Methods and apparatus for increasing lymphatic flow

Abstract

Direct activation of a patient's lymphatic system can induce increased lymphatic flow to treat edema. Stimulation or pacing of the lymphatic system can activate it and trigger contraction of lymphatic smooth muscle to promote lymphatic flow. Stimulation may be performed using one or more implantable electrodes and a stimulator configured to transmit electrical signals to the electrodes. One or more electrodes may be supported by a stent and / or implanted in a blood vessel adjacent to the patient's thoracic duct. Stimulation may utilize one or more sensors to detect the patient's physiological parameters and may be initiated or adjusted based on the detected parameters.

Description

Cross-reference

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 519,204, filed Aug. 11, 2023, the entire disclosure of which is incorporated herein by reference in its entirety. Background

Technical Field

[0002] The present disclosure generally relates to systems and methods for increasing a patient's lymphatic flow.

Background Art

[0003] The lymphatic system plays an important role in fluid transport and immune system function. The lymphatic system moves fluids, large molecules, and lipids from the interstitial space throughout the lymphatic vessels and discharges them into the venous system. Lymphatic system dysfunction results in fluid trapped in the interstitial space, causing edema. [[ID=二十二]]

[0004] Edema is a condition that affects hundreds of millions of people worldwide. Edema typically presents as swelling in the extremities, very often in the legs and feet. Edema can be the result of several underlying causes such as cancer treatment, lymphatic system dysfunction (lymphedema), congestive heart failure, kidney disease, venous insufficiency, or liver disease. It is estimated that 300 million people worldwide suffer from lymphedema.

[0005] Venous lymphedema, the most common form of lymphedema in the United States, is a secondary lymphedema that develops in patients with chronic venous insufficiency when the underlying disease is also not curable. Venous lymphedema is most commonly caused by the lymphatic system's inability to adequately drain the interstitial fluid that accumulates in severe chronic venous hypertension.

[0006] Some treatments for lymphedema include, in addition to treating the underlying disease, manual lymphatic drainage (MLD) by massage, compression garments, and / or a low-salt diet. To date, there is no definitive treatment or cure for lymphedema, and lymphedema is a lifelong condition.

Summary of the Invention

[0007] The systems and methods described herein may be used to modulate a patient's lymphatic flow. Under certain conditions, stimulation of the lymphatic system may lead to an increase in the patient's lymphatic flow. Stimulation may include pacing of the lymphatic system. Such stimulation of a patient's lymphatic system can modulate the patient's lymphatic flow by causing contraction of the lymphatic smooth muscle. Stimulation may be used to modulate lymphatic flow to treat conditions including, but not limited to, edema, lymphedema, venous lymphedema, congestive heart failure (CHF), venous hypertension, or any other condition causing chronic fluid overload.

[0008] The systems and devices described herein may be minimally invasive. The systems and devices described herein may not require sustained stimulation of the patient and may rely on relatively low-frequency stimulation to avoid patient discomfort. The implantable aspects of the system may be small enough to be delivered through a needle. In some embodiments, the system does not necessarily require an implantable stimulator or power source. The system may be temporary or permanent. The system may include one or more implantable electrodes and stimulators. The system may be fully implantable, but in other embodiments, the stimulator may be external, or may be a stimulator with components divided between internal and external (e.g., externally powered via inductive coupling). In the case of multiple electrodes, the electrodes may be on a single implantable structure or implanted separately.

[0009] Certain aspects of this disclosure relate to a system comprising one or more implantable electrodes that can be delivered to electrically communicate with regions of the lymphatic system, e.g., lymphatic vessels and / or lymph nodes. For example, one or more electrodes may be delivered to electrically communicate with one or more segments of the thoracic duct. One or more electrodes may be delivered to electrically communicate with regions of the lymphatic system above (or above) the cisterna chyli of a patient. One or more electrodes may be delivered to a location between the cisterna chyli and the diaphragm. One or more electrodes may be delivered to the aforementioned electrical communication via the venous system. For example, electrodes may be delivered to vessels adjacent to or near regions of the lymphatic system, such as the azygos vein or vessels of the left venous angle. In some embodiments, electrodes may be delivered via the venous system to the outflow portion of the thoracic duct. Electrodes of the one or more electrodes may be delivered to separate locations. For example, some of the one or more electrodes may be delivered to the azygos vein, and some of the one or more electrodes may be delivered to the left venous angle. One or more electrodes may include sensing electrodes. One or more electrodes may be supported by one or more anchors, e.g., tubular structures such as stents. One or more electrodes may be supported by one or more stents by being positioned on or integrated with one or more stents. A stent may support one or more electrodes along its length or at a single point on the stent. One or more stents may fix one or more implantable electrodes within a patient, for example, in a blood vessel or lymphatic vessel.

[0010] Depending on the application, the systems described herein may be open-loop or closed-loop. In an open-loop system, the system may be pre-programmed to start at a specific time of day or at a specific time interval. In a closed-loop system, the system may be equipped with one or more sensors for detecting physiological parameters or conditions.

[0011] Certain aspects of this disclosure relate to a system comprising a stimulator configured to generate electrical signals designed to stimulate a patient's lymphatic system. The stimulation may include pacing. The stimulator may be implantable or external, or may consist of both internal and external components. The system may have one or more electrodes that electrically communicate with the lymphatic system to deliver electrical signals from the stimulator. The stimulator may be electrically connected to one or more electrodes via one or more leaded wires or a leadless design. The stimulator may be configured to receive pre-programmed instructions from a controller and / or processor to transmit signals to one or more electrodes. The controller and / or processor may be mounted on the stimulator or remotely from the stimulator. The pre-programmed instructions may include instructions to transmit signals at predetermined intervals of a day, over predetermined periods of time, and / or with pre-programmed stimulation parameters. For example, the pre-programmed instructions may include activating the stimulator and increasing one or more parameters of stimulation at predetermined time intervals. The stimulator may be capable of stimulating each of the one or more electrodes independently. Each of one or more electrodes can directly deliver electrical stimulation to the lymphatic system, such as the patient's thoracic duct. Stimulation of the lymphatic system with electrical signals can cause contraction of lymphatic smooth muscle cells, leading to an increase in lymphatic flow.

[0012] Certain aspects of this disclosure relate to a system comprising one or more sensors configured to detect a patient's physiological parameters or state. The system may enable closed-loop stimulation. The system may comprise a stimulator that operably communicates with a controller and / or processor configured to receive data from one or more sensors. The stimulator may receive commands from the controller for electrical stimulation based on the detected physiological parameters or state. Commands may include activating the stimulator to transmit electrical signals to one or more electrodes. Commands may include changing one or more parameters of the stimulation, such as frequency, pulse width, current, pulse threshold, and / or duty cycle. Commands may also include interrupting the stimulation.

[0013] One or more sensors may include a flow sensor, pressure sensor, photoplethysmogram (PPG), gyrometer, accelerometer, temperature sensor, and / or any other physiological sensor. One or more sensors may be configured to transmit collected data to a stimulator, processor, and / or controller via a wired or wireless connection, such as Bluetooth. One or more sensors may transmit data to the controller and / or processor continuously or intermittently.

[0014] In some embodiments, the systems described herein may have one or more of the following advantages: improved lymphatic flow, the ability to adjust the treatment to enhance therapeutic efficacy, minimal invasiveness, and reduced need for pharmacological or other therapies.

[0015] Certain aspects of this disclosure relate to a method for delivering one or more implantable electrodes to electrically communicate with a region of the lymphatic system, e.g., lymphatic vessels and / or lymph nodes. For example, one or more electrodes may be delivered to electrically communicate with the thoracic duct. One or more electrodes may be delivered to electrically communicate with a region of the lymphatic system in or above the cisterna chyli of a patient. One or more electrodes may be delivered to a location between the cisterna chyli and the diaphragm. One or more electrodes may be delivered to the aforementioned electrical communication via the venous system. For example, electrodes may be delivered to a vessel adjacent to or near a region of the lymphatic system, such as azygos vein or a vessel of the left venous angle. In some embodiments, electrodes may be delivered via the venous system to the outflow portion of the thoracic duct. Electrodes of the one or more electrodes may be delivered to separate locations. For example, some of the one or more electrodes may be delivered to the azygos vein, and some of the one or more electrodes may be delivered to the left venous angle. Each of the one or more electrodes may directly apply electrical stimulation to the lymphatic system. One or more electrodes may be delivered on one or more anchors (e.g., stents) supporting the electrodes.

