Treatment of hemorrhage and hemorrhagic disorders by high intensity focused ultrasound stimulation of the spleen

Abstract

Devices and methods for reducing or limiting bleeding in an animal by stimulating the spleen with focused ultrasound (FUS). The devices and methods can be used to treat blood disorders such as hemophilia, or to reduce bleeding during surgery or due to trauma. The methods can be administered to a patient non-invasively by applying ultrasound energy transcutaneously.

Description

[0001] Cross-references to related applications

[0002] This patent application claims priority to U.S. Provisional Patent Application No. 62 / 960612, filed January 13, 2020, entitled “TREATING BLEEDING AND BLEEDING DISORDERS VIA HIGH INTENSITY FOCUSED ULTRASOUND STIMULATION OF THESPLEEN”, the entire contents of which are incorporated herein by reference.

[0003] By combining citations

[0004] All publications and patent applications mentioned in this specification are incorporated herein by reference in their entirety, to the extent that each individual publication or patent application is specifically and individually indicated to be incorporated by reference. Technical Field

[0005] This disclosure generally relates to the prevention and / or treatment of bleeding in a subject. More specifically, the present invention relates to devices (apparatus, systems, and methods) for preventing and / or treating bleeding in a patient by stimulating the spleen. Background Technology

[0006] Bleeding and bleeding losses can occur from any of a variety of causes, such as traumatic injuries resulting from accidents or surgery. Therefore, new devices, methods, and systems are needed to prevent and treat bleeding problems.

[0007] This article describes apparatus, methods, and systems for addressing these problems, as well as other issues related to bleeding loss and hemorrhage. Summary of the Invention

[0008] This invention provides a novel method and apparatus for reducing bleeding in patients. More specifically, this disclosure relates to devices (apparatus, systems) and methods for controlling bleeding and the duration of bleeding in patients through mechanical stimulation, such as acoustic stimulation of the spleen. The device can provide non-invasive stimulation of the spleen. Controlling bleeding may include preventing and / or treating bleeding (e.g., surgical bleeding, traumatic bleeding, bleeding associated with other medical procedures or conditions, and hereditary or acquired bleeding disorders).

[0009] Mechanical ultrasound stimulation represents an alternative, non-invasive approach to directly activating the cervical vagus nerve by activating the spleen and the previously described nerve tourniquet. Advantages of this approach over pharmacological methods include potentially higher specificity, fewer side effects, lower cost, and improved compliance. For both the initial procedure and subsequent battery replacement, its advantages over implantable pulse generators for chronic neurostimulation applications include avoidance of surgery and associated complications, and reduced cost.

[0010] For example, this document describes a method for reducing bleeding (e.g., bleeding time) in a subject, the method comprising: applying ultrasound stimulation to the spleen of the subject; and reducing bleeding by at least 20%. The method may include applying ultrasound stimulation at a frequency of, for example, 0.25 to 5.0 MHz, to the spleen of the subject for a predetermined duration of 30 seconds to 5 minutes. Ultrasound stimulation may be applied using an input voltage amplitude within a specified range (e.g., 50 to 350 mVpp). In some examples, ultrasound stimulation comprises applying focused ultrasound stimulation to the spleen of the subject. Ultrasound stimulation may be applied percutaneously / percutaneously. Alternatively or additionally, in some examples, ultrasound may be applied invasively (e.g., during surgery) and / or via an implant. Ultrasound stimulation may be directed and / or focused on the central region of the spleen of the subject and / or the hilum of the spleen. Ultrasound stimulation may be applied without directly stimulating the vagus nerve and / or trigeminal nerve. In some examples, ultrasound stimulation of the spleen is applied in combination with electrical or mechanical stimulation of the vagus nerve and / or trigeminal nerve to reduce bleeding. In some examples, applying ultrasound stimulation to the subject's spleen includes stimulating the splenic nerves. The bleeding rate of the subject can be measured before, during, and / or after ultrasound stimulation is applied to the subject's spleen.

[0011] Generally, the subjects described herein may be referred to as patients or patients requiring bleeding control; these subjects may include (but are not limited to) human subjects. Subjects may also be non-human (e.g., animals, including domestic animals).

[0012] This article also describes a method for treating subjects with bleeding, which includes determining when the subject is bleeding and applying ultrasound stimulation to the subject's spleen (e.g., for the subject's spleen, using a frequency of 0.25 to 5.0 MHz for a duration of 30 seconds to 5 minutes).

[0013] This article also describes a method for reducing bleeding time in subjects undergoing surgery, comprising: applying ultrasound stimulation to the spleen of the subject during surgery or within 2 hours of the surgery being performed on the subject; wherein the ultrasound stimulation comprises, for the spleen of the subject, using an ultrasound frequency of 0.25 to 5.0 MHz, using an input voltage amplitude of 50 to 350 mVpp, for a duration of 30 seconds to 5 minutes.

[0014] In these methods, the subjects can be human or non-human.

[0015] As described above, any of these methods may include reducing bleeding time. For example, reducing bleeding time may include reducing the bleeding time of one or more internal or external hemorrhages. Bleeding time may be reduced by more than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, etc., compared to untreated patients (e.g., by applying sound energy until bleeding time is reduced).

[0016] The devices described herein are generally configured to perform any of these methods. For example, this document describes a system for reducing bleeding in a subject. The system may include: an ultrasound applicator comprising one or more ultrasound transmitters and a housing (e.g., a housing base) configured to apply ultrasound stimulation to the spleen of a subject; and a controller coupled to the ultrasound applicator configured to deliver ultrasound stimulation from the one or more ultrasound transmitters to the spleen of the subject at a frequency between 0.25 and 5.0 MHz for a duration of 30 seconds to 5 minutes to reduce bleeding time in the patient by at least 20%.

