Patent Application
20240206959
The medical methods described herein relate generally to methods for intravenously treating a target organ for cancer or other diseases.
In some instances, systemic treatments are used to treat disease within a patient. The effectiveness of some such systemic treatments can vary due at least in part to the therapy (e.g., a radio-embolization agent, a biologic agent and/or other treatment formulation) not reaching target tissue. For example, in the treatment of some diseases such as cancer and/or diabetes, it may be desirable to deliver biological cells to an organ where efficient and safe engraftment can be achieved.
The ineffective result of systemic chemotherapy is at least in part due to an insufficient drug concentration within the tumor because of dose-limited toxicity in bone marrow and epithelial tissue. Another complication can be peripheral neuropathy. Yet another obstacle can result from the systemic use of check point inhibitors causing over-activation of the immune system. Since systemic chemotherapy is limited in its effectiveness or can have significant complications, treatments other than systemic chemotherapy can be desirable for many types of cancer patients.
One alternative treatment includes local intra-arterial delivery of chemotherapy. Intra-arterial infusion allows higher drug concentration to reach a tumor. Furthermore, intra-arterial chemotherapy can also take advantage of the first pass effect of chemotherapeutics, generating higher-level drug concentrations at the tumor cell membrane and therefore enhancing cellular drug uptake as compared to intravenous systemic infusion. In addition, local delivery can reduce systemic side effects resulting when the drug fails to remain localized and disperses.
Standard end-hole catheters permit limited control of infused local treatment. Contribution of the infusion adds local volume into a nearly incompressible system. The infusion treatment will flow from an area of high pressure to an area of lower pressure. The added fluid volume of the treatment is forced to move somewhere and, if the downstream resistance and pressure is higher than the upstream resistance, reflux to non-target areas will occur.
In order to alleviate certain of these issues, co-owned U.S. Pat. Nos. 8,696,698, 9,968,840, and 10,588,636 describe various pressure-controlled therapeutic delivery devices in the form of an infusion catheter having an integrated microvalve mounted at the distal end of the catheter. The microvalve dynamically expands and contracts within a blood vessel in relation to the surrounding fluid pressure in the vessel. A treatment can be infused through the catheter. When the treatment agent is infused, the pressure in the vessel downstream (distal) of the treatment at times can become higher than that upstream (proximal) of the treatment, allowing the microvalve to block reflux of the agent. In addition, the microvalve permits infusion into the target tissue at modified pressure, targeting the treatment into the desired tissue.
These pressure-controlled therapeutic devices work extremely well for their intended purposes. However, there may be treatment scenarios in which it would be desirable to advance a treatment device into smaller or more tortuous vessels than can accommodate current microvalves. In addition, current size mechanical microvalves have limits on trackability through these vessels.
Systems and methods are provided for the pressure-controlled delivery of a therapeutic. The systems are trackable through vessels feeding tumors and do not rely on mechanical operation of a microvalve. In accord with embodiments, each system includes a microcatheter having a proximal end and a distal end, an infusion lumen extending through the microcatheter from the proximal end to the distal end and opening at a distal orifice. The microcatheter is provided with a vascular spasm-inducing system. For purposes herein, a vasospasm is the narrowing of a vessel caused by constriction of smooth muscle lining the vessel, typically due to irritatation of the vessel. Vasospasm, vasoconstriction and more generally spasm are terms relating to this same phenomena and are used interchangeably herein. The magnitude of vasospasm occurs along a spectrum ranging from mild narrowing of the vessel to complete occlusion. The vascular spasm inducing system includes a spasm-inducing probe at or adjacent the distal end of the microcatheter, and an actuator to trigger the spasm-inducing element. By way of example only, the vascular spasm-inducing probe can be a radiofrequency (RF) emitter, such as of an electric current or voltage or magnetic or electromagnetic field, an ultrasound emitter, a chemical emitter, a thermal probe, and particularly a cryogenic probe, an infrared probe, a mechanical vibratory emitter, or a mechanical irritation device. Vasospasm-inducing systems described herein include devices adapted to causing a constriction of a blood vessel to varying degrees of magnitude.
