Device and method for selectively inducing vasoconstriction to enhance tissue uptake of therapeutic agents - Patent Application 20070122999

Abstract

A microcatheter is provided having a vasospasm-inducing probe at its distal end. The vasospasm-inducing probe may include an electric current, radio frequency, ultrasound, chemical, or thermal modulator. When the vasospasm-inducing probe is activated within a blood vessel, the blood vessel constricts around the element. This constriction acts as a pseudo-valve, preventing backflow of therapeutic agents through the narrowed portion of the blood vessel while allowing therapeutic agents to be delivered under high pressure through the infusion lumen and out the open pores.

Description

[Technical Field]

[0001] This application claims priority to U.S. Patent Application No. 18 / 087,508, filed December 22, 2022, which is incorporated by reference in its entirety into this disclosure.

[0002] The medical procedures described in this disclosure relate generally to methods for intravenous treatment of target organs for cancer or other diseases. [Background technology]

[0003] In some cases, systemic therapies are used to treat diseases in patients. Some of these systemic therapies have variable efficacy, at least in part because the therapeutic agents (e.g., radioembolic agents, biological agents, and / or other therapeutic preparations) do not reach the targeted tissue. For example, in the treatment of some diseases, such as cancer and / or diabetes, it may be desirable to deliver living cells to organs where they can engraft efficiently and safely.

[0004] The ineffectiveness of systemic chemotherapy is at least in part due to insufficient drug concentrations within the tumor due to dose-limiting toxicity in bone marrow and epithelial tissues. Another complication can be peripheral neuropathy. Yet another complication results from the systemic administration of checkpoint inhibitors, which cause overactivation of the immune system. Because systemic chemotherapy has limited efficacy or is significantly complicated, treatments other than systemic chemotherapy may be desirable for many types of cancer patients.

[0005] One option is local intra-arterial delivery of chemotherapy drugs. Intra-arterial infusion can deliver high concentrations of drugs to tumors. Furthermore, intra-arterial chemotherapy can take advantage of the first-pass effect of chemotherapy drugs, resulting in high drug concentrations at tumor cell membranes and therefore higher drug uptake by cells compared to intravenous systemic infusion. Additionally, local delivery can reduce systemic side effects that may occur if the drug disperses rather than remaining localized.

[0006] Standard end-hole catheters offer limited control over the amount of local therapeutic agent injected. Injection adds a local volume to a nearly incompressible system. The injected therapeutic agent flows from an area of ​​higher pressure to an area of ​​lower pressure. The added volume of therapeutic agent has to go somewhere, and if the downstream resistance and pressure are higher than the upstream resistance, backflow to non-target areas will occur.

[0007] To alleviate some of these problems, commonly owned U.S. Patent Nos. 8,696,698, 9,968,840, and 10,588,636 describe various pressure-regulating therapeutic drug delivery devices in the form of an injection catheter with an integrated microvalve attached to its distal end. The microvalve dynamically expands and contracts within the blood vessel in relation to the vessel's surrounding fluid pressure. The therapeutic drug can be injected through the catheter. When the therapeutic drug is injected, the pressure downstream (distal) of the blood vessel from the treatment site can sometimes be higher than the pressure upstream (proximal) of the treatment site, and the microvalve can prevent backflow of the therapeutic drug. Additionally, the microvalve allows injection into the target tissue at a modified pressure, thereby targeting the therapeutic drug to the desired tissue.

[0008] These pressure-regulating therapeutic devices function extremely well for their intended purposes. However, there are therapeutic scenarios in which it is desirable to deliver the therapeutic device through vessels that are too small and tortuous to accommodate current microvalves. Furthermore, current sizes of mechanical microvalves have limited delivery capabilities through these tortuous vessels. Summary of the Invention

[0009] Several systems and methods for pressure-controlled therapeutic agent delivery are provided. The systems of the present invention are capable of introduction into tumor-feeding blood vessels and do not rely on mechanical actuation of microvalves. In some embodiments, each system includes a microcatheter having a proximal end and a distal end, and an infusion lumen extending from the proximal end to the distal end of the microcatheter and opening at a distal orifice. The microcatheter is equipped with a vasospasm-inducing system. For purposes of this disclosure, vasospasm is the narrowing of a blood vessel, typically due to vasoconstriction, caused by contraction of smooth muscle lining the blood vessel. Vasospasm, vasoconstriction, and more generally spasm are terms related to this same phenomenon and are used interchangeably in this disclosure. The severity of vasospasm occurs along a spectrum from mild narrowing of the blood vessel to complete occlusion. The vasospasm-inducing system includes a spasm-inducing probe at or adjacent to the distal end of the microcatheter and an actuator for actuating the spasm-inducing element. By way of example only, vasospasm-inducing probes can be, for example, radio frequency (RF) emitters of current, voltage, or magnetic or electromagnetic fields, cryogenic probes, infrared probes, mechanical vibration emitters, or mechanical stimulation devices. Vasospasm-inducing systems described in the present disclosure include devices configured to constrict blood vessels to various degrees.

