Method and apparatus for increasing lymphatic flow

Abstract

Direct activation of the lymphatic system of a patient can cause an increase in lymphatic flow for treating edema. Stimulation or pacing of the lymphatic system can activate the lymphatic system and trigger contractions of lymphatic smooth muscle to promote lymph flow. The stimulation may be performed with one or more implantable electrodes and a stimulator configured to send an electrical signal to the electrodes. The one or more electrodes may be supported by a stent and / or implanted within a blood vessel in close proximity to the thoracic duct of the patient. The stimulation may utilize one or more sensors to detect a physiological parameter of the patient and may be activated or adjusted based on the detected parameter.

Description

METHOD AND APPARATUS FOR INCREASING LYMPHATIC FLOWREFERENCE TO RELATED APPLICATIONS

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

[0002] The present disclosure relates generally to systems and methods for increasing lymphatic flow in the patient.Description of the Related Art

[0003] The lymphatic system has important roles in body fluid transport and immune system functionality. The lymphatic system moves fluid, large molecules, and lipids from the interstitial space throughout the lymphatic vessels, draining into the venous system. Lymphatic system dysfunction results in fluids trapped in the interstitial space causing edema.

[0004] Edema is a condition effecting hundreds of millions of people worldwide. Edema manifests itself by swelling, typically of the limbs and very often the legs and feet. Edema can be the result of several underlying causes such as cancer treatments, lymphatic system disfunction (lymphedema), congestive heart failure, kidney disease, venous insufficiency, or liver disease. An estimated 300 million people worldwide are affected by lymphedema.

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

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

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

[0008] The systems and devices described herein can be minimally invasive. The systems and devices described herein may not require constant stimulation of the patient, and may rely on a relatively low frequency of stimulation as to avoid patient discomfort. Implantable aspects of the system may be sufficiently small 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 a stimulator. The system may be fully implantable, but in other embodiments, the stimulator may be external or a stimulator with components split between both 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 separately implanted.

[0009] Certain aspects of the disclosure relate to a system comprising one or more implantable electrodes that may be delivered into electrical communication with a region of the lymphatic system, e.g., lymphatic vessels and / or nodes. For example, the one or more electrodes may be delivered into electrical communication with one or more segments of the thoracic duct. The one or more electrodes may be delivered into electrical communication with a region of the lymphatic system at or above (superior to) the cistema chyli of the patient. The one or more electrodes may be delivered to a location between the cistema chyli and the diaphragm. The one or more electrodes may be delivered into said electrical communicationvia the venous system. For example, an electrode may be delivered to a blood vessel in close proximity or adjacent to a region of the lymphatic system, such as the azygos vein or a vessel of the left venous angle. In some embodiments, an electrode may be delivered to the outflow portion of the thoracic duct via the venous system. The 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, while some of the one or more electrodes may be delivered to the left venous angle. The one or more electrodes may comprise a sensing electrode. The one or more electrodes may be supported by one or more anchors, for example a tubular structure like a stent. The one or more electrodes may be supported by the one or more stents by being disposed on or being integral with the one or more stents. A stent may support the one or more electrodes along a length of the stent or at a single point of the stent. The one or more stents may anchor the one or more implantable electrodes within the patient, for example, within a blood vessel or a lymphatic vessel.

[0010] Depending on the indication, the systems described herein may be open or closed loop. In an open loop system, the system may be pre-programmed to activate at certain times of the day or in certain time intervals. In a closed loop system, the system may comprise one or more sensors for detecting a physiological parameter or condition.

[0011] Certain aspects of the disclosure relate to a system comprising a stimulator configured to generate an electrical signal designed to stimulate the lymphatic system of a patient. 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 in electrical communication with the lymphatic system to deliver the electrical signal from the stimulator. The stimulator may be electrically connected to the one or more electrodes via one or more leads or a leadless design. The stimulator may be configured to receive a pre-programmed instruction from a controller and / or processor to send the signal to the one or more electrodes. The controller and / or processor may be on-board or remote from the stimulator. The pre-programmed instruction may comprise instructions to send the signal at pre-determined intervals during a day, for pre-determined periods of time, and / or with preprogrammed stimulation parameters. For example, the pre-programmed instruction may comprise activating the stimulator and increasing one or more parameters of the stimulation at pre-determined time intervals. The stimulator may be able to independently stimulate each ofthe one or more electrodes. Each of the one or more electrodes may directly apply electrical stimulation to the lymphatic system, for example to the thoracic duct of the patient. Stimulation of the lymphatic system with the electrical signal may cause contractions of the lymphatic smooth muscle cells, resulting in an increased lymphatic flow.

[0012] Certain aspects of the disclosure relate to a system comprising one or more sensors configured to detect a physiological parameter or condition of the patient. The system may allow for closed loop stimulation. The system may comprise a stimulator in operational communication with a controller and / or processor configured to receive data from the one or more sensors. The stimulator may receive an instruction from the controller for the electrical stimulation based on the detected physiological parameter or condition. The instruction may comprise activating the stimulator to send an electrical signal to the one or more electrodes. The instruction may comprise varying one or more parameters of the stimulation such as frequency, pulse width, current, pulse threshold, and / or duty cycle.. The instruction may comprise suspending the stimulation.

[0013] The one or more sensors may comprise a flow sensor, pressure sensor, pho toplethy smogram (PPG), gyrometer, accelerometer, temperature sensor, and / or any other physiological sensor. The one or more sensors may be configured to send collected data to the stimulator, processor, and / or controller, through a wired or wireless connection, e.g., Bluetooth. The one or more sensors may continuously or intermittently send data to the controller and / or processor.

[0014] In several embodiments, the systems described herein may have one or more of the following advantages: improving lymphatic flow; enabling adjustment of therapy to increase effectiveness of therapy; minimally invasive; reduces the need for pharmacological or other therapies.

[0015] Certain aspects of the disclosure relate to a method comprising delivering one or more implantable electrodes into electrical communication with a region of the lymphatic system, e.g., lymphatic vessels and / or nodes. For example, the one or more electrodes may be delivered into electrical communication with the thoracic duct. The one or more electrodes may be delivered into electrical communication with a region of the lymphatic system at or above to the cistema chyli of the patient. The one or more electrodes may be delivered to a location between the cisterna chyli and the diaphragm. The one or moreelectrodes may be delivered into said electrical communication via the venous system. For example, an electrode may be delivered to a blood vessel in close proximity or adjacent to a region of the lymphatic system, such as the azygos vein or a vessel of the left venous angle. In some embodiments, an electrode may be delivered to the outflow portion of the thoracic duct via the venous system. The 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, while 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. The one or more electrodes may be delivered on one or more anchors (e.g., stents) supporting the electrodes.

[0016] Certain aspects of the disclosure relate to a method comprising activating a stimulator to send an electrical signal to the one or more electrodes to electrically stimulate the region of the lymphatic system. The electrical stimulation may include pacing. The electrical stimulation may comprise stimulating lymphatic smooth muscle to cause contractions of the smooth muscle and / or lymphatic vessel segments. The electrical stimulation may increase the lymphatic flow of a patient. The electrical stimulation may be continuous or intermittent. The electrical stimulation may be toggled between the one or more implantable electrodes, or may comprise simultaneous stimulation between all of the electrodes. The stimulation may be adjusted by varying one or more parameters of the stimulation such as frequency, pulse width, current, pulse threshold, and / or duty cycle. The stimulation may be synchronized such that the one or more electrodes are activated sequentially in a stepwise function, in the order of most anterior to most superior.

[0017] The stimulator may be activated by a pre-programmed instruction to send the electrical signal at pre-determined intervals during a day, for pre-determined periods of time, and / or with pre-programmed stimulation parameters. For example, the pre-programmed instruction may comprise activating the stimulator and increasing one or more parameters of the stimulation at pre-determined time intervals.