[0016] Certain aspects of this disclosure relate to a method for activating a stimulator to transmit electrical signals to one or more electrodes to electrically stimulate a region of the lymphatic system. The electrical stimulation may include pacing. The electrical stimulation may include stimulating lymphatic smooth muscle to cause contraction of the smooth muscle and / or lymphatic segments. The electrical stimulation may increase lymphatic flow in the patient. The electrical stimulation may be continuous or intermittent. The electrical stimulation may be switched between one or more implantable electrodes or may include simultaneous stimulation between all electrodes. The stimulation may be modulated by changing one or more parameters of the stimulation, such as frequency, pulse width, current, pulse threshold, and / or duty cycle. The stimulation may be synchronized so that one or more electrodes are activated sequentially in a stepwise function, from the front to the top.

[0017] The stimulator may be activated by a pre-programmed command to transmit electrical signals at predetermined intervals of a day, over predetermined periods of time, and / or with pre-programmed stimulation parameters. For example, the pre-programmed command may include activating the stimulator and increasing one or more stimulation parameters at predetermined time intervals.

[0018] Certain aspects of this disclosure relate to a method for detecting a patient's physiological parameters or state using one or more sensors. The method may enable closed-loop stimulation. For example, one or more sensors may include lymphatic flow sensors, and the physiological parameters may include the patient's lymphatic flow rate. The method may include receiving data from one or more sensors. The data from one or more sensors may be received by a controller and / or processor that operably communicates with a stimulator. The method may include receiving commands from the controller for electrical stimulation based on the detected physiological parameters or state. The commands may include activating the stimulator to transmit electrical signals to one or more electrodes. The commands may include changing one or more parameters of the stimulation. The commands may include interrupting the stimulation. The method may include verifying, based on the detected physiological parameters or state, that the electrical stimulation is sufficient to increase the patient's lymphatic flow.

[0019] The method may include electrically stimulating the patient after detecting a lymphatic flow rate below a threshold. For example, the method may include automatically activating a stimulator in response to the detection of low lymphatic flow. The method may include detecting lymphatic flow via a flow sensor, a Doppler flowmeter, and / or Doppler optical coherence tomography. [Brief explanation of the drawing]

[0020] The following drawings are for illustrative purposes only and illustrate non-limiting embodiments. In some embodiments, different features shown in the drawings may be combined.

[0021] [Figure 1] It is a schematic diagram of the lymphatic trunk and the venous system.

[0022] [Figure 2] It is a schematic diagram of an implantable lymphatic vessel stimulation device system.

[0023] [Figure 3] It is a schematic diagram of another implantable lymphatic vessel stimulation device system.

[0024] [Figure 4] It is a schematic diagram of another implantable lymphatic vessel stimulation device system.

[0025] [Figure 5] It is a schematic diagram of another implantable lymphatic vessel stimulation device system.

[0026] [Figure 6] It is a process flow diagram of an exemplary method for increasing lymphatic flow. [Figure 7] It is a process flow diagram of an exemplary method for increasing lymphatic flow. [Figure 8] It is a process flow diagram of an exemplary method for increasing lymphatic flow.

Mode for Carrying Out the Invention

[0027] Despite its importance to the body's immune system, the lymphatic system is one of the least understood systems in the human body. One of the primary tasks of the lymphatic system is the transport of lymph. The body energizes the lymphatic system through a pumping mechanism to overcome opposing pressure gradients in a steady state and propel lymph along the lymphatic network. The pumping mechanism includes contraction pumps and valves to generate lymphatic flow and prevent its backflow. The lymphatic system uses both extrinsic pumps, which rely on the periodic compression and expansion of lymphatic vessels by surrounding tissue forces, and intrinsic pumps, which rely on the intrinsic contractions of lymphatic muscles. Intrinsic lymphatic pump function can be regulated by nerve, fluid, or physical factors.

[0028] The external pump function operates through pressure from skeletal muscles, the diaphragm, and thoracic tissues that compress and release lymphatic vessels, contributing to lymphatic flow. Lymphatic vessels, lacking smooth muscle, rely on these external pumps, such as tissue movement, to form lymph and propel it through the network. However, as suggested by studies showing that respiratory activity promotes lymphogenesis during voluntary but non-mechanical ventilation, active muscle contraction rather than passive tissue displacement is required to support efficient lymphatic drainage.

[0029] In ducts containing lymphoid muscle cells, lymphatic flow is determined by well-synchronized spontaneous contractions. However, the reasons why the lymphatic system malfunctions in the presence of edema are not well understood. Researchers widely hypothesize that the dysfunction is a result of a pressure difference between the lymphatic system and the venous system, where pressure is elevated. Some emphasize creating a pressure difference between the lymphatic and venous systems by lowering venous pressure near the thoracic duct, assuming that a decrease in venous pressure can create a pressure difference that draws fluid out of the lymphatic system. However, in people with a normal lymphatic system, lymphatic pressure is already lower than normal venous pressure. The lymphatic system is also known to be able to transport lymph fluid against hydrostatic pressure. Therefore, pressure difference may not be a complete explanation for lymphatic dysfunction, and treatments aimed at lowering venous pressure and / or regulating the pressure difference may have limited benefits.

[0030] Venous pressure reduction is a passive mechanism, relying on pressure differences to produce an aspiration effect, but is limited because the primary function of the lymphatic system is peristaltic movement mediated by the complex structure of one-way valves. Furthermore, venous pressure reduction does not actively increase lymphatic flow in patients with impaired intrinsic or extrinsic lymphatic constriction. Aspiration and pressure difference methods from venous devices are limited and essentially ineffective in patients with normal venous pressure and in patients with lymphatic dysfunction that does not correlate with high venous pressure.

[0031] Patient populations with lymphedema or other types of edema generally suffer from loss or limitation of lower limb mobility and loss of certain extrinsic pumping capacity, with large muscles having limited usefulness for compression and / or stimulation to aid tissue drainage. Therefore, the intrinsic pumping capacity of the lymphatic system is considered important for patients with edema, regardless of the underlying cause and pressure within the venous system. Generally, increased lymphatic pressure or stretching of myolymphatic vessels activates the intrinsic lymphatic pump, while increased lymphatic flow or shear within myolymphatic vessels can activate or inhibit the intrinsic lymphatic pump depending on the flow pattern and magnitude. To regulate lymphatic transport, lymphatic pumping and resistance must be controlled.

[0032] This disclosure relates to the temporary or permanent regulation of lymphatic flow in patients by activation of the lymphatic system. Direct activation of the lymphatic system can be achieved by stimulation of the lymphatic system. Stimulation may include pacing of the lymphatic system. Stimulation may be effective in activating the lymphatic system when performed in or near the thoracic duct. For example, stimulation may be performed via electrodes in a vessel adjacent to the thoracic duct, such as the azygos vein. Although not bound by any particular theory, lymphatic flow may be enhanced by activating lymphatic smooth muscle cells via electrical stimulation to synchronously trigger contraction and peristalsis of ductal segments, thereby propelling lymph along the lymphatic network. Electrical stimulation may increase the intrinsic velocity of lymphatic flow returning to the circulatory system through the thoracic duct. Advantageously, the increase in intrinsic pumping capacity may provide improved methods and systems for treating edema.

[0033] Figure 1 is a schematic diagram of the lymphatic trunks and surrounding venous system. The thoracic duct 102 is the primary lymphatic vessel of the lymphatic system. The thoracic duct 102 originates from the cisterna chyli 104. In human patients, the cisterna chyli 104 is located posterior to the abdominal aorta and anterior to the first and second vertebral bodies (L1 and L2). The cisterna chyli 104 receives lymph from the left and right lumbar lymphatic trunks and the enteric lymphatic trunk.

[0034] The thoracic duct 102 is the larger of the two lymphatic trunks of the lymphatic system, the other being the right lymphatic trunk 112. In adults, the thoracic duct is approximately 40 cm long and about 5 mm in diameter at its abdominal origin. The thoracic duct 102 is responsible for lymphatic drainage from the entire body except for the right side of the head and neck, the right side of the chest, and the right upper limb, which are primarily drained by the right lymphatic trunk. The thoracic duct 102 is responsible for approximately 75% of the body's lymphatic drainage. The average lymphatic flow rate in a human patient may be about 1.5 mL / min. Originating from the cisterna chyli 104, the thoracic duct 102 extends anterior to the spine between the aorta and the azygos vein 132. Both the azygos vein 132 and the thoracic duct 102 ascend closely together within the posterior mediastinum, positioning the azygos vein suitable for the placement of one or more electrodes used for stimulation. Although not illustrated, the esophagus and descending thoracic aorta are also parallel to the thoracic duct 102.

[0035] Figure 1 also illustrates the superior vena cava (SVC) of the venous system. The thoracic duct 102 continues superiorly, extending behind the aorta and the SVC. In the superior mediastinum, the thoracic duct 102 passes posterior to the left internal jugular vein 120. The thoracic duct 102 then continues to an outflow portion 108 that drains lymph to the junction of the left subclavian vein 116 and the left internal jugular vein 120. This junction into which the thoracic duct drains may also be called the left venous angle. On the opposite side of the SVC, the right lymphatic trunk 112 drains to the junction of the right subclavian vein 124 and the right internal jugular vein 128. This junction into which the right lymphatic trunk drains may also be called the right venous angle.