[0010] When the vasospasm-inducing probe is activated within a blood vessel, the induced spasm within the blood vessel creates a constriction around the spasm-inducing probe, which acts as a pseudo-valve or natural valve, preventing backflow past the constriction in the blood vessel while allowing therapeutic agents to be delivered through the infusion lumen and out the aperture at a pressure range set by the user.

[0011] In one method, the system of the present invention is used to deliver a therapeutic agent downstream of a stenosis under user-set pressure and is then withdrawn from the patient.

[0012] In another approach, the system of the present invention is used to control and modify flow within the vasculature prior to delivery of a therapeutic agent to optimize therapeutic flow to the tumor. Prior to delivery of the therapeutic agent, a spasm-inducing probe is activated to create a stenosis, reducing flow within the vessel. While healthy downstream vessels respond by constricting, tumor vessels do not respond appropriately to the reduced pressure and remain substantially open. This creates a vascular pathway for the trapped flow to be directed toward the tumor. The therapeutic agent is then injected and directed toward the tumor.

[0013] Alternatively, the system of the present invention may be used to induce constriction in the bleeding vasculature to reduce bleeding, and a therapeutic agent may be delivered to treat the bleeding vessel.

[0014] In another embodiment of the system described herein, a microcatheter is provided substantially as described above, but the spasm-inducing probe is replaced by an ablation probe. In a preferred embodiment, the ablation probe can be implemented using the same modality for inducing spasm; i.e., the ablation probe can be an RF emitter, an ultrasound emitter, a chemical emitter, a temperature probe, an infrared emitter, a mechanical vibration emitter, or a stimulus generator, all of which operate with energy sufficient to ablate tissue but not vasospasm. Furthermore, other energy emitters operable to ablate tissue, such as microwave emitters, can also be used as ablation probes. As described above, the system of the present invention includes an actuator at the proximal end of the microcatheter, which is operably connected to the ablation probe. The microcatheter does not necessarily need to infuse a therapeutic agent, as the intended therapeutic effect is provided by tissue ablation, as described below. However, the microcatheter preferably includes a central lumen sized to accommodate a guidewire.

[0015] In use, a mapping procedure is performed to identify distinct arterial vessels feeding a solid tumor. Once the vessel is identified, the femoral or radial artery is accessed, and a guidewire is advanced from the femoral or radial artery to the distinct arterial vessel feeding the tumor. A microcatheter is then advanced over the guidewire to the target vessel. The guidewire is then removed. Alternatively, a microcatheter can be advanced directly without a guidewire. The ablation probe is then activated to ablate the surrounding arterial vessels feeding the tumor. Ablation results in occlusion and / or collapse of the artery, preventing nutrient blood flow to the tumor, thereby preventing further tumor growth and / or shrinking the tumor. The system of the present invention can be repositioned or removed to ablate additional vessels.

[0016] The system of the present invention can be used for treatment in blood vessels where end-hole or conventional catheters, balloon catheters, or microvalve catheters are used to inject therapeutic agents. In particular, the system and method of the present invention can be used in blood vessels to treat tumors in organs throughout the human body. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is a schematic diagram of the treatment system described in this disclosure.

[0018] [Figure 2] FIG. 2 is a schematic diagram of the distal end of the treatment system of FIG.

[0019] [Figure 3] FIG. 3 is a schematic diagram of another embodiment of the distal end of the treatment system of FIG.

[0020] [Figure 4] FIG. 4 is a schematic diagram of another embodiment of the distal end of the treatment system of FIG.

[0021] [Figure 5] FIG. 5 is a schematic diagram of yet another embodiment of the distal end of the treatment system of FIG.

[0022] [Figure 6-8] 6-8 illustrate one method of use of the treatment system described in this disclosure.

[0023] [Figure 9-10] 9 and 10 illustrate another method of using the treatment system described in this disclosure.