[0017] An ultrasound applicator may include a housing configured to be secured to the subject's abdomen above the spleen. The ultrasound applicator may include an array of ultrasound transmitters. In some examples, the ultrasound transmitters are configured to project ultrasound stimulation between 1 cm and 10 cm into the body. The ultrasound applicator may include one or more sensors, wherein a controller is configured to detect intercostal spaces and select one or more ultrasound transmitters covering the intercostal spaces. For example, the one or more sensors may include ultrasound sensors.

[0018] The housing can be a flexible substrate. For example, the housing may include a flexible substrate on which one or more ultrasonic transmitters are fixed or within the flexible substrate.

[0019] In any of these systems, the controller can be configured to apply an input voltage amplitude of 50 to 350 mVpp to drive ultrasound from the ultrasound applicator.

[0020] The housing may include an adhesive pad adapted for application to the subject's abdomen over the spleen. In some examples, the ultrasound applicator is coupled to a controller via a cord; alternatively, in some examples, the controller is enclosed within the housing of the ultrasound applicator and / or attached to the housing of the applicator (e.g., within a secondary housing).

[0021] These and other features and advantages are described here. Attached Figure Description

[0022] The novel features of the invention are set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings, which illustrate illustrative examples utilizing the principles of the invention, in which:

[0023] Figure 1A This is a schematic diagram of an example ultrasound device used to apply stimulation to the spleen to reduce bleeding.

[0024] Figure 1B This is another example of a schematic diagram of an ultrasound device used to apply stimulation to the spleen to reduce bleeding.

[0025] Figure 2A and 2B This is a schematic diagram showing the location and structure of the spleen.

[0026] Figure 2C and 2D An example of applying the device described herein to a patient's body via the spleen method is shown.

[0027] Figure 3 This is a flowchart illustrating an exemplary method for reducing bleeding in a subject.

[0028] Figure 4A and 4B An exemplary experimental setup is shown for ultrasound stimulation of the mouse spleen and control ultrasound stimulation of the mouse quadriceps.

[0029] Figure 5 This is a graph showing the bleeding time in mice after treating the spleen with ultrasound stimulation using parameters that reduce bleeding time.

[0030] Figure 6A and 6B The figure shows the bleeding time of mice after treatment with misaligned ultrasound stimulation and insufficient input voltage. Detailed Implementation

[0031] This invention relates to controlling (e.g., treating and / or preventing) bleeding in a patient by stimulating the spleen. More specifically, this document describes devices (apparatus, systems, and methods) for controlling bleeding to reduce bleeding time by applying mechanical stimulation, such as acoustic (e.g., ultrasound) stimulation, in relation to a corresponding reduction in the amount of bleeding (bleeding loss). The spleen can be stimulated percutaneously and is therefore non-invasive. Controlling bleeding may include preventing and / or treating bleeding, such as surgical bleeding, traumatic bleeding, bleeding associated with childbirth, bleeding associated with other medical procedures or conditions, bleeding mediated or increased by anticoagulants, hereditary or acquired bleeding disorders (e.g., hemophilia), and bleeding for the treatment of other forms and causes.

[0032] As used in this article, “treatment” includes both preventative and therapeutic treatment. “Preventative treatment” refers to treatment that occurs before a symptom (such as bleeding, inflammatory conditions, etc.) develops, in order to prevent, suppress, or reduce its occurrence.

[0033] As used herein, the patient or subject can be any animal, preferably a mammal, including humans, but can also be a companion animal (e.g., a cat or dog), a farm animal (e.g., a cow, goat, horse, sheep), or a laboratory animal (e.g., a guinea pig, mouse, rat) or any other animal, preferably a mammal with a spleen.

[0034] As used in this article, “bleeding time” or “bleeding duration” refers to the length of time it takes for bleeding to stop. Bleeding time is typically controlled or influenced by the degree of platelet embolism. In untreated subjects, bleeding time is often increased by administering anticoagulants such as aspirin, heparin, and warfarin.

[0035] As used herein, when referring to bleeding (e.g., bleeding time), the term “reduction” or “reduction” encompasses at least a small but measurable reduction in bleeding relative to an untreated control. Bleeding time is reduced by approximately 5% to approximately 70%. Bleeding time can be reduced by at least any of the aforementioned percentages. For example, bleeding time can be reduced by at least 5%, at least 10%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 65%, at least 70%, or greater than 70%. Values ​​within these ranges can be selected, for example, to use a protocol or device configured to reduce bleeding while minimizing side effects due to the applied spleen stimulation. For example, in some examples, bleeding time can be reduced by 5% to 70%, 10% to 50%, 20% to 60%, 30% to 70%, 40% to 70%, or 25% to 65%.

[0036] Splenic stimulation as described herein can be non-invasive. Mechanical stimulation can be, for example, percutaneous (without damaging the skin). As used herein, non-invasive stimulation can be achieved, for example, by applying external pressure and / or vibration devices to the subject. Mechanical stimulation can be applied to the patient's skin surface, near and / or toward the patient's spleen, via an acoustic vibrator, such as an ultrasound stimulation device. In some examples, non-invasive acoustic stimulation can be applied to the spleen. For example, electrical stimulation can be applied through the skin (percutaneously) from one or more locations.

[0037] Splenic stimulation can directly or indirectly apply mechanical energy to one or more nerves or nerve plexuses. For example, ultrasound stimulation of the spleen can additionally stimulate the splenic nerves (splenic plexus). Regardless of whether the intrinsic pathways for controlling (accelerating) clot formation (blood clotting) exist in the spleen or splenic nerves, once this procoagulant pathway is activated through vibrational / acoustic stimulation, hemostasis is improved by accelerating clot formation, particularly at the site of tissue injury. This can result in less bleeding loss and a shorter duration of bleeding after tissue trauma.

