Electrical stimulation methods and devices for improved blood management

Abstract

In illustrative embodiments, methods and systems for increasing blood coagulation potential in a subject and / or triggering a higher platelet activation rate in the subject via ear nerve stimulation include contacting the subject's skin with one or more therapeutic electrodes, each electrode is positioned in a respective region of a neural structure of an ear temporal nerve (ATN), a neural structure connected to the ATN, a neural structure of an ear branch (ABVN) of a vagus nerve, or a neural structure connected to the ABVN; one or more stimulation patterns are applied to the electrode.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 447,162, entitled “Electrical Stimulation Methods and Devices for Improving Blood Management,” filed on February 21, 2023; U.S. Provisional Patent Application No. 63 / 535,996, entitled “Electrical Stimulation Methods and Devices for Improving Blood Management,” filed on August 31, 2023; and U.S. Patent Application No. 18 / 583,160, entitled “Electrical Stimulation Methods and Devices for Improving Blood Management,” filed on February 21, 2024. This application is related to the following prior patent applications of Spark Biomedical, Inc. relating to stimulation therapies and stimulation devices: U.S. Patent No. 10,967,182, entitled “Devices and Methods for Reducing Inflammation Using Electrical Stimulation” and issued on April 6, 2021, and U.S. Patent No. 11,351,370, entitled “Devices and Methods for Treating Cognitive Dysfunction and Depression Using Electrical Stimulation” and issued on June 7, 2022. Background Art

[0003] Improper blood management can be life-threatening. Following an injury, blood loss must be minimized.

[0004] Nearly 20 years ago, the inventors of U.S. Patent No. 8,729,129 (including Christopher Czura, the inventor of the present application) proposed vagus nerve stimulation as a potential solution for inducing shorter bleeding times and lower bleeding volumes in humans. The inventors published data from experiments using an implantable vagus nerve stimulator in mice. Interestingly, while they were able to show a reduction in bleeding, they were unable to show a significant change in prothrombin time (PT) (see, e.g., U.S. Patent No. 8,729,129). Figure 5 ). PT assesses the time required for platelets to clot. That is, it is not possible to show an increase in coagulation activity / clotting rate or what is known as coagulation potential (CPot - as used herein, means the potential to accelerate coagulation; specifically at the site of injury). In 2017, inventors including the same individuals named in U.S. Patent No. 8,729,129 proposed a non-invasive method using mechanical stimulation in an application ultimately granted as U.S. Patent No. 10,912,712, allegedly achieving similar results. However, as with the previous patents, the only data related to bleeding regulation presented in U.S. Patent No. 10,912,712 were obtained in rodents using implantable electrical stimulation. Also in 2019, inventors including the two same individuals named in U.S. Patent No. 8,729,129 proposed using invasive and non-invasive trigeminal nerve stimulation to achieve bleeding control in another application recently granted as U.S. Patent No. 11,660,443. As with the earlier patents listed above, only data collected from rodent experiments using subcutaneous electrodes were presented. A few months later, a patent application assigned to the same institution but naming different inventors proposed the combined use of trigeminal and vagus nerve stimulation to control bleeding, resulting in U.S. Patent No. 11,260,229. In contrast to the earlier application, no data were presented in this final application.

[0005] Furthermore, despite a long-standing need in the medical community for bleeding control and publications on the use of neurostimulation to control bleeding, not only have no commercial solutions emerged, but, to the best of the inventors' knowledge, prior to the data presented in this application, no human subject data demonstrating significant bleeding control results have been published. Instead, to the best of the inventors' knowledge, only small animal studies exist to date, and these studies involve major neck surgery involving access to the vagus nerve and stimulation of the vagus nerve using implantable electrodes in direct contact with the nerve. Due to the invasive nature of these studies, they are not easily replicated in human subjects.

[0006] In every case of bleeding or potential bleeding, blood loss must be minimized; furthermore, when the amount of bleeding is sufficient to cause hypovolemia, tissue perfusion and oxygenation, particularly of the brain, must be enhanced to prevent permanent damage and possible death. Furthermore, some bleeding, whether or not it results in hypovolemia, can lead to sepsis. For example, some treatments for postpartum hemorrhage and patients with intracerebral hemorrhage are at increased risk for sepsis. Both hypovolemia and sepsis lead to high levels of systemic inflammation, with proinflammatory cytokines released into the circulation. In the case of sepsis, not only are tissue perfusion and oxygenation important, but it is also necessary to reduce inflammation and circulating proinflammatory cytokines to avoid further complications and organ damage or failure. Furthermore, sepsis may actually lead to hypovolemia. That being said, the primary cause of sepsis is not bleeding, but infection. Sepsis is an extremely costly and resource-intensive condition; for example, in the UK, it is estimated that patients with sepsis account for approximately one-third of hospital stays and slightly less than half (approximately 45%) of intensive care unit (ICU) stays. Sepsis is the most expensive disease in the United States, costing an average of more than $18,000 per hospital stay and $24 billion annually. Sepsis accounts for 13% of all U.S. hospital expenditures, despite only accounting for approximately 3.5% of hospital stays.

[0007] The inventors have recognized a need for new systems and methods that are designed to reduce blood loss following injury while increasing oxygenation and / or perfusion of brain tissue when blood loss is substantial and / or blood flow is significantly compromised. Furthermore, the inventors have recognized a need to achieve lower systemic inflammation during periods of mitigation of blood loss and during episodes of sepsis. Furthermore, the inventors have recognized a need to preventively reduce the likelihood of bleeding before any bleeding occurs by increasing an individual's coagulation potential. Advantageously, the new systems and methods can be readily and rapidly applied in a non-invasive manner in the home, clinical, and / or field settings. Summary of the Invention

[0008] Some use the term hypovolemia to describe a decrease in both systemic and vascular fluid volume. In this description, hypovolemia is used to describe the latter condition. Furthermore, hypovolemia is categorized by severity; however, in this document, hypovolemia is used to describe a significant loss of blood volume that results in compromised tissue oxygenation and perfusion, potentially leading to organ dysfunction or failure.

[0009] Sepsis can be described as an immune overreaction leading to the release of proinflammatory cytokines and systemic inflammation. Like hypovolemia, sepsis is categorized by severity. If left untreated, sepsis often increases in severity and can lead to organ dysfunction or failure. Interestingly, as explained later, modulating splenic activity can reduce sepsis and more rapidly achieve hemostasis.

[0010] In one aspect, the present disclosure relates to systems and methods for increasing the coagulation potential (CPot) of mammals, including humans.

[0011] In certain embodiments, the instantaneous increase in coagulation potential is produced by triggering spleen activity to treat acute conditions. For example, spleen activity can be triggered by activating the splenic nerve via stimulating the descending vagus nerve or vagus efferent nerve fibers (VEF). The splenic nerve and / or directly, the spleen can also be stimulated in a non-invasive manner using ultrasound (e.g., focused or confocal ultrasound / high intensity ultrasound). In some instances, acute conditions may include injuries that may cause a large amount of blood loss, surgical or other medical procedures including the possibility of significant bleeding, medical procedures that may bleed during the recovery phase, and / or temporary systemic conditions, such as nosebleeds, abnormal uterine bleeding and / or heavy menstrual bleeding, including menorrhagia.

[0012] In some embodiments, the systems and methods described herein for direct and / or indirect stimulation of the spleen (e.g., via the VEF, splenic nerve and / or splenic ganglion) are used in a preventative / prophylactic manner. By way of example, stimulation can be performed prior to an anticipated event, such as prior to a menstrual cycle, or prior to a surgical procedure, such as during the time period preceding the event and during the event itself as well as after the event, to prevent or minimize future bleeding. For example, stimulation can be provided before and / or during a surgical procedure to partially offset the effects of an anticoagulant medication in the patient's body. In this way, stimulation can provide the benefit of accelerated approval time for patients who have been taking anticoagulant medications (e.g., to treat blood clots) who need surgery.

[0013] In some embodiments, the systems and methods described herein for direct and / or indirect stimulation of the spleen (e.g., via the VEF, splenic nerve, and / or splenic ganglion) are used in a calibrated / therapeutic manner. For example, stimulation can provide protection for patients undergoing emergency surgery who do not have the opportunity to deactivate anticoagulant medications from their systems. In another example, stimulation can be performed after surgery to accelerate coagulation and thereby shorten postoperative recovery time, such as the time it takes for a wound (e.g., a surgical access site) to close. In some cases, the surgical team may use a combination of hemostatic methods, for example, by applying VEF stimulation in conjunction with another available hemostatic agent. In some cases, non-invasive VEF stimulation can be used to identify people who respond to therapy (responders) by showing an increase in Cpot prior to using invasive methods (e.g., implanting electrodes to stimulate the vagus nerve and / or splenic nerve).

[0014] In certain embodiments where a transient increase in coagulation potential is desired in therapeutic settings, such as post-bleeding applications or pre-surgical scenarios, direct and / or indirect stimulation of the spleen is initiated as quickly as possible and continued as needed to accelerate the ongoing coagulation process and thereby limit blood loss. In such cases, stimulation may be continued until bleeding stops. After bleeding stops, stimulation may be continued, such as in the prophylactic scenario described above, to prevent further bleeding. After stimulation is stopped, coagulation potential gradually returns to pre-stimulation levels.

[0015] In some embodiments, direct and / or indirect spleen stimulation (e.g., via the VEF, splenic nerve, and / or splenic ganglion) is performed to achieve a sustained increase in coagulation potential to treat chronic conditions, such as those described above. Additionally, in some embodiments, spleen stimulation is performed to achieve a sustained increase in coagulation potential in the setting of chronic coagulation deficiencies such as those found in humans with hemophilia (e.g., hemophilia A, hemophilia B, or hemophilia C), von Willebrand Disease (vWD), and other coagulation factor-related deficiencies (e.g., factor I deficiency, factor II deficiency, factor V deficiency, factor VII deficiency, factor X deficiency, factor XII deficiency, or factor XIII deficiency) and / or other chronic conditions such as Bernard-Soulier syndrome and Glanzmann thrombasthenia.

[0016] In some embodiments involving chronic coagulation defects, non-invasive indirect and / or direct stimulation of the spleen can be applied by a clinician while exploring the feasibility of an implantable solution. For example, stimulation can be performed in a clinical setting to test whether a patient responds to stimulation therapy. If the feasibility study is successful, the patient can choose to receive an implantable device rather than relying on external stimulation therapy as described herein. The feasibility study can involve multiple stimulation therapy phases. Multiple therapy phases can include multiple electrode placements, multiple stimulation modes, multiple stimulation intensities, and / or multiple stimulation phase durations to evaluate the patient's response to VEF stimulation.

[0017] In some embodiments, spleen stimulation is applied (e.g., directly and / or indirectly) to achieve a transient anti-inflammatory response, for example, in a preventative / prophylactic or corrected / therapeutic manner. In preventative / prophylactic applications, for example, VEF, splenic ganglion, celiac ganglion and / or spleen stimulation can be applied before a predetermined event in which a pro-inflammatory response is expected, such as before a scheduled surgical procedure or unrelated sporting activity, such as when a baseball pitcher may expect an inflammatory response after pitching. In corrected / therapeutic applications, for example, when an inflammatory response has already begun, such as in the case of trauma, infection, or sepsis or potential sepsis, VEF, splenic ganglion, celiac ganglion and / or spleen stimulation can be applied as quickly as possible and continued as needed to trigger, maintain and / or accelerate an anti-inflammatory response. In these types of situations, stimulation can be applied continuously until the desired response is obtained, and then, as in the preventative scenario described above, to prevent further inflammation.

[0018] On the one hand, by stimulating the trigeminal nerve branches, the present disclosure relates to triggering an increase in cerebral blood flow by increasing blood pressure and / or by increasing vascular patency; referred to herein as a pressor response. For example, in the event of massive blood loss or the potential for massive blood loss, a pressor response may be triggered to instantaneously treat or prevent hypovolemic injury to tissue (including brain tissue). By way of example, in the event of penetrating and / or non-compressible injuries (e.g., bullet or knife wounds, extensive cuts, or in the event of internal bleeding such as gastrointestinal bleeding), triggering a pressor response may be beneficial. For example, the stimulation may be applied as quickly as possible and continued as needed to trigger, maintain, and / or accelerate the desired response.

[0019] In one aspect, the present disclosure relates to triggering a trigeminal parasympathetic response (TPSr) by stimulating the Arnold's nerve (also known as the auricular branch of the vagus nerve - ABVN) and / or the auriculotemporal nerve (ATN). In another aspect, the present disclosure relates to triggering an increase in CPot by modulating VEF activity by stimulating the Arnold's nerve and / or the ATN. In some embodiments, both the TPSr and the increase in CPot are triggered. For example, in situations where there is a large amount of blood loss or the potential for large amounts of blood loss, the triggered increase in TPSr and / or CPot can be used to transiently treat or prevent hypovolemic tissue damage to various organs, including the brain. By way of example, in situations involving penetrating and / or non-compressible injuries (e.g., bullet or knife wounds or internal bleeding), triggering an increase in TPSr and / or CPot may be beneficial. For example, the stimulation can be applied as quickly as possible and continued as needed to trigger, maintain and / or accelerate the desired response.

[0020] The foregoing general description of the illustrative embodiments and the following detailed description thereof are merely exemplary aspects of the teachings of the present disclosure and are not limiting. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate one or more embodiments and, together with the description, explain these embodiments. The drawings are not necessarily drawn to scale. Any values ​​or dimensions described in the accompanying figures and drawings are for illustrative purposes only and may or may not represent actual or preferred values ​​or dimensions. Where applicable, some or all features may not be described to help describe the underlying features. In the drawings:

[0022] Figure 1 is a block diagram of an example anti-inflammatory pathway;

[0023] Figure 2A is a block diagram of an example pressure response and cerebral perfusion pathway;

[0024] Figure 2B is a block diagram of an example trigeminal parasympathetic response and cerebral perfusion pathway;

[0025] Figure 3A is a block diagram of an example platelet calcium accumulation pathway;

[0026] Figure 3B is a block diagram of an example platelet excitation pathway;

[0027] Figure 4 is a block diagram of an example hemostatic pathway;

[0028] Figure 5 It is a block diagram for identifying neural structures and pathways;

[0029] Figure 6A and Figure 6B is a schematic diagram representing an electrode configuration and equivalent circuit for providing therapy according to a first example;

[0030] Figure 6C and Figure 6D is a schematic diagram representing an electrode configuration and equivalent circuit for providing therapy according to a second example;

[0031] Figure 6E and Figure 6F is a schematic diagram representing an electrode configuration and equivalent circuit for providing therapy according to a third example;

[0032] Figure 7A and Figure 7B A timing diagram illustrating an example process for triggering stimulation;

[0033] Figures 8A to 8E is a graph showing the results of stimulating humans according to an embodiment of the present disclosure;

[0034] Figure 9is a block diagram of components of an example pulse generator in communication with an example auris therapy device;

[0035] 10A to 10D 、 Figure 11 and Figure 12 Example target neural regions for guided therapy using a wearable auricular neurostimulator (WANS) device are illustrated;

[0036] Figure 13 An example system including a therapeutic device, a sensor, and sensor signal conditioning and / or analysis circuitry is described; and

[0037] Figure 14 is a block diagram of an example sensor data analysis system for delivering neural stimulation therapy customized to a wearer. DETAILED DESCRIPTION

[0038] The following description, set forth in conjunction with the accompanying drawings, is intended to describe various illustrative embodiments of the disclosed subject matter. Specific features and functions are described in conjunction with each illustrative embodiment; however, it will be apparent to those skilled in the art that the disclosed embodiments can be implemented without each of these specific features and functions.

[0039] Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosed subject matter. Thus, the appearance of the phrase "in one embodiment" or "in an embodiment" throughout this specification does not necessarily refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, it is intended that the various embodiments of the disclosed subject matter cover modifications and variations thereof.

