# Patent

## Title
Devices and methods for photodynamically modulating neural function in a human

## Abstract

Devices and methods for therapeutic photodynamic modulation of neural function in a human. One embodiment of a method in accordance with the technology includes administering a photosensitizer to a human, wherein the photosensitizer preferentially accumulates at nerves proximate a blood vessel compared to non-neural tissue of the blood vessel. The method can further include irradiating the photosensitizer using a radiation emitter positioned within the human, wherein the radiation has a wavelength that causes the photosensitizer to react and alter at least a portion of the nerves thereby providing a therapeutic reduction in sympathetic neural activity. Several embodiments of the technology are useful for disrupting renal nerves, such as renal denervation, for treating hypertension, diabetes, congestive heart failure, and other indications.

## Background
CROSS-REFERENCE TO RELATED APPLICATION(S)
The present application claims priority to U.S. Provisional Patent Application No. 61/666,687, filed Jun. 29, 2012, entitled “DEVICE AND METHOD FOR VASCULAR DELIVERY OF PHOTODYNAMIC THERAPY FOR MODULATING NEURAL FUNCTION,” which is incorporated herein in its entirety by reference.


TECHNICAL FIELD
The present technology relates to modulation of neural function, such as localized tissue denervation, using photodynamic methods and devices.
BACKGROUND
The sympathetic nervous system (SNS) is a primarily involuntary control system typically associated with stress responses. SNS tissue fibers are present in almost every organ system of the human body and can affect characteristics such as pupil diameter, gut motility, and urinary output. Such regulation can have adaptive utility in maintaining homeostasis or preparing the body for rapid response to environmental factors. Chronic activation of the SNS, however, is a common maladaptive response that can drive the progression of many disease states. Excessive activation of the renal SNS in particular has been identified experimentally and in humans as a likely contributor to the complex pathophysiology of hypertension, volume overload states (such as heart failure), and progressive renal disease. For example, radiotracer dilution has demonstrated increased renal norepinephrine (NE) spillover rates in patients with essential hypertension.
Cardio-renal sympathetic nerve hyperactivity can be particularly pronounced in patients with heart failure. For example, an exaggerated NE overflow from the heart and kidneys is often found in these patients. Heightened SNS activation commonly characterizes both chronic and end stage renal disease. In patients with end stage renal disease, NE plasma levels above the median have been demonstrated to be predictive of cardiovascular diseases and several causes of death. This is also true for patients suffering from diabetic or contrast nephropathy. Evidence suggests that sensory afferent signals originating from diseased kidneys are major contributors to initiating and sustaining elevated central sympathetic outflow.
Sympathetic nerves innervating the kidneys terminate in the blood vessels, the juxtaglomerular apparatus, and the renal tubules. Stimulation of the renal sympathetic nerves can cause increased renin release, increased sodium (Na+) reabsorption, and a reduction of renal blood flow. These neural regulation components of renal function are considerably stimulated in disease states characterized by heightened sympathetic tone and likely contribute to increased blood pressure in hypertensive patients. The reduction of renal blood flow and glomerular filtration rate that result from renal sympathetic efferent stimulation are likely a cornerstone of the loss of renal function in cardio-renal syndrome (i.e., renal dysfunction as a progressive complication of chronic heart failure). Pharmacologic strategies to thwart the consequences of renal efferent sympathetic stimulation include centrally acting sympatholytic drugs, beta blockers (intended to reduce renin release), angiotensin converting enzyme inhibitors and receptor blockers (intended to block the action of angiotensin II and aldosterone activation consequent to renin release), and diuretics (intended to counter the renal sympathetic mediated sodium and water retention). These pharmacologic strategies, however, have significant limitations including limited efficacy, compliance issues, side effects, and others. Recently, intravascular devices that reduce sympathetic nerve activity by applying an energy field to a target site in the renal artery have been shown to reduce blood pressure in patients with treatment-resistant hypertension (e.g., radiofrequency, cryogenic or ultrasound ablation of renal nerves).
These devices seek to at least partially disrupt neural function of nerves located in adventitial tissue around the renal artery to achieve a therapeutic reduction in systemic blood pressure. Each of these approaches damages or destroys the neural tissue in the outer layers around the artery, and thus they also affect the intimal, medial, and adventitial layers of the artery to varying extents since the energy or temperature gradient must first transverse the non-neural tissues to reach the intended target.



BRIEF DESCRIPTION OF THE DRAWINGS
Many aspects of the present technology can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Instead, emphasis is placed on illustrating clearly the principles of the present technology. For ease of reference, throughout this disclosure identical reference numbers may be used to identify identical or at least generally similar or analogous components or features.
FIG. 1 is a partially cross-sectional anatomical front view illustrating several embodiments of a method for a therapeutic neural modulation in a human in accordance with the present technology.
FIG. 2 is a schematic cross-sectional view of a distal portion of a treatment device at a target site in a blood vessel in accordance with the present technology.
FIG. 3A is a schematic cross-sectional view of a distal portion of a treatment device in accordance with the present technology, and FIG. 3B is a cross-sectional view of the treatment device taken along line B-B of FIG. 3A.
FIG. 4 is a partial cross-sectional view of a distal portion of a treatment device for therapeutic neural modulation in accordance with an embodiment of the present technology.
FIG. 5 is a partial cross-sectional view of a distal portion of a treatment device for therapeutic neural modulation in accordance with an embodiment of the present technology.
FIG. 6 is a partial cross-sectional view of a distal portion of a treatment device for therapeutic neural modulation in accordance with an embodiment of the present technology.
FIG. 7 is a partial cross-sectional view of a distal portion of a treatment device for therapeutic neural modulation in accordance with an embodiment of the present technology.
FIG. 8 is a partial cross-sectional view of a distal portion of a treatment device for therapeutic neural modulation in accordance with an embodiment of the present technology.
FIG. 9 is an isometric view having a cut-away portion showing a distal portion of a treatment device for therapeutic neuromodulation in accordance with an embodiment of the present technology.
FIG. 10 is an isometric view further illustrating an embodiment of operating the radiation unit.
FIG. 11 is schematic view of a system for operating treatment devices for therapeutic neural modulation in accordance with an embodiment of the present technology.
FIGS. 12-14 are charts showing the effects of UVA radiation and/or oxytetracycline on differentiated PC12 cells from test data.