When the vascular spasm-inducing probe is triggered in a vessel, the induced spasm in the vessel causes a narrowing about the spasm-inducing probe. This permits a therapeutic agent to be delivered through the infusion lumen and out of the orifice a range of pressure determined by the user, while the narrowing of the vessel operates as a pseudo-valve or natural valve and prevents reflux of the therapeutic agent past the narrowing in the vessel.
In one method, the system is used to deliver a therapeutic agent downstream of the narrowing under a pressure determined by the user and is then withdrawn from the patient.
In another method, the system is used to control and modify flow within the vasculature before delivery of the therapeutic agent in order to optimize flow of the agent to the tumor. Before delivery of therapy, the spasm-inducing probe is activated to cause a narrowing and thus reduce flow in a vessel. When flow is reduced, the healthy downstream vessels react by constricting; however, the tumor vessels do not properly react to the lower pressure and remain substantially open. This creates a vascular pathway in which remaining flow is directed toward the tumor. The therapeutic is then infused and is directed to the tumor.
In accord with another method, the system is used to create a constriction leading to a bleeding vessel system to reduce bleeding. Then a therapeutic agent may be delivered to further treat the bleeding vessel.
In accord with another embodiment of a system herein, a microcatheter is provided substantially as described above; however, the spasm-inducing probe is modified to be an ablation probe. In accord with preferred embodiments, the ablation probe can be implemented using the same modalities for inducing spasm; that is, the ablation probe can be an RF emitter, an ultrasound emitter, a chemical emitter, a thermal probe, an infrared emitter, a mechanical vibratory emitter, or an irritation device, but all operated with sufficient energy to cause tissue ablation rather than vascular spasm. In addition, the ablation probe can be other energy emitters that can be operated to ablate vascular tissue, such as a microwave emitter. As described above, the system includes an actuator at the proximal end of the microcatheter, and the actuator is operably connected to the ablation probe. The microcatheter is not necessarily required to infuse a therapeutic agent, as the intended therapeutic effect is provided by ablation of tissue, as described below. However, the microcatheter preferably includes a central lumen sized for receiving a guidewire.
In use, a mapping procedure is performed to identify the significant arterial vessels feeding a solid tumor. Once a vessel is identified, the femoral or radial artery is accessed, and a guidewire is advanced from the femoral or radial artery to a significant vessel feeding the tumor. The microcatheter is then advanced over the guidewire to the target vessel. Then, the guidewire is removed. Alternatively, the microcatheter is advanced directly, without a guidewire. The ablation probe is then activated to ablate the surrounding tumor-feeding arterial vessel. Ablation results in occlusion and/or collapse of the artery, preventing nourishing blood flow to the tumor. This will prevent further growth of the tumor and/or reduce the size of the tumor. The system can be repositioned for ablation in additional vessels or removed.
The systems can be used to provide treatment in vessels wherever an endhole or conventional catheter, a balloon catheter, or microvalve catheter would be used to infuse a therapy into a vessel. In particular, the systems and methods can be used in vessels to treat tumors in organs throughout the human body.
With reference to the following description, the terms “proximal” and “distal” are defined in reference to the hand of a user of the devices and systems described herein, with the term “proximal” being closer to the user's hand, and the term “distal” being further from the user's hand such as to often be located further within a body of the patient during use.
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The proximal end of 14 the microcatheter is preferably provided with a hub 18. The infusion lumen 20 extends from the hub 18 through to the distal end 16 of the microcatheter and exits through a distal tip 22 at a distal orifice 24. The hub 18 and infusion lumen 20 are adapted for delivery of a therapeutic agent from outside the body of a patient to a target vessel (artery or vein) in the patient. The hub 18 is also adapted to facilitate advancement of a guidewire through the infusion lumen 20. Any hub 18 suitable for at least facilitating delivery of a therapeutic into the infusion lumen can be utilized.