[0040] It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. That is, as used herein, the words "a," "an," and "the" have the meaning of "one or more," unless expressly provided otherwise. Additionally, it should be understood that terms such as "left," "right," "top," "bottom," "front," "back," "side," "height," "length," "width," "up," "down," "interior," "exterior," "inner," and "outer" as used herein merely describe reference points and do not necessarily limit embodiments of the present disclosure to any particular orientation or configuration. Furthermore, terms such as "first," "second," and "third" merely identify one of many parts, components, steps, operations, functions, and / or reference points as disclosed herein, and likewise do not necessarily limit embodiments of the present disclosure to any particular configuration or orientation.

[0041] Furthermore, the terms “approximately,” “about,” “close to,” “substantially,” and similar terms generally refer to a range including a certain value within a margin of 20%, 10%, or, in certain embodiments, preferably 5%, and any values ​​therebetween.

[0042] All functionality described in conjunction with one embodiment is intended to be applicable to the additional embodiments described below, unless expressly stated otherwise or the feature or functionality is incompatible with the additional embodiment. For example, where a given feature or functionality is expressly described in conjunction with one embodiment but not expressly mentioned in conjunction with the additional embodiment, it should be understood that the inventors intend that the feature or functionality may be deployed, utilized, or implemented in conjunction with the additional embodiment, unless the feature or functionality is incompatible with the additional embodiment.

[0043] Although hypovolemia has been used to describe a decrease in both systemic and vascular fluid volume, in this disclosure, the term hypovolemia refers to the latter definition. Typically, hypovolemia is classified according to severity; however, in this disclosure, hypovolemia applies to conditions involving a significant loss of blood volume that can have effects on tissue oxygenation and / or perfusion that may lead to organ dysfunction or failure.

[0044] Sepsis can be described as an immune overreaction leading to the release of proinflammatory cytokines and systemic inflammation. Like hypovolemia, sepsis is categorized by severity. If left untreated, sepsis often increases in severity and can lead to organ dysfunction or failure, and in some cases, death. As explained later, modulating spleen activity can reduce sepsis and more rapidly achieve hemostasis.

[0045] Stop bleeding

[0046] Hemostasis is the process of stopping bleeding, which is usually triggered by molecules exposed to circulating blood at the site of vascular injury. Subendothelial collagen (SEndC) and tissue factor (TF, also known as coagulation factor 3 or fIII) are examples of such molecules. When circulating platelets (i.e., thrombocytes) are combined with exposed SEndC, TF is combined with a specific circulating molecule called coagulation factor 7 (fVII). The interaction between TF and fVII causes the activation of fVII (fVIIa) and forms TF-fVIIa complexes, which are called exogenous factor X enzymes (i.e., exogenous Xase). This TF-fVIIa complex starts the so-called coagulation cascade (see below) by activating coagulation factor 10 (fX) and coagulation factor 9 (fIX) to fXa and fIXa respectively. The platelets directly or indirectly adhere to SEndC begin to aggregate and form initial plugs to stop bleeding. This plug is referred to as platelet plug or thrombus. The platelet plug is then strengthened by adhesion and cross-linking of fibrin. The process that causes platelet plug formation is commonly referred to as primary hemostasis, and the process that causes platelet plug enhancement by cross-linked fibrin (i.e. activated coagulation factor 1 or fIa) is called secondary hemostasis. Platelets are the anucleated blood cells that are mainly produced in the bone marrow of megakaryocytes. Under normal circumstances, about 100 billion platelets are produced every day, and the scope of the concentration in the blood produced is 150,000,000 to 400,000,000 per milliliter. Platelets enter the vascular system loop, and circulate about 7 to 10 days in the mankind before being discharged by the liver and spleen. Interestingly, when platelets circulate, about 1 / 3rd of all circulating platelets of platelets at any given time are located in the spleen wherein and assemble. In the mankind, the time that platelets are by spleen is about 30 minutes.

[0047] Platelets contain, among other things, mitochondria and two types of granules, alpha granules (αG) and dense or delta granules (δG). Ionized calcium (Ca 2+ Coagulation factor 4 (also known as factor IV or fIV) is a key component of blood coagulation and is stored in platelets at least within the mitochondria, the dense tubular system (DTS), and delta granules. Platelets circulate in the blood in an inactivated state and therefore do not aggregate; however, after injury, platelets become activated when they bind to exposed SEndC.

[0048] Platelets bind to SEndC directly via GP VI or GP Ia / IIa receptors or indirectly via GP Ib-V-IX receptors via von Willebrand factor (vWF). Activated platelets undergo a shape change and secrete the contents of their granules through their membranes. The contents of α granules include, among other components, fibrinogen (also known as coagulation factor 1 or fI), platelet-derived growth factor (PDGF), vWF, TGFβ, coagulation factor 5 (fV), platelet factor 4 (Pf4), and insulin-like growth factor 1 (IGF1). δ granules (δG) contain, among other components, Ca 2+ , ADP, ATP and serotonin (5-HT). Activated platelets promote changes in membrane receptors GP IIb / IIIa (also known as integrin α IIb β 3), allowing these receptors to bind to vWF and fibrinogen. In addition, thromboxane A2 (TxA2) is secreted by activated platelets. TxA2 and ADP activate circulating platelets, which begin to aggregate with other activated platelets via GP IIb / IIIa-vWF-GP IIb / IIIa and GP IIb / IIIa-fibrinogen-GP IIb / IIIa bridges. This aggregation causes platelets to accumulate at the site of injury, thereby producing the above-mentioned platelet plug. Although this platelet plug is very weak, it is the first step to limit and ultimately prevent blood from leaving the vascular system. Clot retraction is largely affected by the presence of GP IIb / IIIa receptors on the platelet surface. Clot retraction helps wound healing by bringing the separation edges of the wound closer and closer until the wound heals. Thus, by promoting changes in the GP IIb / IIIa receptor, subjects receiving therapy as described herein will enjoy the additional benefit of accelerated healing time.

[0049] As also mentioned previously, the plug is then reinforced by fibrin fibers, and the plug is further enhanced by cross-linking the plug by activating coagulation factor 13 (fXIIIa). Fibrin is produced when the fibrinogen circulating and secreted by platelets is converted into fibrin by thrombin (i.e., activated coagulation factor 2 or fIIa). In turn, thrombin is produced by cutting from circulating prothrombin (also known as coagulation factor 2-fII). Thrombin can be produced from a relatively small amount of prothrombin by fXa bound to the platelet surface. Thrombin can not only convert fibrinogen into fibrin, but also activate other platelets, and convert fV, coagulation factor VIII (fVIII), coagulation factor XI (fXI) and coagulation factor 13 (fXIII) into its activated form (respectively fVa, fVIIIa, fXIa, fXIIIa). fVa is converted to its activated form by Ca 2+The dependent mode combines with fXa on the platelet surface to form prothrombinase (fXa-fVa complex). The prothrombinase complex can convert a large amount of prothrombin into thrombin. In fact, the speed at which the prothrombinase complex cuts thrombin from prothrombin is hundreds of thousands of times (for example, about 250,000 times) faster than using fXa alone. Therefore, the presence of prothrombinase on the platelet surface greatly accelerates the coagulation process.

[0050] As previously mentioned, fX can be activated by exogenous factor X enzyme to fXa;However, fX can also be activated by endogenous factor X enzyme consisting of fVIIIa and fIXa.In order to assemble endogenous factor X enzyme, it is necessary to activate both fVIII and fIX.Thrombin can activate fVIII, and exogenous factor X enzyme and fXIa can activate fIX.

[0051] The pathway in which fXa is activated by exogenous factor X enzyme is generally referred to as the extrinsic pathway, and the pathway in which fXa is activated by endogenous factor X enzyme is referred to as the intrinsic pathway. The steps of coagulation after fXa activation until fibrin is cross-linked by fXIIIa are referred to as the common pathway. Figure 4 As can be appreciated, the figures depict the hemostasis pathway 400, and the action of thrombin is crucial for hemostasis to occur.

[0052] Note the significant quantitative difference between the intrinsic pathway 402 and the extrinsic pathway 404. Under normal circumstances, thrombin 406 is generated 50 to 100 times faster via the intrinsic pathway 402 compared to the extrinsic pathway 404. Therefore, it is reasonable to say that under normal circumstances, the extrinsic pathway 404 initiates the hemostatic process, but it is the intrinsic pathway 402 that gets it to the finish line.

[0053] Platelets are not uniform; they exhibit distinct differences that become apparent upon platelet activation during hemostasis. One of the most important differences between platelet subsets is that some activated platelets become procoagulants (although this is controversial, some refer to these as procoagulant collagen and thrombin-activated, or COAT, platelets), while others activate into non-coagulant platelets (aggregative platelets). While most thrombin 406 is produced by procoagulant platelets, non-coagulant platelets are more likely to aggregate; therefore, both types are necessary for normal clotting. Although there is considerable variability between subjects, on average, only 30% of activated platelets become procoagulant platelets.

[0054] In many or possibly all cases, procoagulant platelets swell, and because phosphatidylserine (PS) is exposed to its membrane surface, its phospholipid membrane becomes more negative. Platelet membrane becomes more negative so that the binding affinity of prothrombinase to the platelet membrane is significantly increased; Therefore, the possibility of prothrombinase being combined with procoagulant platelets (pCP) is much greater than the possibility of being combined with non-coagulation platelets (nCP). Since, as mentioned above, prothrombinase 408 can produce thrombin 406 faster than fXa alone by 250,000 times (250,000 times), it is obvious that most of the thrombin 406 at or near the site of injury will be produced on pCP.

[0055] Given the hemostatic processes described above, it is clear that even a small increase in the pCP / nCP ratio can increase the rate of thrombin generation at or near the site of injury, thereby accelerating platelet and fXIII activation and fibrin production. Thus, in addition to causing faster platelet aggregation, increased thrombin generation also leads to an increase in the rate of fibrin binding and cross-linking 410, which together contribute to shorter bleeding times and lower bleeding volumes.

[0056] In addition, the generation of faster / higher thrombin 406 at the injury site can compensate for the defects and restrictions (for example, bleeding / coagulation disorder) in the hemostatic process, as the endogenous factor X enzyme 412 caused by lacking or being lower than normal (including complete lack) fVIII, fIX or fXI produces lower or lacks, which occurs in hemophilia A, hemophilia B and hemophilia C respectively. Interestingly, studies have shown that the pCP level of the individual with hemophilia is significantly lower than that of healthy individuals. As previously mentioned, vWF promotes platelet adhesion to endothelial tissue at the injury site, and supports platelet-with-platelet adhesion after platelet activation at or near the injury site. In addition, vWF is as the carrier of fVIII in blood plasma in the form of vWF-fVIII complex. Therefore, the amount of less circulation / available fVIII is also observed in vWD 2N type. In some embodiments, the present invention provides the method for the generation of thrombin 406 of the present invention.Because the generation of thrombin 406 faster / higher causes higher platelet activation rate, and thereby causes higher fibrinogen release rate, therefore can be by the generation of thrombin 406 faster / higher near the injury site to compensate for the defect in the hemostatic process and / or another situation of restriction be when because counting is lower or lack available or fully functional vWF, as in vWD 1 type, 2A type, 2M type and 3 type, when platelet adhesion and aggregation are lower.Wherein higher / faster thrombin generation can compensate for another example of existing hemostatic defect and be in the case of vWD 2B type, it causes platelet adhesion / aggregation both lower and platelet count is lower.By compensation, do not show that hemostatic process will return to the level (for example, not having defect and restriction) expected in normal subjects under any circumstances.On the contrary, the term compensation is used to refer to the hemostatic process obviously faster than the hemostatic process that occurs due to defect and restriction when there is no thrombin of additional amount.A kind of mode that this compensation can occur is by the ratio of procoagulant / anticoagulant activity at or near the injury site.

[0057] Platelets must be strongly activated to be activated into procoagulant platelets (pCP); However, this is not enough. Experiments using dual agonists (e.g., collagen and thrombin) have shown that a small proportion of platelets are activated into procoagulant types. Some people believe that the COAT acronym is inaccurate because the activation performed by both collagen and thrombin is not only insufficient to significantly promote platelet activation into procoagulant types, but is also not unique. In the sense that very high concentrations of thrombin can also activate platelets into procoagulant types, this is not unique. Several factors have been identified as factors that determine whether platelets become procoagulant after activation. Some of these elements include platelet age, size, mitochondrial number, granule number and content, and baseline Ca 2+Interestingly, under similar circumstances, younger platelets are more likely to be procoagulants than older platelets (as mentioned earlier, in humans, platelets circulate for approximately 7 to 10 days before being excreted by the liver and / or spleen).

[0058] Recent data from Abbasian and colleagues suggest that cytosolic Ca 2+ Concentration ([Ca 2+ ] cyt ) is [Ca 2+ ] cyt At least 50 times (>100nM compared to 1-2nM). See Abbasian, Nima et al. "Supramaximal calcium signaling triggers procoagulant platelet formation". Blood Advances 4.1 (2020): 154-164. 2+ If treated with [Ca], most platelets can be activated into pCP; however, in general, if stimulated with some platelet activators, most platelets will be activated into nPC. 2+ ] cyt It is one of the factors, if not the most important factor, in determining whether platelet activation is pCP or nCP.

[0059] Platelets have several transmembrane Ca 2+ channels that allow Ca 2+ Exchange between the extracellular and intracellular spaces (see table below). More than one of these channels or a combination of them can be activated to allow a net positive Ca 2+ Influx, thereby increasing Ca in platelets 2+ In platelets, this Ca 2+ Typically taken to internal storage by one or more mechanisms, including mitochondria, dense tubular system (DTS), lysosomes, and deltaG. High [Ca 2+ ] cyt Ca may cause platelet activation, which, if occurring outside the site of injury, may lead to undesirable thrombotic events. 2+ Sequestered into internal (e.g., intracellular) stores so that they are released into the cytoplasmic space only upon damage-related activation. This can be achieved in different ways; for example, by activating transmembrane Ca 2+ channels and temporarily or transiently blocks or partially blocks the Ca 2+ The mechanism of release from internal stores into the cytoplasmic space to induce Ca2+ Influx into platelets. Baseline Ca 2+ (e.g., total intracellular preactivated Ca not in the cytoplasmic space 2+ ) can increase the activation of higher [Ca 2+ ] cyt The possibility of platelet activation is thus increased as the overall probability of pCP, thereby producing higher coagulation potential. In the case of injury, on an individual basis, higher coagulation potential is converted into higher thrombin generation at the injury site. Higher than other thrombin generation at the injury site is converted into faster and local platelet activation and fibrin adhesion and cross-linked to the thrombus. Therefore, higher coagulation potential can cause faster coagulation process, thereby causing lower hemorrhage and shorter bleeding time.

[0060] Table 1: Platelet transmembrane calcium channels

[0061] As shown by Schedel and colleagues, platelets express α7-nicotinic acetylcholine receptors (nAChRα7). See Schedel, Angelika et al. "Human platelets express functional α7-nicotinic acetylcholine receptors". Arteriosclerosis, thrombosis, and vascular biology 31.4 (2011): 928-934. Since the autonomic nervous system (ANS) can control the release of acetylcholine (ACh), and since nAChRα7 is a transmembrane Ca 2+ channel, so the presence of nAChRα7 on the platelet membrane indicates that platelet Ca 2+ Flow can be regulated by the ANS. In addition, since Bennett et al. showed that ACh inhibits platelet activation, ACh can be used to increase Ca via nAChRα7. 2+ , while preventing platelet activation. See Bennett JA, Ture SK, Schmidt RA, Mastrangelo MA, Cameron SJ, Terry LE, Yule DI, Morrell CN, Lowenstein CJ. Acetylcholine Inhibits Platelet Activation. J Pharmacol Exp Ther. 2019 May; 369(2): 182-187. For example, Figure 1 As described in , platelets 124a circulating in the spleen 116 can be enriched by activating VEF to produce Ca 2+ The platelets 124b are enriched, thereby triggering cells in the celiac ganglion 112. In another example, the splenic ganglion and / or spleen 116 can be directly and / or indirectly stimulated to enrich platelets 124a circulating in the spleen 116 to produce Ca 2+ Enriched platelets 124b.