[0036] Implantable lymphatic stimulator (ILS) systems can be implanted to supply electrical signals to the lymphatic system. These electrical signals can activate lymphatic smooth muscle cells, causing them to contract and enhancing lymphatic flow. The stimulator can generate electrical signals and transmit them to one or more implantable electrodes to stimulate the lymphatic system. Direct surgical access to the lymphatic system has historically been difficult due to the delicate nature of the lymphatic vessels and the wide anatomical diversity of the lymphatic systems in different patients. Therefore, components of an ILS system, such as one or more electrodes and / or lead wires, can be implanted in one or more intravascular venous systems adjacent to areas of the lymphatic system. For example, components and / or leads of an ILS system can be positioned along the thoracic duct above the azygos vein, sVC, cisterna chyli, and / or below the diaphragm. Intravascular placement allows electrodes to electrically communicate with key areas of the lymphatic system without the need for surgical access to the lymphatic vessels. In some embodiments, components of an ILS system can be positioned in the outflow portion of the thoracic duct via delivery through the venous system, i.e., the superior vena cava. In other embodiments, treatment may be acute using a non-implantable stimulator. For example, electrical signals may be delivered externally or by using a needle to penetrate tissue near a portion of the lymphatic system, such as near the thoracic duct.

[0037] Stimulation may include pacing, such as intermittent pacing. Pacing may be performed using similar stimulators and / or stimulator parameters used in pacing devices such as pacemakers or diaphragmatic pacers. To avoid patient discomfort, the location and intensity of stimulation and / or pacing may be carefully selected to avoid esophageal or diaphragmatic pacing. In patients where avoiding such discomfort is impossible, the stimulation algorithm may provide intermittent pacing with shorter sequences of pacing followed by longer periods of stimulation or no pacing. Stimulation may include continuous pacing of at least about 1 minute and / or 1 hour or less, for example, 45 minutes or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less. The continuous pacing may be performed at multiple intervals throughout the day, at least twice and / or up to 20 times per day, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times per day. In some embodiments, the stimulation algorithm may provide intermittent pacing to all patients. Intermittent pacing may be more beneficial than continuous pacing so that the patient's lymphatic system does not become accustomed to the electrical stimulation and either ceases to respond to the stimulation or shows a reduced response. Pacing may include field pacing applied to an overall field or area around the electrode(s).

[0038] One or more electrodes may be positioned above the cisterna chyli in the patient where the thoracic duct originates. One or more electrodes may be positioned below the diaphragm in an area adjacent to the cisterna chyli or the origin of the thoracic duct. One or more electrodes may be positioned far enough away from the diaphragm for the pulse intensity and duration of stimulation to minimize or eliminate the possibility of unintentional diaphragmatic pacing that could cause discomfort to the patient. Stimulation or pacing in a position below the diaphragm can activate lymphatic flow in a broad area of ​​the lymphatic system that relies on smooth muscle cell contraction to deliver fluid above the diaphragm. Once above the diaphragm, the fluid can be further delivered by respiratory-circulatory movements to the thoracic duct outflow portion in a manner similar to a relay race. The position below the diaphragm may provide the lymphatic system with the ability to move fluid above the diaphragm and relay it to the respiratory system, thus synchronizing fluid movement. In some other embodiments, one or more electrodes may be positioned above the diaphragm (above the diaphragm) up to the upper chest where the thoracic duct drains into the venous system.

[0039] Figures 2 to 5 illustrate different possible configurations of the system described above. Figure 2 is a schematic diagram of an exemplary system 200 for regulating a patient's lymphatic system. Figure 2 schematically illustrates an implantable stimulator 204 positioned to transmit electrical signals to one or more implantable electrodes. For example, the stimulator 204 may be implanted in the subcutaneous layer of the patient. The stimulator 204 may be implanted subcutaneously in the patient's abdominal cavity or chest. Although the stimulator is illustrated as implantable, in other embodiments the stimulator 204 may be an external stimulator or a stimulator having components divided into both internal and external parts (for example, the stimulator 204 may be powered externally via inductive coupling). The stimulator 204 may have wired or wireless communication (for example, configured to communicate with one or more electrodes, a hospital system, a computer, a controller, a handheld device such as a telephone or tablet, etc.).

[0040] Stimulators can generate electrical signals designed to stimulate areas of the lymphatic system, such as the thoracic duct. Stimulation can include field stimulation, which may be applied across an overall field or area and is generally applied to smooth muscle. Stimulation can directly activate lymphatic smooth muscle cells, causing contraction of the lymphatic smooth muscle and increasing the patient's lymphatic flow. While not bound by any particular theory, electrical stimulation of a specific unit of the lymphatic system may fill and stretch the unit with lymph, thus naturally triggering contraction of lymphatic smooth muscle cells and moving lymph fluid to the next lymphatic unit. This "snowball effect" can lead to improved lymphatic flow throughout the thoracic duct, and stimulation of the cisterna chyli or the area of ​​the thoracic duct above it may result in a restoration or enhancement of the lymphatic's natural peristaltic pumping function, overcoming high venous hydrostatic pressure without directly reducing venous pressure. Therefore, stimulation can cause a delayed effect of increased flow because the contractions continuously produce a suction effect along the lymphatic network. For example, stimulation may result in an increase in lymphatic flow, which may be observed approximately 4–10 minutes after activation, depending on the patient. Stimulation may result in an increase of at least 5% and / or up to 100% of lymphatic flow, e.g., up to 10% increase in lymphatic flow, up to 20% increase in lymphatic flow, up to 30% increase in lymphatic flow, up to 40% increase in lymphatic flow, up to 50% increase in lymphatic flow, up to 60% increase in lymphatic flow, up to 70% increase in lymphatic flow, up to 80% increase in lymphatic flow, or up to 90% increase in lymphatic flow.

[0041] Electrical stimulation can be delivered to areas of the lymphatic system using one or more implantable electrodes. One or more electrodes may be positioned by image guidance and / or other minimally invasive techniques known in the art. Access for implanting electrodes and / or lead wires may be obtained through the femoral vein. One or more electrodes may include at least one stimulating electrode and may further include a sensing electrode. A single electrode may be sufficient to increase lymphatic flow at least in the abdominal cavity. The stimulator 204 may be electrically connected to one or more implantable electrodes via one or more lead wires or a leadless design. In some embodiments, one or more electrodes may be arranged on one or more lead wires fixed to one or more blood vessels. Additionally or alternatively, one or more electrodes may be supported by anchors such as one or more stents or tubular structures implanted in one or more blood vessels. By using stents to support electrodes, occlusion in the vein holding the electrodes and other problems related to blood flow can be prevented. For example, Figure 2 illustrates a stimulator 204 electrically connected to a stent 208 supporting one or more implantable electrodes via lead wires 216.

[0042] Stent 208 may be implanted in the cisterna chyli 104 or in the azygos vein 132 above it. The thoracic duct can be well visualized adjacent to the azygos vein posterior to the esophagus, positioning the azygos vein 132 and smaller adjacent veins suitable for stimulating portions of the cisterna chyli 104 and / or the thoracic duct 102. As illustrated, stent 208 may be implanted above the patient's diaphragm, but in some other embodiments, stent 208 may be implanted between the cisterna chyli 104 and the cranial end of the diaphragm. Stent 208 may be implanted between the cisterna chyli 104 and the bifurcation between the left and right lymphatic trunks of the patient.

[0043] The positioning of the stent 208, fixed along the wall of the azygos vein 132, may allow for field stimulation of the thoracic duct 102 along a greater length of the duct, as the azygos vein extends nearly parallel to the thoracic duct. While a single electrode may trigger contraction of the thoracic duct 102, in some embodiments, the electrical stimulation may include synchronous stimulation along a set of multiple electrodes arranged along the length of the stent 208. For example, the electrodes may be activated sequentially in stages to trigger sequential chamber-to-chamber contraction along the length of the thoracic duct 102. Although the stent 208 is exemplified as being positioned in the azygos vein, the multiple synchronous electrodes may be positioned in the lymphatic system, the lower extremities, the lower abdominal cavity below the diaphragm, and / or within the cisterna chyli or above the thoracic duct. One or more electrodes may be arranged closely together on the stent 208 so that the stimulation may include stimulation at a single point or region of the thoracic duct 102. While not bound by any particular theory, stimulation of the intraperitoneal thoracic duct can trigger the intrinsic "snowball" effect discussed herein with respect to the contraction of lymphatic smooth muscle. When lymph is pushed above the level of the diaphragm, the natural respiratory action can take over the fluid, distributing it into the venous system by moving it upward through the thoracic duct and superior mediastinum into the left subclavian vein at the left venous angle. Functionally, lymphatic flow can increase from within the lymphatic system independently of venous pressure or venous dysfunction.