[0024] [Figure 11] FIG. 11 is a schematic diagram of another processing system described in this disclosure.

[0025] [Figure 12-13] 12 and 13 illustrate the use of the processing system shown in FIG.

[0026] [Figure 14-15] 14 and 15 are schematic diagrams of yet another embodiment of the distal end of the processing system of FIG.

[0027] [Figure 16] FIG. 16 illustrates a method of using the processing system described in this disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0028] In this disclosure, when referring to the human body and to components of devices and systems intended to be manually manipulated by a user, the terms "proximal" and "distal" are defined relative to the user's hand, i.e., unless otherwise specifically indicated, "proximal" means closer to the user's hand and "distal" means farther from the user's hand.

[0029] Referring to FIG. 1, one embodiment of a system 10 of the present disclosure includes a microcatheter 12 having a proximal end 14 and a distal end 16. The microcatheter 12 is preferably 2-8 feet in length, depending on the therapeutic agent used, and has an outer diameter of 0.67 mm to 3 mm (corresponding to catheter sizes 2-12 French). It also has an infusion lumen 20 with an inner diameter of 0.25 mm to 1.85 mm. For example, for relatively low-viscosity liquid therapeutic agents, an inner diameter in the range of 0.254 mm to 0.889 mm is preferred; for relatively medium-viscosity embolic or cellular therapeutic agents, an inner diameter in the range of 0.46 mm to 1.42 mm is preferred; and for relatively high-viscosity gel plugs, an inner diameter in the range of 0.51 mm to 1.85 mm is preferred. The microcatheter 12 preferably includes an inner liner, an inner braid, and an outer coating. By way of example, the liner may be a fluorinated polymer such as polytetrafluoroethylene (PTFE) or fluorinated ethylene propylene (FEP). Illustratively, the braid may be made of a metal such as stainless steel or a nickel-titanium alloy, or a polymer such as polyethylene terephthalate (PET) or a liquid crystal polymer, or other standard or specialized materials used in the manufacture of braids used within the bloodstream. Illustratively, the outer coating may be made of a thermoplastic elastomer resin such as a polyether block amide resin such as Pebax®, polyurethane, polyamide, polyamide copolymer, polyester, polyester copolymer, fluorinated polymer such as PTFE or FEP, polyimide, polycarbonate, or other suitable material, or other standard or specialized materials used in the manufacture of catheters used within the bloodstream.

[0030] The proximal end 14 of the microcatheter preferably includes a hub 18. An infusion lumen 20 extends from the hub 18 through the distal end 16 of the microcatheter and exits via a distal tip 22. The hub 18 and infusion lumen 20 are configured to deliver a therapeutic agent from outside the patient's body to a target blood vessel (artery or vein) of the patient. The hub 18 is also configured to facilitate passage of a guidewire through the infusion lumen 20. Any hub suitable for at least facilitating delivery of a therapeutic agent to the infusion lumen may be utilized.

[0031] In a preferred aspect of the system of the present invention, a vasospasm-inducing system including a probe 26 is provided at or adjacent to the distal end 22 of the microcatheter 12. An actuator 28 is operably connected to the system 10 for powering and / or actuating the probe 26. The distal tip 22 of the microcatheter 12 preferably projects beyond the spasm-inducing probe 26 such that the spasm-inducing probe 26 is spaced proximally from the distal tip.

[0032] One or more marker bands 30 are provided proximal and / or distal to the spasm-inducing probe 26. The marker bands 30 may be radiopaque. During use of the instrument, the internal location of the one or more marker bands 30 as viewed under fluoroscopy or via other imaging techniques indicates the location of the spasm-inducing probe 26 relative to anatomical landmarks.

[0033] Referring to FIG. 2 , in one embodiment of the system of the present invention, the spasm-inducing probe 26 is a radio frequency emitter and the actuator 28 is a sinusoidal current generator. The radio frequency probe 26 includes first and second spaced electrodes 32, 34. Electrical control wires 36, 38 extend along the length of the microcatheter 12 to the first and second electrodes 32, 34. The control wires 36, 38 may be incorporated into the microcatheter braid, extend along the exterior of the microcatheter, extend within the infusion lumen, or otherwise be embedded in the microcatheter's liner or outer polymer coating. When the actuator 28 is activated, it causes a suitable radio frequency to be emitted by the probe 26, causing spasm that narrows a portion of the blood vessel surrounding the probe. In this embodiment, the actuator 28 is configured to deliver energy to the probe 26 that is insufficient to cause ablation or, preferably, other permanent tissue damage.