[0018] Certain aspects of the disclosure relate to a method comprising detecting, by one or more sensors, a physiological parameter or condition of the patient. The method may allow for closed loop stimulation. For example, the one or more sensors may comprise a lymphatic flow sensor and the physiological parameter may comprise a lymphatic flow rate ofthe patient. The method may comprise receiving data from the one or more sensors. The data from the one or more sensors may be received by a controller and / or processor in operational communication with the stimulator. The method may comprise receiving an instruction from the controller for the electrical stimulation based on the detected physiological parameter or condition. The instruction may comprise activating the stimulator to send an electrical signal to the one or more electrodes. The instruction may comprise varying one or more parameters of the stimulation. The instruction may comprise suspending the stimulation. The method may include verifying, based on the detected physiological parameter or condition, that the electrical stimulation is sufficient to increase the lymphatic flow of the patient.

[0019] The method may comprise electrically stimulating after detecting a lymphatic flow rate of a patient that is below a threshold value. For example, the method may comprise automatically activating the stimulator in response to detecting a low lymphatic flow rate. The method may comprise detecting the lymphatic flow rate via a flow sensor, Doppler flow meter, and / or Doppler optical coherence tomography.BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The following drawings are for illustrative purposes only and show nonlimiting embodiments. Features from different figures may be combined in several embodiments.

[0021] FIG. 1 is a schematic diagram of the lymphatic ducts and venous system.

[0022] FIG. 2 is a schematic diagram for an implantable lymphatic stimulator system.

[0023] FIG. 3 is a schematic diagram of another implantable lymphatic stimulator system.

[0024] FIG. 4 is a schematic diagram of another implantable lymphatic stimulator system.

[0025] FIG. 5 is a schematic diagram of another implantable lymphatic stimulator system.

[0026] FIGS. 6-8 are process flow diagrams of example methods for increasing lymphatic flow.DETAILED DESCRIPTION

[0027] The lymphatic system is one of the least understood systems in the human body, despite its significance to the body’s immune system. One of the principal tasks of the lymphatic vascular system is transporting lymph. The body imparts energy to the lymphatic system via pumping mechanisms to overcome the steady state opposing pressure gradients and propel lymph along the lymphatic network. The pumping mechanisms include contraction pumps and valves to generate lymph flow and prevent its backflow. The lymphatic system uses both extrinsic pumps, which rely on the cyclical compression and expansion of lymphatics by surrounding tissue forces, and intrinsic pumps, which rely on intrinsic contractions of lymphatic muscle. The intrinsic lymph pump function can be modulated by neural, humoral, or physical factors.

[0028] The external pump function operates via pressures from skeletal muscle, diaphragm, and thoracic tissues pressing on and releasing lymph vessels, contributing to lymphatic flow. Lymphatics devoid of smooth muscles rely on these external pumps, e.g., tissue motion, to form lymph and propel it across the network. However, active muscle contraction rather than passive tissue displacement is required to support efficient lymphatic drainage, as suggested by studies showing that respiratory activity promotes lymph formation during spontaneous, but not mechanical ventilation.

[0029] In vessels having lymphatic muscle cells, lymph flow is determined by well- synchronized spontaneous contractions. However, it is not well understood why the lymphatic system does not function properly in the presence of edema. Researchers have widely hypothesized that the dysfunction is a result of the pressure differential between the lymphatic system and an increased pressure venous system. Some have focused on causing a pressure differential between the lymphatic system and venous system by reducing the venous pressure near the thoracic duct, assuming that reduction of venous pressure can create a pressure differential that will pull fluid out of the lymphatic system. However, in people with normal lymphatic systems, the lymphatic pressure is already lower than the normal venous pressure. The lymphatic system is also known to be able to transport lymph against hydrostatic pressure. Thus, the pressure differential may not be a complete explanation for lymphatic dysfunction, and treatments directed to reducing venous pressure and / or modulating the pressure differential may have limited benefits.

[0030] Reduction in venous pressure is limited because it is a passive mechanism and relics on a pressure differential to create suction effects, whereas the main functionality of the lymphatic system is through peristaltic motion via a complex structure of one-way valves. Furthermore, reduction in venous pressure does not actively increase lymphatic flow in patients with impaired intrinsic or extrinsic lymphatic contractions. The suction from venous devices and pressure differential methods are limited and inherently would not be effective on patients with normal venous pressure and patients with lymphatic dysfunction that is not correlated to high venous pressure.

[0031] The patient population with lymphedema or other types of edemas generally suffer from loss or restriction of lower extremity mobility and loss of certain extrinsic pumping ability, and the large muscles provide limited utility for compression and / or stimulation to aid in tissue drainage. Thus, it is believed that the intrinsic pumping ability of the lymphatic system is critical to patients suffering from edema regardless of the root cause and the pressures in the venous system. Generally, increased lymph pressure or stretch of the muscular lymphatics activates the intrinsic lymphatic pump, while increased lymph flow or shear in the muscular lymphatics can either activate or inhibit the intrinsic lymphatic pump depending on the pattern and magnitude of the flow. To regulate lymph transport, lymphatic pumping and resistance must be controlled.

[0032] The present disclosure relates to temporary or permanent modulation of a patient’s lymphatic flow by activation of the lymphatic system. Direct activation of the lymphatic system may be achieved by stimulation of the lymphatic system. The stimulation may comprise pacing of the lymphatic system. The stimulation may be effective to activate the lymphatic system when performed at or near the thoracic duct. For example, the stimulation may be performed via an electrode within a blood vessel adjacent to the thoracic duct, such as the azygos vein. Without being bound to any particular theory, lymphatic flow may be enhanced by activating the lymphatic smooth muscle cells via electrical stimulation to trigger contractions of vessel segments and peristaltic motion, in a synchronized manner, and propel lymph along the lymphatic network. The electrical stimulation may increase the intrinsic rate of lymph flow through the thoracic duct and back into the circulatory system. Advantageously, the increased intrinsic pumping ability may provide improved methods and systems for treating edema.

[0033] FIG. 1 is a schematic diagram of the lymphatic ducts and surrounding venous system. The thoracic duct 102 is the primary lymph vessel of the lymphatic system. The thoracic duct 102 originates at the cistema 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 (LI and L2). The cistema chyli 104 receives lymph from the left and right lumbar lymphatic trunks and the intestinal lymphatic trunk.

[0034] The thoracic duct 102 is the larger of the two lymph ducts of the lymphatic system, the other being the right lymphatic duct 112. The thoracic duct is approximately 40 cm in length in adults and approximately 5 mm in diameter at its abdominal origin. The thoracic duct 102 is responsible for lymph drainage from the entire body except for the right sides of the head and neck, the right side of the thorax, and the right upper extremity, which are primarily drained by the right lymphatic duct. The thoracic duct 102 is responsible for about 75% of the body’s lymph drainage. The lymphatic flow rate of an average human patient may be about 1.5 mL / min. Originating from the cistema chyli 104, the thoracic duct 102 runs between the aorta and the azygos vein 132, anterior to the vertebral column. The azygos vein 132 and the thoracic duct 102 both ascend within the posterior mediastinum in close proximity, making the azygos vein a suitable location for placement of one or more electrodes used for stimulation. Although not pictured, the esophagus and the descending thoracic aorta are also parallel to the thoracic duct 102.

[0035] FIG. 1 also illustrates the superior vena cava (SVC) of the venous system. As the thoracic duct 102 continues upwards, it runs behind the aorta and the SVC. In the superior mediastinum, the thoracic duct 102 passes behind the left internal jugular vein 120. The thoracic duct 102 then continues into an outflow portion 108 which drains lymph into 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 referred to as the left venous angle. On the other side of the SVC, the right lymphatic duct 112 drains into the junction of the right subclavian vein 124 and the right internal jugular vein 128. This junction into which the right lymphatic duct drains may also be referred to as the right venous angle.