[0062] For simplicity, reference is made to a single ganglion, however, the left and right celiac ganglia are both connected and therefore activity in one ganglion affects activity in the other, therefore, although activity in one ganglion is most often referenced in this document, it should be understood that any reference to a ganglion encompasses reference to both the right and left ganglia (when present).

[0063] Interestingly, sympathetic and parasympathetic fibers interact at the celiac ganglion, where both can influence the activity of postganglionic sympathetic fibers that weaken the spleen. Specifically, sympathetic preganglionic efferent fibers (SPgF), typically from the T5-T9 spinal cord levels, leave the spine as spinal roots, become the great splanchnic nerves, and synapse onto postganglionic neurons at the celiac ganglion. The SPgF releases ACh when it synapses on its target at the celiac ganglion. The fibers that leave the celiac ganglion form the so-called celiac plexus, whose fibers continue as the splenic plexus. The splenic nerves originate from fibers in the splenic plexus, weakening the spleen. Among other things, the activity of the SPgF is regulated by activity in the RVLM, which in turn is regulated by activity in both the TCC and LC. It is worth noting that the ABVN is also connected to the trigeminal region, specifically the spinal nucleus of the trigeminal nerve, which for the purposes of this document is considered to be part of the TCC. Thus, activation of SPgf via activity in TCCs and / or LCs and / or activation of VEF, among others, may regulate Ca via a common pathway following their interaction at the celiac ganglion. 2+ Platelet-rich production.

[0064] Go to Figure 3A , which illustrates the platelet Ca 2+Block diagram of the enrichment pathway 300. Acetylcholine (ACh) 302 is a natural agonist of nAChRα7 and is an important neurotransmitter that regulates many aspects of the ANS. Increasing the activity of the parasympathetic branch of the ANS (e.g., the parasympathetic nervous system - PNS), for example by activating VEF 304, can trigger the release of ACh 302 in the celiac ganglion 112 and / or in the splenic ganglion 306. The same is true when increasing the activity of the splanchnic nerves 320 synapses on the celiac ganglion 112, as this also releases ACh 302. The innervation of the spleen 116 is via neural connections between the splenic ganglion 306 and its targets in the spleen 116, where norepinephrine (NE) 308 is released. Interestingly, Rosas-Ballina showed that NE 308 released in the spleen 116 activates T cells 312, which in turn release ACh 302. See Rosas-Ballina et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011 Oct 7;334(6052):98-101. doi:10.1126 / Science.1209985. Epub 2011 Sep 15. PMID:21921156; PMCID:PMC4548937. This ACh 302 can trigger Ca 2+ upon reaching nAChRα7 on platelets 314 that are slowly circulating in the spleen 116. 2+ 316 flows into the platelets 314, effectively increasing their baseline Ca 2+ 316 and produces calcium-rich platelets 318, which may also be referred to herein as stimulated platelets. This detailed description refers to the celiac ganglion and the splenic ganglion 306; however, the splenic ganglion 306 is sometimes considered an extension of the celiac ganglion 112. In addition, it is understood that many ganglia form what are known as plexuses (e.g., plexus 306). Therefore, for the purposes of this description, plexus and ganglion are interchangeable.

[0065] Go to Figure 3B In some embodiments, platelets are stimulated via activation of the platelet stimulation pathway 330, which stimulates activity in the spleen 310. Specifically, the ABVN 102 and / or the ATN 104 may be stimulated, which have projections to the NTS 108. As shown, the TCC 106 receives afferent connections from the ATN 104 and projects to the NTS 108 and the RVLM 342, while the ABVN 102 projects directly to the NTS 108.

[0066] like Figure 3B As shown in , certain platelet stimulation pathways also involve other nuclei or regions, such as the locus coeruleus (LC) 332, the periaqueductal gray (PAG) 334, and the nucleus raphe magnus (NRM) 322. Each of these nuclei or regions, in turn, feeds the nucleus ambiguus (NA) 338, which provides a pathway to the vagus nerve 110. Other regions that also feed the vagus nerve 110 are the dorsal motor nucleus of the vagus (DMV) (not shown) and the spinal trigeminal nucleus (herein considered part of the TCC 106). Indirect stimulation of the vagus nerve 110 via various pathways enables the vagus nerve 110 to desensitize the celiac ganglion 112 and / or the splenic plexus 348. The splenic nerve 350 originates from fibers in the splenic plexus 348, desensitizing the spleen 310, thereby increasing platelet stimulation in the spleen 310, causing more unstimulated platelets 340a to be converted into stimulated platelets 340b. For example, stimulation with low-medium range pulses at low frequency on the Arnold nerve and / or low-medium range pulses at high frequency on the ATN for short durations may result in a significant increase in excited platelets, as assessed, for example, by a reduction in PT.

[0067] exist Figure 3B In another pathway shown in FIG, the LC 332 and TCC 106 each provide a pathway to the RVLM 342, which provides a pathway for indirect stimulation of sympathetic preganglionic efferent fibers (SPgF) 344, which exit the spine via the dorsal root ganglia (DRG) 346 at the T5-T9 level to form the greater splanchnic nerve 320, thereby causing stimulation of the postganglionic nerve at the celiac ganglion 112, further triggering activity of the splanchnic nerve 320. Because the splanchnic nerve 320 feeds the celiac ganglion 112, as described above with respect to the vagus nerve-related pathways, indirect stimulation of the SPgF 344 via the various pathways shown and described increases platelet stimulation in the spleen 310, converting more unstimulated platelets 340a to stimulated platelets 340b. As with the pathway via the vagus nerve 110, stimulation using low- to medium-range pulses at a low frequency on the Arnold nerve and / or high-frequency low- to medium-range pulses on the ATN for short durations may result in a significant increase in stimulated platelets, as assessed, for example, by a reduction in PT.

[0068] return Figure 3A , given the higher baseline Ca 2+ Platelets with a higher Ca 316 are more likely to activate into pCP and thereby increase the overall coagulation potential of the subject; it is clear that any situation in which a higher coagulation potential is desired would benefit from a method that, when applied to a subject, causes Ca 316 to activate into pCP and thereby increase the overall coagulation potential of the subject; 2+316 into the platelets 314. As described above, increasing activity in VEF 304 can trigger a cascade of events that results in Ca 2+ 316 has a net influx into platelets 314 as it passes through the spleen 116 .

[0069] An individual's blood clotting ability can be assessed by diagnostic tools such as thromboelastography (TEG). TEG evaluates blood clotting ability and identifies potential abnormalities detected during the clot formation process. TEG results include a reaction time (R-time) that quantifies the duration of blood initiating its coagulation cascade after the addition of a coagulation activator, a kinetic time (K-time) that quantifies the duration of coagulation from the initiation of the coagulation cascade until a hardness of 20 mm is reached, an alpha angle that quantifies the rate of fibrin cross-linking during coagulation, a maximum amplitude (MA) that quantifies the overall strength of coagulation in millimeters, and a lysis (LY30) at thirty minutes that quantifies the resistance of the coagulated blood to decomposition (e.g., the percentage of decomposition half an hour after the MA time).

[0070] In some instances, TEG deficiencies can indicate hypofibrinogenemia (e.g., low fibrinogen levels), thrombocytopenia (e.g., low platelet count), or platelet dysfunction. When a patient's TEG analysis indicates one or more deficiencies, transfusion therapy (e.g., fresh frozen plasma, platelet transfusion, and / or cryoprecipitate transfusion) is often recommended.

[0071] There are many situations in which a higher coagulation potential is needed. These situations include both chronic (persistent) situations and acute situations. As mentioned above, for example, people with a coagulation potential that is lower than normal and / or lower than expected, such as those with hemophilia or von Willebrand's disease, will benefit from a higher coagulation potential. In another example, subjects who take medication to prevent platelets from forming clots in locations other than the site of injury (e.g., anticoagulants or "blood thinners") may benefit from a higher coagulation potential, especially before and during surgery. In general, any patient or person undergoing a medical procedure in which there is a reasonable possibility of bleeding (e.g., undergoing surgery) will benefit greatly from a transient increase in their coagulation potential. An increase in coagulation potential can reduce bleeding time, which in many cases (if not all) means a shorter and less risky operation overall. In addition, increasing coagulation potential in a surgical setting will limit blood loss. For example, limiting blood loss can avoid the need for blood transfusion and / or reduce the amount of replacement required when a blood transfusion is needed; blood transfusion is very expensive and, in some cases, limited or unavailable. In an illustrative example involving childbirth, postpartum hemorrhage is one of the leading causes of maternal mortality worldwide. Furthermore, significant bleeding occurs during any vaginal delivery, and even greater amounts occur during a cesarean section (C-section). There are many other surgical procedures in which the risk of significant bleeding is high, and patients undergoing any of these procedures would benefit from increased coagulation potential. Another situation in which limiting bleeding is highly desirable and beneficial is abnormal uterine bleeding (AUB), including heavy menstrual bleeding (HMB), which in turn includes menorrhagia. This condition / conditions affect one-quarter of women of childbearing age. While death from AUB, including HMB, is rare, in some cases, if left untreated, it can lead to a predisposition to cancer. HMB can cause women to develop severe anemia, which in turn can lead to shortness of breath and an increased risk of cardiac complications. As previously mentioned, HMB is very common, and although it is estimated that one-quarter of women of childbearing age suffer from it, approximately one-third of women of childbearing age actually seek treatment for menstrual bleeding that is considered heavier than ideal. Therefore, new interventions that can help reduce blood loss in HMB, and in general AUB, are highly desirable and would be welcomed by women and physicians, even if used as adjuncts.

[0072] inflammation

[0073] Proinflammatory response is usually triggered when there is the possibility of physical damage, as in some instances, when infection and / or when hemorrhagic injury occurs. Usually, this inflammatory response helps the body to heal. However, in many cases, an overreacting inflammatory response can occur, thereby triggering harmful effects, which may lead to organ failure and death. At least part of the inflammatory response is carried out by the spleen, and therefore, regulating spleen activity may cause changes in the inflammatory response. Specifically, activation of the parasympathetic nervous system causes the anti-inflammatory response in the spleen, thereby causing the minimization of circulating proinflammatory cytokines. The activation of the splenic nerve (for example, directly and / or via vagus nerve efferent fibers (VEF) activity) causes the above-mentioned anti-inflammatory response. In one example, the minimization of circulating proinflammatory cytokines can be achieved by regulating spleen activity via the NTS descending pathway.

[0074] In some embodiments, the anti-inflammatory effect is provided by activating the anti-inflammatory pathway 100 (also known as the cholinergic anti-inflammatory pathway), such as Figure 1 As described in . Specifically, the ABVN 102 and / or ATN 104 may be stimulated, which have projections to the NTS 108; these projections induce cholinergic anti-inflammatory effects via efferent pathways, primarily via the vagus nerve 110. As shown, the TCC 106 receives afferent connections from the ATN 104 and projects to the NTS 108. Modulation of the NTS 108 influences activity in the efferent pathways through the celiac ganglion 112 and parasympathetic ganglia 114 via the vagus nerve 110, which in turn modulates activity in the spleen 116, lungs 118, intestines 120, and / or heart 122, thereby inducing an anti-inflammatory response. When the vagus nerve 110 indirectly mediates spleen 116 function, a systemic anti-inflammatory effect occurs, thereby reducing the amount of circulating proinflammatory cytokines. In addition, local anti-inflammatory effects occur in organs reached by the efferent pathways; for example, in the lungs 118, intestines 120, and heart 122.

[0075] Hypovolemia

[0076] When blood circulation is reduced to a level where tissue perfusion can no longer provide proper oxygenation, organs begin to malfunction until they begin to fail. Organ failure can lead to permanent damage and even death. This is especially true when the organ lacking proper oxygenation is the brain. The brain consumes most of the circulating oxygen in the body, especially when a person is at rest, and is therefore extremely susceptible to conditions of hypoperfusion. There are areas of the brain (e.g., nuclei or regions) that regulate blood pressure and blood flow. Activation of such areas of the brain results in higher blood flow. For example, activation of the rostral ventrolateral medulla (RVLM) has been shown to have a pressor response ( Figure 2A ), which causes increases in blood pressure, perfusion, and blood flow.

[0077] Go to Figure 2AAs illustrated in the example pressor response and cerebral perfusion pathway 200, the RVLM 206 receives connections from several nuclei, including the trigeminal-cervical complex (TCC) 204, which in turn receives afferent connections from branches of the trigeminal nerve. As shown, the TCC 204 receives afferent connections from the auriculotemporal nerve (ATN) 202. In turn, the RVLM 206 regulates the cardiac system 208 (e.g., blood pressure) and the vascular system 210 (e.g., blood flow).

[0078] In addition to the RVLM 206, activation of the trigeminal parasympathetic pathway 220 (at Figure 2B ) have been shown to at least partially dilate the brain vasculature 224 by releasing ACh onto this vasculature 224 by sphenopalatine origin fibers (SPH) 222. The sphenopalatine nucleus (sphenopalatine ganglion) 222 also receives afferent fibers from branches of the trigeminal nerve, specifically the mandibular branch (V3) of the trigeminal nerve, of which the ATN is a part.

[0079] Managing bleeding

[0080] Activity in VEFs can be triggered by direct activation of nerve fibers or by activation of regions that are directly and / or indirectly connected to nerve fibers. Figure 5 , a functional map of neural structures and pathways 500 shows that activity in medullary structures such as the nucleus tractus solitarius (NTS) 504 and the nucleus ambiguus (NA) 522 can trigger VEF activity via efferent pathways 539. The NA 522 receives projections from, among other things, the periaqueductal gray area (PAG) 510. The NTS 504 receives afferent connections from the TCC 502 as well as from ascending vagal branches. In turn, the TCC 502 receives afferent projections from trigeminal and cervical branches and projects to the PAG 510 and RVLM. Activity in RVLM neurons can trigger the pressor response described above, in Figure 2A Interestingly, not all activity in TCC 502 elicits a trigeminal parasympathetic response due to sphenopalatine activity; studies have shown that it is activation of the masseteric branch of the trigeminal nerve (MBTN) that causes this response. One way to activate the MBTN branch is via the auriculotemporal nerve (ATN) 202.

[0081] Activation of VEF can be achieved by stimulation at various locations via invasive methods and / or via non-invasive methods. Some invasive examples include using an implantable pulse generator (IPG) to stimulate cervical vagus nerve fibers and / or using needle electrodes to percutaneously stimulate vagus nerve fibers, such as ABVN and / or trigeminal nerve fibers. Non-invasive methods can percutaneously stimulate fibers of the ABVN and cervical vagus nerve fibers; in addition, trigeminal nerve fibers, such as fibers corresponding to the maxillary, ocular and / or mandibular trigeminal nerve branches. In some examples, VEF activation can be achieved by electrical, mechanical (e.g., ultrasound, pressure, massage, etc.) and / or light (e.g., laser and / or high-intensity light) stimulation. In addition, activation of nAChRα7 on platelets can be achieved by chemical means, such as local or systemic administration of nAChRα7 agonists (e.g., nicotine). nAChRα7 agonists can be injected or applied non-invasively, such as using a transdermal / transdermal patch, or in some cases by a specially designed oral dose. In addition, platelets express other calcium transmembrane channels; thus, one or more of these channels (e.g., the channels identified in Table 1 above) can be activated to increase platelet intracellular baseline Ca 2+ For example, these channels can be chemically activated by their corresponding agonists and / or partial agonists in a manner similar to that described above for nAChRα7. 2+ The pathway through which it leaves the platelet can be temporarily or partially blocked, for example using a partial antagonist, to prevent or slow the flow of Ca 2+ In some or all cases, it is desirable and / or required to increase the intracellular Ca 2+ intervention, so that the Ca 2+ Platelets are not activated upon entering the intracellular space.