[0034] In an optional aspect of the invention, a second infusion lumen 40 accessible through hub 18 leads to one or more openings 42 at the distal end of probe 26. Preferably, multiple openings 42 are circumferentially spaced at or adjacent to the probe for radial distribution of the agent relative to catheter 12. Second infusion lumen 40 and openings 42 are provided for delivery of a vasodilator agent in a manner described below.

[0035] Referring to FIG. 3, in another embodiment of the system of the present invention, the spasm-inducing probe 126 is an ultrasound emitter. The ultrasound emitter is a high-frequency acoustic wave probe. The actuator 28 (FIG. 1) includes an ultrasound generator and a power source. One or more control wires 136 extend along the length of the catheter from the actuator 28 to the probe 126. When the actuator is activated, high-frequency acoustic waves are generated and emitted from the probe, thereby causing spasm of vascular tissue adjacent to the probe. This spasm narrows the vascular tissue relative to the adjacent probe. This system embodiment can be used in the same manner as the system embodiments described above. The probe 126 can also be associated with a second infusion lumen for delivery of a vasodilator, as described above. An exemplary second infusion lumen opening 142 is shown distal to the probe 126.

[0036] Referring now to FIG. 4, in another embodiment of the system of the present invention, the twitch-inducing probe is a chemical emitter 226. The chemical emitter 226 can controllably release a chemical that constricts blood vessels. Such chemicals include, but are not limited to, adrenaline, oxymetazoline, phenylephrine, epinephrine, xylometazoline, naphazoline, tetrizoline, angiotensin II, vasopressin, felypressin, and midodrine. In one embodiment, the emitter 226 is preferably configured to release the chemical that constricts blood vessels by local diffusion from an element on or attached to the catheter, where the chemical slowly dissolves or is released from a compartment on the catheter. In one embodiment, the chemical emitter releases the chemical agent through circumferentially extending holes located around the catheter's circumference. The chemical agent may be injected through a dedicated second lumen in the microcatheter. In such an embodiment, the actuator can be a syringe or other dispenser for the chemical agent. In another embodiment, the chemical agent may be stored at the distal end of the microcatheter and covered by a membrane. The permeability of the membrane to the chemical agent may be altered by passing an electric current through the membrane. A control wire extends to the membrane, and an actuator includes a current source and activates the current extending along the control wire, changing the permeability of the membrane and causing the chemical agent to be released from the element. Alternatively, a retractable cover may be provided over the chemical agent, storing it for exposure at the desired time. In yet another embodiment, the chemical agent may be stored in an electroactive polymer gel on the probe. A current or voltage is applied to the gel to release the chemical agent. If contained in the gel, the chemical agent may be released from the gel by (1) forced convection separating the chemical agent from the gel along with syneresis / released water by an electric field, (2) diffusion, (3) electrophoresis of charged drugs, and (4) drug release upon erosion of electroerodible drugs. Other systems for releasing chemical agents operable to induce contractions may also be used. This system embodiment may be used in the same manner as the system embodiments described above. The second lumen can be used to deliver both chemical vasoconstrictors and chemical vasodilators.Alternatively, and by way of example only, a separate lumen and opening 243 may be provided proximally in the probe for delivering a vasodilator agent versus a vasoconstrictor agent.

[0037] In another embodiment of the system of the present invention, the spasm-inducing probe is a cryoprobe 326. The cryoprobe 326 may be cooled, for example, by a cryogenic coolant circulating within a coil 327. The coolant can be chilled water, air, liquid nitrogen, or other fluids passed through an insulated passage within or around the catheter from the proximal end of the microcatheter to the coil. Alternatively, a thermally conductive band can be used instead of a coil. Alternatively, the coolant can be injected into the inflation balloon to facilitate placement of the coolant adjacent to the vascular tissue. Exemplary coolants include chilled water, liquid argon, or liquid nitrogen, and refrigerated gas. The actuator 28 may include a coolant supply source, the activation of which initiates circulation of coolant from a syringe or pump to the thermally conductive band. In one embodiment, the cryoprobe cools localized tissue in the vasculature by 5-10°C to induce mild to moderate vasoconstriction, by 10-15°C to induce moderate to severe vasoconstriction, and by 15-25°C to induce maximal vasoconstriction. This system embodiment can be used in the same manner as the system embodiments described above. Probe 326 may also be associated with a second infusion lumen for delivery of a vasodilator to dilate constricted blood vessels at the end of treatment. Alternatively, probe 326 may be configured to be heated, for example, by liquid or electricity, to counteract the vasoconstriction caused by cooling.