[0044] Depending on the application, the systems described herein may be open-loop or closed-loop. For example, the systems and devices described herein may be operated manually, semi-automatically, and / or fully automatically. The programming of the stimulator may be adjustable by a physician, a feedback loop, or artificial intelligence.

[0045] In an open-loop system, the system may be programmed to stimulate for a predetermined time at startup, for example, at least about 1 minute and / or up to 2 hours, for example, up to 1 hour, up to 30 minutes, up to 15 minutes, up to 10 minutes, or up to 5 minutes. The stimulator 204 may include a controller (also called a processor) mounted on or remote from the stimulator, configured to be preprogrammed with commands for electrical stimulation. The commands may include one or more parameters for electrical stimulation, including but not limited to the number of times per day, time intervals throughout the day, duration, frequency, current, pulse width, pulse threshold, and / or duty cycle. The stimulator may be preprogrammed to change one or more stimulation parameters at predetermined time intervals. For example, the stimulator may be preprogrammed to increase the stimulation parameters at 2-minute intervals after the stimulator has been started.

[0046] In a closed-loop system, the system may be programmed to activate a stimulus based on readings from one or more sensors configured to detect a patient's physiological parameters or condition. The stimulator 204 may include a controller mounted on or remote from the stimulator, configured to receive data from one or more sensors. Based on the received data, the controller may be configured to send commands to the stimulator. The commands may be to activate the stimulator or to change one or more parameters of the stimulus. The commands may be automatic based on data received from one or more sensors, but in some other embodiments, the system may prompt a user or physician to send a command in response to one or more sensors detecting a patient's physiological parameters or condition.

[0047] The stimulation parameters do not need to be high enough to burn or damage the area surrounding one or more electrodes. The stimulation parameters do not need to be low enough not to induce a response from the lymphatic vessels. The stimulation frequency may be at least about 5 Hz and / or 1000 Hz or less, 500 Hz or less, 100 Hz or less, 50 Hz or less, 35 Hz or less, or 20 Hz or less. The stimulation current may be at least about 10 mA and / or 1000 mA or less, 500 mA or less, 200 mA or less, 100 mA or less, or 50 mA or less. The stimulation pulse may include a pulse width of at least about 50 μs and / or 2000 μs or less, for example, 1000 μs or less, 800 μs or less, 600 μs or less, or 400 μs or less. The stimulation may be provided with a minimum current in the range of 50 mA to 100 mA. The stimulation may be provided with a minimum pulse length of 100 μs to 500 μs. The stimulation may be provided at a minimum frequency in the range of 10 Hz to 20 Hz. The stimulation may be provided in multiple stimulation rounds. Multiple stimulation rounds may include multiple selected durations and residence times between rounds. At implantation, the stimulation pulse may include a pulse threshold of 1.5 V or less and a pulse width in the range of 400 μs to 600 μs. In some embodiments, the pulse threshold and pulse width may exceed 1.5 V and 600 μs, respectively. The stimulation may include pacing in the range of 50 to 500 paces (ppm) per minute. For example, pacing may be performed for 10 minutes at approximately 180 ppm and 20 mA to induce a response in the lymphatic system.

[0048] Stimulation therapy may be intermittent. Intermittent stimulation may be beneficial in preventing the lymphatic system from becoming accustomed to constant stimulation and ceasing to respond. For example, intermittent stimulation may involve sending electrical signals to one or more electrodes multiple times a day over a set time interval. Stimulation may also be continuous over the aforementioned time interval. Stimulation may be performed multiple times throughout the day with intervals of continuous stimulation of 10 to 30 minutes. The stimulator 204 may be activated at least twice a day and / or up to 20 times a day, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times a day. The stimulator 204 may be automatically activated at specific pre-programmed times of the day based on sensor-detected measurements or by other means. Depending on the adaptation, electrical stimulation may be limited to being activated at specific times of the day.

[0049] The stimulation may be adjusted to suit the specific patient being stimulated. For example, the stimulation may be increased for a patient with increased levels of adipose tissue around the thoracic duct. Thus, the parameters for stimulation may be adjusted by the physician during the implantation of the system into the patient or during subsequent outpatient visits. The stimulation parameters may also be adjusted during stimulation by a feedback loop provided by one or more sensors. The positioning of one or more electrodes may also be adjusted by the physician during the implantation procedure based on data from one or more sensors. For example, the physician may use Doppler optical coherence tomography or a Doppler flowmeter to measure lymphatic flow during the implantation procedure and confirm that the stimulation results in an increase in lymphatic flow. The Doppler flowmeter may be used to establish baseline and experimental flow rates. Because lymphatic flow is very low, the flowmeter may be very sensitive, such as being able to detect a change in flow of 0.1 μL.

[0050] System 200 may comprise one or more sensors configured to detect a patient's physiological parameters or conditions. One or more sensors may be implantable or wearable. If implantable, one or more sensors may be implanted near one or more electrodes or at a remote location within the body suitable for sensor operation. One or more sensor readings may trigger electrical stimulation based on a comparison of the detected measurement to a threshold. One or more sensor readings may trigger adjustment of ongoing electrical stimulation based on a comparison of the detected measurement to a threshold. The threshold may be pre-programmed into the system or calibrated based on the patient. One or more sensors may transmit collected data to a processor, which may calculate parameters based on the collected data and compare the calculated parameters to a threshold. For example, one or more sensors may measure one or more characteristics of lymphatic system contraction and transmit the data to a processor to calculate the patient's lymphatic flow. One or more sensors may include gyrometers, accelerometers, electromyographs (EMG), photoplethysmograms (PPG), pressure, flow rates, temperature, and / or other physiological sensors. One or more sensors may be configured to transmit collected data to a stimulator, processor, and / or controller via a wired or wireless connection, such as Bluetooth.

[0051] Referring back to Figure 2, the system 200 may include a flow sensor 212 configured to detect the patient's lymphatic flow. The flow sensor 212 may be located at or near the left venous angle, or at or near the outflow 108 of the thoracic duct into the venous system. For example, the flow sensor 212 may be located in the left subclavian vein 116 adjacent to the junction of the left subclavian vein 116 and the left internal jugular vein 120. The flow sensor 212 may be connected by lead wires or wires configured to enable the transmission of collected data to the stimulator 204. In some embodiments, the flow sensor 212 may transmit data wirelessly to the stimulator 204. Placing the flow sensor 212 at the left venous angle where the thoracic duct drains may allow for accurate reading of lymphatic flow without the need for direct access to the lymphatic system tubules. The flow sensor 212 may be fixed to the vessel by any fixation mechanism known in the art. For example, fixation mechanisms may include hooks, barbs, cusps, prongs, etc. In some embodiments, the sensor may be incorporated into or disposed on a stent or a separate stent supporting one or more electrodes for stimulation, as described herein. Because the lymphatic flow is very low, the flow sensor 212 can be very sensitive, such as being able to detect a change in flow of 0.1 μL. The flow sensor 212 may be about 0.5 mm to 36 mm in size.

[0052] Figure 3 is a schematic diagram illustrating another exemplary system 300 for regulating a patient's lymphatic system. System 300 comprises a stimulator 204, the embodiment of which is described with reference to Figure 2. System 300 may comprise one or more implantable electrodes implanted in or near the left venous angle, within one or more vessels of the left venous angle, e.g., the left brachiocephalic vein 118, the left subclavian vein 116, or the left internal jugular vein 120. One or more electrodes may be positioned at the left venous angle to stimulate the outflow portion 108 of the thoracic duct 102. Stimulation may include pacing of the outflow portion 108. Stimulation may include field stimulation and / or pacing of the outflow portion 108. One or more electrodes may be connected to the stimulator 204 by lead wires 316.

[0053] One or more implantable electrodes may be supported by the stent 308. The stent 308 may be partially fixed in one or more of the left brachiocephalic vein 118, the left internal jugular vein 120, or the left subclavian vein 116. For example, Figure 3 illustrates a stent 308 partially fixed in the left subclavian vein 116 and partially in the left brachiocephalic vein 118. However, in some embodiments, the stent 308 may be entirely fixed in one of the left brachiocephalic vein 118, the left internal jugular vein 120, or the left subclavian vein 116.

[0054] In embodiments of a system having one or more electrodes in the left venous angle, one or more sensors configured to detect physiological parameters or conditions may be integrated with a structure that supports and / or fixes one or more electrodes along the blood vessel(s). For example, referring to Figure 3, a flow sensor 312 may be integrated with a stent 308 that supports one or more electrodes. The flow sensor 312 may be integrated with the stent 308 by being disposed on the stent or by being integrated with the stent, but is not limited to this. In some embodiments, the flow sensor 312 may be separate from the stent 308.