[0082] Under normal circumstances, high concentrations of cytosolic Ca 2+ To prevent thrombus formation outside the injury site, platelet activation should be primarily confined to the injury site. 2+ ] cyt Remains relatively low until platelet activation is required. However, when activated, platelets require high [Ca 2+ ] cyt One method is to allow Ca 2+ Held in internal platelet stores for release into the cytoplasmic space upon platelet activation.

[0083] Pressor response, such as Figure 2AAs shown in , it can be achieved by invasive and / or non-invasive stimulation at various locations. In some instances, the pressor response can be triggered via electrical, mechanical (e.g., ultrasound, pressure, massage, etc.) and / or optical (e.g., laser and / or high-intensity light) stimulation.

[0084] Trigeminal parasympathetic responses, such as Figure 2B As shown in , it can be achieved by invasive and / or non-invasive stimulation at various locations. In some instances, the trigeminal parasympathetic response can be triggered via electrical, mechanical (e.g., ultrasound, pressure, massage, etc.) and / or optical (e.g., laser and / or high-intensity light) stimulation.

[0085]

[0086] Table 2: Example stimulus durations

[0087]

[0088] Table 3: Example treatment cycles

[0089] In some embodiments, the stimulation for producing one or more of the reactions described herein to achieve a transient effect in a preventive / prophylactic situation, such as producing a pressor response, a trigeminal parasympathetic response and / or an increase in CPot, begins in a short period of time before the event and is applied for a very short duration. For example, in the case of an impending trauma, such as an emergency surgical operation, the stimulation may only begin in a brief period before the trauma (e.g., surgical operation). In another embodiment, the stimulation begins in a medium or long period of time before the event and can be applied intermittently and repeatedly for a very short or short duration. For example, to avoid bleeding during childbirth, intermittent or regular stimulation of a short duration can be provided to pregnant women throughout the indefinite duration of childbirth. In another example, in the case of medical intervention, such as a cesarean section, for example, preventive treatment can prevent unnecessary blood loss.

[0090] In some embodiments, repeated intermittent stimulation is applied with a predetermined duty cycle. For example, a 30% on / 70% off duty cycle can be implemented as applying three minutes of stimulation ("on") every ten minutes. In other non-limiting examples, the duty cycle can be configured as a 30% on / 70% off duty cycle (for example, 3 minutes on / 7 minutes off or 6 minutes on / 14 minutes off, etc.), a 50% on / 50% off duty cycle (for example, 1 minute on / 1 minute off, or 5 minutes on / 5 minutes off, etc.), an 80% on / 20% off duty cycle (for example, 4 minutes on / 1 minute off, etc.) or a 97% on / 3% off duty cycle (for example, 5 minutes on 10 seconds off, etc.). In another illustrative example, a platelet donor can start stimulation seven or more days before donating platelets so that the donated platelets are stimulated platelets. In another embodiment, the platelets donated are stimulated platelets, and the total amount of platelets to be donated may be significantly reduced. For example, in this case, stimulation can be applied every day for a short period of time that is repeated. In another example, stimulation can be applied for a short duration, a medium duration, a long duration or a very long duration. In another embodiment, stimulation can be started at a long period of time before an event or a very long period of time before an event.

[0091] To prepare for potentially dangerous situations, such as military operations, military personnel can begin stimulation approximately three weeks or more before the actual operation, while training, and discontinue stimulation once the operation is complete. In this case, stimulation can be applied daily for single or multiple very short, short, or medium periods of time.

[0092] In some embodiments, the stimulation for producing one or more of the reactions described herein, such as producing a pressor response, a trigeminal parasympathetic response and / or an increase in CPot, is applied regularly, for example, in a repetitive mode. In some instances, stimulation can be applied once every 10 minutes, once every 30 minutes, once per hour, 4 times a day or once a day. The duration may depend in part on the frequency of regular stimulation. In some instances, stimulation can be applied once every ten minutes for a short duration, once per hour for a medium duration or once a day for a long duration. In another embodiment, in order to reduce total blood loss and / or total bleeding days per month, for example, women with HMB / menorrhea (including women with any coagulopathy) can start stimulation a few days before the menstrual period begins and continue to stimulate until the end of menstruation. In this case, stimulation can be applied for example once a day for a very short or short period of time. In some instances, other schedules based on the potential severity of the intensity of convenience, comfort, expected effect and / or result (for example, the possibility of causing harm to the patient due to lack / inadequate preventive and therapeutic treatment) are possible.

[0093] In the case where target is to treat chronic disease, in an illustrative embodiment, as long as necessary, produce one or more of the reactions described herein, such as the increase of CPot, pressor reaction and / or trigeminal parasympathetic reaction stimulation can be delivered in a repeated pattern.For example, stimulation can be applied every day or several times every day, and duration (for example, very short, short, medium, long or very long) is partly based on the relative frequency for treatment.In another example, the coagulation potential of (for example, " starting ") initial level can be produced in human body by applying stimulation for the first time period at least every day, then carry out the treatment with lower frequency or gradually reduce the frequency of treatment to maintain coagulation potential at desired level.For example, stimulation can be applied every day for the first time period (for example, 5 to 10 days), then carry out the treatment with lower frequency (for example, once a week or twice in some cases) to maintain coagulation potential within desired range.In another example, stimulation can be applied every day for the first time period, then three times a week for the second time period, then twice a week for the third time period, then once a week to maintain the coagulation potential of desired level. In another example, a therapy schedule involving initial stimulation applications (e.g., 7 times) per week for the first week, followed by a different number of stimulation applications (e.g., 5 times) per week in the second week, etc., can be customized to maintain the desired coagulation potential for a particular individual. Furthermore, in any of the above examples, the duration of treatment can be modified according to the time period.

[0094] Generally, the stimulation duration is defined by the time the device is actively delivering stimulation therapy, rather than by the actual time the stimulation is generated. For example, when stimulation is applied at a specific frequency and a specific pulse duration (e.g., pulse width), the device may be activated (e.g., powered) for one hour, e.g., Figure 7A and / or Figure 7B In addition, stimulation pulses can be applied at a specific duty cycle, for example, 5 minutes of delivery and 20 seconds of no delivery or 30 seconds of delivery and 30 seconds of no delivery, etc. Other example duty cycles are shown in Figure 7A and Figure 7B The timing diagram of

[0095] Go to Figure 6C, the WANS device 630 includes a front portion 632 including a conductive adhesive area 634 and a surrounding non-conductive adhesive area 644b, and a rear portion 636 including conductive adhesive areas 638 and 640 and a surrounding non-conductive adhesive area 644a. For example, the non-conductive adhesive areas 644a, 644b can provide additional adhesion for a robust skin / conductive adhesive contact. For example, the conductive adhesive area 634 of the front portion 632 corresponds to the second electrode (II) 642b. Turning to the rear portion 636, the conductive adhesive area 638 corresponds to the first electrode (I) 642a, and the conductive adhesive area 640 corresponds to the third electrode (III) 642c. In some embodiments, the electrodes 642a-c and their corresponding conductive adhesive areas 634, 638, and 640 each have similar shapes and areas. In other embodiments, the shape and / or surface area of ​​each of the electrodes 642a-c and / or their corresponding conductive adhesive regions 634, 638, and 640 may vary, for example based on the shape of the potential target neural structure and / or the anatomical structure on which the electrodes 642a-c and their corresponding conductive adhesive regions 634, 638, and 640 are configured to be positioned.

[0096] In some embodiments, the conductive adhesive region 634 is configured to contact the wearer's skin in the region of the neural structure of the auriculotemporal nerve (ATN) and / or neural structure connected to the ATN, such that delivery of therapeutic stimulation via the conductive adhesive region 634 modulates ATN activity. For example, Figure 10A and Figure 10B , ATN 1002 relative to the human ear 1000 ( Figure 10A ), which typically runs in front of the ear 1000, and skeletally ( Figure 10B ) is illustrated relative to ear canal 1010. In one illustrative example, an electrode in electrical communication with conductive adhesive region 634 can be positioned proximate to the temporomandibular joint.

[0097] In some embodiments, the conductive adhesive region 638 is configured to contact the wearer's skin in the area of ​​the neural structure of the auricular branch of the vagus nerve (ABVN) and / or neural structures connected to the ABVN, such that delivery of therapeutic stimulation via the conductive adhesive region 638 modulates ABVN activity. For example, 10A to 10D As shown in FIG, ABVN 1004 is shown to be transmitted through the mastoid tubules (MsC) 1012 (also known as Arnold's canals) ( Figure 10D ) and relative to the ear 1000 ( Figure 10A ), relative to the ear canal 1010 ( Figure 10B ) and relative to the back of the ear ( Figure 10C ) is revealed. For example, go to Figure 11, the post-auricular nerve 1100 meets a branch of the ABVN, thereby providing another target for ABVN stimulation. In one illustrative example, an electrode in electrical communication with the conductive adhesive region 638 can be positioned proximal to the MsC.

[0098] In some embodiments, the conductive adhesive region 640 is configured to contact the patient's skin as a return electrode, thereby forming a circuit across the tissue, wherein an electrode corresponds to each of the front conductive adhesive region 634 and the rear conductive adhesive region 636. Although illustrated as a single return electrode (e.g., third electrode 642c) provided for the two electrodes 642a and 642b corresponding to the adhesive region 638 and the adhesive region 634, in other embodiments, a different, separate return electrode can be provided for each electrode 642a, 642b. In further embodiments, three or more return electrode paths can be provided for the two positive electrodes. Other combinations are also possible.

[0099] Go to Figure 6E The wearable ear neurostimulator (WANS) 660 includes a front portion 666, a rear portion 662, and an ear-hook portion 664, each portion including at least one electrode (e.g., electrodes 670a, 670b, and 670c). When worn by a wearer, the WANS 660 can be wrapped around the ear so that the front portion 666 is positioned in front of the ear and the rear portion 662 is positioned behind the ear. The ear-hook portion 664, connected to the front portion 666 by a flexible connector 668, can be retained in the concha auricularis region of the ear by friction and / or adhesive.

[0100] In some embodiments, to enhance the engagement of the WANS 660 with the wearer's tissue and / or to enhance electrical communication between the tissue and the electrodes 670a-c, each electrode 670a-c is positioned in electrical communication with a corresponding conductive adhesive region 672a-c. The conductive adhesive regions 672a-c can create an electrical communication path from the electrodes positioned within or on the WANS 660 to the wearer's skin. In some embodiments, the WANS 660 is provided with one or more pads, such as pads 674a-c, to protect and maintain the cleanliness of the conductive adhesive regions 672a-c prior to wear. In some embodiments, to provide robust skin contact, the conductive adhesive regions 672a-c are surrounded by one or more non-conductive adhesive regions. In some embodiments, the electrodes 670a-c and their corresponding conductive adhesive regions 672a-c have similar shapes and areas. In other embodiments, the size and / or shape vary between electrodes and / or adhesive regions, for example, based on the underlying neural structures being targeted and / or the morphology of the anatomical structure on which the particular electrodes and adhesive regions are configured to be positioned.

[0101] A conductive adhesive region 672a may be provided to create an electrical communication path in the front portion of the ear canal from the electrode 670a positioned on the ear hook portion 664 of the WANS 660 to the wearer's skin. Figure 12 , such electrodes can be positioned to stimulate the external auditory canal nerve branches 1200 of the ATN 1002. In other embodiments, the conductive adhesive region 672a is positioned on the concha, the cymba concha, or the tragus in order to stimulate branches of the ABVN.

[0102] Go to Figure 7A , a timing diagram 700 illustrates triggering multiple channels 704, 706 using a master clock 702 according to an example. In an exemplary embodiment, the clock 702 triggers pulses 708 at a predetermined clock frequency. In an example, the first channel 704 can be configured to trigger stimulation patterns 710-712, and the second channel 706 can be configured to trigger second stimulation patterns 714-716.

[0103] As shown, each cycle of the stimulation patterns 710-712 of the first channel 704 is configured to be triggered by a corresponding pulse 708 of the master clock 702; that is, at a 1 to 1 ratio. In this example, each stimulus 712 (e.g., 712a, 712b, etc.) is configured to be triggered a specific time interval after the end of the pulse 708 (e.g., 708a, 708b, etc.) in the corresponding stimulus 710 (e.g., 710a, 710b, etc.).

[0104] As shown, each cycle of stimulation pattern stimuli 714-716 is configured to be triggered by every other pulse 708 of the master clock 702; that is, at a 2:1 ratio with the master clock 702. However, the triggering of each stimulus 714 (e.g., 714a, 714b, etc.) is configured to occur after a specific time delay after the corresponding master clock pulse 708 (e.g., 708a, 708b, etc.). In some embodiments, each stimulus 714 (e.g., 714a, 714b, etc.) is configured to trigger after a specific time interval after the end of the corresponding pulse in stimulus 712 (e.g., 712a, 712b, etc.). In one example, each stimulus 714 is offset from each corresponding stimulus 712 by a synchronization delay 718. As shown, the synchronization delay 718 is 2 ms. However, in some embodiments, the synchronization delay 718 can be as small as zero, thereby causing both channels 704, 706 to trigger simultaneously according to the master clock ratio of each channel 704, 706. Furthermore, synchronization delay 718 may be at most the master clock 702 period minus the combined duration of each period of stimuli 710-712 and each period of stimuli 714-718 plus the time interval between periods 710-712, 714-718. Outside of the illustrated example, this delay may be equivalent to at most approximately 10 ms.

[0105] In some embodiments, the channels 704, 706 are synchronized using a master clock counter and registers for each channel 704, 706. By setting each register to a multiple of the master clock pulse 708 to trigger the corresponding channel 704, 706, each channel 704, 706 can be configured to trigger when the channel register value equals the master clock pulse 708. Outside of the example, the counter for each channel 704, 706 can be reset after the channel 704, 706 is triggered. In the illustration, using a 6-bit counter and a 6-bit register, the trigger frequency can be as high as the master clock frequency (1:1) and as low as 1 / 64 of the clock frequency (64:1).

[0106] Go to Figure 7B , timing diagram 720 illustrates the use of a neuromodulatory device (such as the various devices described herein) to trigger multiple stimulation modes 722 (ATN stimulation mode 722a and Arnold nerve stimulation mode 722b) for concurrent stimulation. In some embodiments, stimulation triggering is performed using a single master clock, such as Figure 7A For example, the stimulation modes 722a, 722b can be configured to deliver platelet enrichment therapy via the platelet stimulation pathway 330, as described with respect to Figure 3A and Figure 3B As stated.

[0107] As shown, the duty cycle 724 for each of the stimulation modes 722a, 722b is configured as five minutes of active stimulation followed by ten seconds of no stimulation (e.g., according to the "short duration" of Table 2 above). In other examples, the stimulation modes 722a, 722b can be configured as four minutes of active stimulation followed by ten seconds of no stimulation, four minutes of active stimulation followed by twenty seconds of no stimulation, and / or four minutes of active stimulation followed by one minute of no stimulation. In other embodiments, the duty cycles 722a, 722b can include different stimulation durations (e.g., medium duration, long duration, or very long duration). While in some cases a high duty cycle (e.g., 90% on time) may be required to achieve the desired therapeutic effect, in other cases a lower duty cycle (e.g., 50% on or even 30% on) may be sufficient; this may depend on the specific circumstances of the particular user. However, user preferences may be taken into account, given that a sufficiently high duty cycle is selected to be effective. For example, lengthy stimulation durations may fatigue the wearer (e.g., feel tedious), whereas lengthy pause durations may be more noticeable to the wearer, which may prove to be a welcome interruption in sensation for some and a irritation for others. Thus, in some embodiments, the duty cycle may be customizable to some extent based on user preferences / tolerances.

[0108] In addition, the duty cycles of the stimulation patterns 722a, 722b are aligned so that no stimulation is delivered during a ten second period. Although only 10 minutes of active stimulation is described (e.g., a "very short cycle" according to Table 3 above), in some embodiments, the duty cycles 722a, 722b can be repeated for longer treatment cycles (e.g., a short cycle, a medium cycle, a long cycle, a very long cycle, or an extremely long cycle).