DETAILED DESCRIPTION
Specific details of several embodiments of the technology are described below with reference to FIGS. 1-14. Although many of the embodiments are described below with respect to systems, devices, and methods for renal neuromodulation using photodynamic therapies, other applications and other embodiments in addition to those described herein are within the scope of the technology. Additionally, several other embodiments of the technology can have different configurations, components, or procedures than those described herein. A person of ordinary skill in the art, therefore, will accordingly understand that the technology can have other embodiments with additional elements, or the technology can have other embodiments without several of the features shown and described below with reference to FIGS. 1-14.
As used herein, the terms “distal” and “proximal” define a position or direction with respect to the treating clinician or clinician's control device (e.g., a handle assembly). “Distal” or “distally” can refer to a position distant from or in a direction away from the clinician or clinician's control device. “Proximal” and “proximally” can refer to a position near or in a direction toward the clinician or clinician's control device.
Renal neuromodulation is the partial or complete incapacitation or other effective disruption of nerves innervating the kidneys (e.g., rendering neural fibers inert or inactive or otherwise completely or partially reduced in function). For example, renal neuromodulation can include inhibiting, reducing, disrupting, and/or blocking neural communication along neural fibers innervating the kidneys (i.e., efferent and/or afferent nerve fibers). Such incapacitation can be long-term (e.g., permanent or for periods of months, years, or decades) or short-term (e.g., for periods of minutes, hours, days, or weeks). Renal neuromodulation is expected to efficaciously treat several clinical conditions characterized by increased overall sympathetic activity, and, in particular, conditions associated with central sympathetic overstimulation such as hypertension, heart failure, acute myocardial infarction, metabolic syndrome, insulin resistance, diabetes, left ventricular hypertrophy, chronic and end stage renal disease, inappropriate fluid retention in heart failure, cardio-renal syndrome, osteoporosis and sudden death, among others. The reduction of afferent neural signals typically contributes to the systemic reduction of sympathetic tone/drive, and renal neuromodulation is expected to be useful in treating several conditions associated with systemic sympathetic over activity or hyperactivity. Renal neuromodulation can potentially benefit a variety of organs and body structures innervated by sympathetic nerves. For example, a reduction in central sympathetic drive may reduce insulin resistance that afflicts patients with metabolic syndrome and Type II diabetics.
Several embodiments of the present technology selectively disrupt, and in many instances destroy, perivascular nerves without adversely impairing the function of the non-neural tissues of the blood vessel (e.g., intimal, medial and adventitial tissues of the blood vessel). For example, several embodiments of methods for therapeutic neural modulation in a human can include administering a photosensitizer to a human that preferentially accumulates at selected nerves compared to other tissues proximate the selected nerves. For example, more of the photosensitizer can accumulate in perivascular nerves around a blood vessel than in the non-neural tissues of the blood vessel. The mechanisms for preferentially accumulating the photosensitizer at the nerves can include faster uptake by the nerves, longer residual times at the nerves, or a combination of both. After a desired dosage of the photosensitizer has accumulated at the nerves, the photosensitizer is irradiated using a treatment device positioned within the human. The treatment device delivers radiation to the target nerves at a wavelength that causes the photosensitizer to react such that it damages or disrupts the nerves. For example, the photosensitizer can become toxic upon exposure to the radiation. Because the photosensitizer preferentially accumulates at the nerves and not the other tissue proximate the nerves, the toxicity and corresponding damage is localized primarily at the nerves. Several embodiments of the present technology are expected to be particularly useful for denervation of perivascular nerves while protecting the non-neural tissue of the blood vessel.
Selected Embodiments of Photodynamic Neuromodulation Methods and Devices
FIG. 1 is a partially cross-sectional anatomical front view illustrating several embodiments of methods for therapeutic neural modulation in a human (H). An embodiment includes providing a photosensitizer to neural tissue associated with sympathetic neural activity. Several embodiments of the methods include providing the photosensitizer to perivascular nerves, but other embodiments include providing the photosensitizer to nerve ganglia, peripheral nerves, and spinal nerves. The photosensitizer, for example, can be administered either orally or by injecting the photosensitizer into the human (H). For example, the photosensitizer can be injected directly into the vasculature for systemic distribution, or the photosensitizer can be injected into tissue proximate the target nerves using appropriately sized needles for localized application. In other embodiments, the photosensitizer can be delivered from within the body lumen using an intravascular device. In any of these embodiments, the photosensitizer is selected to preferentially accumulate at the nerves as described in more detail below.
FIG. 1 further illustrates delivering a treatment device 100 having a shaft 110 and a radiation unit 120 at a distal end of the shaft 110 positioned within the vasculature of the patient. Intravascular delivery of the radiation unit 120 can include percutaneously inserting a guide wire (not shown) within the vasculature at an access site (e.g., the femoral, brachial, radial, or axillary artery). The shaft 110 and the radiation unit 120 are moved along the guide wire in a low-profile delivery state until at least a portion of the radiation unit 120 reaches a desired treatment location. The shaft 110 and the radiation unit 120 can include a guide wire lumen configured to receive a guide wire in an over-the-wire or rapid exchange configuration. As illustrated, a section of the proximal portion of a shaft 110 can be extracorporeally positioned and manipulated by an operator via an actuator 130 to advance the shaft 110 and radiation unit 120 along an intravascular path (P) and remotely manipulate a distal portion of the shaft 110.
The positioning and manipulation of the radiation unit 120 can be carried out using computed tomography (CT), fluoroscopy, intravascular ultrasound (IVUS), optical coherence tomography (OCT), intercardiac echocardiography (ICE), combinations thereof, or other suitable guidance modalities. For example, a fluoroscopy system including a flat-panel detector, x-ray or c-arm can rotated to accurately visualize and identify the target treatment site. Other embodiments can include locating the treatment site using IVUS, OCT and other suitable imaging mapping modalities that can correlate the target treatment site with an identifiable anatomical structure (e.g., a spinal feature) and/or a radiopaque ruler positioned under or on the patient before delivering the radiation unit 120 to the target site. Further, in some embodiments, image guidance components (e.g., IVUS or OCT) may be integrated with the treatment device 100 and/or running parallel with the treatment device 100 to provide image guidance during positioning of the radiation unit 120. This can be carried out by coupling IVUS, OCT or other image-guidance components to a distal portion of the shaft 100 to provide three-dimensional images of the vasculature proximate to the target site to facilitate positioning or deploying the radiation unit 120 within the target blood vessel. In the specific example shown in FIG. 1, the radiation unit 120 is positioned in the renal artery (RA) at a suitable location between the renal ostium (RO) and the kidney (K).
After the radiation unit 120 has been positioned at a treatment location, the radiation unit 120 can be transformed or otherwise manipulated from a low-profile delivery state suitable for passing through the vasculature (e.g., the femoral artery (FA), the iliac artery (IA), and aorta (A)) to a deployed state in a target vessel (e.g., the renal artery (RA)). In the deployed state, for example, the radiation unit 120 can securely contact the wall of the blood vessel or other body lumen to stabilize the radiation unit 120 for delivering energy to the target nerves. In some embodiments, the radiation unit 120 may be delivered to a treatment site using a guide sheath (not shown) with or without using a guide wire. When the radiation unit 120 is at the target site, the guide sheath may be at least partially withdrawn or retracted so that the radiation unit 120 can transform to the deployed state. For example, the radiation unit 120 can have a balloon, basket, spiral member (e.g., helical), or other suitable positioning member that can be inflated, self-expanded, or manipulated by a wire to move from the delivery state to the deployed state. In some other embodiments, the shaft 110 may itself be steerable such that the radiation unit 120 can be delivered to the treatment site without the aid of a guide wire and/or guide sheath.