[0038] In addition to the spasm-inducing probes exemplified above, other types of probes can be used as well. For example, an infrared light probe can be used as the probe. The probe can include optical fibers and elements that can focus and / or disperse infrared energy to heat and stimulate the blood vessel wall sufficiently to cause the blood vessel to contract.

[0039] The probe may also include a mechanical vibrator. The actuator for the vibrating element can adjust the frequency and amplitude of vibration in the probe. By way of example, the vibrating element may be a piezoelectric or electromechanical vibrator. The vibrating element may operate in the range of 5 Hz to 20,000 kHz. More preferably, the element operates in the range of 10 to 100 Hz. Low-frequency, high-amplitude vibrations are expected to provide the stimulation necessary to induce vasoconstriction. Various controls for the actuator also provide suitable stimulation. The vibrating element probe may be associated with a second infusion lumen for delivery of a vasodilator, as described above.

[0040] 14 and 15, in yet another embodiment of the system of the present invention, spasm-inducing probe 826 is a mechanical stimulation generator. Probe 826 includes bristles 827 at the end of catheter 812. Bristles 827 are deployable from a retractable sheath 830 (FIG. 14) or otherwise covered until ready for use, at which point sheath 830 is retracted by manipulating an actuator, such as a handle, to expose bristles 827 (FIG. 15). Bristles 827 may be of fine, elastic structure, such as nickel titanium or plastic. Bristles 827 should be extremely short to avoid trauma to tissue. Bristles 827 are short so that their ends contact and rub against the vessel wall, creating a stimulating tickling action. Bristles may be coupled to a vibrating element (described above) to amplify the stimulation of vasculature tissue and, consequently, spasm. Probe 826 may be associated with a second infusion lumen for delivery of a vasodilator, as described above.

[0041] System 10 can be used to inject therapeutic agents into targeted blood vessels that branch off from large main blood vessels and are connected to, for example, solid tumors in an organ. In some cases, the tumors may be cancerous, such as those characteristic of cancers of the pancreas, spleen, or small intestine. Additionally, other non-cancerous pathological conditions in organs may also be treatable using the systems and methods of the present invention.

[0042] As described below, the treatment system of the present invention is used to deliver a therapeutic agent to a tumor within a target region of an organ, allowing for targeted treatment of the target region with the therapeutic agent and substantial isolation of the therapeutic agent within the target region, all without isolating an unduly large region from the bloodstream during treatment, as opposed to treatment delivered to the systemic circulation throughout the body.

[0043] 1 and 6, the distal end of the system of the present invention is introduced into a site of interest, such as a small blood vessel 400 feeding a tumor 402. A guidewire 404 may be advanced into the target vessel 400 to facilitate introduction. Furthermore, intravascular introduction of the microcatheter system 10 into the vessel 400, whether along or with the guidewire 404, is preferably performed during imaging. Positioning of the spasm-inducing probe 26 (probe 26 is intended to refer to any of the spasm-inducing probe embodiments) at the intended location within the vasculature can be confirmed by injecting contrast through the infusion lumen 20 and out of the distal aperture 24 of the microcatheter to visualize the position of the one or more markers 30 relative to the vasculature and the irradiated structure.

[0044] 1 and 7, once the treatment system 10 is confirmed to be in place within the target blood vessel 400, the actuator 28 is activated so that the spasm-inducing probe 26 induces spasm 406 within the blood vessel. The spasm narrows the blood vessel relative to the system at the location of the spasm-inducing probe 26.

[0045] 1 and 8, while the blood vessel 400 is in a spasm state 406, a therapeutic agent 408 is infused under pressure through the hub 18 and the infusion lumen 20 and out the distal aperture 24 into the tumor 402 or other target tissue. The narrowed blood vessel at the spasm 406 prevents backflow of the therapeutic agent 408, maintaining high pressure delivery of the therapeutic agent into the tumor or other target tissue downstream of the spasm 406.

[0046] Once the therapeutic agent is delivered, a therapeutic action can be taken to at least counteract the constriction of the blood vessels before removing the catheter. A chemical vasodilator can be delivered through the second lumen, as described above. Alternatively, if constriction is induced by cooling, the tissue can be heated. Other suitable methods can be used to constrict or reduce the blood vessels or to dilate the blood vessels. The treatment system can then be withdrawn from the patient.