[0036] An implantable lymphatic stimulator (ILS) system may be implanted to provide electrical signals to the lymphatic system. The electrical signals may activate the lymphatic smooth muscle cells to cause contractions thereof and enhance lymphatic flow. Astimulator may generate the electrical signals and send the signals 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 variation of the lymphatic systems of different patients. Thus, components of the ILS system, such as one or more electrodes and / or leads, may be implanted in the venous system within one or more blood vessels in close proximity to regions of the lymphatic system. For example, components of the ILS system and / or leads may be positioned in the azygos vein, the SVC, above the cistema chyli, and / or along the thoracic duct below the diaphragm. The placement in the blood vessels allows for the electrodes to be in electrical communication with important regions of the lymphatic system without needing to surgically access the lymphatic vessels. In some embodiments, components of the ILS system may be placed in the outflow portion of the thoracic duct via delivery through the venous system, i.e., the superior vena cava. In other embodiments, the treatment may be acute using a non-implantable stimulator. For example, the electrical signals may be provided externally or using needles to penetrate the tissue near a portion of the lymphatic system, for example near the thoracic duct.

[0037] The stimulation may comprise pacing, for example, intermittent pacing. The pacing may be performed with a similar stimulator and / or stimulation parameters used in pacing devices, such as pacemakers or diaphragm pacers. To avoid patient discomfort, the stimulation and / or pacing location and intensity may be carefully selected to avoid pacing the esophagus or diaphragm. In patients where it is impossible to avoid such discomfort, a stimulation algorithm may provide intermittent pacing with short sequences of pacing followed by longer periods without stimulation or pacing. The stimulation may comprise continuous pacing for at least about one minute and / or less than or equal to an hour, for example less than or equal to forty-five minutes, less than or equal to thirty minutes, less than or equal to fifteen minutes, less than or equal to ten minutes, or less than or equal to five minutes. Said continuous pacing may occur at multiple intervals throughout the day, for at least two times per day and / or up to 20 times per day, for example two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, or twenty times a day. In some embodiments, a stimulation algorithm may provide intermittent pacing for all patients. Intermittent pacing may be beneficial over continuous pacing so thatthe lymphatic system of the patient does not get used to the electrical stimulation and stops responding, or exhibits a reduced response, to the stimulation. The pacing may comprise field pacing, applied to a general field or area around the electrode(s).

[0038] The one or more electrodes may be placed above the cistema chyli of the patient, where the thoracic duct originates. The one or more electrodes may be placed below the diaphragm at an area adjacent to the cisterna chyli or the origin of the thoracic duct. The one or more electrodes may be placed far enough from the diaphragm, relatively to the pulse strength and duration of the stimulation, to minimize or eliminate the possibility of unintended diaphragmatic pacing that may cause patient discomfort. Stimulating or pacing in a location below the diaphragm may activate lymphatic flow in a large area of the lymphatic system that relies on smooth muscle cell contractions to deliver fluids above the diaphragm. Once above the diaphragm, the fluid can be further delivered by respiratory cyclic movement to the thoracic duct outflow portion in a manner similar to a relay race. The placement below the diaphragm may provide the ability for the lymphatic system to move fluids above the diaphragm to relay to the respiratory system and synchronize fluid motion. In some other embodiments, the one or more electrodes may be placed above (superior to) the diaphragm up to the upper chest, where the thoracic duct drains into the venous system.

[0039] FIGS. 2-5 illustrate different possible configurations of the above-described system. FIG. 2 is a schematic diagram of an example system 200 for modulating the lymphatic system of a patient. FIG. 2 schematically illustrates an implantable stimulator 204 positioned to send electrical signals to one or more implantable electrodes. For example, the stimulator 204 may be implanted into a subcutaneous layer of the patient. The stimulator 204 may be implanted subcutaneously in the abdominal space or the chest of a patient. Although the stimulator is illustrated as implantable, in other embodiments, the stimulator 204 may be an external stimulator or a stimulator with components split between both internal and external (e.g., the stimulator 204 may be externally powered via inductive coupling). The stimulator 204 may comprise wired or wireless communication (e.g., configured to communicate with the one or more electrodes, a hospital system, a computer, a controller, a handheld device such as a phone or tablet, etc.).

[0040] The stimulator may generate an electrical signal designed to stimulate a region of the lymphatic system, for example, the thoracic duct. The stimulation may comprise-l ifield stimulation, which may be stimulation applied over a general field or area and commonly applied to smooth muscle. The stimulation may directly activate the lymphatic smooth muscle cells to cause contractions of lymphatic smooth muscle to increase the lymph flow of a patient. Without being bound to any particular theory, the electrical stimulation of a particular unit of the lymphatic system may cause the unit to fill up with lymph and stretch, thus naturally triggering the contraction of lymphatic smooth muscle cells to move the lymph to the next lymphatic unit. This “snowball” effect may cause improved lymph flow throughout the thoracic duct, where stimulation of a region of the thoracic duct at or above the cisterna chyli can result in restoring or enhancing the natural peristaltic pumping function of the lymph and overcome high venous hydrostatic pressure without directly reducing the venous pressure. Thus, the stimulation may cause a delayed effect of increased flow, as the contractions continue along the lymphatic network to create a suction effect. For example, the stimulation may result in an observed increased lymphatic flow around 4-10 minutes after activation, depending on the patient. The stimulation may result in at least a 5% increase in lymphatic flow rate and / or up to a 100% increase in lymphatic flow rate, for example, up to a 10% increase in lymphatic flow rate, up to a 20% increase in lymphatic flow rate, up to a 30% increase in lymphatic flow rate, up to a 40% increase in lymphatic flow rate, up to a 50% increase in lymphatic flow rate, up to a 60% increase in lymphatic flow rate, up to a 70% increase in lymphatic flow rate, up to a 80% increase in lymphatic flow rate, or up to a 90% increase in lymphatic flow rate.

[0041] The one or more implantable electrodes may be used to deliver the electrical stimulation to a region of the lymphatic system. The one or more electrodes may be placed by image guidance and / or other minimally invasive techniques known in the art. Access for implanting the electrodes and / or leads may be gained through the femoral vein. The one or more electrodes comprises at least one stimulation electrode, and may further comprise a sensing electrode. A single electrode may be enough to sufficient to increase lymphatic flow in at least the abdominal space. The stimulator 204 may be electrically connected to the one or more implantable electrodes via one or more leads or a leadless design. In some embodiments, the one or more electrodes may be disposed on one or more leads anchored to one or more blood vessels. Additionally or alternatively, the one or more electrodes may be supported by anchors such as one or more stents, or tubular- like structures, implanted within one or more blood vessels. Using a stent to support electrodes may prevent blockage and other issues withblood flow within the vein holding the electrodes. For example, FIG. 2 illustrates the stimulator 204 electrically connected via the lead 216 to a stent 208 supporting one or more implantable electrodes.

[0042] The stent 208 may be implanted within the azygos vein 132 at or above the cisterna chyli 104. The thoracic duct may be well visualized adjacent to the azygos vein, posterior to the esophagus, making the azygos vein 132 and smaller adjacent veins suitable locations for stimulation of portions of the cisterna chyli 104 and / or portions of the thoracic duct 102. As illustrated, the stent 208 may be implanted above the diaphragm of the patient, but in some other embodiments, the stent 208 may be implanted between the cistema chyli 104 and the cranial end of the diaphragm. The stent 208 may be implanted between the cistema chyli 104 and the bifurcation between left and right lymphatic ducts of the patient.

[0043] The positioning of the stent 208 anchored 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 runs almost parallel to the thoracic duct. A single electrode may trigger contractions of the thoracic duct 102, but in some embodiments, the electrical stimulation may comprise synchronized stimulation along a set of multiple electrodes disposed along the length of the stent 208. For example, the electrodes may be activated sequentially, in a stepwise fashion, to trigger sequential contractions, from chamber to chamber, along a length of the thoracic duct 102. Although the stent 208 is illustrated as placed in the azygos vein, the multiple synchronized electrodes may be placed in the lymphatic system, in the lower limbs, lower abdominal space below the diaphragm, and / or within the thoracic duct at or above the cistema chyli. The one or more electrodes may be disposed closely together on the stent 208, such that the stimulation may comprise stimulation at a single point or region of the thoracic duct 102. Without being bound to any particular theory, the stimulation of the thoracic duct in the abdominal space may trigger an intrinsic “snowball” effect discussed herein with respect to contractions of the lymphatic smooth muscle. Once the lymph is pushed above the level of the diaphragm, natural respiratory action may take over and move the fluid up the thoracic duct through the superior mediastinum into the left subclavian vein at the left venous angle for dispersal into the venous system. Functionally, the lymphatic flow rate may increase from within the lymphatic system, independent of venous pressure or venous dysfunction.