FIG. 2 is a schematic cross-sectional view of a distal portion of the treatment device 100 at a target site in a body lumen 200, such as a blood vessel, airway, or other naturally occurring passageway. The radiation unit 120 can include a positioning member 112 at the distal end of a shaft 110 and an emitter 122. The positioning member 112 can be expanded to contact the inner wall of the body lumen 200 such that the emitter 122 is positioned at a desired location relative to the target site. The positioning member 112, for example, can be a balloon, basket, spiral member, or other structure. In one embodiment, the emitter 122 is an optical element coupled to a fiber optic line 124 that extends to an external radiation source. In other embodiments, the emitter 122 itself can be a radiation source coupled to an electrical lead that generates the radiation from within the body lumen 200. For example, the emitter 122 can be a light emitting diode (LED) or an array of LEDs. When the emitter 122 is centered in the body lumen as shown in FIG. 2, the positioning member 112 is generally expanded using an inflation medium that does not overly attenuate the energy of the radiation such that the positioning member contacts the inner wall of the body lumen so that blood does not absorb the energy of the radiation.
FIG. 2 further illustrates an embodiment of the operation of the treatment device 100. After the positioning member 112 has been transformed into the deployed state in which it contacts at least a portion of the inner wall of the body lumen 200, radiation 130 is delivered from the emitter 122. The radiation 130 passes through the positioning member 112, tissue 202 and 204 of the inner wall of the body lumen 200, and nerves 206 in the tissue around the body lumen 200. When the body lumen 200 is a blood vessel, such as the renal artery, tissue 202 can be the intimal tissue, tissue 204 can be the medial tissue, and the nerves 206 can be the renal nerves. The radiation 130 is applied to the nerves 206 after a sufficient quantity of the photosensitizer 208 has accumulated at the nerves 206 and either before an undesirable amount of the photosensitizer has accumulated in and/or in the tissues 202 and 204 or after a sufficient quantity of photosensitizer 208 has dissipated from the tissues 202 and 204. In several embodiments, the photosensitizer 208 can accumulate in and/or on the nerves 206 by preferentially binding to the nerves 206 as shown schematically in FIG. 2. The radiation 130 causes to the photosensitizer 208 to react such that the photosensitizer 208 damages or otherwise disrupts at least the nerves 206. For example, the photosensitizer 208 can become toxic to the nerves 206 and possibly the other tissues proximate the nerves 206. Since the concentration of the photosensitizer 208 is greater at the nerves 206 than the tissues 202 and 204, greater damage is caused to the nerves 206. Thus, several embodiments for therapeutically modulating perivascular nerves in a human in accordance with the present technology selectively disrupt the perivascular nerves such that neural communication is at least partially inhibited along the targeted perivascular nerves without disrupting the function of the other tissues of the wall of the blood vessel.
Selected Embodiments of Photosensitizers and Dosages
The photosensitizer 208 can be any suitable compound that preferentially accumulates at neural tissue compared to other tissues proximate the nerves. For example, the photosensitizer 208 can accumulate in and/or on the neural tissue over a period of time to a greater extent than other tissue proximate the neural tissue. In one embodiment, the photosensitizer can be oxytetracycline, a suitable tetracycline analog, or other suitable photosensitive compounds that preferentially bind to neural tissue. Oxytetracycline is expected to preferentially bind to calcium in the nerves such that more oxytetracycline remains at the nerves than in the non-neural tissue proximate to the nerves after a sufficient period of time has elapsed after administering the oxytetracycline.
When the photosensitizer 208 is oxytetracycline, the radiation delivered from the emitter 122 has a wavelength of 350 nm-365 nm, and often more specifically 351 nm-355 nm. In one particular embodiment, the oxytetracycline is administered at a dosage of 0.5-1 mg/kg, and in other embodiments the oxytetracycline can be administered at a dosage of 1-49 mg/kg, 50-300 mg/kg, or 300-600 mg/kg. The radiation can have a dosage of 0.5-5 J/cm2, 5-25 J/cm2, 25-100 J/cm2, or 100-500 J/cm2 depending on a number of parameters such as the thickness and type of tissue between the radiation emitter and the target neural tissue, and the radiation can be continuous or pulsed irradiation exposure. In the case of pulsed radiation, the pulse rate can be approximately 10-50 ps, 15-40 ps, 20-30 ps, or 20-25 ps (e.g., 24 ps). The oxytetracycline can be administered approximately 30-180 minutes, or 3-24 hours, before being irradiated with radiation at a wavelength of approximately 351 nm-365 nm.
In another example, the photosensitizers can be furocoumarins (psoralens) or porphyrins administered at a dosage of 0.5-1 mg/kg, 1-49 mg/kg, 50-300 mg/kg, or 300-600 mg/kg. Approximately 30-180 minutes, or 3-24 hours, after administering the furocoumarins (psoralens) or porphyrins, a radiation dosage of 0.5-5 J/cm2, 5-25 J/cm2, 25-100 J/cm2, or 100-500 J/cm2 is delivered to the target site.
In another example, the photosensitizers can be benzoporphyrin or a derivative of benzoporphyrin (such as lemuteporfin) administered at a dosage of 0.5-1 mg/kg, 1-49 mg/kg, 50-300 mg/kg, or 300-600 mg/kg. Approximately 30-180 minutes, or 3-24 hours, after administering the lemuteporfin, a radiation dosage of 0.5-5 J/cm2, 5-25 J/cm2, 25-100 J/cm2, or 100-500 J/cm2 is delivered to the target site.
In another example, the photosensitizers can be phthalocyanines administered at a dosage of 0.5-1 mg/kg, 1-49 mg/kg, 50-300 mg/kg, or 300-600 mg/kg. Approximately 30-180 minutes, or 3-24 hours, after administering the lemuteporfin, a radiation dosage of 0.5-5 J/cm2, 5-25 J/cm2, 25-100 J/cm2 or 100-500 J/cm2 is delivered to the target site.
Additional Embodiments of Photodynamic Neuromodulation Devices
FIG. 3A is a schematic cross-sectional view of a treatment device 300 for therapeutic neuromodulation in accordance with the present technology, and FIG. 3B is a cross-sectional view of the treatment device 300 taken along line B-B of FIG. 3A. Referring to FIG. 3A, the treatment device 300 can include an elongated shaft 310 having a plurality of openings 311a-b and a radiation unit 320 attached to a distal portion of the shaft 310. The radiation unit 320 can include a positioning member 312 attached to the shaft 310 and an emitter 322 configured to deliver radiation through the openings 311a-b such that the radiation projects radially outward with respect to the shaft 310. The radiation passes through a chamber 313 defined by the positioning element 312 to irradiate the target tissue as explained above. The emitter 322 can be an optical element coupled to a fiber optic cable 324 that directs the light in the desired radial distribution relative to the shaft 310. The radiation source in such embodiments can be positioned at an extracorporeal location and configured to direct light through the fiber optic cable 324 to the emitter 322. In other embodiments, the emitter 322 can be an internal radiation source, such as an LED or other small radiation emitter. The emitter 322, for example, can be an array of one or more LEDs that emit radiation in a desired bandwidth.
Referring to FIG. 3B, the positioning element 312 can be an inflatable balloon having a first portion 314 configured to contact an inner wall of a blood vessel or another body lumen in a deployed state. For example, other body lumens can be the esophagus, trachea, lung airways, and/or the gastro-intestinal system. The first section 314 is configured to securely position the emitter 322 at a desired location with respect to the target tissue in the deployed state. The positioning element 312 can further include a second portion 316 defining a channel or other external passageway configured to allow blood, air, or another body fluid to pass through the channel when the positioning element 312 is in the deployed state (e.g., inflated or expanded to securely position the emitter 322 at a desired location with respect to the target tissue). The radiation emitter 320 is expected to be particularly useful for applications in the renal artery because it only partially occludes the blood vessel to allow blood flow during the procedure. This will allow exposure times longer than the 2-5 minutes that the renal arteries can be occluded, if necessary.