[0047] 1, 9, and 10, in another method applicable to any of the systems described above, a system 10 can be used to control flow within a vasculature before and during therapeutic agent delivery to direct (divert) and optimize therapeutic agent flow to a tumor 502. The distal end 16 of a microcatheter 12 of the system 10 is introduced into a target blood vessel 500 of interest. This may be accomplished using a guidewire, contrast agent, and / or imaging, as described above. The introduction location is preferably upstream (proximal) of a branching system 510 that leads to both healthy vasculature 512 and tumor-bearing vasculature 514. Once the spasm-inducing probe 26 of the treatment system 10 is confirmed to be in place within the target blood vessel 500, the actuator 28 is activated, causing the spasm-inducing probe 26 to induce spasm 506 within the blood vessel 500. With spasm induced, flow to and pressure within both the healthy blood vessel 512 and the tumor-bearing blood vessel 514 are reduced. The healthy blood vessel 512 responds to the reduced flow and pressure by constricting. However, due to disease in the tumor vasculature 514, the tumor vasculature does not constrict in the same way when exposed to similar low fluid pressures, and the tumor vasculature does not constrict or constricts only to a very small extent.

[0048] Next, with spasm-inducing probe 26 still activated, therapeutic agent 508 is injected through the infusion lumen of the system, configured to be directed to flow into tumor 502 primarily through the tumor vasculature, which remains substantially open due to vasoconstriction of healthy blood vessel branches 512, and remains substantially unconstricted. Additionally, the available vascular volume downstream of the spasm allows for high pressure injection into the tumor.

[0049] At the end of the infusion, pressure within the vessels rises, and healthy tissue attempts to dilate the vessels to reduce the pressure. The tumor's vasculature does not do the same, so it redirects flow toward the healthy tissue. This counters the goal of minimizing flow to the diseased tissue, so the spasm-inducing probe 26 preferably remains active, restricting antegrade flow within the vessels even at the end of the infusion to limit dilation of healthy vessels. While dilation of healthy vessels is inhibited, this provides the best route for the therapeutic agent to the tumor through the tumor vasculature.

[0050] In one aspect of the method of the present invention, the spasm-inducing probe may be activated and the therapeutic agent may be injected in pulses to minimize constriction of healthy blood vessels. Pulses may be spaced 0.3 to 60 seconds apart. The pulses optimize constriction and prevent dilation of healthy vasculature to redirect the flow of the therapeutic agent, aiding in uptake of the therapeutic agent at the tumor.

[0051] At the end of treatment, a therapeutic action can optionally be taken to at least partially counteract the constriction of the blood vessels before removing the treatment system from the patient. A chemical vasodilator can be delivered through the second lumen, as described above. Alternatively, if constriction was induced by cooling, the tissue can be heated. Other suitable methods can be used to reduce constriction or otherwise dilate the blood vessels. The treatment system is then withdrawn from the patient.

[0052] Referring now to FIG. 11 , another system 610 is shown. System 610 is substantially similar to system 10 described above (similar parts are numbered with the addition 600). In contrast to spasm-inducing probe 26, system 10 includes an ablation probe 626. Ablation probes and spasm-inducing probes are substantially similar in structure, differing only in the energy output by the probes. That is, spasm-inducing probe 26 is configured to temporarily induce spasm in vascular tissue but not intentionally cause permanent occlusion of the blood vessel, whereas ablation probe 626 is configured to emit sufficient energy to cause longer-term, even permanent, changes in vascular tissue, resulting in occlusion of the blood vessel or disruption of the blood vessel's supply to the organ or tissue it nourishes. Thus, the actuator 628 may be configured to generate different radio frequency energies (e.g., from high currents), different ultrasonic energies (e.g., from different frequencies and / or amplitudes), different chemical energies (e.g., from different chemicals and / or different amounts of chemicals), or different thermal energies (e.g., from cooling or heating temperatures using the same or different cryogenic fluids). Additionally, other methods of ablation may be used. For example, a microwave emitter may be provided in the ablation probe 626. The actuator 628 may power and activate the ablation emitter. By way of example, the actuator is configured to operate at 50 W and 5.80 GHz, although other suitable frequency bands and powers may be used. The microcatheter 612 need not necessarily be infused with a therapeutic agent, as the intended therapeutic effect is achieved by tissue ablation, as described below. However, the microcatheter 612 includes an infusion lumen 620 sized for advancing the microcatheter over a guidewire.