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

[0045] In an open-loop system, the system may be programmed to stimulate for a pre-determined amount of time upon activation, for example at least about one minute and / or up to two hours, such as 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 referred to as a processor), that is on-board or remote from the stimulator, configured to be pre-programmed with instructions for electrical stimulation. The instructions may include one or more parameters for electrical stimulation, including but not limited to, a number of times per day, a time intervals throughout a day, a duration, a frequency, a current, a pulse width, a pulse threshold, and / or a duty cycle. The stimulator may be pre-programmed to vary one or more stimulation parameters at pre-determined time intervals. For example, the stimulator may be preprogrammed to increase the parameters of stimulation in intervals of 2 minutes after the stimulator is activated.

[0046] In a closed-loop system, the system may be programmed to activate stimulation based on a reading from one or more sensors configured to detect a physiological parameter or condition of the patient. The stimulator 204 may include a controller, on-board or remote from the stimulator, configured to receive data from the one or more sensors. Based on the received data, the controller may be configured to send an instruction to the stimulator. The instruction may be to activate the stimulator or to vary one or more parameters of the stimulation. The instruction may be automatic based on the data received from the one or more sensors, but in some other embodiments, the system may prompt the user or a physician to send the instruction in response to the one or more sensors detecting a physiological parameter or condition of the patient.

[0047] The stimulation parameters may not be so high as to burn or damage the surrounding area of the one or more electrodes. The stimulation parameters may not be so low as to not elicit a response from the lymphatics. The stimulation frequency may be at least about 5 Hz and / or less than or equal to 1000 Hz, less than or equal to 500 Hz, less than or equal to 100 Hz, less than or equal to 50Hz, less than or equal to 35 Hz, or less than or equal to 20 Hz.The stimulation current may be at least about 10 mA and / or less than or equal to 1000 mA, less than or equal to 500 mA, less than or equal to 200 mA, less than or equal to 100 mA, or less than or equal to 50 mA. The stimulation pulse may comprise a pulse width of at least about 50 ps and / or less than or equal to 2000 ps, such as less than or equal to 1000 ps, less than or equal to 800 ps, less than or equal to 600 ps, or less than or equal to 400 ps. The stimulation may be provided with a minimum current in the range of 50mA to 100 mA. The stimulation may be provided with a minimum pulse length of 100 ps to 500 ps. The stimulation may be provided with a minimum frequency in the range of 10Hz to 20Hz. The stimulation may be provided in multiple stimulation rounds. The multiple stimulation rounds may comprise multiple selected durations and dwell times between rounds. Upon implantation, a stimulation pulse may comprise a pulse threshold that is less than or equal to 1.5V and a pulse width in the range of 400 ps to 600 ps. In some embodiments, the pulse threshold and pulse width may exceed 1.5V and 600 ps, respectively. The stimulation may comprise pacing at a range of 50 to 500 paces per minute (ppm) For example, the pacing may be performed at around 180 ppm and 20 mA for 10 minutes to elicit a response in the lymphatic system.

[0048] The stimulation therapy may be intermittent. The intermittent stimulation may be beneficial so that the lymphatic system does not get used to the constant stimulation and stop responding. For example, intermittent stimulation may comprise sending electrical signals to the one or more electrodes multiple times per day for an interval of time. The stimulation may be continuous for said interval of time. The stimulation may occur in multiple instances throughout the day in intervals of 10 to 30 minutes of continuous stimulation. The stimulator 204 may be activated at least two times a day and / or up to 20 times a day, for example for example two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, or twenty times a day. The stimulator 204 may be automatically activated at pre-programmed specific times of the day, based on a sensor detected measurement, or otherwise. Depending on the indication, the electrical stimulation may be limited to activating during a specific time of the day.

[0049] The stimulation may be tailored to the specific patient to which it is administered. For example, the stimulation for patients with an increased level of fat tissue around the thoracic duct may be increased. Thus, the parameters for stimulation may beadjusted by a physician during implantation of the system within a patient, or during subsequent outpatient clinic visits. The stimulation parameters may also be adjusted during stimulation by a feedback loop provided by one or more sensors. The positioning of the one or more electrodes may also be adjusted by the physician based on data from one or more sensors during an implantation procedure. For example, the physician may use Doppler optical coherence tomography or a Doppler flow meter to measure lymphatic flow during the implantation procedure to verify that the stimulation results in an increased lymphatic flow. The Doppler flow meter may be used to establish baseline flow rates and experimental flow rates. Since the lymphatic flow rates are very low, the flow meters may be extremely sensitive, such as being able to detect 0.1 pL of change in flow.

[0050] The system 200 may comprise one or more sensors configured to detect a physiological parameter or condition of the patient. The one or more sensors may be implanted or wearable. If implanted, the one or more sensors may be implanted near the one or more electrodes or at a remote location within the body that is appropriate for the operation of the sensor. The one or more sensor readings may trigger electrical stimulation based on a comparison between the detected measurement and a threshold value. The one or more sensor readings may trigger an adjustment of ongoing electrical stimulation based on a comparison between the detected measurement and a threshold value. The threshold value may be preprogrammed into the system or calibrated based on the patient. The one or more sensors may send collected data to the processor, which may calculate a parameter based on the collected data and compare the calculated parameter to the threshold value. For example, one or more sensors may measure one or more characteristics of contractions of the lymphatic system and send the data to the processor to calculate a lymphatic flow of the patient. The one or more sensors may include a gyrometer, accelerometer, electromyograph (EMG), pho toplethy smogram (PPG), pressure, How, temperature, and / or other physiological sensor. The one or more sensors may be configured to send collected data to the stimulator, processor, and / or controller, through a wired or wireless connection, e.g., Bluetooth.

[0051] Referring back to FIG. 2, the system 200 may comprise a flow sensor 212 configured to detect the lymphatic flow rate of the patient. The flow sensor 212 may be placed at or near the left venous angle or the outflow of the thoracic duct 108 into the venous system. For example, the flow sensor 212 may be placed in the left subclavian vein 116 adjacent to thejunction of the left subclavian vein 1 16 and the left internal jugular vein 120. The flow sensor 212 may be connected by a lead or wire configured to allow the transmittal of collected data to the stimulator 204. In some embodiments, the How sensor 212 may wirelessly transmit data to the stimulator 204. The placement of the flow sensor 212 at the left venous angle, where the thoracic duct drains, may allow for accurate readings of the lymphatic flow rate without having to directly access the vessels of the lymphatic system. The flow sensor 212 may be anchored to the blood vessel by any anchoring mechanisms known in the art. For example, the anchoring mechanisms may comprise hooks, barbs, tines, prongs, etc. In some embodiments, the sensor may be built into or disposed upon a stent supporting the one or more electrodes for stimulation or a separate stent, as described herein. Since the lymphatic flow rates are very low, the flow sensor 212 may be extremely sensitive, such as being able to detect 0.1 pL of change in flow. The flow sensor 212 may be about 0.5 mm to 36 mm in size.

[0052] FIG. 3 is a schematic diagram illustrating another example system 300 for modulating the lymphatic system of a patient. The system 300 comprises a stimulator 204, embodiments of which are described in reference to FIG. 2. The system 300 may comprise one or more implantable electrodes implanted within one or more of the blood 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, at or near the left venous angle. The one or more electrodes may be placed in a location at the left venous angle in order to stimulate the outflow portion 108 of the thoracic duct 102. The stimulation may comprise pacing of the outflow portion 108. The stimulation may comprise field stimulation and / or pacing of the outflow portion 108. The one or more electrodes may be connected to the stimulator 204 by the lead 316.