[0109] The stimulation pattern 722a configured to stimulate the ATN is delivered at a frequency 726a of approximately 100 Hz (e.g., a high frequency according to Table 5 below). In some embodiments, very high frequencies (e.g., 150-200 Hz or higher) may be used. In addition, the pulse width 728 of each triggered stimulation (e.g., a low-medium range pulse according to Table 6 below) is 250 microseconds, and the inter-pulse interval 730 is 100 microseconds.

[0110] The stimulation pattern 722b configured for the Arnold nerve is delivered at a frequency 726b of approximately 15 Hz (e.g., a low frequency according to Table 5 below). In some embodiments, a mid-range frequency (e.g., 30-40 Hz or higher) may be used. For example, 5 Hz stimulation may be uncomfortable or irritating to some wearers, while higher frequency stimulation (e.g., a mid-range frequency rather than a low frequency) may be more comfortable for some wearers. Thus, in some embodiments, the stimulation frequency may be customizable to a certain extent (e.g., within a therapeutic range) based on user preferences / tolerances.

[0111] Stimulation mode 722b uses the same pulse width 728 and inter-pulse interval 730 as ATN stimulation mode 722a. The pulse width 728 and inter-pulse interval 730 can vary, particularly to account for the trade-off between amplitude and pulse width when signaling an activation threshold (e.g., for lower amplitudes, the pulse width becomes wider). In addition, the selected pulse width 728 and inter-pulse interval 730 (e.g., the activation threshold) may depend in part on the fiber type and / or diameter of the sensory fibers targeted by the stimulation. For example, certain devices described herein are designed to target Aβ fibers at current levels of 1 to 5 mA. Other fibers that can be targeted for treatment include Aα and Aδ fibers, shown in Table 4 below. In contrast, C fibers are mostly painful and would not be provided as an effective treatment.

[0112]

[0113] Table 4: Sensory Fiber Types

[0114] As shown, the pulse timing 732a of the ATN stimulation pattern 722a is offset from the pulse timing 732b of the Arnold neural stimulation pattern 722b by a gap 734 of approximately two to five milliseconds. Thus, the ATN stimulation pattern 722a is configured to be delivered simultaneously with the Arnold neural stimulation pattern 722b without requiring simultaneous pulse triggering between the two stimulation patterns 722a and 722b. For example, to achieve pulse timing, the frequency of the stimulation pattern 722b can be set to 14.28 Hz (e.g., 1 / 7 of the frequency of the stimulation pattern 722a).

[0115] In some embodiments where stimulation is applied at more than one site (e.g., to two or more nerve branches, etc.), the stimulation duration, frequency, pulse width, and / or duty cycle may vary from stimulation site to stimulation site. In some embodiments, it may be beneficial to use different frequencies at different stimulation sites.

[0116] Stimulation delivery can be varied depending on the therapy provided by the therapeutic device. For example, frequency and / or pulse width parameters can be adjusted for one or more stimulation sites where stimulation is being delivered.

[0117] In some embodiments, frequency and / or pulse width parameters are adjusted during therapy, for example, in response to feedback received from monitoring the patient. In some instances, feedback can be obtained using one or more sensors or other devices that assess heart rate, heart rate variability, electroencephalogram (EEG), blood pressure, and / or blood oxygen concentration.

[0118] In some embodiments, the system utilizes feedback to monitor and / or modify therapy. Feedback can be obtained from one or more sensors capable of monitoring one or more symptoms being treated by the therapy. For example, after one or more symptoms are alleviated or eliminated, the therapeutic output may similarly be reduced or stopped. Conversely, when one or more symptoms increase or are supplemented, the therapeutic output may similarly be activated or adjusted (increased, expanded, etc.). In some instances, sensors can monitor one or more of electrodermal activity (e.g., sweating), motor activity (e.g., tremors, physiological movements), blood sugar levels, neural activity (e.g., via EEG), muscle activity (e.g., via EMG), and / or cardiopulmonary activity (e.g., EKG, heart rate, blood pressure (systolic, diastolic, and / or mean)). Imaging techniques such as MRI and fMRI can be used to adjust therapy for a given user in a clinical setting. In other embodiments, imaging of pupil changes (e.g., pupil dilation) using, for example, a standard mobile phone and / or smart glasses can be used to provide feedback for therapy adjustments. In some embodiments, one or more sensors are integrated into an earpiece and / or ear concha device. In some embodiments, one or more sensors are integrated into a pulse generator. For example, periodic monitoring can be achieved by prompting the wearer to touch one or more electrodes on the system (e.g., electrodes built into the surface of the pulse generator) or otherwise interact with the pulse generator (e.g., extending the pulse generator away from the body to monitor tremors using a motion detector in the pulse generator). In other embodiments, one or more sensor outputs can be obtained from an external device (such as a fitness computer, smart watch, or wearable health monitor).

[0119] Optical techniques have been used to assess thrombin concentrations (see Martínez-Pérez, Paula et al. "Continuous detection of increasing concentrations of thrombin employing alabel-free photonic crystal aptasensor". Micromachines 11.5(2020):464.). It is expected that thrombin concentration will increase after the stimulation therapy described herein; therefore, thrombin concentration can be measured and applied by the devices and / or systems described herein to assess the effect of the therapy and adjust delivery parameters. Outside of the examples described, blood from the wound can be used to assess thrombin concentration measurements, and the resulting measurements can be delivered to the therapeutic device and / or system to adjust the therapy application.

[0120] In another example, a microfluidic chip can be used as a sensor system for real-time active monitoring of coagulation (see Lei, Kin Fong et al., "Real-time electrical impedimetric monitoring of blood coagulation process under temperature and hematocrit variations conducted in a microfluidic chip." PLoS One 8.10 (2013): e76243.). Beyond this example, the electrical impedance measurements collected via the microfluidic chip can be analyzed to assess the effectiveness of therapy in real time and make adjustments as needed.

[0121] In another example, the "lab-on-a-chip" concept can be used to monitor and / or control therapeutic applications. Closed-loop neuromodulation of hemostasis can be achieved using "lab-on-a-chip" microfluidics. For example, a drop of blood collected from a finger puncture performed by a lancet can be collected in a capillary tube and then placed on a test strip preloaded with a bioreceptor that selectively recognizes and binds to the biomarker of interest. The bioreceptor is immobilized on the surface of the component of the test strip, and the binding of the biomarker to the bioreceptor produces a signal that can be detected by a device engineered to receive the test strip and detect the signal. The biomarkers of interest include, for example, thrombin or thrombin-antithrombin III complexes. The bioreceptor can be an antibody, a synthetic chemical, or an engineered biological derivative (e.g., a nucleic acid, protein, or enzyme). The signal can be detected by various means including electrical, mechanical, thermal, piezoelectric, or optical. Examples of optical sensing include spectral analysis of light at a specific wavelength, such as a streptavidin-peroxidase reaction that produces a yellow color, the intensity of which is proportional to the concentration of the biomarker being analyzed. The device that receives the test strip and reads the signal can use microfluidics to wash away unbound material, or it can operate on the intact sample.

[0122] In another example, as shown elsewhere by Murphy and colleagues (Murphy, Peter R. et al. "Pupil diameter covaries with BOLD activity in human locus coeruleus." Human brain mapping 35.8 (2014): 4140-4154.), activity in the locus coeruleus can be measured indirectly by pupillometry. As previously mentioned, activity at the LC can drive activity in sympathetic pathways, leading to activation of the spleen, and therefore, pupillometry can be used not only to assess response to therapy, but also to control its delivery. Several portable automated pupillometers are available (e.g., -200, Neurooptics Inc., Irvine, CA, USA), the portable automatic pupillometer can be used (e.g., with minor modifications) to automatically transmit pupil diameter information to a therapeutic device and / or system and is described herein. In addition, as described above, imaging of pupil changes (e.g., pupil dilation) captured by a common portable computing device (e.g., a cell phone and / or smart glasses) can be used to monitor pupil diameter.

[0123] The monitoring used can be based in part on the treatment setting. For example, EEG monitoring is easier to do in a hospital setting, while heart rate monitoring can be achieved with a sensor such as a pulse meter built into an earpiece or another sensor built into a low-budget health monitoring device such as a fitness monitor or smartwatch. Additionally, microfluidic chip and lab-on-a-chip monitoring may be more practical in a hospital or clinical setting, while pupil dilation can be easily monitored in a variety of settings.

[0124] In an illustrative example, feedback related to electrodermal activity can be used to monitor and detect the speed or timing of symptoms and / or treatment results. In one example, electrodermal activity can be sensed by electrodes on a therapeutic earpiece device. In another example, electrodermal activity can be detected by electrodes on another part of the body and communicated to the system. In some embodiments, electrodermal electrodes can enable electrochemical detection of specific substances (e.g., cortisol) in the skin.

[0125] In some embodiments, the system may further include one or more motion detectors, such as accelerometers or gyroscopes, which can be used to collect information to adjust therapy. In one example, the one or more motion detectors are configured to detect tremors and / or physiological movements. In one aspect, tremors and / or physiological movements may indicate an underlying condition and / or treatment for the underlying condition. In one example, tremors and / or physiological movements may indicate symptoms associated with substance withdrawal. In one aspect, feedback from blood glucose monitoring can be used to adjust therapy.

[0126] In yet other embodiments, an EKG can be used to assess heart rate and heart rate variability to determine the general activity of the autonomic nervous system and / or the relative activity of the sympathetic and parasympathetic branches of the autonomic nervous system and to adjust therapy. Autonomic nervous activity may indicate symptoms associated with substance withdrawal. In one aspect, the therapeutic device can be used to provide therapy for treating heart conditions such as atrial fibrillation and heart failure. In one example, therapy can be provided for regulating the autonomic nervous system. In some embodiments, the therapeutic device can be used to provide therapy to balance the ratio between any combination of the autonomic nervous system, the parasympathetic nervous system, and the sympathetic nervous system.

[0127] In one aspect, the system can monitor impedance measurements that allow for closed-loop neural stimulation. In one example, monitoring feedback can be used to alert the patient / caregiver whether therapy is being adequately delivered and whether the therapy device is removed.

[0128] In some embodiments, sensor data can be monitored to determine whether and when to start a specific therapy. For example, one or more blood tests can be performed automatically or semi-automatically (e.g., regularly) to monitor the differences in the coagulation pathway function of the subject. For example, the test can be manually activated and automatically analyzed. As previously mentioned, the coagulation pathway is generally divided into three types: intrinsic, extrinsic, and common pathways. Different tests are usually used to evaluate the function of the intrinsic and extrinsic pathways. For example, a test called activated partial thromboplastin time (aPTT), also known as partial thromboplastin time (PPT), can be used to evaluate the coagulation function via the intrinsic and common coagulation pathways. Therefore, the aPPT test evaluates coagulation factors XII, XI, IX, VIII, X, V, II, and I. For example, the PTT of a person suffering from a coagulation defect such as hemophilia can be prolonged or increased. However, since the various embodiments of the blood management therapy described herein enhance platelet-driven coagulation in a manner independent of or quasi-independent of coagulation factors, even in hemophilia patients, the PTT can be shortened by the therapy. Another test that also assesses the same pathway as PTT is the activated clotting time (ACT) test. Thus, PTT (or ACT) can be used to assess when to apply neurostimulation therapy. On the other hand, prothrombin time (PT) is typically used to test coagulation via the extrinsic and common coagulation pathways; thus, PT assesses the function of coagulation factors VII, X, V, II, and I. In another example, PT can be used to assess the effectiveness of therapy and thereby determine when to restart stimulation therapy. PT, as well as PTT and ACT, can be assessed via various handheld devices available on the market today (e.g., the PT from Coag-Sense, Inc.). Pt meter, https: / / coag-sense.com / , CL1000 (from EasyDiagnosis, https: / / www.easydiagnosis.com / CL1000.html). For example, PTT, PT, and / or ACT measurements can be automatically delivered (e.g., via a wireless connection) to a therapeutic device and / or system as described herein (e.g., a cloud-based analysis engine) for analysis to determine how to control therapy delivery.

[0129] In some embodiments, the stimulation pulses are delivered in a pulse pattern. The frequency and / or pulse width of the individual pulses in the pattern may vary. The pattern may repeat during a stimulation cycle. For example, the pulse pattern may be designed in part to increase the stimulation, thereby establishing a comfort level with the stimulation sensation in the wearer. In another example, the pulse pattern may be designed in part to alternate stimulation between stimulation sites where two or more sites are stimulated during therapy. In examples involving multiple stimulation sites, the stimulation pattern may be designed so that the stimulation frequency is different at all sites where the stimulation is delivered.

[0130] In some embodiments involving electrical stimulation using percutaneous or transcutaneous (i.e., non-penetrating) electrodes, the stimulation frequency varies within a set range. For example, the stimulation frequencies applied in the stimulation pattern may include a first or low frequency in the range of about 1 to 30 Hz, a second or medium range of frequencies in the range of about 30 to 70 Hz, a third or high frequency in the range of about 70 to 150 Hz; and / or a fourth or very high frequency in the range of about 150 to 300 Hz.

[0131]

[0132] Table 5: Electrotherapy: Frequency Table

[0133] In one embodiment, the stimulation frequency varies between 2 Hz and 100 Hz. In yet another embodiment, the pulse width can be adjusted between 20 and 1000 microseconds to further allow for customization of therapy. Stimulation frequency is an important distinction between neural networks; for example, the use of high frequencies has been shown to be beneficial for activating the desired trigeminal system features; in contrast, low frequencies are preferred in activating the desired vagus nerve features. Therefore, in a preferred embodiment, a combination of low and high frequencies is applied to activate the vagus nerve branches and the trigeminal nerve branches, respectively, according to the various embodiments described herein. In yet another embodiment, a variable frequency (e.g., stimulating at a non-constant frequency) can be used at one or more of the electrodes. The variable frequency can be a sweep, and / or a random / pseudo-random frequency variation around a center frequency (e.g., 15 Hz + / - 1.5 Hz or 100 Hz + / - 10 Hz). Changing the stimulation frequency in a random or pseudo-random manner can help prevent neural adaptation.

[0134] When electrical stimulation is used, different combinations of pulse widths can be used at each electrode. In some examples, the pulse width can range from one or more of the following: a first or short pulse width in the range of about 10 to 50 microseconds, or more specifically 10 to 20 microseconds, 20 to 30 microseconds, 30 to 40 microseconds, 40 to 50 microseconds; a first or short pulse width in the range of about 50 to 250 microseconds, or more specifically 50 to 70 microseconds, 70 to 90 microseconds, 90 to 110 microseconds, 110 to 130 microseconds, 130 to 150 microseconds, 150 to 170 microseconds, 170 to 190 microseconds, 190 to 210 microseconds. a second or lower mid-range pulse width in the range of about 250 to 550 microseconds, or more specifically 250 to 270 microseconds, 270 to 290 microseconds, 290 to 310 microseconds, 310 to 330 microseconds, 330 to 350 microseconds, 350 to 370 microseconds, 370 to 390 microseconds, 390 to 410 microseconds, 410 to 430 microseconds, 430 to 450 microseconds, 450 to 470 microseconds, 470 to 490 microseconds; a third or high medium range pulse width in the range of about 550 to 1000 microseconds, or more specifically 550 to 600 microseconds, 600 to 650 microseconds, 650 to 700 microseconds, 700 to 750 microseconds, 750 to 800 microseconds, 800 to 850 microseconds, 850 to 900 microseconds, 900 to 950 microseconds, or 950 to 1000 microseconds; and / or a fourth or long pulse width in the range of about 550 to 1000 microseconds, or more specifically 550 to 600 microseconds, 600 to 650 microseconds, 650 to 700 microseconds, 700 to 750 microseconds, 750 to 800 microseconds, 800 to 850 microseconds, 850 to 900 microseconds, 900 to 950 microseconds, or 950 to 1000 microseconds;

[0014] A fifth or very long pulse width in the range of about 1000 to 4000 microseconds, or more specifically 1000 to 1250 microseconds, 1250 to 1500 microseconds, 1500 to 1750 microseconds, 1750 to 2000 microseconds, 2000 to 2250 microseconds, 2250 to 2500 microseconds, 2500 to 2750 microseconds, 2750 to 3000 microseconds, 3000 to 3250 microseconds, 3250 to 3500 microseconds, 3500 to 3750 microseconds, or 3750 to 4000 microseconds. Different embodiments may use different ranges of pulse widths at one or more of the electrodes. The selection of the stimulation pulse width depends on the desired target fibers and the output intensity. For example, at similar intensities, activation of C-type fibers generally requires a longer pulse width than activation of myelinated Aβ fibers. In a preferred embodiment, the use of low to mid range pulses is used to preferentially activate myelinated fibers.