FIG. 4 is a schematic cross-sectional view of another embodiment of a treatment device 400 in accordance with the present technology for therapeutically modulating neural function. The treatment device 400 can include an elongated shaft and a radiation unit 420 having a positioning member 412 defined by an expandable basket having a plurality of supports 414. The proximal ends of the supports 414 are attached to a proximal hub 416a, and the distal end of the supports 414 are attached to a distal hub 416b. At least one of the proximal and distal hubs 416a and 416b is moveable along the longitudinal dimension of the shaft 410 to transform the positioning member 412 from a low-profile delivery state to an expanded deployed state in which the supports 414 contact in inner wall of a body lumen (BL) at a target site. The radiation unit 420 further includes a plurality of radiation emitters 422 attached to the supports 414. The radiation emitters 422 can be optical elements coupled to fiber optic cables for delivering radiation from a radiation source at an extracorporeal location to the target tissue at the body lumen (BL). In other embodiments, the radiation emitters 422 can be internal radiation sources, such as LEDs, that are electrically coupled to a power source at an extracorporeal location via electrical leads within the shaft 410. In the embodiment shown in FIG. 4, the radiation emitters 422 are angularly spaced apart from each other around a longitudinal dimension A-A of the shaft 410 at a common area along the length of the longitudinal dimension A-A. This arrangement of radiation emitters 422 provides a circumferential exposure in a common plane perpendicular to the longitudinal dimension A-A of the shaft 410.
In operation, a photosensitizer is administered to the patient as described above and the treatment device 400 is positioned at the target site with the supports 414 in the low-profile delivery state. The supports 414 are expanded to the deployed state such that the radiation emitters 422 contact the inner wall of the body lumen (BL) or are positioned apart from the inner wall of the body lumen depending on the type of fluids within the body lumen. For example, in the case of blood vessels or other body lumens with fluids that attenuate the radiation, the supports are generally expanded such that the emitters 422 contact the vessel wall to directly irradiate the inner wall of the vessel so that blood does not block the radiation. Radiation is then delivered to the target neural tissue from the radiation emitters 422 to react the photosensitizer as described above.
FIG. 5 is a cross-sectional view of another embodiment of a treatment device 500 in accordance with the present technology for delivering radiation to target tissue. The treatment device 500 can be similar to the treatment device 400 shown in FIG. 4, and like reference numbers refer to similar or identical components in these figures. Referring to FIG. 5, the treatment device 500 has one or more proximal radiation emitters 422a coupled to first supports 414a and one or more distal radiation emitters 422b coupled to second supports 414b. The proximal and distal radiation emitters 422a and 422b are spaced longitudinally apart from each other along the length of the longitudinal dimension A-A of the shaft 410, and the proximal and distal radiation emitters 422a and 422b are also angularly offset from each other relative to the longitudinal dimension A-A. Although eight supports 414 and eight radiation emitters 422 are shown in FIG. 5, any suitable number supports and emitters may be used. For example, the treatment device 500 may have two first supports 414a, two first proximal radiation emitters 422a (one on each first support 414a), two second supports 414b, and two distal radiation emitters 422b (one on each second support 414b). Such a configuration of proximal and distal radiation emitters provides angularly offset exposure zones such that the radiation does not completely expose the full circumference of the lumen in a plane perpendicular to the longitudinal dimension A-A of the shaft.
FIG. 6 is a cross-sectional view of another embodiment of a treatment device 600 in accordance with the present technology. The treatment device 600 is similar to the treatment devices 400 and 500, and like reference numbers refer to similar or identical components in FIGS. 4-6. The treatment device 600 has first-fourth supports 414a-d, respectively, and first-fourth radiation emitters 422a-d, respectively. The radiation emitters 422a-d are spaced apart from each other at different longitudinal and angular locations with respect to the longitudinal dimension A-A of the shaft 410 such that the radiation is delivered to different longitudinal and angular locations along the inner wall of the body lumen (BL). This arrangement of emitters provides another pattern of non-circumferential exposure zones.
The positioning elements 412 of the treatment devices 400, 500 and 600 shown in FIGS. 4-6 can be self-expanding baskets or pull-wire actuated baskets. For example, self-expanding supports 414 can comprise a shape-memory metal, or they can be springs that expand outwardly after being released from a sheath. In pull-wire embodiments, the distal hub 416b can be coupled to a pull-wire to expand the supports 414 outwardly when the pull-wire is retracted proximally.
FIG. 7 is a cross-sectional view of an embodiment of a treatment device 700 for therapeutically modulating neural function in accordance with the technology. The treatment device 700 can include an elongated shaft 710 and a radiation unit 720 having a positioning element 712 at a distal portion of the shaft 710 and a plurality of radiation emitters 722 coupled to the positioning element 712. In the illustrated embodiment, the positioning element 712 is a balloon and the radiation emitters 722 are arranged such that they are spaced apart from each other longitudinally and angularly with respect to the longitudinal dimension A-A of the shaft 710. The device 700 can include a suitable number of radiation emitters 722 depending on the size of the body lumen (BL). For example, 2, 4, 6, 8, 10 or 12 radiation emitters 722 can be spaced apart from each other angularly and/or longitudinally with respect to the longitudinal dimension A-A of the shaft 710 to provide the desired pattern of radiation along the inner wall of the body lumen (BL).
FIG. 8 is a partial cross-sectional side view of a treatment device 800 for therapeutically modulating neural function in accordance with another embodiment of the present technology. The treatment device 800 includes an elongated shaft 810 and a radiation unit 820 having a positioning member 812 and a plurality of radiation emitters 822 coupled to the positioning member 812. In this embodiment, the positioning member 812 is a self-expanding or pull-wire actuated member that has a substantially linear low-profile delivery state configured to be contained in a sheath and a spiral (e.g., helical) deployed state configured to position in the emitters 812 against the inner wall of the body lumen (BL). The positioning element 812 can be a helix with a constant pitch and diameter, or the helix can have a pitch and/or diameter that varies at different portions along the positioning member 812.
FIG. 9 is an isometric view having a cut-away portion showing a distal portion of a treatment device 900 for therapeutic neuromodulation in accordance with an embodiment of the present technology. The treatment device 900 can include a shaft 910 and a radiation unit 920 attached to a distal portion of the shaft 910. The radiation unit 920 can include a positioning member 912 defined by a balloon and a radiation emitter 922 carried by the shaft 910 within the positioning member 912. The radiation emitter 922 can include a fiber optic cable 924 configured to transmit electromagnetic radiation from a source to the radiation unit 920 and a reflector 925 configured to direct the electromagnetic radiation from the fiber optic cable 924 to target tissue outside of the radiation unit 920. In one embodiment, the reflector 925 has a base 926 mounted to or otherwise carried by the shaft 910, a slot 927 at a proximal end of the base 926 to retain a distal end of the fiber optic cable 924, and an inclined reflective surface 928 configured to direct light transmitted through the fiber optic cable 924 at non-parallel angles (e.g., transverse) to the longitudinal axis of the shaft 910. In one embodiment, the inclined reflective surface 928 is in a plane at an angle of 45° relative to the shaft to direct light through the positioning member 912 perpendicularly to the shaft 910. In other embodiments, the inclined surface 928 can be at other angles to direct the light at transverse angles with respect to the shaft 910. The inclined surface 928 can be spaced apart from the distal terminus of the fiber optic cable 924 by a channel 929.