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

[0054] In embodiments of the system having one or more electrodes at the left venous angle, one or more sensors configured to detect a physiological parameter or conditionmay be integrated with the structure supporting and / or anchoring the one or more electrodes along the blood vcsscl(s). For example, referring to FIG. 3, the flow sensor 312 may be integrated with the stent 308 supporting the one or more electrodes. The flow sensor 312 may be integrated with the stent 308, without limitation, by being disposed upon the stent or by being integral with the stent. In some embodiments, the flow sensor 312 may be separate from the stent 308.

[0055] FIG. 4 is a schematic diagram illustrating another example system 400 for modulating the lymphatic system of a patient. The system 400 comprises a stimulator 204, embodiments of which are described in reference to FIG. 2. The system 400 may comprise two or more electrodes comprising a first implantable electrode and a second implantable electrode. The first implantable electrode may be implanted in the azygos vein 132 above the cistema chyli 104, and the second implantable electrode may be implanted within one of the blood vessels of the left venous angle, at or near the angle. The multiple electrode arrangement of system 400 may beneficially increase lymphatic stimulation and / or provide greater control over the modulation of the lymphatic system by selectively and / or simultaneously electrically stimulating at or near the origin and drainage regions of the thoracic duct.

[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 anchored partially within one or more of the left brachiocephalic vein 118, the left internal jugular vein 120, or the left subclavian vein 116. For example, FIG. 4 illustrates the stent 408A anchored partially within the left subclavian vein 116 and partially within the left brachiocephalic vein 118. However, in some embodiments, the stent 408 A may be anchored fully within 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 within the azygos vein 132 at or above the cisterna chyli 104. The second stent 408B may be implanted between the cisterna chyli 104 and the bifurcation into left and right lymphatic ducts of the patient. The stent 408B may be implanted above the diaphragm of the patient, but in other embodiments, the stent 408B may be implanted between the cranial end of the diaphragm and the cistema chyli 104. The stent 408B may allow for synchronized or single point stimulation, as described in reference to stent 208.

[0058] The multiple electrode system 400 may comprise one or more sensors configured to detect a physiological parameter or condition of the patient. The one or more sensors may send data to the controller of the stimulator 204, such that the controller may send an instruction to the stimulator based on the received data. The instruction may comprise activating the stimulator to send an electrical signal to only one of the first or second electrodes, or to simultaneously send an electrical signal to both of the first and second electrodes. The instruction may comprise varying one or more stimulation parameters for only one of the first or second electrodes, or simultaneously varying the stimulation par ameters of both of the first and second electrodes. The instruction may comprise stopping the sending of an electrical signal to only one of the first or second electrodes, or simultaneously stopping the sending of an electrical signal to both of the first and second electrodes. The instruction may comprise stopping the sending of an electrical signal to one of the first or second electrodes, and simultaneously starting the sending of an electrical signal to the other of the first and second electrodes.

[0059] Referring back to FIG. 4, the flow sensor 312 may be configured to detect the lymphatic flow rate of the patient. The flow sensor 312 may be placed at or near the left venous angle, or 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 a lead or wire configured to allow the transmittal of collected data to the stimulator 204. In some embodiments, the flow sensor 312 may wirelessly transmit data to the stimulator 204. The stimulator 204 may control stimulation to the first and second electrodes supported by first and second stents 408A, 408B based on the received lymph flow data from flow sensor 312.

[0060] FIG. 5 is a schematic diagram of another example system 500 for modulating the lymphatic system. The system 500 comprises a stimulator 204, embodiments of which are described in reference to FIG. 2. The system 500 may comprise one or more implantable electrodes including an electrode implanted within the thoracic duct, for example anywhere between the outflow portion 108 to the cisterna chyli. In some embodiments, the electrode may be implanted in near the venous access. The electrode may be implanted within the outflow portion 108 of the thoracic duct 102. The outflow portion 108 of the thoracic duct102 may be easier to access in the patient anatomy than other regions of the thoracic duct, due to less variance in its location between patients. For example, the outflow portion 108 may be located and accessed through the opening at which lymph exits into the venous system at or near the left venous angle, instead of directly accessing the lymphatic system.

[0061] The system 500 may comprise a tubular support or stent 508 for supporting the one or more electrodes that is implanted within the thoracic duct. Using the stent 508 to support the one or more electrodes within the thoracic duct may prevent clogging or impedance of the lymph flow and facilitate decompression. In some embodiments, the stent 508 may be partially anchored within the outflow duct and partially anchored within one or more of the surrounding veins forming the left venous angle. The system 500 further comprises a flow sensor 312 that may be separate or integrated with the stent 508 and connected to the stimulator 204.

[0062] The systems 200, 300, 400, and 500 are shown and described separately for purposes of illustrating various positions for implantation of the one or more electrodes. However, it is to be understood and appreciated that the present disclosure is not so limited, as some components of one system may be present in the other system. For example, the system 500 may further comprise the electrode supporting stent 208 of system 200. Moreover, not all illustrated aspects may be required for the systems 200, 300, 400, 500, nor are they necessarily limited to the illustrated aspects.

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

[0064] For purposes of simplicity, the methods 600 and 700 are shown and described as being executed serially; however; it is to be understood and appreciated that the present disclosure is not limited by the illustrated order, as some steps or boxes could occur indiff erent orders and / or concurrently with other steps or boxes shown and described herein. Furthermore, for purposes of simplicity, the methods 600 and 700 arc shown and described separately. However, it is to be understood and appreciated that the present disclosure is not so limited, as some steps or boxes of one method may be present in the other method. Moreover, not all illustrated aspects may be required to implement the methods 600, 700, nor are the methods 600, 700 necessarily limited to the illustrated aspects.

[0065] Referring now to FIG. 6, illustrated is a method 600 for modulating the lymphatic system of a patient. The modulation 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, phlebolymphedema, venous hypertension, and / or the like.

[0066] In step 604, one or more implantable electrodes arc delivered into electrical communication with a region of the lymphatic system of the patient. The one or more electrodes may each comprise one or more electrode contacts, which can be contacts of an implantable electrode (e.g., lead, paddle electrodes, cuff electrodes, percutaneous electrodes, helical lead, etc.). The one or more implantable electrodes may be delivered by implanting one or more stents supporting the one or more electrodes within the patient. In such embodiments, the one or more electrode contacts may be disposed on, or integral with, the stent. The one or more implantable electrodes may be delivered to the venous system near the region of the lymphatic system. For example, the one or more electrodes supported by one or more stents may be delivered to the azygos vein or the left venous angle, such that the one or more electrodes are in close proximity with the thoracic duct of the lymphatic system. In some embodiments, the one or more electrodes may be delivered to the outflow portion of the thoracic duct through the venous system of the patient.

[0067] In step 608, a stimulator (e.g., an external stimulator, an internal stimulator, or a stimulator with a combination of external and implantable parts, etc.) can be activated to generate and / or send a signal to the one or more implantable electrodes. The signal may be an electrical signal comprising a repeating sequence of pulses for a first time and a delay for a second time. Each of the pulses may deliver an intensity that can include at least a portion of the stimulation intensity required to cause contractions of the lymphatic smooth muscle cells of a patient. In some embodiments, the intensity can be a multiple of the stimulation intensity required to cause the contractions (e.g., O.lx - 15x).

[0068] The electrical stimulation may be open-loop. The stimulation may be activated at present times as set by a clinician or a programmer of the stimulator. For example, the stimulation may be activated at least two times per day and / or less than 20 times per day, for example two times, three times, four times, five times, six times, seven times, eight times, nine times, ten times, eleven times, twelve times, thirteen times, fourteen times, fifteen times, sixteen times, seventeen times, eighteen times, nineteen times, or twenty times a day. The stimulation may be programmed to activate at specific times of each day.