[0053] Referring to Figures 12 and 13, in use, a mapping procedure is performed to identify distinct arterial vessels feeding a solid tumor. Once the target vessel 700 is identified, the femoral or radial artery is accessed, and a guidewire is advanced through the artery to the target vessel feeding the tumor. A microcatheter 612 is then advanced over the guidewire into the target vessel 700. The guidewire is then removed. Alternatively, the microcatheter can be advanced directly without a guidewire. The ablation probe 626 is then activated to ablate the artery 700 feeding the tumor. In one embodiment, the ablation probe is first activated to induce spasm, followed by activation to induce ablation. This is accomplished by first activating the probe 626 with low energy or by first releasing a small amount of chemical agent, followed by activation to induce ablation. Ablation results in occlusion and / or collapse of the artery 700, preventing blood flow from nourishing the tumor 702, thereby preventing further tumor growth and / or shrinking the tumor 702a. The system of the present invention can be repositioned or removed to ablate additional blood vessels.

[0054] The above-described system may be used to control subcutaneous bleeding. Additionally, physicians may use embolization to stop subcutaneous bleeding in, but not limited to, the lungs, spleen, and pancreas. By manipulating the system to induce constriction in either the vasospasm or vascular ablation embodiments, the above-described system can be used to immediately slow or stop blood loss upon placement and activation of the device. A second therapeutic agent can then be locally injected into the patient. The second therapeutic agent may include a gel, glue, or liquid embolic agent, an embolic coil, or embolic beads. Referring to FIG. 16 , a bleeding vessel 900 is identified. The system is delivered to a target vessel 902 upstream of the bleeding vessel 900. The system is activated to induce vasoconstriction at 904. The vasoconstriction 904 creates a local pressure drop at 906 between the constriction 904 and the bleeding vessel 900. Normal vessel 908 exhibits a higher resistance than the bleeding vessel 900. Thus, when the second therapeutic agent 910 is injected, the therapeutic agent 910 flows well along the high resistance normal blood vessels 908 to the site of the injury 900 .

[0055] In any of the methods of the present invention, the targeted blood vessel extends within or near a tumor or other diseased tissue. The targeted blood vessel may feed or drain any of a variety of organs, such as, but not limited to, the pancreas, spleen, gastrointestinal tract, liver, lungs, uterus, prostate, or brain, and the targeted blood vessel may also lead to tumors in the head and neck. The targeted blood vessel may also lead to other organs or tissues of interest for treatment in other parts of the body. In some embodiments, the treatment system of the present invention may be introduced intravascularly into the targeted blood vessel adjacent to the targeted blood vessel.

[0056] This disclosure has described and illustrated embodiments of systems and methods for therapeutic agent delivery, as well as embodiments of pressure-enabled therapeutic agent delivery. While specific embodiments have been described, the invention is not limited thereto. The invention is intended to be as broad as technically possible, and this disclosure should be construed accordingly. Thus, while the systems and methods of the present invention are primarily suited to therapeutic treatment of humans, they have also been demonstrated in porcine tissues and organs and can be used for general mammalian treatment. Both humans and animals are considered "patients" for purposes of this disclosure. Furthermore, the therapeutic agents delivered in this disclosure may be a single therapeutic agent or a combination of multiple therapeutic agents. Accordingly, those skilled in the art will recognize that the present invention can be further modified without departing from the scope of the claims.

Claims

1. 1. A therapeutic system for intravascular treatment of a patient, the system comprising: a) a catheter having a proximal end and a distal tip, and a first lumen defined from the proximal end, extending to the distal tip, and opening at an opening hole passing through the distal tip; b) a spasm induction system including an actuatable probe at the distal end of the catheter configured to induce stenosis spasm in a blood vessel upon actuation; Including, the system.

2. The treatment system of claim 1 , wherein the distal tip projects beyond the probe.

3. The treatment system of claim 1 , further comprising at least one marker associated with the emitter for identifying the position of the probe during imaging.

4. The treatment system of claim 3 , wherein the at least one marker is radiopaque.

5. The treatment system of claim 1 , further comprising a hub at the proximal end of the catheter.

6. The treatment system of claim 1 , wherein the spasm induction system is configured to emit probe radio frequency (RF) energy.

7. The treatment system of claim 1 , wherein the probe of the spasm induction system is configured to emit ultrasound waves.