The reflector 925 can be made of glass, silicon, metals, or other materials covered with reflective materials. In other embodiments, the reflector 925 can be a prism with an inclined surface or other structure that deflects the light in a desired direction. In still other embodiments, the radiation unit 920 may not include the reflector, but instead the fiber optic cable 924 can be bent or have a tip that diverts the radiation at a desired angle with respect to the shaft 910.
The balloon-type positioning member 912 can be filled with a saline solution or other solution through which the light can pass. In one embodiment, the shaft 910 and positioning member 912 are configured to provide fluid flow through the positioning member 912 to cool the tissue being irradiated. Although cooling is not necessary in many embodiments, some photonic methods may cause the tissue of the inner wall of the body lumen to heat to temperatures that can be uncomfortable or otherwise undesirable. The fluid flow through the positioning member 912 is accordingly useful in such situations to maintain the temperature of the inner wall of the body lumen. Additionally, the radiation unit 920 can include a temperature sensor on the positioning member 912 to monitor the temperature of the tissue. The temperature sensor, for example, can be mounted to the surface of a balloon-type positioning member 912 to accurately sense the temperature at the inner wall of the body lumen.
FIG. 10 is an isometric view further illustrating an embodiment of operating the radiation unit 920. The light (L) is projected from the terminus of the fiber optic cable 924 and reflected from the inclined surface 928 to form a light cone (LC) that projects out of the positioning element 912 (FIG. 9). The light cone (LC) can be rotated such that it continuously scans the full circumference of the inner wall of the body lumen, or the light cone (LC) can irradiate one or more discrete areas of the inner wall. For example, the shaft 910 and the radiation unit 920 can be rotated (R) around a guide wire (GW) such that the light cone (LC) continuously irradiates a full 360° circumference of the body lumen or intermittently irradiates only discrete areas around the circumference of the body lumen. In this embodiment, the positioning member 912 can be freely rotated within the body lumen because the positioning member 912 is inflated so that it substantially occludes the body lumen without contacting the inner wall of the body lumen. In another embodiment, the reflector 925 and the fiber optic cable 924 can be mounted onto a separate shaft that can rotate with respect to the shaft 910. This allows the positioning member 912 to be inflated such that the positioning member 912 contacts the inner wall and remains stationary with respect to the body lumen while the reflector 925 and the fiber optic cable 924 rotate and scan the light cone (LC) around the body lumen. The radiation unit 920 can also be translated along the longitudinal direction of the body lumen and rotated to provide a continuous helical lesion or a plurality of separate lesions having a helical/spiral pattern or other desired pattern.
In another embodiment of the treatment device shown in FIGS. 9 and 10, the radiation unit 920 can include a plurality of fiber optic cables and a corresponding plurality of reflectors 925. For example, two reflectors 925 could be mounted on opposite sides of the shaft 910 and two fiber optic cables 924 could extend along the length of the shaft 910 such that two separate light cones project from opposite sides of the positioning member 912. Similarly, any number of reflectors can be arranged in an array along the length of the shaft 910 and/or around the circumference of the shaft 910 to form a continuous circumferential or spiral lesion, or several lesions in a circumferential, spiral, offset, or other pattern.
The radiation emitters 422, 722, 822 and 922 shown in FIGS. 4-10 can be independently operable to provide a desired radiation pattern. As such, only certain emitters may be active for a particular procedure or for a specific patient. The emitters can be fired simultaneously, or in other embodiments the emitters can be fired sequentially or in different groups or other patterns. Additionally, the radiation units 120, 320, 420, 720, 820 and 920 can be activated at several different locations along the length of a vessel and at different rotational orientations within a vessel. For example, referring to FIG. 1, the radiation unit 120 can be activated at the location shown for a suitable period to sufficiently irradiate the photosensitizer at that location. The radiation unit 120 can then be transformed to a low-profile state, moved distally or proximally along the renal artery (RA) to a different location, transformed to a deployed state, and then re-activated to irradiate another area of the renal artery (RA). The procedure can also be performed in both the left and right renal arteries for a bi-lateral therapy.
Additionally, other embodiments of treatment devices can have a fiber optic cable or an in vivo emitter at a distal tip of the shaft that can be placed against the inner wall of a body lumen to irradiate discrete areas. For example, the device in International Publication No. WO 2008/003058, filed Jun. 28, 2007, and incorporated by reference herein, can be modified to have a fiber optic cable and/or an LED at the distal tip in addition to or in lieu of an electrode.
FIG. 11 is a schematic view of a system having a controller 1100 that includes a control algorithm 1110 for operating any of the treatment devices 100, 300, 400, 500, 600, 700, 800 and 900 described above with reference to FIGS. 1-10. The controller 1000 can optionally include a radiation source 1020 that generates the radiation for transmission via fiber optic lines or other light guides through the shaft of the treatment device to the radiation emitters 122, 322, 422, 722, 822 and 922 at the distal end of the shaft. In other embodiments, the controller includes a power source electrically coupled to LED type or other in vivo radiation emitters 122, 322, 422, 722, 822 and 922 at the distal end of the shaft. The algorithm 1110 can include instructions contained on a computer operable medium that operates the radiation emitters to provide the desired radiation pattern and extent of irradiation. In one embodiment, the algorithm 1110 causes the controller 1100 to deliver radiation via the radiation emitter(s) 122, 322, 422, 722, 822 and 922 at a wavelength of 350 nm-365 nm, and in some embodiments within the range of 351 nm-355 nm. The controller 1000 can further cause 0.5-5 J/cm2, 5-25 J/cm2, 25-100 J/cm2, or 100-500 J/cm2 of radiation to be delivered. Any of the foregoing ranges of radiation dosage can be delivered from a single emitter or from each emitter of a plurality of emitters.
Selected Applications, Test Results and Examples
Several embodiments of the present technology can be used intravascularly in the renal arteries, renal ostium, renal veins, renal pelvis, renal calyx (e.g., through the ureter), and/or the renal branch arteries near the renal parenchyma to affect the renal plexus/renal nerve including afferent renal nerves and/or efferent renal nerves. Applications that target the renal plexus/renal nerve through the renal artery, renal ostium and/or renal vein are often directed to treating hypertension, left ventricular hypertrophy, ventricular arrhythmias, sudden cardiac death, insulin resistance, diabetes, metabolic syndrome, hyperaldosteronism, erectile dysfunction, Polycystic Ovary Syndrome (PCOS), infertility (female), Polycystic Kidney Disease (PKD), renal failure, and pain associated with the kidneys. Applications that target efferent renal nerves at the renal pelvis or renal calxy (e.g., through the ureter) can be directed toward decreasing central sympathetic drive to treat hypertension, other cardiac conditions, diabetes, etc. Treatments that target efferent and/or afferent renal nerves at the renal artery and/or the renal branch arteries can be used for treating kidney disease (PKD, renal failure, etc.) and reducing central sympathetic drive (e.g., for treatment of hypertension in patients diagnosed having cystinuria or having an increased risk of developing kidney stones).
Several other non-renal nerve targets, treatment locations, and diseases/conditions/etiologies are listed below in TABLE 1. In each of these additional non-renal applications, the photosensitizer is administered to the patient and the radiation unit of the treatment device is intravascularly positioned at the treatment location to target the nerves for treating the particular disease, condition, and/or etiology as set forth in TABLE 1.