[0069] In step 612, the signal sent by the stimulator to the one or more electrodes results in electrical stimulation of the region of the lymphatic system. The stimulation may occur for a preset duration, for example at least about one minute and / or less than or equal to an hour, for example less than or equal to forty-five minutes, less than or equal to thirty minutes, less than or equal to fifteen minutes, less than or equal to ten minutes, or less than or equal to five minutes. The stimulation parameters may not be so high as to burn or damage the surrounding area of the one or more electrodes. The stimulation parameters may not be so low as to not elicit a response from the lymphatics. The stimulation frequency may be at least about 5 Hz and / or less than or equal to 1000 Hz, less than or equal to 500 Hz, less than or equal to 100 Hz, less than or equal to 50Hz, less than or equal to 35 Hz, or less than or equal to 20 Hz. The stimulation current may be at least about 10 mA and / or less than or equal to 1000 mA, less than or equal to 500 mA, less than or equal to 200 mA, less than or equal to 100 mA, or less than or equal to 50 mA. The stimulation pulse may comprise a pulse width of at least about 50 ps and / or less than or equal to 2000 ps, such as less than or equal to 1000 ps, less than or equal to 800 ps, less than or equal to 600 ps, or less than or equal to 400 ps. The stimulation may be provided with a minimum current in the range of 50mA to 100 mA. The stimulation may be provided with a minimum pulse length of 100 ps to 500 ps. The stimulation may be provided with a minimum frequency in the range of 10Hz to 20Hz. The stimulation may be provided in multiple stimulation rounds. The multiple stimulation rounds may comprise multiple selected durations and dwell times between rounds. Upon implantation, a stimulation pulse may comprise a pulse threshold that is less than or equal to 1.5V and a pulse width in the range of 400 ps to 600 ps. In some embodiments, the pulse threshold and pulse width may exceed 1.5V and 600 ps, respectively.

[0070] In some embodiments, the electrical stimulation may be closed-loop and triggered when one or more sensors detect a particular physiological parameter or condition of the patient, which is further described in reference to method 700 shown by FIG. 7. The one or more sensors may include a flow sensor, pressure sensor, optical sensor for PPG, gyrometer / accelerometer, or otherwise. The one or more sensors may be external to the patient or implantable.

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

[0072] In step 708, one or more sensors may detect a physiological parameter or condition of the patient, as described herein. The physiological parameter or condition may be, without limitation, a lymphatic flow rate, a venous pressure, a heart rate, a temperature, lymph flow velocity or vessel contractions using Doppler optical coherence tomography, a change in skin color, and / or a change in swelling.

[0073] The method may comprise verifying, based on the detected physiological parameter or condition, that the electrical stimulation is sufficient to increase the electrical stimulation. In some embodiments, the physiological parameter or condition may be compared to a threshold value (e.g., stored in memory, retrieved from a remote source, and / or the like). The comparison may be performed, for example, by the stimulator, a component associated with the stimulator, and / or a component in communication with the stimulator, etc. The threshold value may be specific to the physiological parameter and can be determined for the patient based on previous data from the patient or previous data from a similar patient population. The threshold value may be based on the immediately preceding data collected by the one or more sensors.

[0074] In step 712, an instruction is sent to the stimulator for electrical stimulation based on the detected physiological parameter or condition. The instruction for electrical stimulation may comprise activating the stimulator, and / or varying one or more parameters of the electrical stimulation. In such embodiments, the system may be described as closed-loop, as stimulation and / or adjustment of stimulation is triggered when the one or more sensorsdetect a particular physiological parameter or condition. The instruction may comprise varying one or more parameters of ongoing electrical stimulation, such that the system may optimize stimulation a real time feedback loop as data is collected by the one or more sensors. For example, in some embodiments, a flow sensor may directly measure a lymphatic flow rate at the outflow portion of the thoracic duct. The flow sensor may be connected to the stimulator and / or a component associated with the stimulator (e.g., a controller or processor internal or external to the stimulator), such that the flow measurements are sent to the stimulator to provide a feedback loop for stimulation. A poor lymph flow rate may trigger activation of the stimulator and / or adjustment of the stimulation parameters. A high flow rate may trigger deactivation of the stimulator and / or adjustment of the stimulation parameters. The stimulation parameters that may be varied include, but are not limited to, one or more of a frequency, a current, a pulse width, a pulse threshold, and a duty cycle.

[0075] Although methods 600 and 700 are shown separately in FIGS. 6 and 7, it may be understood and appreciated that the present disclosure is not so limited, as steps of methods 600, 700 may be combine, without limitation to a particular order. For example, a method disclosed herein may comprise, in order, the steps 604, 608, 612, 708, 712. In another example, a method disclosed herein may comprise, in order, the steps 604, 708, 712, 608, 612. The steps disclosed in methods 600 and 700 may be repeated multiple times. For example, a method disclosed herein may comprise, in order, 604, 708, 712, 608, 612, 708, 712.

[0076] FIG. 8 shows an example that illustrates an example implementation of method 700. In step 804, a lymphatic flow rate may be detected by one or more sensors. The lymphatic flow rate is detected by a flow sensor implanted at or near the left venous angle, or the outflow portion of the thoracic duct. The lymphatic flow rate may be detected by a Doppler flow meter. In some embodiments, a lymphatic flow velocity and / or lymphatic flow rate is detected by Doppler optical coherence tomography.

[0077] In step 808, the detected lymphatic flow rate is compared to a threshold value, as described in relation to step 708 of method 700. The threshold value may be preprogrammed, or based on real time data detected by one or more sensors. In some embodiments, one or more sensors separate from the one or more sensors used in step 804 may be used to determine the threshold value. In the specific example illustrated by FIG. 8, if the detected lymphatic flow rate exceeds the threshold value, no stimulation or adjustment tostimulation parameters is required (do nothing in step 812). In the same example, if the detected lymphatic flow rate docs not exceed the threshold value, an electrical signal may be sent to the one or more implantable electrodes in electrical communication with the lymphatic system (in step 816) for stimulation. The step 816 may additionally or alternatively comprise varying one or more parameters of the electrical stimulation, for example, to increase the intensity of the stimulation.

[0078] A method of implanting the device may comprise delivering one or more electrodes into electrical communication with a region of the lymphatic system of a patient, e.g. lymphatic vessels or lymphatic nodes. For example, the 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 comprise activating a stimulator to send an electrical signal to the one or more electrodes to electrically stimulate the region of the lymphatic system via the electrodes. The stimulator may be activated to stimulate with low intensity, and may be configured to increase stimulation parameters at pre-determined time intervals after activation. The method may further comprise detecting, by one or more sensors, a physiological parameter or condition of the patient. The data from the one or more sensors may be received by a controller and / or processor, for example, to determine a lymphatic flow rate of the patient or contractions of the lymphatic vessels. The one or more sensors may comprise a Doppler flow meter, external sensors used for Doppler optical coherence tomography, or other flow sensors configured to detect a physiological parameter associated with lymphatic flow rate of the patient, such as the flow rate or lymphatic contractions. In some embodiments, the one or more sensors may comprise an EMG sensor configured to detect electrical feedback to identify contractions of the lymphatic system. The one or more sensors may comprise imaging sensors that detect markers or tracers injected into the lymphatic system of the patient and used to detect lymphatic activity. For example, a optical lymphatic flow meter may detect the movement of an injected air bubble in the thoracic duct.

[0079] The method may further comprise verifying, based on the detected physiological parameter or condition, that the stimulation is sufficient to increase a lymphatic flow rate of the patient. The lymphatic flow rate may exhibit a delayed response relative to the start of stimulation. If an increase in lymphatic flow rate is not observed after a certain period of time, for example, after about 5 to 10 minutes, then the stimulation parameters may beincreased. Patients may have varying levels of fat tissue around the portion of the lymphatic system to be stimulated. Thus, the stimulation parameters may be adjusted in situ during implantation to account for possible transmission issues. The method may comprise reimplanting some or all of the one or more electrodes and / or associated leads, for example if the stimulation parameters may not be increased further because of a risk of damaging the surrounding area(s) of the one or more electrodes. If the electrodes and / or leads are moved, some or all of the steps of the method may be repeated.