In accord with a preferred aspect of the system, a vascular spasm-inducing system including a probe 26 is provided at or adjacent the distal end 22 of the microcatheter 12. An actuator 28 is operably coupled to the system 10 to power and/or trigger the probe 26. Preferably, the distal tip 22 of the microcatheter 12 protrudes beyond the spasm-inducing probe 26 such that the spasm-inducing probe is proximally displaced from the distal tip.
One or more marker bands 30 are provided proximal and/or distal of the spasm-inducing probe 26. The marker bands 30 may be radio-opaque. During use of the device, the in vivo positions of the one or more marker bands 30 viewed fluoroscopically or via other imaging technique indicates the location of the spasm-inducing probe 26 relative to anatomical landmarks.
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In accord with optional aspect of the system, a secondary infusion lumen 40 accessible via the hub 18 lead to one or more openings 42 at a distal end of the probe 26. Preferably a plurality of openings 42 are circumferentially displaced at or adjacent the probe to disperse an agent radially relative to the catheter 12. The secondary infusion lumen 40 and the openings 42 are provided for delivery of a vasodilator, in accord with the method described below.
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In accord with another embodiment of the system, the spasm-inducing probe is a cryogenic probe 326. The cryogenic probe 326 may be cooled by a cryogenic cooling fluid that is, for example, circulated through a coil 327. The cryogenic fluid can be cooled water or air, or even liquid nitrogen or other fluid, through an insulative pathway in or about the catheter, from the proximal end of the microcatheter to the coil. Alternatively, a thermoconductive band can be utilized rather than a coil. As yet another alternative, the cryogenic fluid can be injected into an expandable balloon to facilitate placement of the cooling fluid in proximity to the tissue of the vessel. Exemplar cryogenic fluids include cooled water, liquid argon or liquid nitrogen, and cooled gases. The actuator 28 may include a source of cryogenic fluid, and the trigger may initiate circulation of the cryogenic fluid to the thermoconductive band from a syringe or pump. In an embodiment, the cryogenic probe cools the local tissue of the vasculature by 5 to 10 C to produce mild to moderate vasoconstriction, 10 to 15 C to produce moderate to high vasoconstriction, and 15 to 25 C to produce maximal vasoconstriction. This embodiment of the system can be used in the same manner as the prior embodiment of the system. The probe 326 can also be provided in association with a secondary infusion lumen for delivery of a vasodilator to dilate the constricted the vessel at the end of a procedure. Alternatively, the probe 326 can be adapted to also be warmed, e.g., by fluid or electricity, to reverse the vasoconstrictive effect of cooling.
In addition, to the above exemplar spasm-inducing probes, other probe types can similarly be used. For example, the probe can be an infrared light probe. The probe can include fiber optics and elements that can focus and/or disperse the infrared energy in a manner that sufficiently heats up and irritates the vessel wall to cause vessel constriction.
Further, the probe can include a mechanical vibrator. The actuator for the vibratory element can adjust the frequency and amplitude of the vibration at the probe. By way of example, the vibratory element can be a piezoelectric or electromechanically vibrator. The vibratory element may operate in the range of 5 Hz to 20.00 kHz. More preferably, the element may operate in the 10-100 Hz range. It is expected that a lower frequency and higher amplitude vibration provides the stimulus necessary to cause spasm of the vessel. Other variations of the controls of the actuator may also provide suitable stimulus. The vibratory element probe can be provided in association with a secondary infusion lumen for delivery of a vasodilator as described above.
Referring to
The system 10 can be used to inject a therapy into a target vessel branching from a larger primary vessel and communicating with, for example, a solid tumor of an organ. In some cases, the tumor can be a cancerous tumor, such as a tumor specific to, for example, cancer of the pancreas, spleen, or small intestines. In addition, other non-cancerous diseased states of organs can also be treated using the systems and methods.