[0038] In some cases, mechanical stimulation of the spleen can also activate other physiological pathways, such as anti-inflammatory pathways (e.g., cholinergic anti-inflammatory pathways). However, the conditions used to target activation of coagulation pathways can differ from those used to target activation of anti-inflammatory pathways. For example, optimized parameters for ultrasound stimulation of the spleen to activate anti-inflammatory pathways may not effectively activate blood coagulation to achieve a reduction in bleeding time within a minimum threshold. The minimum threshold for reduced bleeding time can vary depending on the condition being treated. For example, the bleeding time reduction requirements for treating hereditary or acquired bleeding disorders may differ from those for treating / preventing surgical bleeding. In some examples, the minimum threshold for reduced bleeding time compared to untreated subjects is at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70%. In some cases, it may be desirable to reduce bleeding only to a certain extent. In such cases, a maximum threshold for reduced bleeding time may exist. In some examples, the maximum threshold for the reduction in bleeding time compared to untreated subjects is up to 10%, up to 20%, up to 30%, up to 40%, up to 50%, up to 60%, or up to 70%. In some cases, the reduction in bleeding time can be within any of the above values ​​(e.g., 10% to 70%, 20% to 70%, 40% to 60%, 50% to 70%, 50% to 60%, etc.).

[0039] Any spleen stimulation method described herein can be achieved by applying acoustic energy to the spleen. In some examples, the acoustic energy is applied as a pulsed wave. In some examples, the acoustic energy is applied continuously. In other examples, a combination of pulsed waves and continuous application of acoustic energy is used. In some examples, acoustic energy is applied from a single ultrasound transmitter. In other examples, acoustic energy is applied from a combined array of ultrasound transmitters. The method may involve focused ultrasound (FUS) technology, in which acoustic lenses are used to focus the acoustic energy to target the target tissue. In some examples, high-intensity focused ultrasound (HIFU) technology is used.

[0040] Typically, the splenic stimulation described herein is sufficient to reduce bleeding loss in patients. Therefore, acoustic stimulation can be applied without concurrent application of other treatments for bleeding loss. For example, splenic stimulation can be applied without simultaneous pharmacological treatment. Acoustic stimulation can be applied without direct electrical stimulation of the vagus and / or trigeminal nerves. Direct electrical nerve stimulation can refer to stimulation provided by one or more electrodes (e.g., nerve sleeves) in physical contact with the vagus and / or trigeminal nerves. Acoustic stimulation can be applied without indirect electrical stimulation of the vagus and / or trigeminal nerves. Indirect electrical nerve stimulation can refer to stimulation provided by one or more electrodes not in physical contact with the vagus and / or trigeminal nerves, such as through transcutaneous electrical stimulation. Acoustic stimulation of the vagus and / or trigeminal nerves can be applied without direct or indirect mechanical stimulation, such as through transcutaneous oscillatory mechanical force and / or pressure (e.g., sound waves or ultrasound vibrations) on the vagus and / or trigeminal nerves.

[0041] Generally, the spleen stimulation methods described in this article are safer than conventional therapies. They are also generally more effective, safer, and cheaper than traditional pharmacological therapies. For example, non-invasive stimulation methods offer higher specificity, fewer side effects, lower costs, and improved patient compliance compared to pharmacological therapies. Non-invasive stimulation avoids the complications associated with invasive treatments compared to invasive methods such as surgery.

[0042] While effective spleen stimulation can be applied to reduce bleeding loss in the absence of other treatments, in some instances, acoustic spleen stimulation may be used in combination with one or more other types of bleeding loss reduction therapies. For example, in some instances, the acoustic stimulation therapy described herein may be used in combination with vagus nerve and / or trigeminal nerve stimulation (e.g., electrical and / or mechanical stimulation) to reduce bleeding. Examples of suitable neurostimulation methods for reducing bleeding loss are described in U.S. Patent No. 8,729,129 and U.S. Patent Application No. 16 / 391,155, the entire contents of which are incorporated herein by reference.

[0043] The methods for controlling bleeding described herein can be performed using any suitable device, including ultrasound devices for stimulating the spleen. Preliminary work has proposed modified versions of ultrasound devices incorporating focused ultrasound therapeutic transducers, such as the SonicConcept H106 ultrasound transducer (manufactured by Sonic Concepts, based in Bothell, Washington, USA). The ultrasound transducer can be connected to power amplifiers and waveform generators, such as those from Keysight Technologies. TM The 33120A waveform generator (manufactured by Keysight Technologies, based in Santa Rosa, California, USA) delivers non-invasive focused ultrasound stimulation to the spleen.

[0044] Figure 1A This is a schematic diagram of a general-purpose ultrasound stimulation device 100 for treating bleeding. In this example, the device typically includes an applicator 109 having at least one ultrasound transducer 103 for applying ultrasound stimulation to the spleen, connected to a controller 101 for controlling the aspects of the ultrasound stimulation. The one or more transducers may be high-intensity focused ultrasound transducers. The controller includes a waveform generator 105 and an optional power amplifier 107 for generating electrical signals to the transducers. The controller may include one or more processors to control stimulation parameters, such as focal length, power, and the duration of the applied acoustic stimulation. The controller may be a dedicated computing device for applying ultrasound stimulation. In some examples, the controller is a tablet, telephone, laptop, watch, or other computing device. The power amplifier and waveform generator may be separate units or part of the same unit (e.g., packaged within a single housing).

[0045] An ultrasound transducer can be a probe, or a part thereof, for direct or indirect application to a patient's skin. In some examples, amplifiers and waveform generators may be integrated with the probe. Ultrasonic cleaning solutions or gels may be used to aid in the transmission of ultrasound waves. In some examples, the probe is a handheld unit or part of a handheld unit. In some cases, the probe includes a fixation device for securing the probe / transducer to the patient's body. For example, strips, straps, and / or adhesives may be used to secure the probe / transducer to the patient. In some cases, the probe / transducer may be integrated into clothing or accessories worn by the subject. In some cases, the probe / transducer is part of a surgical apparatus for treating or controlling bleeding before, during, and / or after surgery.