TABLE 1






Intravascular



Nerve Target
treatment location
Disease/Condition/Etiology







Ovarian
Ovarian Artery/Vein
PCOS, infertility


plexus/Ovarian


Nerve


Spermatic
Testicular Artery/Vein
Testicular pain (orchialgia)


Plexus


Genital branch of
External iliac
Testicular pain (orchialgia), vasectomy


genitofemoral
artery/vein, testicular
complications, vulvodynia, pain associated with


nerve (Lumbar
vessels,
scrotum,


Plexus)


Ilioinguinal nerve
Deep circumflex iliac
Pain associated with injury, scrotal skin, skin over


(Lumbar Plexus)
artery (or vein) which
the root of the penis, groin



is a branch of the



external iliac artery


Sacral Plexus
Internal iliac artery,
Genital (male and female) pain (orchialgia,



internal iliac vein
vulvodynia, clitorodynia, injury)


Pudendal nerve
Internal pudendal
Genital (male and female) pain (orchialgia,


(sacral plexus)
vessels (artery)
vulvodynia, clitorodynia), erectile dysfunction


Perineal nerve
Internal pudendal
Genital (male and female) pain (orchialgia,


(from pudendal
artery
vulvodynia, clitorodynia, scrotum)


nerve)


Vaginal plexus
Branches of the
Pain or spasm (vaginismus) associated with vagina



internal iliac artery
and clitoris



(e.g., vaginal arteries,



vaginal venous



plexus)


Uterine Plexus
Uterine artery
Uterine pain, vaginal pain, vaginismus


Lumbosacral
Internal iliac artery,
Pain in pelvic region


plexus (anterior
internal iliac vein, the


divisions of the
ureter, superior


lumbar nerves,
gluteal artery and


sacral nerves,
vein


and coccygeal


nerve)


Celiac Plexus
Celiac Artery
Pain in abdominal viscera (pancreas (pancreatitis,




pancreatic cancer), Hepatobiliary diseases (liver and




biliary tract and gallbladder), spleen (inflammation,




leukemia, lymphoma, etc), stomach (cancer), small




intestine and large bowel (cancer), kidney)


Superior
Superior Mesenteric
Pain associated with pancreas (pancreatitis,


Mesenteric
Artery/Vein
pancreatic cancer) and small intestine and colon


Plexus

(cancer); treatment of gastrointestinal disorders




(inflammatory bowel disease, e.g., Crohn's disease




and ulcerative colitis)


Hepatic plexus
Hepatic artery
Pain associated with Hepatobiliary diseases (liver




and biliary tract and gallbladder)


Splenic plexus
Splenic artery/vein,
Pain associated with spleen (inflammation, leukemia,



splenic branch
lymphoma, etc), treat inflammation (e.g., overactive



arteries
immune response), inflammation associated with




autoimmune diseases (Multiple sclerosis, lupus,




psoriasis)


Gastric plexus
Gastric artery,
Gastrointestinal disorders (inflammatory bowel



superior mesenteric
disease, e.g., Crohn's disease and ulcerative colitis,



artery/vein, inferior
collagenous colitis, lymphocytic colitis, ischaemic



mesenteric
colitis, diversion colitis, and Behcet's disease),



artery/vein
obesity, overeating


Pancreatic
Pancreatic artery
Pain associated with pancreas (pancreatitis,


plexus

pancreatic cancer)









Several embodiments of the present technology are also applicable to extravascular locations. For example, neural structures such as ganglia, peripheral nerves, spinal nerves, cranial nerves, and/or cortical or deep brain neural structures can be modulated in accordance with the present technology. In these embodiments, a neural photosensitizer is administered to the patient and a percutaneous treatment device with a radiation unit is inserted into the patient and positioned proximate to the target neural structures. The treatment device, for example, can be a probe or surgical instrument that can penetrate tissue, and the radiation unit can have a fiber optic emitter and/or internal radiation source at a distal end of the probe. The photosensitizers, radiation, and dosages can be any of the foregoing dosages used for intravascular applications.
The selective disruption of neural cells using oxytetracycline was evaluated to determine whether irradiated oxytetracycline produced a lower cell count compared to control cells. PC12 cells were seeded into collagen coated 96 well plates, and a nerve growth factor (NGF) was added seven days before PC12 to induce cell differentiation. To determine an amount of UVA radiation that would have a nominal effect on cell death, the cells were exposed to titrating amounts of radiation, and then post-exposure cells were incubated for 24 hours before being washed twice, allowed to incubate for one hour, stained with Pico Green, and then counted using a Wallace plate reader. FIG. 12 is a graph showing that at a treatment time of 30-60 seconds the UVA alone started to reduce the cell count. An exposure time of 1 minute was selected for the test as being representative of an exposure where UVA would not significantly affect cell count. Another test was performed to assess the cell count of smooth muscle cells (SMC) and PC12 cells treated with oxytetracycline without irradiation. In this procedure, SMC and PC12 cells were seeded into collagen dishes, NGF was added seven days before PC12 to induce cell differentiation, both the SMC and PC12 cells were dosed with titrating amounts of tetracycline (e.g., 0 μg/ml, 20 μg/ml, 200 μg/ml, and 2 mg/ml), the oxytetracycline dosed cells were incubated for 24 hours, and then the cells were stained with Calcein AM-EtBr 1 μM for 30 minutes. FIG. 13 is a series of views showing the cell loss (dark areas) due to the oxytetracycline. Based on FIG. 13, a dosage of 20 μg/ml was selected as an amount that generally produced the same cell count in SMC and PC12 cells over a 24 hour incubation period.
The final phase of the test included seeding PC12 cells into collagen coated 96 plates. An NGF was added seven days before PC12 cells to induce cell differentiation. The control cells and the PC12 cells were then dosed with 20 μg/ml of oxytetracycline for 24 hours. The test cells were exposed to UVA radiation at a wavelength of approximately 365 nm using an LEDMOD® Series Laser manufactured by Omicron-Laser, Germany, and an X-Cite® optical power measurement system, Lumen Dynamics Group, Inc., washed twice, stained with Pico Green, and then counted using a Wallace plate reader. FIG. 14 is a graph showing that the cells irradiated by the oxytetracycline were approximately 20% less than the cells of the carrier control group that were not irradiated. This test shows that neuronal cells exposed to UVA radiation and a dosage of oxytetracycline have a lower survival rate than the control cells.
EXAMPLES
Example 1
A method for therapeutic neural denervation in a human, comprising:

    
    
        administering a photosensitizer to a human, wherein the photosensitizer preferentially accumulates at nerves proximate a blood vessel compared to non-neural tissue of the blood vessel; and
        irradiating the photosensitizer using a radiation emitter positioned within the human, wherein the radiation has a wavelength that causes the photosensitizer to react and alter at least a portion of the nerves thereby providing a therapeutic reduction in sympathetic neural activity.
    