[0135]

[0136] Table 6: Electrotherapy: Pulse Width Table

[0137] The activity on VEF can be regulated by electrical stimulation at different parts. For example, the vagus nerve rises in the carotid sheath along the neck (such as cervical vagus nerve), wherein the vagus nerve can be non-invasively stimulated percutaneously, for example, using patch electrodes or devices, such as the device described in the United States Patent (USP) the 10th, 207,106 issued to Simon et al. The cervical vagus nerve can also be invasively stimulated using externally powered implanted electrodes or using a fully implantable system (such as the system described in the United States Patent (USP) the 8th, 571,654 issued to Libbus et al.). For example, an implantable system can provide low-frequency stimulation (such as 1 to 30 Hz) for the cervical vagus nerve and / or descending vagus nerve pathway. These same invasive / implantable methods can be used to stimulate the splenic nerve, and thus increase spleen activity. In some instances, other stimulation methods may be used, such as ultrasound (see, e.g., U.S. Patent Application Publication No. 2011 / 0190668 to Mishelevich) or light (see, e.g., U.S. Patent No. 8,562,658 to Shoham et al.), which may also be used to directly activate the spleen.

[0138] Activity on the VEF can also be modulated by stimulating the auricular branch of the vagus nerve (ABVN) and / or by stimulating branches of the trigeminal nerve. Each of these pathways activates neurons in the nucleus tractus solitarius (NTS), which directly or indirectly increases VEF activity. The trigeminal nerve is close to the subcutaneous area at several locations in the face; for example, the auriculotemporal nerve (ATN), supraorbital nerve, supratrochlear nerve, infratrochlear nerve, palpebral branch of the lacrimal nerve, external nasal nerve, infraorbital nerve, zygomaticofacial nerve, zygomaticotemporal nerve, mental nerve, and buccal nerve are potential trigeminal targets for delivering transcutaneous stimulation. A device in which electrodes are placed so that any of these branches is stimulated can be used to increase coagulation potential via activation of the VEF. For example, a device such as the device described in U.S. Pat. No. 10,207,106 to Simon et al. can be used to stimulate branches of the vagus nerve. In a similar manner, a device described in U.S. Pat. No. 8,914,123 to Rigaux can be used to stimulate branches of the trigeminal nerve. Furthermore, although cumbersome, both devices can be used simultaneously or alternately to elicit vagal, trigeminal, or trigemino-vagal responses. The ABVN can be stimulated at the pinna, with preferred targets for this purpose being the cymba concha, concha, tragus, and / or within the ear canal, as well as behind the ear in or around the mastoid canal (McS), also known as Arnold's canal. The ATN can be stimulated in or around the pinna; for example, just above and / or on the rostral side of the pinna, at the top of the temporomandibular joint (TMJ). The ABVN and trigeminal nerve branches can be activated individually, simultaneously, or sequentially, such as in an interleaved manner. Furthermore, these nerves can be stimulated invasively using transcutaneous electrodes (e.g., as described in U.S. Patent No. 8,942,814 to Szeles or U.S. Patent Application Publication No. 2018 / 0200522 to Taca Jr.) or non-invasively using transcutaneous electrodes (e.g., as described in U.S. Patent No. 11,351,370 to Covalin et al.).

[0139] Go to Figure 6A and Figure 6BIn a preferred embodiment, stimulation can be provided transcutaneously using an ear stimulation device 600. Ear stimulation device 600 is shown having electrodes 602, 604, 606, and 608. For example, electrodes 602, 604, 606, and 608 can be configured to form corresponding circuits 610a and 610b according to an example. In one example, an equivalent circuit 610a can be formed by electrode 602 and electrode 606, which are configured to stimulate tissue portion 620. In this example, tissue portion 620 is positioned to target the cymba concha area that is weakened by branches of the auricular branch of the vagus nerve and the post-auricular area that is weakened by branches of the greater auricular nerve and the lesser occipital nerve. In one example, an equivalent circuit 610b can be formed by electrode 604 and electrode 608, which are configured to stimulate tissue portion 622. In this example, tissue portion 622 can be positioned to target the rostral area of ​​the ear where the auriculotemporal nerve travels inferiorly and branches out, as well as the posterior ear area which is weakened by branches of the greater auricular nerve and the lesser occipital nerve.

[0140] In one example, tissue portion 620 can be a portion of the concha, cymba concha, or both, which allows ABVN stimulation and can be performed at approximately 5 Hz, 15 Hz, or 30 Hz. In one example, tissue portion 620 can be placed in the area of ​​the trigeminal nerve, which can be stimulated at approximately 80 Hz, 100 Hz, 120 Hz, or 150 Hz.

[0141] In one example, equivalent circuit 610a is stimulated by a first channel, and equivalent circuit 610b is stimulated by a second channel.

[0142] Go to Figure 6C and Figure 6D In some embodiments, stimulation may be provided transcutaneously using electrodes 642a, 642b, and 642c of ear stimulation device 630. For example, electrodes 642a, 642b, and 642c may be configured to form corresponding circuits 650a and 650b.

[0143] In a first example, equivalent circuit 650a can be formed by electrodes 642b and 642c, which are configured to stimulate tissue portion 652a. In this example, tissue portion 652a can be positioned to target the ATN in or around the rostral region of the auricle near the TMJ. For example, equivalent circuit 650a can be designed to deliver stimulation to modulate activity in the VEF.

[0144] In a second example, an equivalent circuit 650b can be formed by electrodes 642a and 642c configured to stimulate tissue portion 652b. In this example, tissue portion 652b can be positioned to modulate activity in the VEF by stimulating the AVBN in or around the McS.

[0145] In yet another example, to achieve synergistic results, both the AVBN and the ATN are stimulated in or around the McS and in or around the rostral region of the auricle near the TMJ, respectively. For example, in this case, both the AVBN and the ATN can be stimulated approximately simultaneously in an alternating manner. In the illustration, each of electrodes 642a and 642b can be multiplexed with electrode 642c to form a circuit and apply current to tissue 652a and tissue 652b in an alternating manner. In another example, the AVBN and the ATN can be stimulated simultaneously.

[0146] In some embodiments, equivalent circuit 650a is stimulated by a first channel, and equivalent circuit 650b is stimulated by a second channel.

[0147] Go to Figure 6E and Figure 6F , ear stimulation device 660 is shown having electrodes 670a, 670b, and 670c. For example, electrodes 670a, 670b, and 670c can be configured to form corresponding circuits 680a and 680b according to an example. In one example, equivalent circuit 680a can be formed by electrode 670a and electrode 670c, which are configured to stimulate tissue portion 682. In this example, tissue portion 682 can be positioned to target the cymba concha area that is weakened by branches of the auricular branch of the vagus nerve (e.g., positioned for stimulation by the first electrode 670a) and the post-auricular area that is weakened by branches of the greater auricular nerve and the lesser occipital nerve (e.g., positioned for stimulation by the third electrode 670c). In a second example, equivalent circuit 680b can be formed by electrode 670b and electrode 670c, which are configured to stimulate tissue portion 684. In this example, tissue portion 684 can be positioned to target the oral region of the ear that is attenuated by the auriculotemporal nerve (e.g., positioned for stimulation by second electrode 670b) and the post-auricular region that is attenuated by branches of the greater auricular nerve and branches of the lesser occipital nerve (e.g., positioned for stimulation by third electrode 670c).

[0148] In some embodiments, tissue portion 682 is a tissue region of the concha, cymba concha, or a portion of both, which is stimulated at approximately 5 Hz, 15 Hz, or 30 Hz. In some embodiments, tissue portion 684 is positioned in the region of the trigeminal nerve, which is stimulated at approximately 80 Hz, 100 Hz, 120 Hz, or 150 Hz.

[0149] In some embodiments, equivalent circuit 682 is stimulated by a first channel and equivalent circuit 684 is stimulated by a second channel. The first channel and the second channel can be activated simultaneously and / or in an interleaved manner.

[0150] In some embodiments, the electrical stimulation therapy for bleeding management as described herein is performed using splenic nerve stimulation. In other embodiments, the spinal roots (sometimes referred to as dorsal root ganglia or DRG) that produce the great thoracic splanchnic nerve can be stimulation targets (also known as visceral DRG). In another embodiment, the celiac ganglion can be targeted for stimulation. For example, these neural structures, and directly the spleen can be stimulated percutaneously using ultrasound (e.g., focused or confocal ultrasound / high-intensity ultrasound). In another example, implantable electrodes or devices can be used to stimulate these neural structures (i.e., splenic nerve, celiac ganglion, DRG) and spleen. Outside the examples, the implantable mechanism can be configured to provide low-frequency stimulation (e.g., 1-30Hz) when activated. Activation can be achieved by programming (e.g., regular activation), external triggering (e.g., by wireless signals) and / or external power supply (e.g., by placing an external inductively coupled power supply within the range of an inductively charged implantable mechanism). For example, using external triggering, treatment can be scheduled according to the patient's needs, for example, this can retain power in a battery-powered device. For example, each therapeutic activation of the spleen or splenic nerve may involve a sequence of short pulses, such as an on-state stimulation duration of a short period of time (e.g., 0.5, 1, 2, or 5 seconds, etc.), followed by a rest period of at least the same duration (e.g., 0.5, 1, 2, or 5 seconds, etc.) or up to about 5 times longer than the on-state duration (e.g., up to about 2.5, 5, 10, or 25 seconds, etc.).

[0151] Example human study involving non-invasive stimulation using an ear nerve stimulation device

[0152] Figures 8A to 8E Results from three human studies using a non-invasive dual-nerve, dual-frequency approach are presented. Using this novel approach, the inventors were able to enhance hemostasis in both healthy humans and humans with platelet dysfunction for the first time. In all three experiments, the inventors achieved relevant and clinically meaningful results showing a significant enhancement of the hemostatic process.

[0153] In one experiment, blood loss was assessed during a clinical study in which subjects with chronic conditions requiring continuous dialysis underwent a dialysis port removal procedure. The subjects were randomly divided into a sham group and an active group. Subjects in both groups were fitted with an ear-hook neurostimulation device, such as the one described in the present disclosure; however, only the active group received the neurostimulation therapy described herein.

[0154] The therapy provided to the active group consisted of stimulation 30 minutes prior to surgical dialysis port removal. Specifically, 30 Hz and 100 Hz stimulation was delivered transcutaneously (transcutaneous auricular stimulation - tAN) to the skin in close proximity to the AVBN and trigeminal nerve branches, respectively, in and around the pinna.

[0155] The study demonstrated a significant difference in blood loss between the two groups. Figure 8A As shown in the , blood loss in the participants in the sham group was, on average, nearly four times (367%) the blood loss of the participants in the active group. As shown in the figure, the estimated blood loss in the sham group was approximately 37-38 ml, while the estimated blood loss in the active group was approximately 11-12 ml. This is a remarkable result given that the participants had platelet dysfunction.

[0156] In a second human study, prothrombin time (PT) was measured before and after stimulation was applied to healthy human participants. PT assesses how quickly clotting occurs and, therefore, plays an important role in the amount of blood lost after an injury. In this experiment, PT was measured from blood samples collected from participants before any stimulation was delivered. Next, the subjects were fitted with an ear-hook neurostimulator, such as the one described in the present disclosure; and a PT was placed in the ear-hook neurostimulator, similar to that described in the present disclosure. Figure 7B A similar stimulation protocol (e.g., short duration) was applied to all subjects for fifteen minutes as depicted in the timing diagram 720. In this study, a first stimulation pattern with a frequency of 100 Hz was directed to the ATN, and a second stimulation pattern with a frequency of 30 Hz was directed to the Arnold nerve. Following the stimulation period, a new blood sample was obtained from each participant, and PT was assessed from the new blood sample.

[0157] Go to Figure 8B , graph 810 shows the difference in human prothrombin time before stimulation 812 (e.g., about 11.2 seconds) compared to after stimulation 814 (e.g., about 9.8 seconds). This represents a 12% increase in clotting speed (normalized to 0.013) (i.e., increased clotting potential). Notably, all subjects had identical qualitative responses and very similar quantitative responses, as can be seen from the standard deviation (STD) and coefficient of variation (CV) in Table 7 below. In the study, PT was measured using whole blood via a fingertip lancet both before stimulation began and approximately one minute after stimulation ceased.

[0158]

[0159] Table 7: Human Study Results: Prothrombin Time

[0160] Figure 8C 、 8D8E and 8E show the results obtained by the third study, which involved healthy human subjects divided into two groups (ABVN and tAN groups). All participants in both groups were equipped with ear-hook neurostimulation devices, such as the ear-hook neurostimulation devices described herein, and all participants received a sham stimulation period followed by an active stimulation period. In all cases, baseline measurements were taken before sham measurements. Data analysis showed that there was no significant difference between baseline and sham measurements; therefore, only sham measurements are provided herein.

[0161] For the third study, the ABVN group received stimulation therapy as described herein on the skin of the auricle at a location adjacent to or very close to the area weakened by the ABVN; specifically, at the cymba concha. The tAN group received stimulation therapy as described herein on the skin of the auricle at a location adjacent to or very close to the area weakened by the ABVN (specifically, at the cymba concha) and at an area adjacent to or very close to the surface of the auriculotemporal nerve. In addition, both groups received "sham" stimulation, in which the electrodes were located in the same locations as when the stimulation was actually applied (active stimulation). The only difference between active stimulation and sham stimulation was that during sham stimulation, the stimulation intensity was set to zero; that is, no current was delivered during sham stimulation.

[0162] Both groups showed increased hemostatic activity. The results differed qualitatively and, initially, quantitatively between the groups. The experiments evaluated, among other things, changes in surface expression of two key molecules: glycoprotein (GP) IIb / IIIa and P-selectin. Some platelets showed an increase in only one of these molecules, while others showed an increase in both (double staining). Figure 8C Graph 820 shows sham group results 822a and 822b, providing a point of comparison. As shown in measurements 826a and 826b sixty minutes after activation, both groups demonstrated increased expression of glycoprotein (GP) IIb / IIIa on the platelet surface. However, the increase in GP IIb / IIIa in the ABVN group was slower, resulting in a lack of evidence of efficacy in the initial measurement period 824b, taken ten minutes after the stimulation therapy. In contrast, the initial tAN measurement 824a was essentially identical to the sixty-minute post-activation measurement 826.

[0163] A similar response was obtained when looking at the amount of platelets, which showed changes in both P-selectin and GPIIb / IIIa surface expression; this was Figure 8D830. As shown, both groups exhibited an increase in cells expressing P-selectin and GP IIb / IIIa 836a, 836b, although the tAN group responses 834a, 836a were more rapid compared to the sham group measurements 832a, 832b, while the ABVN group responses 834b, 836b did not show an increase until sixty minutes into the measurement.

[0164] Clot retraction is largely influenced by the presence of GPIIb / IIIa receptors on the platelet surface. Clot retraction aids wound healing by bringing the wound edges closer together until the wound is healed. Therefore, by promoting changes in GPIIb / IIIa receptors, subjects in both groups are expected to benefit from accelerated healing time.

