greater paclitaxel uptake or exposure of the lumen surface to paclitaxel in the test group.

(110) Medial Smooth Muscle Cell (SMC) loss and Medial Fibrosis (Proteoglycans and Collagen)

(111) Subjectively, medial smooth muscle cell (SMC) loss and the presence of proteoglycans and collagen in the media were greater in the test group when compared to the control group. These differences were likely due to greater paclitaxel uptake or exposure of the lumen surface to paclitaxel in the test group.

(112) Adventitial Fibrosis

(113) Adventitial fibrosis was greater in the test group when compared to the control group. These differences may be due to greater paclitaxel uptake or exposure of the lumen surface to paclitaxel in the test group.

(114) Mineralization

(115) Mineralization was more frequent in the test group when compared to the control group. These differences may be due to greater paclitaxel uptake or exposure of the lumen surface to paclitaxel in the test group.

(116) Results Summary

(117) Lower re-endothelialization, lower neointimal maturity, greater SMC loss, increased collagen/proteoglycans in the media, increased inflammation and increased adventitial fibrosis were all noted in the treatment group as compared to the control group. All of these characteristics have been reported following vascular exposure to paclitaxel (drug effects). However, since both groups received the same paclitaxel treatment and since these drug effects were more evident in the treatment group, it is likely that laser atherectomy prior to drug-coated balloon use enhances the paclitaxel related drug effects. This may occur as a result of the removal of atherosclerotic tissue that can act as a barrier to paclitaxel uptake, by the creation of (micro) channels in the atherosclerotic tissue that can facilitate paclitaxel uptake or a combination thereof. Regardless, adjunctive therapy of paclitaxel delivery with a balloon catheter post laser revascularization of a chronic total occlusion (CTO) does appear to show an appreciable treatment effect beyond that of balloon angioplasty and drug-coated balloon, which may provide a translational perspective of this therapy in maintaining long-term patency for the treatment of peripheral artery disease.

(118) Grading

(119) A histopathological grading scale that was used to evaluate each animal is as follows. The results obtained by applying the histopathological grading scale are shown below in Tables VI A and B.

(120) Luminal Thrombus

(121) Luminal thrombus was defined as any thrombus not covered with endothelial cells and consisting of some combination of leukocytes, erythrocytes, platelets and fibrin. Grade 0: No luminal thrombus Grade 1 (Minimal): Occupies <5 percent of the lumen area Grade 2 (Mild): Occupies 5-35 percent of the lumen area Grade 3 (Moderate): Occupies 35-70 percent of the lumen area Grade 4 (Severe): Occupies >70 percent of the lumen area

(122) Endothelial Cell Coverage Grade 0 (Absent): <5 percent of the luminal surface covered Grade 1 (Minimal): 5-25 percent of the luminal surface covered Grade 2 (Mild): 25-50 percent of the luminal surface covered Grade 3 (Moderate): 50-90 percent of the luminal surface covered Grade 4 (Complete): >90 percent of the luminal surface covered

(123) Inflammation Grade 0: No inflammatory response Grade 1: Minimal response Grade 2: Mild response Grade 3: Moderate response Grade 4: Severe response

(124) Fibrin Grade 0: Not present Grade 1: Minimal Grade 2: Mild Grade 3: Moderate Grade 4: Severe

(125) SMC Loss Grade 0: No medial SMC loss Grade 1: Minimal <5 percent medial SMC loss Grade 2: Mild 5-25 percent medial SMC loss Grade 3: Moderate 25-50 percent medial SMC loss Grade 4: Severe >50 percent medial SMC loss

(126) Medial Fibrosis (Proteoglycans and Collagen) Grade 0: No changes Grade 1: Minimal <5 percent of the area with changes Grade 2: Mild 5-25 percent of the area with changes Grade 3: Moderate 25-50 percent of the area with changes Grade 4: Severe >50 percent of the area with changes

(127) Disruption of the Internal Elastic Lamina (IEL) Grade 0: No disruption Grade 1: Minimal <5 percent disruption Grade 2: Mild 5-25 percent disruption Grade 3: Moderate 25-50 percent disruption Grade 4: Severe >50 percent disruption

(128) Adventitial Fibrosis Grade 0: No changes Grade 1: Minimal <5 percent of the area with changes Grade 2: Mild 5-25 percent of the area with changes Grade 3: Moderate 25-50 percent of the area with changes Grade 4: Severe >50 percent of the area with changes