[0046] In an example where the ultrasound transducer is a focused ultrasound transducer (FUS), the transducer may include an acoustic lens such that it emits a focused ultrasound beam having a corresponding focal area (e.g., focal point) and focal length. The probe may be positioned such that the spleen is located within the focal area / focal length of the transducer.

[0047] Figure 1B Another example of an ultrasound stimulation device for treating bleeding is shown. In this example, device 100' includes an array of ultrasound transducers 103' for applying ultrasound stimulation to the spleen. The transducer array is part of an applicator 109', which may be configured to be applied to a patient's torso above the upper thoracic cavity (e.g., above the spleen). For example, the applicator may include a housing configured to fit onto the patient's torso. In some examples, the housing may be a flexible substrate to which one or more ultrasound transducers are attached. In some examples, the applicator includes an adhesive and / or hydrogel material 119 that helps to secure it to the patient's skin and form a connection between the skin and the ultrasound transducers. The applicator may be single-use (e.g., disposable) or reusable. In some examples, the applicator includes a removable skin contact portion that can be replaced onto a reusable portion (including one or more transducers). The one or more transducers may be high-intensity focused ultrasound transducers.

[0048] exist Figure 1B In this design, the applicator is connected to a controller 101 for controlling parameters of the ultrasonic stimulation. The controller may include a waveform generator 105 and an optional power amplifier 107 for generating electrical signals to the transducer. The controller may include one or more processors for controlling parameters such as focal length, power, and the duration of the applied acoustic stimulation. The controller may be a dedicated computing device for applying the ultrasonic stimulation. In some examples, the controller is a tablet computer, telephone, laptop, watch, or other computing device. The power amplifier and waveform generator may be separate units or part of the same unit (e.g., packaged in a single housing).

[0049] In any of these devices (e.g., systems, apparatuses, etc.), the device may be configured to apply ultrasound energy to the spleen by identifying an intercostal region (between two or more ribs, specifically, between the 9th and 10th ribs or the 10th and 11th ribs in a patient to which the applicator has been applied). The device may automatically identify the intercostal region and may be configured to apply energy from a subset of an array of ultrasound transducers located on the intercostal region for applying energy to the spleen, as described herein. Therefore, these devices may include one or more intercostal sensors for detecting the intercostal region. In some examples, the same ultrasound transducers used to apply energy to the body may be used to detect the intercostal spaces between the ribs. For example, a controller may be configured to apply a sequence of probing ultrasound pulses and detect returning ultrasound signals to identify the rib below the applicator. The controller may then determine which ultrasound transducers are located above the intercostal spaces and / or possibly above the spleen, and may select this subset of one or more ultrasound transducers to apply energy as described herein.

[0050] In some examples, the controller unit can be directly connected to the transducer via one or more conductors 111. Alternatively, the controller can be located within the applicator housing and can be coupled to or integrated with the housing (see, for example, below). Figure 2D Any device described herein may include one or more inputs, including user (physician, caregiver, nurse, self / patient, etc.) control. Any of these devices may also, or optionally, include one or more sensors 113 for detecting patient conditions, which may be (wired and / or wirelessly) connected 115 to controller 101 or one or more other computing devices. These sensors may detect one or more physiological conditions of the subject, such as one or more of the following: bleeding loss / bleeding, blood pressure, heart rate, etc. Sensor data can be used to control devices in a feedback loop. For example, one or more sensors may be used to modify (e.g., automatically and / or manually) the parameters of ultrasound stimulation. In some cases, this is done in real time.

[0051] The ultrasound devices described herein can be integrated into surgical apparatuses configured to position and / or immobilize the subject to undergo surgery. Ultrasound therapy can be applied continuously or discretely before a planned surgery (e.g., 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, or more before surgery), and / or during and / or after surgery to reduce or control bleeding. In some examples, these methods can be used to treat patients post-operatively and / or after childbirth (e.g., to reduce bleeding due to postpartum hemorrhage or any other medical procedure where bleeding may be a problem, such as joint replacement or spinal surgery).

[0052] In addition to acute bleeding, the methods and devices described herein can be used to treat chronic bleeding. For example, any of these methods and devices that reduce bleeding through spleen stimulation can be used to treat subjects with hemophilia. Subjects with hemophilia may be at risk of bleeding throughout their lives. Patients with chronic bleeding can be treated with ultrasound stimulation at prescribed intervals, such as once or more per day, week, or month. In some cases, the device is portable, allowing the patient to keep it at hand to apply ultrasound stimulation when there is a risk of bleeding. Alternatively, patients can use wearable units (e.g., strips, straps, etc.) to attach the ultrasound transducer to the patient or apply ultrasound stimulation.

[0053] The methods and apparatus described herein can be configured to treat bleeding by applying stimulation to one or more areas of the spleen. Figure 2A A schematic diagram of the general location 221 of the spleen is shown. The spleen is typically located in the left upper quadrant of the abdomen, below and to the left of the diaphragm. The spleen is usually at least partially located behind the thoracic cavity, for example, below the ninth, tenth, and eleventh ribs. To apply acoustic energy to the spleen, the transducer / applier is typically placed on the left posterolateral and / or lateral side of the patient's trunk, with the head of the transducer pointing towards the spleen. In other cases, the transducer / applier is placed on or near the lower ribs on the left anterior upper trunk. The transducer / applier may be positioned at an angle relative to the skin surface to avoid or reduce interference from the ribs. In some cases, the surface of the transducer head is at an angle between approximately 5 degrees and approximately 90 degrees relative to the skin surface (e.g., approximately 5°, 10°, 15°, 20°, 25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, 85°, or 90°).