[0165] In addition, go to Figure 8E , using thromboelastography (TEG) to analyze the coagulation function spectrum, the maximum blood clot density (TEG MA) in the tAN group increased significantly, while the ABVN group did not. As shown in the figure, ten minutes after active stimulation, the tAN group result 844a showed an average increase of approximately 20% in TEG MA compared to the sham group results 842a, 842b. In addition, one hour after the active stimulation stopped, the average increase in the tAN group result 846a showed an increase of nearly 30%. By the 60-minute analysis, all individuals represented in the tAN group showed an increase of at least 10% in TEG-MA, while most subjects showed an increase of at least 20% at the 60-minute analysis. The increase in clot density makes the clot stronger and stops bleeding faster. In contrast, individuals with low TEG MA (e.g., those with thrombocytopenia, thrombocytopathy, etc.) are often treated with platelet transfusions to manage bleeding because there are no available drug solutions to increase clot density. Therefore, based on preliminary results and without being bound by theory, the inventors anticipate that the electrical stimulation therapy described herein provides the benefit of enhancing platelet-mediated coagulation. In other words, individual platelets are enhanced to perform better at clotting than before stimulation.

[0166] Go to Figure 9, a block diagram 900 of example components of a pulse generator 950 in communication with example components of an auricle assembly 960 is shown. In some embodiments, the multi-channel pulse generator circuit 950 has at least one microcontroller or microprocessor 910 having at least one core. For example, when there are multiple microcontrollers or multiple cores, wireless communication 920 can be controlled, and other cores can be dedicated to controlling therapy. In some embodiments, low-power programmable logic circuitry (e.g., a field programmable gate array (FPGA) or a programmable logic device (PLD)) 912 is also provided. For example, the microcontroller 910 can be configured to switch to a low-power mode as frequently as possible, while the programmable logic circuitry 912 controls therapy delivery.

[0167] In some embodiments, inverter circuits 945a-n are used to generate biphasic / bipolar pulses. In some embodiments, one inverter circuit 945a-n is used for each channel 970a-n, while in other embodiments, a single inverter circuit 945 is used for multiple channels 970a-n. For example, each channel 970a-n can target a different anatomical region (e.g., tissue area) 948a-n. High voltage compliance (e.g., >50V, >70V in other embodiments, and >90V in yet other embodiments) can be used to ensure sufficient potential margin to generate the current required for intensity control 942a-n of each inverter circuit 945a-n by providing one or more high voltage inverters 940a-n to each inverter circuit 945a-n. In some embodiments, for increased safety, overcurrent detection circuitry 944a-n is provided in each inverter circuit 945a-n. In some embodiments, impedance measurement circuitry 946a-n is provided in each inverter circuit 945a-n. For example, the impedance measurement circuits 946a-n may enable tracking of impedance over time to identify failures in adequate therapy delivery. In some instances, therapy delivery may be affected when an electrode is not in contact or is not in good contact with the target tissue 948a-n, when a cable or connector between the multi-channel pulse generator 950 and one of the auricle assemblies 960 is disconnected, or when an electrode has deteriorated or is defective. Monitoring impedance over time provides the additional advantage of tracking the condition of the contact electrodes; thereby allowing the controller to alert the user when a contact electrode is nearing its useful life or is no longer usable. The FPGA 912 may control the inverter circuits 945a-n and receive feedback from the inverter control assemblies 938a-n.

[0168] In some embodiments, a battery 932 is used to power the pulse generator 950. For example, the battery 932 can power the components of the pulse generator 950 and / or the pinna assembly 960 via one or more low-voltage converters 934. Additionally, the pulse generator 950 can include a high-voltage converter 936 coupled to one or more high-voltage inverters 940a-940n for delivering electrical stimulation therapy via one or more channels 945a-n.

[0169] In some embodiments, an isolated port 918, such as a serial bus (USB), is used to charge the battery 932. In other embodiments, battery charging is accomplished wirelessly using inductive coupling (not shown). The battery 932 can be charged via a battery charging circuit 930.

[0170] In some embodiments, the isolated port 918 is used to communicate with the microcontroller 910 (e.g., via the communication port 916). The communication can be bidirectional, so that instructions or entire new code can be uploaded to the microcontroller 910, and information stored in the memory 922 can be downloaded. In some embodiments, the memory 922 or additional memory can be added to the circuit system as an external component (e.g., wireless or wired communication with the pulse generator 950). For example, the isolated port 918 (e.g., USB) can be used to connect the memory to the pulse generator 950. In other embodiments, at least a portion of the memory 922 can be internal to the microcontroller 910. In some embodiments, the FPGA 912 can also have internal memory.

[0171] In some embodiments, an external trigger circuit 924 is included so that stimulation can be started and / or stopped via an external signal. In some embodiments, the external trigger signal can be delivered through the isolated port 918; in yet other embodiments, a modified USB configuration (i.e., not using the standard USB pin configuration) can be used to deliver the trigger signal. Using a modified USB configuration will force the use of a custom USB cable, thereby ensuring that the external trigger is not provided by mistakenly using an off-the-shelf USB cable. In another example, the external trigger signal can be transmitted wirelessly from a separate source (e.g., via Bluetooth).

[0172] In some embodiments, a hardware user interface is provided for interacting with the multi-channel pulse generator 950 via the user interface circuitry 926. In one example, the user interface circuitry 926 can include buttons, LEDs, tactile (e.g., piezoelectric) devices (such as buzzers), and / or displays, or any combination thereof. In some embodiments, the user interface circuitry 926 includes a signal processing component for interpreting user interface commands delivered via an external device (e.g., via wireless communication 920). In some examples, the external device can be a smartphone application, a tablet computer, or a medical monitoring device (e.g., in a hospital setting).

[0173] In some embodiments, an external master clock 928 is used to drive the microcontroller 910 and / or FPGA 912. In other embodiments, the clocks for the components may be internal or integrated or co-packaged with the microcontroller 910 and / or FPGA 912. In some embodiments, one or more oscillators (including, in some cases, an adjustable oscillator 914) are used to set pulse parameters, such as frequency and / or pulse width.

[0174] In some embodiments, the pinna assembly 960 is made of a thin, flexible PCB or printed electronics so that it is lightweight and can be easily bent to accommodate different anatomies. In some embodiments, the pinna assembly 960 has more than one channel. The pinna assembly 960, or each of its channels, can include spike suppression circuits 947a-n and electrodes 965a-n to contact the skin at the location of target tissue 948a-n. In some embodiments, the pinna assembly 960 includes a unique chip identifier or unique ID chip 949. The unique ID chip can be used to track usage and prevent other unauthorized circuits from connecting to the multi-channel pulse generator 950. At least one pinna assembly 960 is connected to the multi-channel pulse generator 950.

[0175] In some embodiments, the pinna assembly 960 is made of a thin, flexible PCB or printed electronics so that it is lightweight and can be easily bent to accommodate different anatomies. In some embodiments, the pinna assembly 960 has more than one channel. The pinna assembly 960, or each of its channels, can include spike suppression circuits 947a-n and electrodes 965a-n to contact the skin at the location of target tissue 948a-n. In some embodiments, the pinna assembly 960 includes a unique chip identifier or unique ID chip 949. The unique ID chip can be used to track usage and prevent other unauthorized circuits from connecting to the multi-channel pulse generator 950. At least one pinna assembly 960 is connected to the multi-channel pulse generator 950.

[0176] In some embodiments, the methods and systems of the present disclosure use feedback to monitor and / or modify therapy. Figure 13, illustrates an environment 1350 and system 1360 for using feedback in neural stimulation. The environment 1350 and / or system 1360 can incorporate elements of various therapeutic devices described herein, such as Figure 6A Treatment device 600, Figure 6C The treatment device 630 and / or Figure 6E 660 of the therapeutic device. In addition, the environment 1350 may include peripheral devices 1354, 138, 1356, 1390 and / or a network system 1532. In addition, the system 1360 may include various aspects of a multi-channel pulse generator, described in detail below. For example, the environment 1350 and the system 1360 may be used to analyze sensor data in real time, thereby allowing closed-loop neurostimulation based on feedback data related to the wearer of the neurostimulation device. In another example, feedback monitoring may be used to alert the patient, caregiver, and / or clinical resources regarding the progress of therapy and / or problems with therapy. For example, if therapy is not being adequately delivered and / or the therapeutic device has been removed, a caregiver or clinician may be contacted at the clinical / caregiver computing system 1390.

[0177] In some embodiments, the system 1360 is activated at least in part by initiating power delivery to the system 1360 via the power control circuitry 1384. For example, one or more control elements 1386 can provide the wearer or patient with the ability to activate the system 1360 and / or set initial treatment parameters. In certain embodiments, therapy can be remotely activated and / or adjusted via an external device, such as the portable computing device 1354.

[0178] In some embodiments, one or more sensor interfaces 1362 of the system 1360 obtain feedback from one or more sensors 1370. For example, various sensors 1370 can be provided to monitor one or more symptoms being treated by the therapy, such as, in some instances, symptoms of stress and / or anxiety, pain, nausea, fatigue, inflammation, and / or disorientation / dizziness. In another example, certain sensors 1370 can be provided to monitor the wearer's activity or movement to coordinate therapeutic stimulation with the activity / movement. In some instances, the sensors 1370 can include one or more motion sensors 1370a (e.g., motion sensors, accelerometers, and / or gyroscopes) for monitoring motion activity (e.g., tremors, physiological movements), one or more galvanic skin sensors 1370b (in some cases, including electrochemical sensors) for monitoring galvanic skin activity (e.g., sweating, cortisol, etc.), one or more glucose sensors 1370c for monitoring blood glucose levels, one or more neural sensors 1370d for monitoring neural activity (e.g., via electroencephalogram (EEG) sensing electrodes), one or more cardiopulmonary sensors 1370e for monitoring cardiopulmonary activity (e.g., electrocardiogram (EKG) sensing electrodes, heart rate sensors, blood pressure (systolic, diastolic, and mean) sensors, etc.), and / or muscle response sensors 1370f (e.g., electromyogram (EMG) sensors) for monitoring muscle response activity. In another example, the sensors 1370 may include one or more audio sensors 1370g (e.g., microphones, bone conduction microphones, vibration sensors, etc.) for acquiring acoustic signals (e.g., speech and / or voice, breathing sounds, heart sounds, etc.). In yet another example, the sensors 1370 may include one or more ultrasound sensors 1370h for measuring deep tissue signals, such as, in some examples, central blood pressure, cerebral blood flow velocity (CBFV), heart rate, and / or cardiac output.

[0179] The sensors 1370 can communicate wired and / or wirelessly with the sensor interface 1362 of the system 1360. For example, certain sensors 1370 can be integrated into the earpiece and / or concha device of an ear-hook neurostimulation device (such as the various devices described in this disclosure). In another example, one or more sensors 1370 can be integrated into a pulse generator for delivery of neurostimulation therapy. Beyond the example described, regular monitoring can be achieved by prompting the wearer to touch one or more electrodes on the system 1360 (e.g., electrodes built into the surface of the pulse generator) or otherwise interact with a component of the system 1360 (e.g., the pulse generator) (e.g., extending the pulse generator away from the body to monitor tremors using a motion detector in the pulse generator). For example, prompts can be provided via the user interface 1366 by one or more speaker elements 1380a (e.g., verbal commands) and / or one or more lighting elements 1380b (e.g., an LCD display, an LED display, a 7-segment digital display, and / or an LED indicator next to printed information on the surface of the system 1360).

[0180] In some embodiments, the user interface 1366 is used to deliver a portion of the therapy to the wearer. For example, the system 1360 can coordinate neurostimulation therapy with a virtual reality (VR) device 1392. In some instances, the VR device 1392 can deliver audio, visual, and / or tactile outputs consistent with the goals of a particular therapy. For example, to reduce stress and anxiety, the system can configure the VR device 1392 to provide relaxing audio and / or visual outputs to the wearer during neurostimulation therapy. In another example, to overcome PTSD, phobias, cravings, and / or other addiction-related triggers, the VR device 1392 can be configured to present triggering audio and / or visual content during neurostimulation therapy. Although shown as a separate VR device 1392, in other embodiments, the neurostimulation electrodes are built into a VR device (e.g., a VR headset) as a neurostimulation therapy device that supports virtual reality.

[0181] In some embodiments, feedback data (such as sensor feedback) collected by system 1360 can be supplied by the pulse generator to one or more of peripheral devices 1354, 1390. For example, the feedback can include sensor signals related to the symptoms of the patient being treated by system 1360. A clinical user monitoring sensor indicators related to these signals can use one or more adjustable controls provided by the application to manually adjust the delivery of therapy accordingly. In addition, in some embodiments, the feedback can be used by one of peripheral devices 1354, 1390 to generate notifications for review by the patient, caregiver, or clinician. For example, the notifications can include low battery notifications, device removal notifications, or malfunction notifications. In an illustrative example, system 1360 can monitor impedance measurements to allow closed-loop neurostimulation. For example, if the impedance measurement results indicate a lack of proper contact between one or more electrodes of the treatment device and tissue on or around the patient's ear, a notification regarding removal or malfunction may be issued. For example, the notification can be delivered to the patient and / or one or more third parties via an application executed on one of peripheral devices 1354, 1390. For example, the application may sound an audible alarm, present a visual notification, or generate a tactile output on the peripheral device 1354, 1390. In addition, in some embodiments, the application may issue a notification via a communication method, such as sending an email, text message, or other electronic message to one or more authorized users (e.g., the patient, caregiver, and / or clinician).

[0182] In contrast, in some embodiments, a cloud platform with sensor data analytics 1352 available via a network can receive feedback, review current metrics, and pass instructions to the pulse generator (e.g., via a Wi-Fi network or indirectly via a local portable device 1354). In other examples, the pulse generator can collect feedback from one or more fitness monitors and / or health monitor devices 1354, 1390, analyze the feedback, and determine whether to adjust treatment accordingly.

[0183] In other embodiments, the pulse generator is included in the auricle component of the treatment device; that is, the pulse generator and the auricle component can be co-located so that there is no need to use an extended cable to connect them. The auricle component and the pulse generator can be wirelessly connected to the electronic device (e.g., a personal computer, tablet or mobile phone) 1354, 1390 and / or the remote server 1352. Conversely, in some embodiments, the electronic device 1354, 1390 is also wirelessly connected to the remote server 1352.

[0184] In some embodiments, the system 1360 includes at least one isolated port for wired communication with the peripheral devices 1354, 1390. In some instances, the isolated port can be a universal serial bus (USB) connection (e.g., a mini-USB connection, a micro-USB connection, a USB-C port, etc.), an Ethernet port, or a serial ATA (SATA) connector. For example, the isolated port can be included in the pulse generator for updating the software version running on the pulse generator or for reprogramming the treatment settings of the pulse generator. The isolated port can be connected to the network communication interface 1368 to enable communication between the peripheral devices 1354, 1390 and the system 1360 via the isolated port. The network communication interface 1368 can couple the isolated port to the system control circuit system 1372. For example, the network communication interface 1368 can establish a direct (e.g., wired) communication link with one of the peripheral devices 1354, 1390 to transfer data from the memory 1376 to the peripheral device 1354, 1390.

[0185] Additionally, in some embodiments, a wireless radio frequency (RF) antenna (e.g., a transmitter or a transmitter / receiver) is included in the network communication interface 1368. The RF antenna can communicate wirelessly with the peripheral devices 1354, 1358, either directly or via a network. The RF antenna, in combination with processing circuitry for generating wireless communications, can function as a broadcast antenna, providing information to any RF receiver within the reception area of ​​the system 1360. For example, the RF antenna can broadcast sensor data, sensor indicators, alarms, alerts, or other operational information received by one or more peripheral devices 1354, 1390. In other embodiments, the RF antenna, in combination with additional processing circuitry, can establish a wireless communication link with a specific peripheral device 1354, 1390. In some embodiments, the wireless communication link is a secure wireless communication link (e.g., HIPAA compliance) for sharing patient data with the peripheral devices 1354, 1390. For example, the wireless communication link can be used to receive control settings from the peripheral device 1354, 1390 to control the functions of the pulse generator.