(129) Neointimal Hyperplasia and Maturity Grade 0: Not present Grade 1: Minimal Grade 2: Mild Grade 3: Moderate Grade 4: Severe

(130) Mineralization Grade 0: Not present Grade 1: Minimal Grade 2: Mild Grade 3: Moderate Grade 4: Severe

(131) TABLE-US-00006 TABLE VI A Histopathology scoring for Animals 1-6. A value of p 0.05 was considered statistically significant. Neointimal Neointimal Neointimal Group Thrombus Endothelialization Hyperplasia Maturity Inflammation Fibrin Laser and 2.3 2 1 1.5 0.6 2.3 D-C Ballon- Mean Balloon 0.2 2.8 1.2 2.9 0.1 0.7 Angioplasty and D-C Ballon- Mean T-test 0.001* 0.044* 0.250 0.007* 0.061 0.006* p 0.05*

(132) As indicated in Table VI A. above, the thrombus, the endothelialization, the neointimal maturity and the fibrin each had a p-value of less than 0.05, thereby indicating that delivering paclitaxel via a drug-coated balloon catheter after laser revascularization of a chronic total occlusion, in comparison to performing balloon angioplasty followed by delivering paclitaxel via a drug-coated balloon catheter, provides an appreciable therapy in maintaining long-term patency for the treatment of peripheral artery disease.

(133) TABLE-US-00007 TABLE VI B Histopathology scoring for Animals 1-6. A value of p 0.05 was considered statistically significant. IEL SMC Medial Adventitial Advential Group disruption loss Inflammation Inflammation Fibrosis Mineralization Laser and 2.3 2 1 1.5 0.6 2.3 D-C Ballon- Mean Balloon 0.2 2.8 1.2 2.9 0.1 0.7 Angioplasty and D-C Ballon- Mean T-test 0.001* 0.044* 0.250 0.007* 0.061 0.006* p 0.05*

(134) As indicated in Table VI B. above, the adventitial inflammation and the adventitial fibrosis each had a p-value of less than 0.05, thereby indicating that delivering paclitaxel via a drug-coated balloon catheter after laser revascularization of a chronic total occlusion, in comparison to performing balloon angioplasty followed by delivering paclitaxel via a drug-coated balloon catheter, provides an appreciable therapy in maintaining long-term patency for the treatment of peripheral artery disease.

(135) A number of variations and modifications of the disclosure can be used. As a specific example, the methods described above employ separate laser catheters and balloon systems. However, methods according to embodiments of the present disclosure could be performed using a laser catheter and balloon system that are part of a common or all-in-one device. As another example, it would be possible to provide for some features of the disclosure without providing others.

(136) The present disclosure, in various aspects, embodiments, and configurations, includes components, methods, processes, systems and/or apparatus substantially as depicted and described herein, including various aspects, embodiments, configurations, subcombinations, and subsets thereof. Those of skill in the art will understand how to make and use the various aspects, aspects, embodiments, and configurations, after understanding the present disclosure. The present disclosure, in various aspects, embodiments, and configurations, includes providing devices and processes in the absence of items not depicted and/or described herein or in various aspects, embodiments, and configurations hereof, including in the absence of such items as may have been used in previous devices or processes, for example, for improving performance, achieving ease and/or reducing cost of implementation.

(137) The foregoing discussion of the disclosure has been presented for purposes of illustration and description. The foregoing is not intended to limit the disclosure to the form or forms disclosed herein. In the foregoing Detailed Description for example, various features of the disclosure are grouped together in one or more, aspects, embodiments, and configurations for the purpose of streamlining the disclosure. The features of the aspects, embodiments, and configurations of the disclosure may be combined in alternate aspects, embodiments, and configurations other than those discussed above. This method of disclosure is not to be interpreted as reflecting an intention that the claimed disclosure requires more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single foregoing disclosed aspects, embodiments, and configurations. Thus, the following claims are hereby incorporated into this Detailed Description, with each claim standing on its own as a separate preferred embodiment of the disclosure.

(138) Moreover, though the description of the disclosure has included description of one or more aspects, embodiments, or configurations and certain variations and modifications, other variations, combinations, and modifications are within the scope of the disclosure, for example, as may be within the skill and knowledge of those in the art, after understanding the present disclosure. It is intended to obtain rights which include alternative aspects, embodiments, and configurations to the extent permitted, including alternate, interchangeable and/or equivalent structures, functions, ranges or steps to those claimed, whether or not such alternate, interchangeable and/or equivalent structures, functions, ranges or steps are disclosed herein, and without intending to publicly dedicate any patentable subject matter.