[0055] Figure 4 is a schematic diagram illustrating another exemplary system 400 for regulating a patient's lymphatic system. System 400 comprises a stimulator 204, the embodiment of which is described with reference to Figure 2. System 400 may comprise two or more electrodes, including a first implantable electrode and a second implantable electrode. The first implantable electrode may be implanted in the azygos vein 132 above the cisterna chyli 104, and the second implantable electrode may be implanted in one of the vessels of the left venous angle, at or near that angle. The multi-electrode configuration of System 400 may beneficially increase lymphatic stimulation and / or provide greater control over the regulation of the lymphatic system by selectively and / or simultaneously electrically stimulating the origin and drainage area of ​​the thoracic duct or its vicinity.

[0056] The first and second electrodes may be supported by a first stent 408A and a second stent 408B, respectively. The first stent 408A may be partially fixed in one or more of the left brachiocephalic vein 118, the left internal jugular vein 120, or the left subclavian vein 116. For example, Figure 4 illustrates a stent 408A partially fixed in the left subclavian vein 116 and partially fixed in the left brachiocephalic vein 118. However, in some embodiments, the stent 408A may be entirely fixed in one of the left brachiocephalic vein 118, the left internal jugular vein 120, or the left subclavian vein 116.

[0057] The second stent 408B may be implanted in the cisterna chyli 104 or in the azygos vein 132 above it. The second stent 408B may be implanted between the cisterna chyli 104 and the branching points to the left and right lymphatic trunks of the patient. The stent 408B may be implanted above the patient's diaphragm, but in other embodiments, the stent 408B may be implanted between the cranial end of the diaphragm and the cisterna chyli 104. The stent 408B may allow synchronous or single-point stimulation as described with reference to stent 208.

[0058] The multiple electrode system 400 may include one or more sensors configured to detect a patient's physiological parameters or state. One or more sensors may transmit data to the controller of the stimulator 204 so that the controller can send commands to the stimulator based on the received data. Commands may include activating the stimulator to transmit an electrical signal to only one of the first or second electrodes, or to transmit an electrical signal to both the first and second electrodes simultaneously. Commands may include changing one or more stimulation parameters for only one of the first or second electrodes, or to simultaneously change stimulation parameters for both the first and second electrodes. Commands may include stopping the transmission of an electrical signal to only one of the first or second electrodes, or simultaneously stopping the transmission of an electrical signal to both the first and second electrodes. Commands may include stopping the transmission of an electrical signal to one of the first or second electrodes, and simultaneously starting the transmission of an electrical signal to the other of the first and second electrodes.

[0059] Referring back to Figure 4, the flow sensor 312 may be configured to detect the patient's lymphatic flow. The flow sensor 312 may be located at or near the left venous angle, or at or near the outflow portion 108 of the thoracic duct 102 into the venous system. As illustrated, the flow sensor 312 is integrated with the stent 408A, but in some embodiments, the flow sensor 312 may be separate from the stent 408A. The flow sensor 312 may be connected by lead wires or wires configured to enable the transmission of collected data to the stimulator 204. In some embodiments, the flow sensor 312 may transmit data wirelessly to the stimulator 204. Based on the lymphatic flow data received from the flow sensor 312, the stimulator 204 may control the stimulation of the first and second electrodes supported by the first and second stents 408A, 408B.

[0060] Figure 5 is a schematic diagram of another exemplary system 500 for regulating the lymphatic system. System 500 comprises a stimulator 204, the embodiment of which is described with reference to Figure 2. System 500 may comprise one or more implantable electrodes, including an electrode implanted somewhere within the thoracic duct, for example, between the outflow portion 108 and the cisterna chyli. In some embodiments, the electrode may be implanted near venous access. The electrode may be implanted within the outflow portion 108 of the thoracic duct 102. The outflow portion 108 of the thoracic duct 102 may be more easily accessible in the patient's anatomical structure than other areas of the thoracic duct due to less variation in its location among patients. For example, instead of directly accessing the lymphatic system, the outflow portion 108 may be located and accessed through an opening where lymph exits the venous system at or near the left venous angle.

[0061] The system 500 may include a tubular support or stent 508 for supporting one or more electrodes implanted in the thoracic duct. Using a stent 508 to support one or more electrodes in the thoracic duct can prevent lymphatic blockage or impedance and facilitate decompression. In some embodiments, the stent 508 may be partially fixed in the outflow duct and partially fixed in one or more of the surrounding veins forming the left venous angle. The system 500 further includes a flow sensor 312 which may be separate from or integrated with the stent 508 and may be connected to the stimulator 204.

[0062] Systems 200, 300, 400, and 500 are shown and described separately for the purpose of illustrating various locations for the implantation of one or more electrodes. However, it should be understood and acknowledged that this disclosure is not so limited, as some components of one system may be present in other systems. For example, system 500 may further comprise the electrode support stent 208 of system 200. Furthermore, not all illustrated embodiments are required for, and not necessarily limited to, systems 200, 300, 400, and 500.

[0063] Figures 6–8 are process flow diagrams of exemplary methods for modulating a patient's lymphatic system. Figure 6 shows method 600 for modulating a patient's lymphatic system using one or more implantable electrodes. Figure 7 shows method 700 for modulating a patient's lymphatic system using one or more implantable electrodes and one or more sensors for collecting data used to generate commands for electrical stimulation. Methods 600, 700 may be performed using any of the systems 200, 300, 400, 500 shown in Figures 2–5. One or more aspects of method 600 and / or 700 may be stored in non-temporary memory (e.g., any computer memory that is not temporary signals) and executed by a processor (e.g., any hardware processor).

[0064] For simplicity, methods 600 and 700 are shown and described as being performed sequentially. However, since some steps or boxes can be performed in a different order and / or simultaneously with other steps or boxes shown and described herein, it should be understood and acknowledged that this disclosure is not limited by the illustrated order. Furthermore, for simplicity, methods 600 and 700 are shown and described separately. However, since some steps or boxes of one method may be present in the other method, it should be understood and acknowledged that this disclosure is not so limited. Furthermore, not all illustrated embodiments are required to implement methods 600, 700, and methods 600, 700 are not necessarily limited to the illustrated embodiments.

[0065] Referring here to Figure 6, a method 600 for modulating a patient's lymphatic system is illustrated. The modification of the lymphatic system provided by method 600 may be used to treat patients with a variety of medical conditions, including but not limited to lymphedema, venous lymphedema, venous hypertension and / or similar conditions.

[0066] In step 604, one or more implantable electrodes are delivered to electrically communicate with a region of the patient's lymphatic system. Each of the one or more electrodes may have one or more electrode contacts that can be contacts for an implantable electrode (e.g., a lead wire, paddle electrode, cuff electrode, transcutaneous electrode, helical lead wire, etc.). The one or more implantable electrodes may be delivered by implanting one or more stents that support the one or more electrodes within the patient. In such embodiments, the one or more electrode contacts may be arranged on or integrated with the stent. The one or more implantable electrodes may be delivered to the venous system near a region of the lymphatic system. For example, one or more electrodes supported by one or more stents may be delivered to the azygos vein or left venous angle such that one or more electrodes are close to the thoracic duct of the lymphatic system. In some embodiments, the one or more electrodes may be delivered through the patient's venous system to the outflow portion of the thoracic duct.

[0067] In step 608, a stimulator (e.g., an external stimulator, an internal stimulator, or a stimulator having a combination of external and implantable components) can be activated to generate and / or transmit a signal to one or more implantable electrodes. The signal may be an electrical signal comprising a repeating sequence of pulses of a first time interval and a delay of a second time interval. Each pulse may deliver an intensity that includes at least a portion of the stimulation intensity required to induce contraction of the patient's lymphatic smooth muscle cells. In some embodiments, the intensity may be a multiple of the stimulation intensity required to induce contraction (e.g., 0.1x to 15x).

[0068] The electrical stimulation may be in an open loop. The stimulation may be initiated at any given time, as set by the clinician or the programmer of the stimulator. For example, the stimulation may be initiated at least twice per day and / or less than 20 times per day, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 times per day. The stimulation may be programmed to be initiated at a specific time each day.