[0054] According to some examples, the transducer / applier is positioned to stimulate the central region of the spleen. Figure 2B A diagram illustrating the general anatomical structure of the spleen 220 is shown. The hillock 226 corresponds to a long fissure near the middle of the spleen and is the junction of the gastrosplenic ligament, including the insertion points of the splenic artery 223 and splenic vein 225. In some examples, ultrasound energy is focused on or near the central region of the spleen, including at least a portion of the splenic hilum. For example, the surface of the transducer head may be pointed towards the central region of the spleen located at or near the splenic hilum, and the focal area (focal length) of the focused ultrasound transducer is adjusted to include the central region of the spleen located at or near the splenic hilum.

[0055] Figure 2C An example of the device as described herein, applied to patient 250, is shown. Figure 2CThe image shows an applicator 209 applied to a patient 250. The applicator can be adhesively attached to the patient, for example, by an adhesive and / or an ultrasound-conducting gel (e.g., hydrogel). The applicator is attached to the trunk region above the spleen. In this example, the applicator is coupled to a controller 201, which drives ultrasound energy and / or can determine which ultrasound transducer to use to apply energy to the spleen. Figure 2D In this embodiment, the applicator 209 includes a second housing 231 surrounding the controller, which is integrated into or with the applicator. In any of these examples, the applicator may be said to include a housing. The housing may be rigid or flexible. For example, the housing may be made of fabric material. The housing may also be referred to as a substrate. Typically, the housing (or housing substrate) may support one or more transducers and may be applied to the patient's torso over the spleen. In some examples, the housing is configured, for example, by including curved or pre-curved surfaces, to fit over the subject's torso.

[0056] When acoustic energy is applied to stimulate the spleen to control bleeding, the acoustic energy can be applied within an effective range of parameters (intensity, frequency, and / or duration) to achieve a reduction in bleeding time of at least a minimum threshold and / or at most a maximum threshold, as described herein. In some examples, the ultrasound (e.g., FUS) frequency range is approximately 0.25 to 10.0 MHz (e.g., approximately 0.25 to 5.0 MHz, approximately 0.25 to 2.5 MHz, approximately 0.1 to 2 MHz, approximately 0.25 to 1.5 MHz, etc.). In some examples, the frequency is constant. In some examples, the frequency can be varied, for example, by - / +5%, 10%, 15%, 20%, 25%, 30%, 35%, 50%, etc.

[0057] The intensity of ultrasound (e.g., FUS), measured by the input voltage amplitude (mVpp), can be approximately 50 to 400 mVpp (e.g., approximately 100 to 300 mVpp, approximately 50 to 350 mVpp, approximately 10 to 250 mVpp, approximately 10 to 200 mVpp, etc.). In some examples, the input voltage amplitude does not exceed 400 mVpp (e.g., not exceeding 350 mVpp, not exceeding 350 mVpp, not exceeding 300 mVpp, not exceeding 250 mVpp, not exceeding 200 mVpp, not exceeding 150 mVpp, not exceeding 100 mVpp, etc.). The input waveform of ultrasound (e.g., FUS) stimulation can be characterized as having any of a variety of waveform shapes, such as a sine wave, a square, a triangle, a sawtooth, etc.

[0058] The duty cycle of ultrasound (e.g., FUS) therapy (within the "on-time" of stimulation) can range from approximately 10 to 500 cycles / bursts (e.g., approximately 50 to 300 cycles / bursts, approximately 100 to 300 cycles / bursts, approximately 100 to 200 cycles / bursts, etc.). The duration of an ultrasound (e.g., FUS) burst can range from approximately 50 microseconds (μsec) to 10 milliseconds (ms) (e.g., approximately 100 μsec to 5 ms, approximately 500 μsec to 2 ms, approximately 100 μsec to 2 ms, approximately 200 μsec to 10 ms, etc.).

[0059] In any ultrasound (e.g., FUS) stimulation treatment described herein, the total treatment duration can be from approximately 30 seconds (sec) to 2 hours (hrs) (e.g., approximately 30 seconds to 5 minutes (min), approximately 1 minute to 10 minutes, approximately 1 minute to 5 minutes, approximately 30 seconds to 5 minutes, approximately 1 minute to 30 minutes, approximately 30 seconds to 5 minutes, approximately 30 seconds to 1 hr, etc.). In some examples, stimulation may be applied for more than 1 hour. In some examples, stimulation may be applied until a reduction in bleeding is detected or the device is manually turned off. There may be “off time” or delays (e.g., rest intervals) between rounds of stimulation. For example, the off time or delay can be from approximately 1 second to 30 minutes (e.g., approximately 30 seconds to 1 minute, approximately 15 seconds to 5 minutes, approximately 30 seconds to 2 minutes, approximately 30 seconds to 10 minutes, etc.).

[0060] The devices and methods described herein are applicable for the therapeutic or prophylactic treatment of subjects suffering from or at risk of suffering from unwanted bleeding caused by factors such as hemorrhagic conditions including but not limited to fibrinogenemia, factor II deficiency, factor VII deficiency, fibrin stabilizing factor deficiency, coagulation factor X deficiency, hemophilia A, hemophilia B, hereditary platelet dysfunctions (e.g., Allport syndrome, Bernard-Sollier syndrome, Granzman thrombocytopenia, grey platelet syndrome, May Hegglin abnormality, Scott syndrome, and Wescott-Aldrich syndrome), parahemorrhagic disease, Tourette power factor deficiency, von Willebrand disease, thrombotic tendency, or acquired platelet disorders (e.g., those caused by common medications: antibiotics, anesthetics, blood thinners, and medications caused by medical conditions such as chronic kidney disease, coronary artery bypass surgery, and leukemia), childbirth, injury, menstruation, and surgery. Unwanted bleeding treated using any of the devices or methods described herein may include internal or external bleeding. Internal bleeding includes the loss of blood from the body's vascular system, such as bleeding into body cavities or spaces. External bleeding includes loss of blood outside the body. In some cases, the methods and apparatus are used to control acute bleeding resulting from trauma (e.g., from traffic accidents and other incidents) and / or from combat.