[0080] Although primarily described herein with respect to electrical stimulation, other types of stimulation and / or modulation are also contemplated. For example, the system may comprise one or more of the following means for modulation: a pressure element, a radiofrequency electrode, high power short duration RF (HPSD RF), an ultrasound element, a laser element, steam, thermal element, alcohol, a microwave element, an acoustic element, a vibratory element, a cryogenic element, a thermal delivery device, a chemical delivery device, and / or the like. But in some embodiments, the only modulation applied by the system may be electrical stimulation to the exclusion of the other modulation methods described here.

[0081] Additionally or alternatively to the sensor-based systems described above, the system may collect feedback from the patient, for example from a dedicated device or a general purpose external device like an application on a smartphone or tablet. The patient can indicate when they are experiencing an uncomfortable side effect. The patient could deactivate stimulation using, for example, the dedicated device or the general purpose external device. The stimulator could be configured to respond to the presence of a side effect by automatically adjusting stimulation parameters (amplitude, frequency, pulse width, duty cycle, and / or stimulation vector) according to a specified algorithm. Upon adjustment, the system would repeat detection of a side effect and make further adjustments if the side effect condition remains.

[0082] Lymphatic activity may be different based on the patient’ s autonomic state. For example, lymph flow may be different during exercise / activity or during sleep. As a result, it may be advantageous to provide different levels of lymphatic stimulation during these different states, both to enhance the efficacy of the therapy (avoid understimulation) and to improve the safety of the therapy (avoid overstimulation). Any stimulation parameter may beincreased or decreased, including but not limited to, any of amplitude, frequency, pulse width, and / or duty cycle.

[0083] For the systems described herein, stimulation parameters may be selected and adjusted. The stimulation parameters may be selected and adjusted without physically repositioning the stimulation lead. For example, the stimulation parameters may include amplitude, frequency, pulse width, duty cycle, and / or stimulation vector. The stimulation parameter could be adjusted during the implant visit, or during subsequent outpatient clinic visits. Alternatively, the adjustment could occur outside of the clinic, on a regular' schedule or in response to a physician trigger.

[0084] Detection of activity may be done with one or more sensors. The sensors may be the same or different from those used for activation or detection of side effects. For example, the system may include an accelerometer to detect activity or posture. The accelerometer could detect whether the patient is upright or prone. This may be indicative of whether the patient is asleep.

[0085] The lymphatic system is involved with almost all transports of fluids from body tissues. The treatment systems and methods described herein may be used in various patient populations with conditions other than intrinsic lymphedema such as phlebolymphedema, congestive heart failure (CHF), or venous hypertension. The treatment systems and methods described herein may also be used in any patient populations that suffer from chronic fluid overload or any pathological condition of the lymphatic vasculature, superficial or internal, regional or systemic, that is predominated by the appearance of tissue edema characteristic of lymphatic dysfunction.

[0086] In several embodiments, the modulation therapies described herein may be used to replace other therapies such as pharmacological (drug) or other device related therapies. In other embodiments, however, other drug or device related therapies may be used in combination with the modulation therapies described herein, but with reduced frequency, dose, or usage, thus reducing undesired side effects. For example, a certain drug (or drug combination) may be administered for a shorter overall duration, fewer times per day / week / month, and / or at a lower dose when combined with the modulation described herein. In addition to reducing undesired pharmacological side effects, this may also reduce addictionor dependence. The modulation described herein may also be used to taper or otherwise wean subjects off certain medications.

[0087] Certain experiments are described with respect to application of medicaments, for example, to induce certain physiological conditions before, during, and / or after stimulation. The devices and methods described herein can be used without medicaments (e.g., without medicaments inducing certain physiological conditions). Anesthetics and other medicaments that enable electrode placement, for example, may be used.

[0088] While the methods and devices described herein may be susceptible to various modifications and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular devices or methods disclosed, but, to the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the various examples described and the appended claims. Further, the disclosure herein of any particular feature, aspect, method, property, characteristic, quality, attribute, element, or the like in connection with an example can be used in all other examples set forth herein. Any methods disclosed herein need not be performed in the order recited. Depending on the example, one or more acts, events, or functions of any of the algorithms, methods, or processes described herein can be performed in a different sequence, can be added, merged, or left out altogether (e.g., not all described acts or events are necessary for the practice of the algorithm). Algorithms, modules, blocks, steps, boxes, elements, features, etc. may be stored in machine-readable memory. In some examples, acts or events can be performed concurrently, e.g., through multi-threaded processing, interrupt processing, or multiple processors or processor cores or on other parallel architectures, rather than sequentially. Further, no element, feature, block, box, or step, or group of elements, features, blocks, boxes, or steps, are necessary or indispensable to each example. Additionally, all possible combinations, subcombinations, and rearrangements of systems, methods, features, elements, modules, blocks, boxes, and so forth are within the scope of this disclosure. The use of sequential, or time-ordered language, such as “then,” “next,” “after,” “subsequently,” and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to facilitate the flow of the text and is not intended to limit the sequence of operations performed. Thus, some examples may be performed using the sequence of operationsdescribed herein, while other examples may be performed following a different sequence of operations.

[0089] The various illustrative logical blocks, boxes, modules, processes, methods, and algorithms described in connection with the examples disclosed herein can be implemented as electronic hardware, computer software, or combinations of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, operations, and steps have been described above generally in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. The described functionality can be implemented in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the disclosure.

[0090] The various illustrative logical blocks and modules described in connection with the examples disclosed herein can be implemented or performed by a machine, such as a general purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general purpose processor can be a microprocessor, but in the alternative, the processor can be a controller, microcontroller, or state machine, combinations of the same, or the like. A controller and / or processor can also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

[0091] The blocks, operations, or steps of a method, process, or algorithm described in connection with the examples disclosed herein can be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. A software module can reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, an optical disc (e.g., CDROM or DVD), or any other form of volatile or non-volatile computer-readable storage medium known in the art. A storage medium can be coupled to the processor such that the processor can read information from, and write information to, the storage medium. In thealtemative, the storage medium can be integral to the controller and / or processor. The controller and / or processor and the storage medium can reside in an ASIC. The ASIC can reside in a user terminal. In the alternative, the processor and the storage medium can reside as discrete components in a user terminal.

[0092] Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise,” “comprising,” “include,” “including” and the like are to be construed in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to.” The word “coupled,” as generally used herein, refers to two or more elements that may be either directly connected, or connected by way of one or more intermediate elements. Likewise, the word “connected,” as generally used herein, refers to two or more elements that may be either directly connected, or connected by way of one or more intermediate elements. Additionally, the words “herein,” “above,” “below,” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of this application. Where the context permits, words in the above Detailed Description using the singular or plural number may also include the plural or singular number, respectively. The word “or” in reference to a list of two or more items, that word covers all of the following interpretations of the word: any of the items in the list, all of the items in the list, and any combination of the items in the list.

[0093] Moreover, conditional language used herein, such as, among others, “can,” “could,” “might,” “may,” “e.g.,” “for example,” “such as” and the like, unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include, while other embodiments do not include, certain features, elements and / or states. Thus, such conditional language is not generally intended to imply that features, elements and / or states are in any way required for one or more embodiments or whether these features, elements and / or states are included or are to be performed in any particular embodiment.

[0094] The methods disclosed herein may include certain actions taken by a practitioner; however, the methods can also include any third-party instruction of those actions, either expressly or by implication. For example, actions such as “delivering one or more implantable electrodes” include “instructing delivering of one or more electrodes.”

[0095] While certain embodiments have been described, these embodiments have been presented by way of example only and arc not intended to limit the scope of the disclosure. Indeed, the novel apparatus, methods, and systems described herein may be embodied in a variety of other forms; furthermore, various omissions, substitutions, and changes in the form of the methods and systems described herein may be made without departing from the spirit of the disclosure. For example, while features are presented in a given arrangement, alternative embodiments may perform similar functionalities 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. Any suitable combination of the elements and acts of the various embodiments described above can be combined to provide further embodiments. The various features and processes described above may be implemented independently of one another or may be combined in various ways. All possible combinations and subcombinations of features of this disclosure are intended to fall within the scope of this disclosure.