[0069] In step 612, the signal transmitted by the stimulator to one or more electrodes results in electrical stimulation of a region of the lymphatic system. The stimulation may be performed for a preset duration, for example, at least about 1 minute and / or 1 hour or less, such as 45 minutes or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less. The stimulation parameter does not have to be high enough to burn or damage the area surrounding one or more electrodes. The stimulation parameter does not have to be low enough to not induce a response from the lymphatic vessels. The stimulation frequency may be at least about 5 Hz and / or 1000 Hz or less, 500 Hz or less, 100 Hz or less, 50 Hz or less, 35 Hz or less, or 20 Hz or less. The stimulation current may be at least about 10 mA and / or 1000 mA or less, 500 mA or less, 200 mA or less, 100 mA or less, or 50 mA or less. The stimulation pulse may include a pulse width of at least approximately 50 μs and / or 2000 μs or less, for example, 1000 μs or less, 800 μs or less, 600 μs or less, or 400 μs or less. The stimulation may be provided with a minimum current in the range of 50 mA to 100 mA. The stimulation may be provided with a minimum pulse length of 100 μs to 500 μs. The stimulation may be provided with a minimum frequency in the range of 10 Hz to 20 Hz. The stimulation may be provided in multiple stimulation rounds. Multiple stimulation rounds may include multiple selected durations and residence times between rounds. At implantation, the stimulation pulse may include a pulse threshold of 1.5 V or less and a pulse width in the range of 400 μs to 600 μs. In some embodiments, the pulse threshold and pulse width may exceed 1.5 V and 600 μs, respectively.

[0070] In some embodiments, the electrical stimulation may be in a closed loop and may be triggered when one or more sensors detect specific physiological parameters or conditions of the patient, as further described with reference to method 700 shown in Figure 7. One or more sensors may include flow sensors, pressure sensors, optical sensors for PPG, gyrometers / accelerometers, or others. One or more sensors may be external to the patient or implantable.

[0071] Figure 7 shows a method 700 for modulating a patient's lymphatic system. One or more steps included in method 700 may be used in method 600 to implement closed-loop electrical stimulation. In step 604, described with reference to Figure 6, one or more implantable electrodes are delivered to electrically communicate with a region of the patient's lymphatic system.

[0072] In step 708, one or more sensors may detect the patient's physiological parameters or condition, as described herein. These physiological parameters or conditions may include, but are not limited to, lymphatic flow, venous pressure, heart rate, temperature, lymphatic velocity or tubular constriction using Doppler optical coherence tomography, changes in skin color, and / or changes in swelling.

[0073] The method may include verifying, based on detected physiological parameters or conditions, that an electrical stimulus is sufficient to increase the electrical stimulation. In some embodiments, the physiological parameters or conditions may be compared to a threshold (e.g., one stored in memory, retrieved from a remote source, and / or similar). The comparison may be performed, for example, by the stimulator, components associated with the stimulator, and / or components communicating with the stimulator. The threshold may be specific to the physiological parameter and may be determined for a patient based on previous data from the patient or from a similar patient population. The threshold may also be based on the most recent data collected by one or more sensors.

[0074] In step 712, a command is sent to the stimulator for electrical stimulation based on the detected physiological parameters or conditions. The command for electrical stimulation may include activating the stimulator and / or changing one or more parameters of the electrical stimulation. In such embodiments, the system can be described as a closed loop, as stimulation and / or adjustment of stimulation are triggered when one or more sensors detect a particular physiological parameter or condition. The command may include changing one or more parameters of the ongoing electrical stimulation so that the system can optimize the stimulation through a real-time feedback loop as data is collected by one or more sensors. For example, in some embodiments, a flow sensor may directly measure lymphatic flow in the outflow portion of the thoracic duct. The flow sensor may be connected to the stimulator and / or components associated with the stimulator (e.g., an internal or external controller or processor of the stimulator) so that the flow measurement is sent to the stimulator to provide a feedback loop for stimulation. Low lymphatic flow may trigger the activation of the stimulator and / or adjustment of stimulation parameters. High flow may trigger the deactivation of the stimulator and / or adjustment of stimulation parameters. The stimulus parameters that can be changed include, but are not limited to, one or more of the following: frequency, current, pulse width, pulse threshold, and duty cycle.

[0075] Although methods 600 and 700 are shown separately in Figures 6 and 7, it should be understood and recognized that the disclosure is not so limited, as the steps of methods 600 and 700 can be combined without being limited to a specific order. For example, the methods disclosed herein may include steps 604, 608, 612, 708, and 712 in order. In another example, the methods disclosed herein may include steps 604, 708, 712, 608, and 612 in order. The steps disclosed in methods 600 and 700 may be repeated multiple times. For example, the methods disclosed herein may include steps 604, 708, 712, 608, 612, 708, and 712 in order.

[0076] Figure 8 illustrates an exemplary embodiment of Method 700. In step 804, lymphatic flow may be detected by one or more sensors. Lymphatic flow is detected by a flow sensor implanted in or near the left venous angle or in the outflow portion of the thoracic duct. Lymphatic flow may also be detected by a Doppler flowmeter. In some embodiments, lymphatic velocity and / or lymphatic flow are detected by Doppler optical coherence tomography.

[0077] In step 808, the detected lymphatic flow is compared to a threshold, as described in relation to step 708 of method 700. The threshold may be pre-programmed or based on real-time data detected by one or more sensors. In some embodiments, the threshold may be determined using one or more sensors separate from the one or more sensors used in step 804. In the specific example illustrated by Figure 8, if the detected lymphatic flow exceeds the threshold, no stimulation or adjustment of stimulation parameters is required (nothing is done in step 812). In the same example, if the detected lymphatic flow does not exceed the threshold, an electrical signal may be sent to one or more implantable electrodes electrically communicating with the lymphatic system for stimulation (in step 816). Step 816 may additionally or alternatively include changing one or more parameters of the electrical stimulation, for example, to increase the intensity of the stimulation.

[0078] A method for implanting a device may include delivering one or more electrodes to electrically communicate with a region of the patient's lymphatic system, such as a lymphatic vessel or lymph node. For example, one or more electrodes may be delivered to the thoracic duct or a blood vessel adjacent to the thoracic duct, such as the azygos vein. The method may further include activating a stimulator to transmit electrical signals to one or more electrodes to electrically stimulate a region of the lymphatic system via the electrodes. The stimulator may be activated to stimulate at a low intensity and may be configured to increase the stimulation parameter at predetermined time intervals after activation. The method may further include detecting the patient's physiological parameters or condition by one or more sensors. Data from one or more sensors may be received by a controller and / or processor to determine, for example, the patient's lymphatic flow or lymphatic vessel contraction. One or more sensors may include a Doppler flowmeter, an external sensor used for Doppler optical coherence tomography, or other flow sensors configured to detect physiological parameters related to the patient's lymphatic flow, such as flow or lymphatic vessel contraction. In some embodiments, one or more sensors may include an EMG sensor configured to detect electrical feedback to identify lymphatic system contraction. One or more sensors may include imaging sensors that detect markers or tracers that are injected into the patient's lymphatic system and used to detect lymphatic activity. For example, an optical lymphatic flowmeter may detect the movement of injected air bubbles within the thoracic duct.

[0079] The method may further include verifying, based on detected physiological parameters or conditions, that the stimulation is sufficient to increase the patient's lymphatic flow. Lymphatic flow may show a delayed response to the initiation of stimulation. If no increase in lymphatic flow is observed after a certain period, for example, about 5-10 minutes, the stimulation parameter may be increased. The patient may have varying levels of adipose tissue around the portion of the lymphatic system being stimulated. Therefore, the stimulation parameter may be adjusted in situ during implantation to account for possible transmission problems. The method may include, for example, reimplanting some or all of one or more electrodes and / or associated lead wires if it is not possible to further increase the stimulation parameter due to the risk of damaging the area(s) around one or more electrodes. If electrodes and / or lead wires are moved, some or all of the steps of the method may be repeated.

[0080] While this specification primarily describes electrical stimulation, other types of stimulation and / or modulation are also possible. For example, a system may include one or more means for modulation, such as pressure elements, high-frequency electrodes, high-power short-duration RF (HPSD RF), ultrasonic elements, laser elements, vapor, thermal elements, alcohol, microwave elements, acoustic elements, vibration elements, cryogenic elements, heat delivery devices, chemical delivery devices, and / or similar. However, in some embodiments, the sole modulation applied by the system may be electrical stimulation, excluding other modulation methods described herein.

[0081] In addition to, or instead of, the sensor-based system described above, the system may collect feedback from the patient from a general-purpose external device, such as a dedicated device or an application on a smartphone or tablet. The patient can indicate when they are experiencing unpleasant side effects. The patient can stop the stimulation using, for example, a dedicated device or a general-purpose external device. The stimulator can be configured to respond to the presence of side effects by automatically adjusting the stimulation parameters (amplitude, frequency, pulse width, duty cycle, and / or stimulation vector) according to a specified algorithm. After adjustment, the system repeats the detection of side effects and makes further adjustments if the side effect condition persists.

[0082] Lymphatic activity can vary based on the patient's autonomic nervous system state. For example, lymphatic flow may differ during exercise / activity or sleep. Consequently, providing different levels of lymphatic stimulation during these different states may be advantageous to enhance the effectiveness of treatment (avoiding understimulation) as well as improve the safety of treatment (avoiding overstimulation). Any stimulation parameters, including but not limited to amplitude, frequency, pulse width, and / or duty cycle, may be increased or decreased.