[0061] Figure 3 A flowchart illustrating an example method for controlling / reducing bleeding in a patient is shown. Patients requiring reduced bleeding (e.g., experiencing acute bleeding or suffering from a bleeding disorder) can be treated by positioning an ultrasound probe on or near the subject's spleen (301). In some cases, a gel, lotion, or other conductive medium is used between the probe and the patient's skin. The ultrasound probe may include a fixation device to maintain the probe's position relative to the spleen. For example, the fixation device may position the probe relative to the spleen at a predetermined angle and / or distance. Positioning the ultrasound probe may include adjusting the angle / distance of the probe such that the spleen is within the focal area / focal length of the ultrasound transducer. In some cases, one or more specific regions of the spleen (e.g., the central portion of the spleen and / or the splenic hilum) are located within the focal area / focal length of the ultrasound transducer.

[0062] Once properly positioned, ultrasound stimulation therapy can be applied to the spleen (303). Treatment parameters may vary depending on the severity and / or type of bleeding (e.g., acute or chronic). In some cases, ultrasound therapy is adjusted until the patient's bleeding is reduced (or estimated to be reduced) by a predetermined amount. For example, bleeding loss / bleeding may be measured after a specific period of treatment to determine if the ultrasound therapy has effectively reduced bleeding loss. Stimulation parameters (e.g., frequency, input voltage, etc.) may be adjusted based on the measurements until the desired bleeding rate is achieved.

[0063] Example

[0064] Figures 4A-4B An experimental apparatus for illustrating the application of ultrasound stimulation to the spleen of rodents to reduce bleeding is shown, serving as an experimental model system for predicting the reduction of bleeding time in individuals with this need through ultrasound application to the spleen. The animals used were adult male 8–12-week-old C57BL / 6J mice (20–25 g, Taconic), housed at 25°C with a 12-hour light / dark cycle. Standard animal feed and water were readily available. All animal experiments were conducted in accordance with National Institutes of Health (NIH) guidelines approved by the Animal Care and Use Committee of the Feinstein Institute for medical research.

[0065] Figure 4AThe setup for ultrasound stimulation applied to the spleen of mice is shown. Animals were anesthetized with ketamine (144 mg / kg, ip) and toluenethiazide (14 mg / kg, ip). The left side of the animal was shaved with animal scissors. After 7 minutes, the animal was placed in a right lateral decubitus position. The spleen was located by palpating the tail border of the thoracic cavity along a line between the ventral surface of the ear and the base of the tail. A spot was drawn on the animal's skin at the intersection of these two lines to aim at the opening of a 1.1 MHz FUS transducer (SonicConcepts, H106). The transducer was tilted 20 degrees to the head to avoid the ribs. Ultrasound gel was applied to the area. The transducer was connected to a 350L RF power amplifier (Electronics & Innovations), and the signal was controlled by a 33120A function / waveform generator (Keysight Technologies). The function / waveform generator parameters were set to provide stimulation according to specified parameters (e.g., frequency, pulse amplitude, duration).

[0066] Figure 4B The setup for applying control ultrasound stimulation to the leg of a mouse serving as a control is shown. The animal receiving control stimulation was anesthetized and placed in a left lateral decubitus position. The lateral region of the right quadriceps muscle was shaved with animal scissors. The transducer was placed on the line between the ventral side of the ear and the base of the tail in the middle of the muscle. The control animal experienced the same conditions as the experimental animal (…). Figure 4A The same stimulus paradigm.

[0067] In the first set of experiments, the waveform generator parameters were set to a 1.1MHz sine wave, 200mVpp, 0 offset, 150 cycles / pulse train, and a 500µs pulse train. The stimulation lasted for 60 seconds, followed by a 30-second rest interval, and then another 60-second stimulation. Experimental animals ( Figure 4A ) and control stimulation animals ( Figure 4B The waveform generator parameters are the same.

[0068] In both experimental and control animals, following focused ultrasound stimulation (FUS), the tail was immersed in water at 37 ± 1 °C for 5 minutes. The tail was then removed from the solution, and a 2 mm section was severed with a razor blade and immediately placed in a 50 mL beaker containing water at 37 °C. Uncontrolled bleeding was allowed until it ceased for at least 10 seconds. The duration of bleeding was recorded as the bleeding time.

[0069] like Figure 5As shown, high-intensity FUS stimulation of the spleen significantly reduced bleeding time in a mouse model of arterial tail injury and hemorrhage compared to control stimulation (quadriceps stimulation) using the same stimulation parameters. Specifically, the bleeding time in animals with spleen stimulation was 56.3 ± 2.7 seconds, while the bleeding time in animals with control stimulation was 105.6 ± 5.1 seconds (n=7-8 / group, p<0.0001). In some cases, the ultrasound stimulator was placed at an angle of approximately 20 degrees to the skin surface under the left thoracic cavity, targeting the head, and the probe was pushed into the skin to a depth of approximately 5-10 mm. Preliminary data from humans suggest that similar targeting may be useful.

[0070] In humans, although spleen size may vary among subjects, it is typically about 3–5.5 inches long (e.g., about 1 inch × 3 inches × 5 inches) and located between the 9th and 11th ribs. The ultrasound stimulation described herein can be configured to apply most of the ultrasound energy to the splenic region within the external capsule, particularly the white pulp region or the nerves innervating the white pulp. In some examples, ultrasound energy may be primarily or specifically targeted at the white pulp. In some examples, ultrasound energy may be targeted at the red pulp (or the nerves innervating the red pulp). In some examples, both the red and white pulp regions may be targeted.