    


Example 2
A therapeutic neural modulation method in a human for therapeutically reducing sympathetic neural activity, comprising:

    
    
        providing a photosensitizer to perivascular neural tissue associated with sympathetic neural activity, wherein the photosensitizer selectively binds to perivascular neural tissue compared to non-neural vascular tissue;
        positioning a radiation emitter of treatment device in a blood vessel of the human at a target site for the perivascular neural tissue; and
        emitting radiation from the radiation delivery device such that the perivascular neural tissue is irradiated by the radiation, wherein the radiation causes the photosensitizer to react and thereby disrupt the perivascular neural tissue such that neural communication along the perivascular neural tissue is at least partially inhibited.
    
    


Example 3
A method for operating a photodynamic system, comprising:

    
    
        providing a photosensitizer that preferentially binds to calcium;
        generating radiation at a wavelength; and
        delivering the radiation to the photosensitizer.
    
    


Example 4
The method of any of examples 1-3, wherein the radiation has a wavelength of 350 nm-365 nm.
Example 5
The method of any of examples 1-3, wherein the radiation has a wavelength of 351 nm-355 nm.
Example 6
The method of any of examples 1-5, wherein the photosensitizer is administered or provided at a dosage of 0.5-1 mg/kg.
Example 7
The method of any of examples 1-5, wherein the photosensitizer is administered or provided at a dosage of 1-49 mg/kg.
Example 8
The method of any of examples 1-5, wherein the photosensitizer is administered or provided at a dosage of 50-300 mg/kg.
Example 9
The method of any of examples 1-5, wherein the photosensitizer is administered or provided at a dosage of 300-600 mg/kg.
Example 10
The method of any of examples 1-9, wherein the radiation has a dosage of 0.5-1 J/cm2.
Example 11
The method of any of examples 1-9, wherein the radiation has a dosage of 5-25 J/cm2.
Example 12
The method of any of examples 1-9, wherein the radiation has a dosage of 25-100 J/cm2.
Example 13
The method of any of examples 1-9, wherein the radiation has a dosage of 100-500 J/cm2.
Example 14
The method of any of examples 1-13, wherein the radiation is pulsed at a pulse rate of 2 ps-50 ps.
Example 15
The method of any of examples 1-14, wherein the photosensitizer is administered or provided approximately 30-180 minutes before irradiating the photosensitizer.
Example 16
The method of any of examples 1-14, wherein the photosensitizer is administered or provided approximately 3-24 hours before irradiating the photosensitizer.
Example 17
The method of any of examples 1-16, wherein the photosensitizer becomes toxic to the nerves proximate the blood vessel upon reacting with the radiation without impairing function of the non-neural tissue of the blood vessel.
Example 18
The method of any of examples 1-17, wherein the photosensitizer preferentially binds to calcium in the nerves proximate the blood vessel.
Example 19
The method of any of examples 1-18, wherein administering or providing the photosensitizer comprises injecting the photosensitizer into tissue for systemic distribution of the photosensitizer.
Example 20
The method of any of examples 1-18, wherein administering or providing the photosensitizer comprises orally ingesting the photosensitizer for systemic distribution of the photosensitizer.
Example 21
The method of any of examples 1-18, wherein administering or providing the photosensitizer comprises injecting the photosensitizer proximate perivascular nerves that extend along the blood vessel.
Example 22
The method of any of examples 1-21, wherein irradiating the photosensitizer comprises inserting a catheter into the renal artery and directing the radiation through the renal artery wall to renal nerves.
Example 23
The method of any of examples 1-22, wherein irradiating the blood vessel includes emitting the radiation in a spiral pattern about an inner wall of the blood vessel.
Example 24
The method of any of examples 1-22, wherein irradiating the blood vessel includes emitting the radiation at a plurality of locations spaced apart from each other at offset circumferential positions along a length of the blood vessel.
Example 25
The method of any of examples 1-22, wherein irradiating the blood vessel includes emitting a circumferential pattern of radiation around a common plane perpendicular to the blood vessel.
Example 26
The method of any of examples 1-25, further comprising positioning the radiation emitter in a blood vessel as set forth in TABLE 1 for modulating the corresponding target nerve and thereby treating the corresponding disease/condition/etiology.
Example 27
The method of any of examples of 1-26, wherein the photosensitizer comprises oxytetracycline.
Example 28
The method of any of examples 1-26, wherein the photosensitizer comprises furocoumarins.
Example 29
The method of any of examples 1-26, wherein the photosensitizer comprises prophyrins.
Example 30
The method of any of examples 1-26, wherein the photosensitizer comprises benzoporphyrin or a derivative thereof.
Example 31
The method of any of examples 1-26, wherein the photosensitizer comprises phthaloxyanines.
Example 32
A system for performing photodynamic therapy, comprising:

    
    
        a treatment device having an elongated shaft and a radiation unit at a distal portion of the elongated shaft, wherein the radiation unit has a positioning member and at least one radiation emitter, and wherein the positioning member is configured to have a low-profile delivery state for intravascular passage to a target site and a deployed state in which the positioning member is configured to contact a wall of a body lumen such that the radiation emitter is stabilized at a desired location relative to target tissue; and
        a controller configured to be coupled to the treatment device, wherein the controller is adapted to cause radiation at a wavelength of 351 nm-365 nm to be delivered from the radiation unit to deliver 0.5-5 J/cm2, 5-25 J/cm2, 25-100 J/cm2, or 100-500 J/cm2 of radiation to a target.
    
    


Example 33
The system of example 32, wherein the controller has a radiation source and the radiation emitter of the radiation unit comprises an optic element configured to distributed the radiation to the target tissue, and wherein the system further comprises a light guide coupled to the controller and the optic element to transmit the radiation from the controller to the optic element.
Example 34
The system of example 32, wherein the controller has a power source and the radiation emitter of the radiation unit comprises a radiation generator coupled to the positioning member, and wherein the system further comprises an electrical lead electrically coupled to the power source and the radiation generator.
Example 35
The system of example 34, wherein the radiation generator comprises a light emitting diode.
Example 36
The system of example 34, wherein the radiation generator comprise an array of light emitting diodes.
Example 37
A device for therapeutically modulating sympathetic neural system activity, comprising:

    
    
        an elongated shaft configured to pass through vascular passages of a human;
        a balloon at a distal portion of the elongated shaft, the balloon having a wall configured to contact an inner wall of a blood vessel and an exterior channel through which blood can flow when inflated to a deployed state; and
        a radiation element at the balloon configured to deliver radiation to perivascular nerves along the blood vessel.