8. The treatment system of claim 1 , wherein the probe of the spasm induction system is configured to emit a chemical substance.

9. The therapeutic system of claim 1 , wherein the probe of the spasm induction system is a cryogenic element.

10. The therapeutic system of claim 1 , wherein the probe of the spasm induction system is a vibrating element.

11. The therapeutic system according to claim 1 , wherein the probe of the spasm induction system is an infrared light emitting element.

12. The treatment system of claim 1 , wherein the probe of the spasm induction system includes bristles configured to stimulate blood vessels.

13. The treatment system of claim 1 , wherein the catheter defines a second lumen opening at or adjacent to the probe.

14. 14. The treatment system of claim 13, wherein the second lumen is open to distribute infusate radially relative to the catheter.

15. 1. A therapeutic system for treatment of a blood vessel in a patient, the system comprising: a) a catheter having a proximal end and a distal tip, and a first lumen defined from the proximal end, extending to the distal tip, and opening at an opening hole passing through the distal tip; b) a probe at the distal end of the catheter; c) an actuator that operates the probe; wherein upon actuation of the probe, the probe is configured to cause a physical change in the blood vessel.

16. The treatment system of claim 15 , configured to induce stenosis and spasm in a blood vessel by actuation of the probe.

17. The treatment system of claim 15 , configured to ablate a blood vessel upon actuation of the probe.

18. The treatment system of claim 15 , wherein the probe is configured to emit radio frequency (RF) energy.

19. The treatment system of claim 15 , wherein the probe is configured to emit ultrasound waves.

20. The treatment system of claim 15 , wherein the probe is configured to emit a chemical agent.

21. The treatment system of claim 15 , wherein the probe is a cryogenic element.

22. The treatment system of claim 15 , wherein the probe is configured to emit microwave energy.

23. The treatment system of claim 15 , wherein the probe is configured to emit thermal energy.

24. The therapeutic system of claim 15 , wherein the probe of the spasm induction system is a vibrating element.

25. The therapeutic system of claim 15 , wherein the probe of the spasm induction system is an infrared light emitting element.

26. 16. The treatment system of claim 15, wherein the probe of the spasm induction system includes bristles configured to stimulate blood vessels.

27. The treatment system of claim 15 , wherein the catheter is provided with a second lumen that opens to the probe or adjacent to the probe.

28. 28. The treatment system of claim 27, wherein the second lumen is open to distribute infusate radially relative to the catheter.

29. 1. A method of therapeutic treatment, said method comprising: a) providing a catheter having a proximal end and a distal tip, and a lumen defined from the proximal end, extending to the distal tip and opening at an aperture passing through the distal tip, the catheter having an actuatable probe disposed at the distal end; b) delivering the distal end of the catheter into the blood vessel; c) actuating the probe to constrict the blood vessel around the probe; d) injecting a therapeutic agent through the lumen and out the distal aperture into the blood vessel to a location distal to the constriction of the blood vessel while the blood vessel is constricted around the probe; A method comprising:

30. 30. The method of claim 29, wherein the therapeutic agent is injected into the tumor via a blood vessel.

31. 30. The method of claim 29, wherein the blood vessel between the distal end of the catheter and the tumor bifurcates into healthy vasculature and tumor-bearing vasculature, and the probe is subsequently activated to narrow the healthy vasculature more than the tumor-bearing vasculature before injecting the therapeutic agent.

32. 30. The method of claim 29, wherein the injection comprises multiple injections spaced apart in time.

33. 30. The method of claim 29, wherein the therapeutic treatment is for treating subcutaneous bleeding.

34. 34. The method of claim 33, wherein the therapeutic agent is one of a gel, glue or liquid embolic, an embolic coil or an embolic bead.

35. 30. The method of claim 29, wherein the narrowed blood vessel contracts upon contact with the probe.

36. 30. The method of claim 29, further comprising dilating the narrowed blood vessel after injecting the therapeutic agent.

37. 37. The method of claim 36, wherein the dilating comprises introducing a vasodilator into the narrowed blood vessel.

38. 1. A method of therapeutic treatment, said method comprising: a) providing a catheter having a proximal end and a distal tip, and a lumen defined from the proximal end, extending to the distal tip and opening at an aperture passing through the distal tip, the catheter having an actuatable probe disposed at the distal end; b) directing the distal end of the catheter into an artery feeding the tumor; c) actuating the probe to cause ablation of the artery feeding the tumor; A method comprising:

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