[0071] In some cases, appropriate targeting, such as to the spleen (e.g., the splenic portion innervated by the white pulp), can lead to a significant reduction in bleeding time. In some examples, the red pulp region can be the target. Applying ultrasound energy to areas other than the spleen or insufficiently targeting the white pulp region of the spleen may be less effective or ineffective. Figure 6A The results of the second set of experiments are shown, in which ultrasound stimulation of wild-type C57BL / 6J mice was used to illustrate the localization effect of the ultrasound stimulation probe. In this set of experiments, ultrasound stimulation was applied to mice using the same stimulation parameters (1.1 MHz sine wave, 200 mVpp, 0 offset, 150 cycles / pulse, 500 microsecond (μsec) pulses). The same experimental setup was used to set up the control (quadriceps) stimulation described above. Figure 4B In these experiments, instead of correctly positioning the ultrasound probe at the center of the spleen, the probe was positioned off-center relative to the spleen and splenic hilum (misaligned U / S). As described above, bleeding time was recorded after tail transection. Furthermore, an autopsy was performed to determine the anatomical location of the spleen relative to skin surface markings on the ultrasound probe. These results indicate that failure to adequately target the ultrasound probe (e.g., on the spleen itself, or, for example, targeting the splenic hilum instead) does not adequately reduce bleeding time (control). Figure 6A (Marked as "false") 105.6 seconds, compared to a misaligned U / S of 130.7 seconds, p = 0.26).

[0072] Figure 6BThe results of the third set of experiments are shown, in which ultrasound stimulation of wild-type C57BL / 6J mice was used to illustrate the effect of input voltage on the ultrasound stimulation probe. In this set of experiments, in addition to input voltage, the above reference was used. Figure 4A The same stimulation parameters described (1.1 MHz sine wave, 0 offset, 150 cycles / burst, 500 microsecond (μsec) burst) were applied to mice with ultrasound stimulation. Specifically, an input voltage of 400 mVpp (400 mV) was used instead of 200 mVpp. Bleeding time was recorded after tail transection as described above. The results showed that higher voltage did not more effectively and adequately reduce bleeding time (200 mVpp, at...). Figure 6B (Marked as "false") 173.3 seconds, compared to 158 seconds for 400 mV U / S, p = 0.64). Therefore, the applied ultrasound energy can have a saturation power level (e.g., input voltage), and above this level, there is no further improvement in achieving consistency and significant reduction in bleeding time.

[0073] While most of the embodiments provided herein describe non-invasive (e.g., percutaneous) stimulation, any of these methods and devices can be used to stimulate the spleen during open surgery (e.g., surgical procedures), such as intraoperative stimulation of the spleen. For example, the device can be used during surgery to reduce bleeding during medical procedures. In any of these methods and devices, a physician (e.g., a surgeon) can use ultrasound stimulation of the spleen to alter bleeding after attempting other hemostasis methods (e.g., prior to spleen stimulation). Furthermore, any of these methods or devices may include implanting an ultrasound transducer at or near the spleen to provide ultrasound stimulation of the spleen.

[0074] As mentioned above, this article also describes systems for reducing bleeding time (reducing clotting time, etc.), as above. Figure 1A As shown and described. Any of these systems may include software, hardware, and / or firmware to control the applied power (e.g., voltage, frequency, etc.), dose timing, and / or targeting (identifying the spleen, splenic regions, etc.). The applicator (transducer) may be adapted to deliver a dose to the spleen and / or subregions of the spleen. For example, the applicator may be configured to be positioned between the ribs (between the 9th and 10th or the 10th and 11th) for targeting the spleen, etc. In some examples, the applicator may be adhesively applied to the body for repetitive stimulation. For example, the applicator may be placed on the back of the subject above the spleen for dose delivery.

[0075] Preliminary data suggest that similar results from the aforementioned mouse data are also applicable to human subjects; specifically, direct ultrasound stimulation applied to the spleen resulted in a significant reduction in bleeding time. Ultrasound can be applied from 1 second to 10 minutes, and one or more treatments (e.g., two treatments, three treatments, four treatments, etc.) at intervals from 1 minute to 12 hours (e.g., 1 minute and 8 hours, 1 minute and 4 hours, 1 minute and 2 hours, 1 minute and 1 hour, 10 minutes and 8 hours, 10 minutes and 4 hours, 10 minutes and 2 hours, 30 minutes and 12 hours, 30 minutes and 8 hours, 30 minutes and 4 hours, 1 hour and 12 hours, 1 hour and 8 hours, 1 hour and 4 hours, etc.) can be used to provide a significant reduction in bleeding, for example, reducing the time for hemostasis. This could also reduce the time for clot formation at the bleeding site.

[0076] When a feature or element is referred to herein as “located on another feature or element,” it may be directly on the other feature or element, or there may be intermediate features and / or elements present. Conversely, when a feature or element is referred to as “directly located” on another feature or element, there are no intermediate features or elements. It should also be understood that when a feature or element is referred to as “connected,” “attached,” or “joined” to another feature or element, it may be directly connected, attached, or joined to the other feature or element, or there may be intermediate features or elements present. Conversely, when a feature or element is referred to as “directly connected,” “directly attached,” or “directly joined” to another feature or element, there are no intervening features or elements. Although described or illustrated with regard to one example, features and elements thus described or illustrated may be applied to other examples. Those skilled in the art will also understand that references to structures or features set “adjacent” to another feature may have overlapping or subordinate portions.

[0077] The terminology used herein is for the purpose of describing particular examples only and is not intended to limit the invention. For example, as used herein, the singular forms “a,” “an,” and “the” are also intended to include the plural forms unless the context clearly indicates otherwise. It will also be understood that, when used in this specification, the terms “comprising” and / or “including” specify the presence of the stated features, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups thereof. As used herein, the term “and / or” includes any and all combinations of one or more associated listed items and may be abbreviated to “ / ”.

[0078] Spatially relative terms such as “below,” “under,” “below,” “above,” “above,” etc., may be used herein to describe the relationship of one element or feature to another element or feature as shown in the figure. It should be understood that, in addition to the orientations shown in the figure, spatially relative terms are intended to cover different orientations of the device in use or operation. For example, if the device in the figure is inverted, an element described as “below” or “below” other elements or features would be oriented as “above” other elements or features. Thus, the exemplary term “below” can include both above and below orientations. The device may be oriented in other ways (rotated 90 degrees or otherwise), and the spatially relative descriptive terms used herein are interpreted accordingly. Similarly, the terms “up,” “down,” “vertical,” “horizontal,” etc., are used herein for their intended purpose unless otherwise specifically indicated.