[0083] In the systems described herein, stimulation parameters can be selected and adjusted. Stimulation parameters can be selected and adjusted without physically repositioning the stimulation leads. For example, stimulation parameters may include amplitude, frequency, pulse width, duty cycle, and / or stimulation vector. Stimulation parameters can be adjusted during the implantation visit or during subsequent outpatient clinic visits. Alternatively, adjustments can be made outside the clinic, on a regular schedule, or upon physician trigger.

[0084] Activity detection may be performed using one or more sensors. The sensors may be the same as or different from those used to detect activation or side effects. For example, the system may include an accelerometer for detecting activity or posture. The accelerometer can detect whether the patient is standing or lying prone. This may indicate whether the patient is asleep.

[0085] The lymphatic system is involved in almost all transport of fluids from body tissues. The therapeutic systems and methods described herein may be used in various patient populations with conditions other than endogenous lymphedema, such as venous lymphedema, congestive heart failure (CHF), or venous hypertension. The therapeutic systems and methods described herein may also be used in any patient population suffering from chronic fluid overload or any pathological condition of the superficial or internal, local or systemic lymphovascular structure, where the appearance of tissue edema characteristic of lymphatic dysfunction is predominant.

[0086] In some embodiments, the modulatory therapies described herein may be used to replace other therapies, such as pharmacological (drug) or other device-related therapies. However, in other embodiments, other drugs or device-related therapies may be used in combination with the modulatory therapies described herein, but with reduced frequency, dose, or amount used, and thus reduced undesirable side effects. For example, a particular drug (or combination of drugs), when combined with the modulatory therapies described herein, may be administered for a shorter overall period, fewer times per day / week / month, and / or at a lower dose. In addition to reducing undesirable pharmacological side effects, this may also reduce addiction or dependence. The modulatory therapies described herein may also be used to gradually reduce or otherwise remove a particular drug from a subject.

[0087] Certain experiments are described, for example, with regard to the application of drugs to induce a specific physiological state before, during, and / or after stimulation. The devices and methods described herein can be used without drugs (for example, without drugs to induce a specific physiological state). For example, anesthetics and other drugs that enable electrode placement may be used.

[0088] The methods and devices described herein may be subject to various modifications and alternative forms, specific examples of which are shown in the drawings and described in detail herein. However, it should be understood that the present invention is not limited to any specific device or method disclosed, but rather encompasses all modifications, equivalents, and alternative forms that fall within the spirit and scope of the various examples described and the accompanying claims. Furthermore, any particular features, aspects, methods, properties, characteristics, qualities, attributes, elements, etc., disclosed herein relating to one example may be used in all other examples described herein. None of the methods disclosed herein have to be performed in the order listed. Depending on the example, one or more actions, events, or functions of any algorithm, method, or process described herein may be performed in different sequences, added, merged, or completely excluded (for example, not all actions or events described are necessarily required for the practice of an algorithm). Algorithms, modules, blocks, steps, boxes, elements, features, etc., may be stored in machine-readable memory. In some examples, actions or events may not be performed sequentially, but rather simultaneously, for example, through multithreading, interrupt handling, or across multiple processors or processor cores, or on other parallel architectures. Furthermore, elements, features, blocks, boxes, or steps, or groups of elements, features, blocks, boxes, or steps, are not essential or indispensable to each example. In addition, all possible combinations, partial combinations, and rearrangements of systems, methods, features, elements, modules, blocks, boxes, etc., are within the scope of this disclosure. Unless otherwise specified or understood in the context in which they are used, the use of sequential or chronological terms such as “then,” “next,” “after,” and “subsequently” is generally intended to facilitate the flow of text and not to limit the sequence of actions performed.Therefore, some examples may be carried out using the sequence of operations described herein, while others may be carried out according to a different sequence of operations.

[0089] The various exemplary logic blocks, boxes, modules, processes, methods, and algorithms described in connection with the examples disclosed herein can be implemented as electronic hardware, computer software, or a combination of both. To clearly illustrate this compatibility between hardware and software, various exemplary components, blocks, modules, operations, and steps are described above in relation to their functions. Whether such functions are implemented as hardware or software depends on the specific application and the design constraints imposed on the overall system. The described functions can be implemented in various ways for each specific application, but such implementation decisions should not be construed as causing a departure from the scope of this disclosure.

[0090] The various exemplary logic blocks and modules described in relation to the examples disclosed herein may be implemented or carried out by machines such as general-purpose processors, digital signal processors (DSPs), application-specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs) or other programmable logic devices, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general-purpose processor may be a microprocessor, but in alternative examples, the processor may be a controller, a microcontroller, or a state machine, or a combination thereof. Controllers and / or processors may also be implemented as a combination of computing devices, for example, a combination of a DSP and a microprocessor, multiple microprocessors, one or more microprocessors combined with a DSP core, or any other such configuration.

[0091] Blocks, operations, or steps of methods, processes, or algorithms described in relation to the examples disclosed herein can be directly embodied in hardware, software modules executed by a processor, or a combination of the two. Software modules may reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disks, removable disks, optical disks (e.g., CD-ROMs or DVDs), or any other form of volatile or non-volatile computer-readable storage medium known in the art. The storage medium may be coupled to a processor so that the processor can read information from and write information to the storage medium. In alternative examples, the storage medium may be integrated with a controller and / or processor. The controller and / or processor and the storage medium may reside within an ASIC. The ASIC may reside within a user terminal. In alternative examples, the processor and storage medium may reside as separate components within a user terminal.

[0092] Unless the context clearly requires otherwise, terms such as “comprise,” “comprising,” “include,” and “including” throughout the specification and claims should be interpreted in a comprehensive sense, as opposed to an exclusive or exhaustive sense; that is, in the sense of “includes but not limited.” The term “combined” as generally used herein refers to two or more elements that are directly connected or that can be connected by one or more intermediate elements. Similarly, the term “connected” as generally used herein refers to two or more elements that are directly connected or that can be connected by one or more intermediate elements. In addition, the terms “as specified herein,” “above,” “below,” and similar terms, when used in this application, refer to the entire application and not to any particular part of this application. Where the context allows, terms in the above detailed description that use singular or plural may also include plural or singular. The term “or” in relation to a list of two or more items covers all of the following interpretations of the term, namely any of the items in the list, all of the items in the list, and any combination of the items in the list.

[0093] Furthermore, conditional language used herein, in particular "can," "could," "might," "may," "eg," "for example," and "such as," is generally intended to convey that a particular embodiment includes certain features, elements, and / or states, but other embodiments do not, unless otherwise specified or understood to have a different meaning in the context in which they are used. Therefore, such conditional language is generally not intended to imply that features, elements, and / or states are required in any way in one or more embodiments, or that these features, elements, and / or states are included in any particular embodiment or are to be implemented in any particular embodiment.

[0094] The methods disclosed herein may include certain actions performed by a practitioner, but the methods may also include, explicitly or implicitly, instructions for such actions by any third party. For example, an action such as "delivering one or more implantable electrodes" may include "instructing the delivery of one or more electrodes."

[0095] While certain embodiments have been described, these embodiments are presented only as examples and are not intended to limit the scope of this disclosure. In fact, the novel devices, methods, and systems described herein may be embodied in a variety of other forms, and various omissions, substitutions, and modifications may be made to the forms of the methods and systems described herein without departing from the spirit of this disclosure. For example, while features are presented in a given configuration, alternative embodiments may perform similar functions with different components and / or sensor topologies, and some features may be deleted, moved, added, subdivided, combined, and / or modified. Each of these features may be implemented in a variety of different ways. Further embodiments can be provided by combining any suitable combination of elements and actions of the various embodiments described above. The various features and processes described above may be implemented independently of each other or combined in a variety of ways. All possible combinations and partial combinations of the features of this disclosure are intended to fall within the scope of this disclosure.

[0096] As used herein, the term “electrical signal” may refer to a voltage or current that changes over time. For example, an electrical signal can be represented by a waveform (a graphical representation of the change in current or voltage over time). As used herein, the term “electrode contact” may refer to a material that acts as a conductor through which electricity enters and leaves. At least a portion of the material may be a biocompatible material. As used herein, the terms “subject” and “patient” may be used interchangeably and refer to any warm-blooded organism, including but not limited to humans, pigs, rats, mice, dogs, cats, goats, sheep, horses, monkeys, apes, rabbits, and cattle.

Claims

1. A method for inducing lymphatic vasoconstriction in a patient, Delivering one or more implantable electrodes to electrically communicate with the lymphatic smooth muscle cells of the patient, The stimulator is activated to transmit a signal to one or more implantable electrodes, Electrically stimulating the lymphatic smooth muscle cells via one or more implantable electrodes, Methods that include...