[0096] As used herein, the term “electrical signal” can refer to a time-varying voltage or current. As an example, the electrical signal can be represented by a waveform (a graphical representation of changes in current or voltage over time). As used herein, the term “electrode contact” can refer to a material acting as a conductor through which electricity enters or leaves. At least a portion of the material can be a biocompatible material. As used herein, the terms “subject” and “patient” can be used interchangeably and refer to any warm-blooded organism including, but not limited to, a human being, a pig, a rat, a mouse, a dog, a cat, a goat, a sheep, a horse, a monkey, an ape, a rabbit, a cow, etc.

Claims

WHAT TS CLAIMED TS:

1. A method of causing lymphatic contractions in a patient, the method comprising: delivering one or more implantable electrodes into electrical communication with lymphatic smooth muscle cells of the patient; activating a stimulator to send a signal to the one or more implantable electrodes; and electrically stimulating the lymphatic smooth muscle cells via the one or more implantable electrodes.

2. The method of Claim 1, wherein delivering the one or more implantable electrodes comprises delivering the one or more electrodes to a location at or above the cisterna chyli.

3. The method of Claim 1, wherein delivering the one or more implantable electrodes comprises delivering a stent supporting the one or more electrodes.

4. The method of Claim 3, wherein delivering the one or more electrodes comprises placing at least a portion of the stent in a vein near the thoracic duct.

5. The method of Claim 4, wherein the vein is the azygos vein.

6. The method of 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 of Claim 3, wherein the stent further supports one or more sensors configured to detect a physiological parameter or condition of the patient.

8. The method of Claim 1, further comprising implanting the stimulator in a subcutaneous layer of the patient.

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

10. The method of any one of Claims 1-9, further comprising detecting, by one or more sensors, a physiological parameter or condition of the patient.

11. The method of Claim 10, further comprising receiving, by a controller, an instruction for the electrical stimulation based on the detected physiological parameter or condition.

12. The method of any one of Claims 1-9, further comprising increasing one or more parameters of the electrical stimulation at pre-determined time intervals.

13. The method of 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 of Claim 10, wherein the one or more sensors comprises a flow sensor or a pressure sensor.

15. The method of Claim 14, wherein the physiological parameter comprises a lymphatic flow rate of the patient.

16. The method of Claim 11, wherein the instruction for the electrical stimulation comprises activating the stimulator.

17. The method of Claim 11, wherein the instruction for the electrical stimulation comprises varying one or more parameters of the stimulation.

18. The method of Claim 17, wherein the one or more parameters comprise a pulse width, a current, a frequency, a pulse threshold, and / or a duty cycle of the stimulation.

19. The method of Claim 10, further comprising verifying, based on the detected physiological parameter or condition, that the electrical stimulation is sufficient to increase the lymphatic flow of the patient.

20. A method of modulating a lymphatic flow in a patient, the method comprising: delivering one or more implantable electrodes into electrical communication with a region of the lymphatic system at or above the cisterna chyli; activating a stimulator to send a signal to the one or more implantable electrodes; electrically stimulating the region via the one or more implantable electrodes; detecting, by one or more sensors, a physiological parameter or condition of the patient; receiving, by a controller, an instruction for the electrical stimulation based on the detected physiological parameter or condition.

21. The method of Claim 20, wherein delivering the one or more electrodes comprises delivering a stent supporting the one or more electrodes.

22. The method of Claim 21, wherein delivering the one or more electrodes comprises placing at least a portion of the stent in a vein near the thoracic duct.

23. The method of Claim 22, wherein the vein is the azygos vein or one of the veins of the left venous angle.

24. The method of any one of Claim 20, further comprising implanting the stimulator in a subcutaneous layer of the patient.

25. The method of Claim 20, further comprising increasing one or more parameters of the electrical stimulation at pre-determined time intervals.

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

27. The method of any one of Claims 20-25, 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 of any one of Claims 20-25, wherein the one or more sensors comprises a flow sensor or a pressure sensor.

29. The method of Claim 28, wherein the physiological parameter comprises a lymphatic flow rate of the patient.

30. The method of any one of Claims 20-25, wherein the instruction for the electrical stimulation comprises activating the stimulator.

31. The method of any one of Claims 20-25, wherein the instruction for the electrical stimulation comprises varying one or more parameters of the electrical stimulation.

32. The method of Claim 31, wherein the one or more parameters comprise a pulse width, a current, a frequency, a pulse threshold, and / or a duty cycle of the electrical stimulation.

33. The method any one of Claims 20-25, further comprising verifying, based on the detected physiological parameter or condition, that the electrical stimulation is sufficient to increase the lymphatic flow of the patient.

34. A system for electrically stimulating a region of the lymphatic system of a patient, the system comprising: one or more implantable electrodes configured to be delivered into electrical communication with a region of the lymphatic system; a stimulator configured to send a signal to the one or more implantable electrodes to electrically stimulate the region of the lymphatic system;one or more sensors configured to detect a physiological parameter or a condition of the patient; a controller configured to receive data from the one or more sensors; and wherein the stimulator is configured to receive an instruction from the controller to send the signal to the one or more implantable electrodes based on the data received from the one or more sensors.

35. The system of Claim 34, further comprising a stent supporting the one or more implantable electrodes.

36. The system of 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 of Claim 36, wherein the vein is the azygos vein.

38. The system of 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 of Claim 38, wherein the stent further comprises the one or more sensors.

40. The system of Claim 34, wherein the stimulator is implantable into a subcutaneous layer of the patient.

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

42. The system of any one of Claims 34-40, wherein the one or more sensors are implantable 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 of any one of Claims 34-40, wherein the one or more sensors comprises a flow sensor or a pressure sensor.

44. The system of Claim 43, wherein the physiological parameter comprises a lymphatic flow rate of the patient.

45. The system of any one of Claims 34-40, wherein the controller is on-board the stimulator.

46. The system of any one of Claims 34-40, wherein the controller is remote from the stimulator.

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

48. The system of any one of Claims 34-40, wherein the instruction from the controller comprises activating the stimulator.

49. The system of any one of Claims 34-40, wherein the instruction from the controller comprises varying one or more parameters of the electrical stimulation.

50. The system of Claim 49, wherein the one or more parameters comprise a pulse width, a current, a frequency, a pulse threshold, and / or a duty cycle of the electrical stimulation.

51. A system for electrically stimulating a region of the lymphatic system of a patient, the system comprising: 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 be in electrical communication with the thoracic duct; a stimulator configured to send a signal to the one or more implantable electrodes to electrically stimulate the thoracic duct; and a controller configured to send an instruction for electrical stimulation to the stimulator.

52. The system of Claim 51, wherein the vein is the azygos vein.

53. The system of 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 of Claim 51, wherein the stimulator is implantable into a subcutaneous layer of the patient.

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

56. The system of any one of Claims 51-55, further comprising one or more sensors configured to detect a physiological parameter or condition of the patient.

57. The system of Claim 56, wherein the stent supports the one or more sensors.

58. The system of Claim 56, wherein the one or more sensors comprises a flow sensor or a pressure sensor.

59. The system of Claim 58, wherein the physiological parameter comprises a lymphatic flow rate of the patient.

60. The system of Claim 56, wherein the one or more sensors are implantable 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 of any one of Claims 51-55, wherein the controller is on-board the stimulator.

62. The system of any one of Claims 51-55, wherein the controller is remote from the stimulator.

63. The system of Claim 56, wherein the controller is configured to receive data from the one or more sensors and send the instruction for electrical stimulation based on the received data.

64. The system of any one of Claims 51-55, wherein the instruction comprises a preprogrammed instruction to activate the stimulator.

65. The system of Claim 63, wherein the instruction comprises activating the stimulator based on the data received from the one or more sensors.

66. The system of Claim 63, wherein the instruction comprises varying one or more parameters of the electrical stimulation based on the data received from the one or more sensors.

67. The system of Claim 66, wherein the one or more parameters comprise a pulse width, a current, a frequency, a pulse threshold, or a duty cycle of the electrical stimulation.

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