[0079] Although the terms “first” and “second” may be used herein to describe various features / elements (including steps), these features / elements should not be limited by these terms unless the context otherwise requires. These terms are used to distinguish one feature / element from another. Thus, the first feature / element discussed below may be referred to as the second feature / element, and similarly, the second feature / element discussed below may be referred to as the first feature / element, without departing from the teachings of the invention.

[0080] In this specification and the appended claims, unless the context otherwise requires, the word "comprising" and examples such as "including" and "comprising" mean that various components may be used together in a method and article of manufacture (e.g., a composition and apparatus, including devices and methods). For example, the term "comprising" will be understood to imply the inclusion of any of the stated elements or steps, but does not exclude any other elements or steps.

[0081] Generally, any device and method described herein should be understood as inclusive, but all or a subset of components and / or steps may alternatively be exclusive and may be expressed as “consisting of various components, steps, sub-components or sub-steps” or alternatively “consisting substantially of various components, steps, sub-components or sub-steps”.

[0082] As used herein in the specification and claims, including as in the examples, and unless otherwise expressly stated, all figures may be interpreted as if they begin with the words “about” or “approximately,” even if the term is not explicitly stated. When describing values ​​and / or locations, the phrase “about” or “approximately” may be used to indicate that the described value and / or location is within a reasonably expected range of the value and / or location. For example, a numerical value may have a value + / - 0.1% of the value (or range of values), a value + / - 1% of the value (or range of values), a value + / - 2% of the value (or range of values), a value + / - 5% of the value (or range of values), a value + / - 10% of the value (or range of values), etc. Unless the context otherwise requires, any numerical value given herein should also be understood to include approximately or approximate values. For example, if the value “10” is disclosed, “about 10” is also disclosed. Any numerical ranges listed herein are intended to include all subranges contained therein. It should also be understood that when a numerical value is disclosed, as those skilled in the art will understand appropriately, the terms "less than or equal to" the value, "greater than or equal to" the value, and possible ranges between the value are also disclosed. For example, if the value "X" is disclosed, then "less than or equal to X" and "greater than or equal to X" (e.g., where X is a numerical value) are also disclosed. It should also be understood that throughout the application, data is provided in a variety of different formats, and the data represents endpoints and starting points, as well as a range of any combination of data points. For example, if a specific data point "10" and a specific data point "15" are disclosed, then it should be understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15, as well as between 10 and 15, are disclosed. It should also be understood that each unit between two specific units is also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0083] Although various illustrative examples have been described above, any of the many changes that may be made to the various examples without departing from the scope of the invention as described in the claims. For example, in alternative examples, the order in which the various described method steps are performed may often be changed, and in other alternative examples, one or more method steps may be skipped entirely. Optional features of the various device and system examples may be included in some examples but not in others. Therefore, the above description is provided primarily for illustrative purposes and should not be construed as limiting the scope of the invention, which is set forth in the claims.

[0084] The examples and descriptions included herein illustrate, by way of illustration and not limitation, specific examples from which the subject matter may be practiced. As stated above, other examples can be utilized and derived from them, allowing for structural and logical substitutions and changes without departing from the scope of this disclosure. Where more than one invention or inventive concept is actually disclosed, these examples of the subject matter may be referred to herein individually or collectively by the term "invention," merely for convenience and not intended to voluntarily limit the scope of this application to any single invention or inventive concept. Thus, although specific examples are shown and described herein, any arrangement calculated to achieve the same purpose may replace the specific examples shown. This disclosure is intended to cover any and all modifications or examples of the various examples. Combinations of the above examples, as well as other examples not specifically described herein, will be apparent to those skilled in the art upon reading the above description.

Claims

1. A system for reducing bleeding loss in a subject, the system comprising: An ultrasound applicator, comprising a housing and one or more ultrasound transmitters, the housing being configured to apply ultrasound stimulation to the spleen of the subject; as well as A controller connected to the ultrasound applicator is configured to deliver ultrasound stimulation from the one or more ultrasound transmitters at a frequency between 0.25 and 5.0 MHz for a duration of 30 seconds to 5 minutes, wherein the controller is configured to apply an input voltage amplitude of 50 to 350 mVpp to drive ultrasound from the ultrasound applicator to the spleen of the subject, thereby targeting and activating the coagulation pathway and reducing the subject's bleeding time by at least 20%.

2. The system according to claim 1, wherein, The housing is configured to be secured to the subject's abdomen above the subject's spleen.

3. The system according to claim 1, wherein, The ultrasonic applicator includes an array of ultrasonic transmitters.

4. The system according to claim 1, wherein, The ultrasound transmitter is configured to project ultrasound stimuli between 1 cm and 10 cm onto the subject's body.

5. The system according to claim 1, wherein, The ultrasonic applicator includes one or more sensors to detect the interrib gap, thereby allowing the controller to select one or more ultrasonic transmitters of the ultrasonic applicator covering the interrib gap.

6. The system according to claim 5, wherein, The one or more sensors include ultrasonic sensors.

7. The system according to claim 1, wherein, The housing includes a flexible substrate, and the one or more ultrasonic transmitters are fixed on the flexible substrate.

8. The system according to claim 1, wherein, The housing includes an adhesive pad adapted to be applied over the spleen of the subject to the abdomen of the subject.

9. The system according to claim 1, wherein, The ultrasonic applicator is connected to the controller via an electrical conductor.

10. The system according to claim 1, wherein, The controller is encapsulated within the housing of the ultrasonic applicator.

11. The system according to claim 1, wherein, The applicator is a transdermal ultrasonic applicator.

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