As described below, the treatment system is used to provide the therapy to the tumor within a target region of the organ, to enable targeted treatment of the targeted region by the therapy, and substantial isolation of the therapy within the target region, all without isolating a larger region than necessary from blood flow during the treatment procedure. This is in contrast from treatment that are provided in systemic circulation through the body.
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Once the therapeutic agent has been delivered, before removing the catheter a therapeutic action can be taken to at least partially reverse the constriction on the vessel. As discussed above, a chemical vasodilator can be delivered through a secondary infusion lumen. Alternatively, where the constriction was caused by cooling, the tissue can be warmed. Any other suitable method can be used to alleviate the constrict or dilate the vessel. Then, the treatment system can be withdrawn from the patient.
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Then, a therapeutic agent 508 is infused through the infusion lumen of the system, while the spasm-inducing probe 26 remains activated. The vasoconstriction of the healthy branches 512 causes the flow of the therapeutic agent 508 to be primarily directed through the tumor vasculature 514, which remains substantially open and substantially unconstricted, and into the tumor 502. Further, the vascular volume available downstream of the spasm also allows the infusion into the tumor to be at a higher pressure.
At the end of infusion, the pressure in the vessels is high, and the healthy tissue will attempt to vasodilate to reduce pressure. As the tumor vasculature is unable to similarly adapt, this would redirect flow toward healthy tissue. As this is counter to the purpose of maximizing flow toward diseased tissue, the spasm-inducing probe 26 preferably remains active, reducing antegrade flow in the vessels even at the end of the infusion to limit healthy vessel dilation. With the healthy vessels restrained from dilation, the therapy is provided the best route through tumor vasculature to the tumor.
In accord with one aspect of the method, the spasm-inducing probe may be actuated and the therapy may be infused in pulses to maximize the constriction of the healthy vessels. The pulses may be spaced apart by 0.3 to 60 seconds. The pulses may optimize the constriction and prevent dilation of the healthy vasculature for therapeutic redirection and aid in uptake of the agent at the tumor.
At the end of the therapeutic procedure, optionally before removing the treatment system from the patient, a therapeutic action can be taken to at least partially reverse the constriction on the vessel. As discussed above, a chemical vasodilator can be delivered through a secondary infusion lumen. Alternatively, where the constriction was caused by cooling, the tissue can be warmed. Any other suitable method can be used to alleviate the constriction or otherwise dilate the vessel. The treatment system is then withdrawn from the patient.
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The systems described above may be used to control internal bleeding. It is noted that physicians may use embolics to stop internal bleeding in, without limitation, the lungs, the spleen, and the pancreas. The above described systems, in any of the vasospasm or vasoablative embodiments, by operation to cause constriction, can be used to immediately slow or stop blood loss as soon as the device is placed and activated. Then, a secondary therapy can be infused locally into the patient. The secondary therapy may include a gel-foam, glue or liquid embolics, embolic coils, or embolic beads. In accord therewith, turning to
In any of the methods, the target vessel extends into or near a tumor or other diseased tissue. The target vessel may feed or drain from any of various organs, including, but not limited to, the pancreas, spleen, gastrointestinal tract, liver, lung, uterus, prostate or brain, as well as target vessels communicating with head and neck tumors. The target vessels may also be in communication with other organs or tissues of interest for treatment in other parts of the body. In embodiments, the treatment system may be introduced into or adjacent the target vessel non-endovascularly.
There have been described and illustrated herein embodiments of systems and methods for therapeutic delivery, and in embodiment pressure-enabled therapeutic delivery. While particular embodiments of the invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. Thus, while the systems and methods are primarily adapted for therapeutic treatment of humans, it has been demonstrated on porcine tissues and organs, and can be used for the treatment of mammals, in general. Both humans and animals shall be considered ‘patients’ for purpose of this disclosure. Also, the therapy delivered herein can be a single therapeutic agent, or a combination of therapeutic agents. It will therefore be appreciated by those skilled in the art that, yet other modifications could be made to the provided invention without deviating from its scope as claimed.