Conclusion

    
    


This disclosure is not intended to be exhaustive or to limit the present technology to the precise forms disclosed herein. Although specific embodiments are disclosed herein for illustrative purposes, various equivalent modifications are possible without deviating from the present technology, as those of ordinary skill in the relevant art will recognize. In some cases, well-known structures and functions have not been shown and/or described in detail to avoid unnecessarily obscuring the description of the embodiments of the present technology. Although steps of methods may be presented herein in a particular order, in alternative embodiments the steps may have another suitable order. Similarly, certain aspects of the present technology disclosed in the context of particular embodiments can be combined or eliminated in other embodiments. Furthermore, while advantages associated with certain embodiments may have been disclosed in the context of those embodiments, other embodiments can also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages or other advantages disclosed herein to fall within the scope of the present technology. Accordingly, this disclosure and associated technology can encompass other embodiments not expressly shown and/or described herein.
Certain aspects of the present technology may take the form of computer-executable instructions, including routines executed by a controller or other data processor. In some embodiments, a controller or other data processor is specifically programmed, configured, and/or constructed to perform one or more of these computer-executable instructions. Furthermore, some aspects of the present technology may take the form of data (e.g., non-transitory data) stored or distributed on computer-readable media, including magnetic or optically readable and/or removable computer discs as well as media distributed electronically over networks. Accordingly, data structures and transmissions of data particular to aspects of the present technology are encompassed within the scope of the present technology. The present technology also encompasses methods of both programming computer-readable media to perform particular steps and executing the steps.
The methods disclosed herein include and encompass, in addition to methods of practicing the present technology (e.g., methods of making and using the disclosed devices and systems), methods of instructing others to practice the present technology. For example, a method in accordance with a particular embodiment includes locating a distal end portion of an elongate shaft within or otherwise proximate to a vessel or lumen of a human patient, partially decoupling a neuromodulation element from the distal end portion, expanding a support structure of the neuromodulation element radially outward relative to a central longitudinal axis of the vessel or lumen so as to move a therapeutic element carried by the support structure toward a wall of the vessel or lumen, modulating one or more nerves of the patient using the therapeutic element while the neuromodulation element is partially decoupled from the distal end portion, conveying energy toward the therapeutic element via a flexible tether extending between the distal end portion and the neuromodulation element while modulating the one or more nerves. A method in accordance with another embodiment includes instructing such a method.
Throughout this disclosure, the singular terms “a,” “an,” and “the” include plural referents unless the context clearly indicates otherwise. Similarly, unless the word “or” is expressly limited to mean only a single item exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. Additionally, the terms “comprising” and the like are used throughout this disclosure to mean including at least the recited feature(s) such that any greater number of the same feature(s) and/or one or more additional types of features are not precluded. Directional terms, such as “upper,” “lower,” “front,” “back,” “vertical,” and “horizontal,” may be used herein to express and clarify the relationship between various elements. It should be understood that such terms do not denote absolute orientation. Reference herein to “one embodiment,” “an embodiment,” or similar formulations means that a particular feature, structure, operation, or characteristic described in connection with the embodiment can be included in at least one embodiment of the present technology. Thus, the appearances of such phrases or formulations herein are not necessarily all referring to the same embodiment. Furthermore, various particular features, structures, operations, or characteristics may be combined in any suitable manner in one or more embodiments.

## Claims

1. A method for therapeutic neural denervation in a human patient, the method comprising:
administering a photosensitizer to the patient, wherein
the photosensitizer comprises oxytetracycline administered at a dosage of 0.5-600mg/kg body weight, and
wherein the photosensitizer selectively accumulates at nerves proximate a blood vessel compared to non-neural tissue of the blood vessel;

irradiating the photosensitizer at the nerves proximate the blood vessel via radiation from a radiation emitter positioned within the human, wherein
the oxytetracycline is administered 0.5-24 hours before irradiating the photosensitizer, and the radiation is pulsed at of 2 ps- 50 ps to a dosage of 0.5-500 J/cm2,and

wherein the radiation has a wavelength that causes the photosensitizer to react and alter at least a portion of the nerves thereby providing a therapeutic reduction in sympathetic neural activity.

2. The method of claim 1, wherein the radiation has a wavelength of 350 nm - 365 nm.

3. The method of claim 1, wherein the radiation has a wavelength of 351 nm - 355 nm.

4. The method of claim 1, wherein the photosensitizer becomes toxic to the nerves proximate the blood vessel upon reacting with the radiation without impairing function of the non-neural tissue of the blood vessel.

5. The method of claim 1, wherein the photosensitizer selectively binds to calcium in the nerves proximate the blood vessel.

6. The method of claim 1, wherein administering the photosensitizer comprises injecting the photosensitizer into tissue for systemic distribution of the photosensitizer.

7. The method of claim 1, wherein administering the photosensitizer comprises orally ingesting the photosensitizer for systemic distribution of the photosensitizer.

8. The method of claim 1, wherein administering the photosensitizer comprises injecting the photosensitizer proximate perivascular nerves that extend along the blood vessel.

9. The method of claim 1, wherein irradiating the photosensitizer comprises inserting a catheter into the renal artery and directing the radiation through the renal artery wall to renal nerves.

10. The method of claim 1, wherein irradiating the photosensitizer includes emitting the radiation in a spiral pattern about an inner wall of the blood vessel.

11. The method of claim 1, wherein irradiating the photosensitizer includes emitting the radiation at a plurality of locations spaced apart from each other at offset circumferential positions along a length of the blood vessel.

12. The method of claim 1, wherein irradiating the photosensitizer includes emitting a circumferential pattern of radiation around a common plane perpendicular to the blood vessel.

13. A therapeutic neural modulation method in a human for therapeutically reducing sympathetic neural activity, the method comprising:
providing a photosensitizer to perivascular neural tissue of the human associated with sympathetic neural activity, wherein
the photosensitizer comprises oxytetracycline administered at a dosage of 0.5-600 mg/kg body weight, and
the photosensitizer selectively binds to perivascular neural tissue compared to non-neural vascular tissue;

positioning a radiation emitter in a blood vessel of the human at a target site for the perivascular neural tissue; and
emitting radiation from the radiation emitter such that the perivascular neural tissue is irradiated by the radiation, wherein
the oxytetracycline is administered 0.5-24 hours before the perivascular neural tissue is irradiated, and
the radiation is pulsed at 2 ps-50 ps to a dosage of 0.5-500 J/cm2, and

wherein the radiation causes the photosensitizer to react and thereby disrupt the perivascular neural tissue such that neural communication along the perivascular neural tissue is at least partially inhibited.

14. The method of claim 13, wherein the radiation has a wavelength of 350 nm - 365 nm.

15. The method of claim 13, wherein the radiation has a wavelength of 351 nm - 355 nm.

16. The method of claim 13, wherein the photosensitizer becomes toxic to the perivascular nerves upon reacting with the radiation without impairing function of the non-neural tissue of the blood vessel.

17. The method of claim 13, wherein the photosensitizer selectively binds to calcium in the nerves proximate the blood vessel.

18. The method of claim 13, wherein providing the photosensitizer to the perivascular neural tissue comprises injecting the photosensitizer into tissue for systemic distribution photosensitizer.

19. The method of claim 13, wherein providing the photosensitizer to the perivascular neural tissue comprises orally ingesting the photosensitizer for systemic distribution.

20. The method of claim 13, wherein providing the photosensitizer to the perivascular neural tissue comprises injecting the photosensitizer proximate perivascular nerves that extend along the blood vessel.

21. The method of claim 13, wherein;
positioning a radiation emitter in a blood vessel of the human comprises inserting a catheter carrying the radiation emitter into a renal artery; and
emitting radiation from the radiation emitter comprises directing the radiation through the renal artery wall to renal nerves that extend along the renal artery.

22. The method of claim 13, wherein emitting radiation from the radiation emitter includes emitting the radiation in a spiral pattern about an inner wall of the blood vessel.

23. The method of claim 13, wherein emitting radiation from the radiation emitter includes emitting the radiation at a plurality of locations spaced apart from each other at offset circumferential positions along a length of the blood vessel.

24. The method of claim 13, wherein emitting radiation from the radiation emitter includes emitting a circumferential pattern of radiation around a common plane perpendicular to the blood vessel.