2. The method according to claim 1, wherein delivering the one or more implantable electrodes includes delivering the one or more electrodes to the chylial cavity or a position above it.

3. The method according to claim 1, wherein delivering the one or more implantable electrodes includes delivering a stent that supports the one or more electrodes.

4. The method according to claim 3, wherein delivering one or more electrodes includes positioning at least a portion of the stent in a vein near the thoracic duct.

5. The method according to claim 4, wherein the vein is the azygos vein.

6. The method according to claim 4, wherein the vein is one of the left brachiocephalic vein, the left subclavian vein, or the left internal jugular vein.

7. The method according to claim 3, wherein the stent further supports one or more sensors configured to detect the patient's physiological parameters or condition.

8. The method according to claim 1, further comprising implanting the stimulator in the subcutaneous layer of the patient.

9. The method according to claim 1, wherein electrically stimulating lymphatic smooth muscle cells causes a change in the lymphatic flow of the patient.

10. The method according to any one of claims 1 to 9, further comprising detecting the patient's physiological parameters or condition using one or more sensors.

11. The method according to claim 10, further comprising receiving a command for the electrical stimulation based on the detected physiological parameters or state by a controller.

12. The method according to any one of claims 1 to 9, further comprising increasing one or more parameters of the electrical stimulation at predetermined time intervals.

13. The method according to claim 10, further comprising implanting at least one of the one or more sensors in the left subclavian vein of the patient at or near the junction of the left subclavian vein and the left internal jugular vein.

14. The method according to claim 10, wherein the one or more sensors include a flow sensor or a pressure sensor.

15. The method according to claim 14, wherein the physiological parameters include the lymphatic flow rate of the patient.

16. The method according to claim 11, wherein the command for the electrical stimulation includes activating the stimulator.

17. The method according to claim 11, wherein the command for the electrical stimulation includes changing one or more parameters of the stimulation.

18. The method according to claim 17, wherein the one or more parameters include the pulse width, current, frequency, pulse threshold, and / or duty cycle of the stimulus.

19. The method according to claim 10, further comprising verifying that the electrical stimulation is sufficient to increase the lymphatic flow of the patient based on the detected physiological parameters or conditions.

20. A method for regulating lymphatic flow in a patient, Delivering one or more implantable electrodes so as to be electrically connected to the cisterna chyli or the region of the lymphatic system above it, The stimulator is activated to transmit a signal to one or more implantable electrodes, Electrically stimulating the region via one or more implantable electrodes, One or more sensors are used to detect the patient's physiological parameters or state, The controller receives commands for the electrical stimulation based on the detected physiological parameters or state, Methods that include...

21. The method according to claim 20, wherein delivering the one or more electrodes includes delivering a stent that supports the one or more electrodes.

22. The method according to claim 21, wherein delivering one or more electrodes includes placing at least a portion of the stent into a vein near the thoracic duct.

23. The method according to claim 22, wherein the vein is one of the azygos vein or the vein of the left venous angle.

24. The method according to any one of claims 20, further comprising implanting the stimulator in the subcutaneous layer of the patient.

25. The method according to claim 20, further comprising increasing one or more parameters of the electrical stimulation at predetermined time intervals.

26. The method according to any one of claims 20 to 25, wherein the electrical stimulation comprises stimulating the lymphatic smooth muscle cells of the patient.

27. The method according to any one of claims 20 to 25, further comprising implanting at least one of the one or more sensors in the left subclavian vein of the patient at or near the junction of the left subclavian vein and the left internal jugular vein.

28. The method according to any one of claims 20 to 25, wherein the one or more sensors include a flow sensor or a pressure sensor.

29. The method according to claim 28, wherein the physiological parameters include the lymphatic flow rate of the patient.

30. The method according to any one of claims 20 to 25, wherein the command for the electrical stimulation includes activating the stimulator.

31. The method according to any one of claims 20 to 25, wherein the command for the electrical stimulation includes changing one or more parameters of the electrical stimulation.

32. The method according to claim 31, wherein the one or more parameters include the pulse width, current, frequency, pulse threshold, and / or duty cycle of the electrical stimulation.

33. The method according to any one of claims 20 to 25, further comprising verifying that the electrical stimulation is sufficient to increase the lymphatic flow of the patient based on the detected physiological parameters or conditions.

34. A system for electrically stimulating the lymphatic system of a patient, One or more implantable electrodes configured to be delivered so as to be electrically connected to the region of the lymphatic system, A stimulator configured to transmit signals to one or more implantable electrodes in order to electrically stimulate the region of the lymphatic system, One or more sensors configured to detect the physiological parameters or condition of the patient, A controller configured to receive data from one or more of the aforementioned sensors, Equipped with, A system in which the stimulator is configured to receive commands from the controller to transmit the signals to the one or more implantable electrodes based on the data received from the one or more sensors.

35. The system according to claim 34, further comprising a stent supporting one or more implantable electrodes.

36. The system according to claim 35, wherein at least a portion of the stent is placed in a vein near the thoracic duct of the patient.

37. The system according to claim 36, wherein the vein is an azygos vein.

38. The system according to claim 36, wherein the vein is one of the left brachiocephalic vein, the left subclavian vein, or the left internal jugular vein.

39. The system according to claim 38, wherein the stent further comprises one or more sensors.

40. The system according to claim 34, wherein the stimulator is implantable in the subcutaneous layer of the patient.

41. The system according to any one of claims 34 to 40, wherein one or more electrodes are configured to electrically stimulate the lymphatic smooth muscle cells of the patient.

42. The system according to any one of claims 34 to 40, wherein one or more sensors can be implanted in the left subclavian vein of the patient at or near the junction of the left subclavian vein and the left internal jugular vein.

43. The system according to any one of claims 34 to 40, wherein the one or more sensors include a flow sensor or a pressure sensor.

44. The system according to claim 43, wherein the physiological parameters include the patient's lymphatic flow rate.

45. The system according to any one of claims 34 to 40, wherein the controller is mounted on the stimulator.

46. The system according to any one of claims 34 to 40, wherein the controller is located remotely from the stimulator.

47. The system according to any one of claims 34 to 40, wherein the controller is configured to continuously receive data from one or more sensors.

48. The system according to any one of claims 34 to 40, wherein the command from the controller includes activating the stimulator.

49. The system according to any one of claims 34 to 40, wherein the command from the controller includes changing one or more parameters of the electrical stimulation.

50. The system according to claim 49, wherein one or more of the parameters include the pulse width, current, frequency, pulse threshold, and / or duty cycle of the electrical stimulation.

51. A system for electrically stimulating the lymphatic system of a patient, A stent configured to be implanted in a vein near the thoracic duct of the patient, and supporting one or more implantable electrodes configured to communicate electrically with the thoracic duct, A stimulator configured to transmit signals to one or more implantable electrodes in order to electrically stimulate the thoracic duct, A controller configured to transmit commands for electrical stimulation to the stimulator, A system that includes these features.

52. The system according to claim 51, wherein the vein is an azygos vein.

53. The system according to claim 51, wherein the vein is one of the left brachiocephalic vein, the left subclavian vein, or the left internal jugular vein.

54. The system according to claim 51, wherein the stimulator is implantable in the subcutaneous layer of the patient.

55. The system according to claim 51, wherein one or more electrodes are configured to electrically stimulate the lymphatic smooth muscle cells of the thoracic duct of the patient.

56. The system according to any one of claims 51 to 55, further comprising one or more sensors configured to detect the physiological parameters or condition of the patient.

57. The system according to claim 56, wherein the stent supports one or more sensors.

58. The system according to claim 56, wherein the one or more sensors include a flow sensor or a pressure sensor.

59. The system according to claim 58, wherein the physiological parameters include the lymphatic flow rate of the patient.

60. The system according to claim 56, wherein one or more sensors can be implanted in the left subclavian vein of the patient at or near the junction of the left subclavian vein and the left internal jugular vein.

61. The system according to any one of claims 51 to 55, wherein the controller is mounted on the stimulator.

62. The system according to any one of claims 51 to 55, wherein the controller is located remotely from the stimulator.

63. The system according to claim 56, wherein the controller is configured to receive data from one or more sensors and to transmit the command for electrical stimulation based on the received data.

64. The system according to any one of claims 51 to 55, wherein the command includes a pre-programmed command for activating the stimulator.

65. The system according to claim 63, wherein the command includes activating the stimulator based on the data received from one or more sensors.

66. The system according to claim 63, wherein the command includes changing one or more parameters of the electrical stimulation based on the data received from one or more sensors.

67. The system according to claim 66, wherein one or more of the parameters include the pulse width, current, frequency, pulse threshold, or duty cycle of the electrical stimulation.

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