[0186] In some embodiments, sensor data is received from one or more portable wireless computing devices 1354 via a network communication interface 1368. In some instances, sensor elements of common smartphones, smart glasses, smart rings, and / or smart watches (e.g., accelerometers, gyroscopes, microphones, image sensors (e.g., cameras), heart rate monitors, blood oxygen saturation, blood pressure, glucose sensors, etc.) can be used by applications designed to interoperate with system 1360 to provide sensor data to system 1360. In the illustration, imaging (e.g., video) of pupil changes (e.g., pupil dilation) can be captured by a smartphone or smart glasses and used by system 1360 as feedback for making therapy adjustments. For example, pupillometry measurements can be used as a measure of attention, alertness, or wakefulness (or lack thereof). Thus, feedback can be used to adjust therapy to maintain a desired level of attention, alertness, and / or wakefulness.

[0187] In some embodiments, sensor data is received from one or more additional sensor devices 1356 via the network communication interface 1368. In some examples, the additional sensor devices 1356 may include a fitness monitor and / or activity tracker (e.g., to provide data similar to the data collected by the motion sensor 1370a, the galvanic skin sensor 1370b, and / or the cardiopulmonary sensor 1370e), a home health monitoring device (e.g., a digital smart blood pressure cuff, a digital smart thermometer, etc. to provide data similar to the data collected by the cardiopulmonary sensor 1370e), and / or a remote patient monitoring device (e.g., a blood glucose meter to provide data similar to the data collected by the blood glucose sensor 1370c, a pulse oximeter, a wearable heart monitor (e.g., a Holtermonitor) to provide data similar to the data collected by the cardiopulmonary sensor 1370e).

[0188] In some embodiments, sensor data is received from one or more clinical devices and / or equipment 1358 via a network communication interface 1368. In the illustration, imaging techniques such as magnetic resonance imaging (MRI) and / or functional MRI (fMRI) can be used to tailor therapy to a specific user in a clinical setting. In other examples, data similar to that collected by neural sensors 1370d, cardiopulmonary sensors 1370e, blood glucose sensors 1370c, and / or muscle response sensors 1370f can be provided by various clinical devices 1358.

[0189] In some embodiments, the type of monitoring used by system 1360 and / or the reliance on (e.g., trust in) various incoming sensor data can be based in part on the treatment setting. For example, neural data captured by a sensor such as neural sensor 1370d may be more easily captured in a hospital setting, while certain cardiopulmonary data (e.g., heart rate monitoring) captured by a sensor such as cardiopulmonary sensor 1370e may be achieved by capturing signals from a pulse meter built into an earpiece or another sensor (e.g., additional sensor device 1356) built into a low-budget health monitoring device (e.g., a fitness monitor or smartwatch).

[0190] In some embodiments, sensor interface 1362 collects signals from sensor 1370 and provides the signals to signal processing circuitry 1364. For example, signal processing circuitry 1364 may include one or more filters (e.g., bandpass filters), amplifiers, and / or other circuitry to eliminate noise, isolate valid input signals, and / or increase signal strength. In some embodiments, signal processing circuitry 1364 converts analog signals into digital signal components.

[0191] In some embodiments, sensor signals from the sensor 1370, the portable wireless computing device 1354, the additional sensor device 1356, and / or the clinical device / equipment 1358 are provided to the system control circuit system 1372 for data analysis. In some instances, the system control circuit system 1372 can perform threshold processing, pattern analysis, and / or time-varying analysis to identify physiological, biological, and / or physical behavior of the wearer of the therapeutic stimulation device that corresponds to a therapeutic adjustment. For example, the sensor data can be collected in a memory or temporary data storage area 1376 to analyze the sensor data over a predetermined time period. In some instances, the time period may vary depending on the type of therapy being provided, the type of data being analyzed, and / or the therapeutic goals. In some instances, adjustments to the therapy can include starting therapy, stopping therapy, and / or adjusting one or more therapy parameters (e.g., voltage, frequency, stimulation mode, stimulation location, etc.).

[0192] In some embodiments, the system control circuitry 1372 provides sensor data to an external sensor data analysis system 1352 via the network communication interface 1368. In some instances, the sensor data analysis system 1352 can include an edge router, a cloud computing platform, and / or one or more networked servers configured to analyze the sensor data to identify conditions that trigger therapeutic adjustments. In some embodiments, the analysis involves biometric fingerprint analysis, in which the physiological, biological, and / or physical behaviors captured in the sensor data are analyzed based on a baseline or historical physiological, biological, and / or physical behavior of a particular wearer.

[0193] In some embodiments, based on analysis of sensor data by the system control circuitry 1372 and / or the sensor data analysis system 1352, therapy parameter adjustments are provided to the therapy controller 1374 for adjusting stimulation parameters delivered via the therapy delivery circuitry 1378 (e.g., pulse generator circuitry) to a set of stimulation electrodes 1382. The therapy delivery circuitry 1378 and stimulation electrodes 1382 are described above with reference to FIG. Figure 9 Discussed in more detail.

[0194] In the first illustrative example, upon reduction or elimination of one or more symptoms, the therapeutic output may similarly be reduced or stopped. Conversely, as one or more symptoms increase or are added, the therapeutic output may similarly be activated or adjusted (increased, expanded, etc.).

[0195] In another illustrative example, feedback related to electrodermal activity can be used to monitor and detect the speed or timing of symptoms and / or treatment results. In one example, electrodermal activity can be sensed by electrodermal sensor 1370b. For example, an electrodermal patch with one or more electrodermal sensors 1370b can be used to estimate an individual's stress level by assessing cortisol levels in sweat.

[0196] In one example, one or more motion detectors 1370a can be configured to detect tremors and / or physiological movements. In one aspect, tremors and / or physiological movements can indicate an underlying condition and / or treatment for that condition. In one example, tremors and / or physiological movements can indicate symptoms associated with substance withdrawal. In another example, movements and combinations of movement sequences can be used to assess the results of a training program designed to restore these motor performances.

[0197] In another example, feedback from blood glucose sensor 1370c can be used to adjust therapy. People with type 2 diabetes lack the ability to control their blood glucose levels, and vagus nerve stimulation has been shown to reduce hyperglycemia. Therefore, assessing blood glucose levels can be used to trigger stimulation to increase blood glucose control.

[0198] In another example, neural sensors 1370d and / or cardiopulmonary sensors 1370e can be used to assess heart rate and heart rate variability to determine general activity of the autonomic nervous system and / or the relative activity of the sympathetic and parasympathetic branches of the autonomic nervous system and to adjust therapy. Autonomic nervous activity may indicate symptoms associated with substance withdrawal. In one aspect, the therapeutic device can be used to provide therapy for treating heart conditions such as atrial fibrillation and heart failure. In one example, therapy can be provided for regulating the autonomic nervous system. In some embodiments, the therapeutic device can be used to provide therapy to balance the ratio between any combination of the autonomic nervous system, the parasympathetic nervous system, and the sympathetic nervous system.

[0199] In another illustrative example, feedback signals collected by the muscle response sensors 1370f can be analyzed to trigger stimulation during body movement recovery, such as arm movement recovery. For arm movement recovery, multiple muscle response sensors 1370f can be placed in a cannula, such as those provided by Battelle Memorial Institute of Norwell, Massachusetts. EMG cannula.

[0200] In a final illustrative example, attention, alertness, and / or wakefulness can be assessed by measuring cerebral blood flow velocity (CBFV) via ultrasound sensor 1370h. In such an example, CBFV can be used as feedback to adjust therapy.

[0201] In some embodiments, the sensor data analysis system 1352 collects historical sensor data and treatment parameters for a patient population and applies the collected data to perform machine learning analysis to improve treatment plans and parameters at the individual level. For example, this can result in faster and / or higher functional recovery. After a stroke or TBI, in an illustrative example that can be used in a hospital environment (such as an intensive care unit (ICU) or a neonatal intensive care unit (NICU)), data collected via sensors 1370 (e.g., in some instances, heart rate (ECG), arterial oxygen saturation (SpO2), arterial blood pressure (in some cases using an arterial catheter), central venous pressure, core temperature, blood glucose level, respiratory rate and / or respiratory volume, urine output and / or cardiac output sensors) can be analyzed and applied to automatically guide and / or adjust neuromodulation therapy. In other examples, the sensor data can provide insights into osmotic pressure, serum electrolytes and / or blood gases (arterial), which can then assist in making decisions when automatically guiding and / or adjusting neuromodulation therapy. In some instances, sensor data may be analyzed for evidence of the patient's comfort level (e.g., indicators of the patient's underlying pain and / or stress), evidence of inflammation, and / or evidence of ischemic processes (e.g., evidence of metabolic waste accumulation).

[0202] In some embodiments, the sensor data analysis system 1352 applies machine learning and / or artificial intelligence (AI) analysis to optimize therapy phases to deliver more effective and / or efficient treatment. Figure 14 , an example sensor data analysis system 1402 and platform environment 1400 obtains data from a neural stimulation system (e.g., device and / or pulse generator) 1404 and / or a computing device 1406 and analyzes the data to confirm whether treatment goals are being met and / or automatically optimize treatment parameters to improve the effectiveness of the therapy.

[0203] In some embodiments, the sensor data analysis system 1352 includes a therapy data collection engine 1408 configured to collect data from the neurostimulation system 1404 and associate the data with individual users. In some instances, the therapy data collection engine 1408 can collect data associated with each user of each neurostimulation system 1404 and store the data in a computer-readable data storage area (user data storage) 1410. In some instances, the user data can include active therapy parameter data 1412 (e.g., stimulation pattern, frequency, identification of a specific therapy routine, identification of specific therapy settings, etc.), active therapy feedback data 1414 (e.g., sensor data collected by the neurostimulation system 1404 and / or one or more other sensor devices in communication with the neurostimulation system 1404), and / or active therapy context data 1416 (e.g., geographic location, time of day, day of week, ambient temperature, wearer's speed / acceleration, ambient noise level, etc.).

[0204] In some embodiments, the external sensor data collection engine 1418 collects sensor data obtained by one or more devices external to the neurostimulation system 1404 and communicates it to the sensor data analysis system 1402. In some examples, the devices may include fitness monitoring devices (e.g., Fitbit, Apple Watch, or Garmin smartwatch) and / or health monitoring devices (e.g., blood glucose meters, Holter monitors, electrocardiogram (EKG) monitors, or electroencephalogram (EEG) monitors). In other examples, the external devices may include clinical patient monitoring and / or management devices (e.g., brain monitoring, carbon dioxide monitoring, brain / body oximetry, pulse oximetry, local and / or body temperature management, etc.).

[0205] In some embodiments, the therapy data analysis engine 1420 analyzes user data stored in the user data store 1410 to measure the efficacy of ongoing and / or recently completed therapies. For example, evidence of efficacy can be based on a set of therapy goal parameters 1422 associated with a given therapy. For example, the therapy data analysis engine 1420 can compare user positive therapy feedback data 1414 to a threshold and / or target value range. In another example, the therapy data analysis engine 1420 can compare the duration of each symptom, as evidenced by sensor data, to a threshold duration before the symptom is alleviated or ceases. In some embodiments, the therapy goal parameters 1422 can be clinician-adjustable, allowing clinicians to customize the target parameters for specific patients. In certain embodiments, different sets of therapy goal parameters 1422 are provided based on, in some examples, user demographics 1424 (e.g., age, gender, etc.), user medical status 1426 (e.g., diagnosed diseases and / or conditions), and / or user clinical data 1428 (e.g., weight, body mass index (BMI), smoking status, medication use, pregnancy status, etc.). In further embodiments, the treatment target parameters 1422 are adjusted based on user physiological characteristics 1430 (eg, a baseline or typical physiological pattern exhibited by a particular wearer).

[0206] In some embodiments, the therapy analysis engine 1420 provides parameter increments and / or other feedback information to the therapy parameter adjustment engine 1432 based on the difference between the treatment target parameters 1422 and the user active treatment feedback data 1414 to determine a set of adjusted treatment parameters. A set of adjusted treatment parameters may include one or more device settings (e.g., frequency, mode, repetition, etc.). In an illustration involving repeated rehabilitation exercises, the stimulation duration can be systematically varied so that the rate of improvement after triggering relative to the stimulation duration can be determined using a motion sensor (including, for example, a three-axis accelerometer and / or a gyroscope). For example, the steps for changing the stimulation can be stored as therapy stimulation parameters and / or routines 1438. The stimulation duration can be automatically adjusted to increase the success rate and / or accelerate the recovery of a specific function.

[0207] In an example illustration of motor skill rehabilitation training for a stroke patient, based at least in part on user-positive therapy feedback data 1414 corresponding to the current activity or rehabilitation exercise, the therapy parameter adjustment engine 1432 can determine the next therapy routine and / or stimulation parameters. For example, after the current task is sufficiently performed, the therapy parameter adjustment engine 1432 can provide instructions for the next task to the neural stimulation system 1404. In some instances, the next task may be more challenging, exercise different muscle groups, and / or focus on linking the learned skills to a series of performances. The next task can be selected from a hierarchy or series of tasks stored, for example, as part of the therapy stimulation parameters and / or routine 1438.

[0208] In some embodiments, therapy stimulation parameters and / or routines 1438 include one or more priming routines applied to the wearer of the neurostimulation system 1404 prior to commencing therapeutic stimulation (e.g., a motor skill training session or a PTSD recovery session). In the illustration, neurostimulation for priming or preparing cognitive pathways for the therapy / training session can begin within at least one minute, between one and ten minutes, and up to 30 minutes, and / or approximately one hour of the therapy training session. In another example, the priming routine can be introduced in the middle of a larger therapy routine involving multiple therapy sessions or treatment periods. In a first example, the therapeutic stimulation can be paired with activities during the first training session, such as developing new pathways to restore a specific function. During a second priming session, the priming stimulation can be used for general cognitive enhancement, such as while performing a motor skill routine encompassing multiple functions (e.g., a combination of multiple actions / tasks). In a second example, the therapeutic stimulation can be paired during the first training session with exposure to stimulating input (e.g., auditory, visual, and / or tactile, etc.) to, for example, overcome adverse reactions. During the second priming session, the priming stimulation can be used to enhance overall emotional well-being, such as during rest periods between exposures to stimulating input.

[0209] In some embodiments, the sensor data analysis system 1402 provides the adjusted therapy parameters to the corresponding neurostimulation system 1404, either directly or via another computing device 1406. The user data archiving engine 1434 can also archive the user active therapy parameter data 1412 to capture the therapy parameters before adjustment as user historical therapy parameter data 1436. Further, the adjusted therapy parameters can be added to or replace a previous version of the user active therapy parameter data 1412 corresponding to the subject neurostimulation system 1404.

[0210] In some embodiments, the user data archiving engine 1434 collects user data stored in the user data store 1410 to archive it as corresponding user historical treatment parameter data 1436, user historical treatment feedback data 1440, and / or user historical treatment context data 1442. In some embodiments, the user data archiving engine 1434 de-identifies at least a portion of the archived user data 1436, 1440, and / or 1442 for use in big data analysis across multiple users of the neurostimulation system 1404.

[0211] In some embodiments, in addition to automatically acquired sensor data and / or contextual data, the user feedback collection engine 1444 also collects information about the wearer's experience using the neurostimulation system 1404 from the wearer and / or the clinician working with the wearer. For example, the user feedback collection engine 1444 can collect user survey data 1446 about the wearer's experience during and / or after therapy. For example, the user can have a corresponding software application running on one of the computing devices 1406 and / or the user's user interface with the neurostimulation device 1404 to submit feedback about their experience. In some examples, the wearer feedback can include information about stimulation comfort level, symptom improvement level, and / or wearing comfort level. In some examples, feedback can be provided using a numerical scale or descriptors associated with the numerical scale (e.g., excellent, good, fair, not very good, unpleasant). In another example, the wearer can submit feedback in real time regarding distress (symptoms not improving / seemingly worse, stimulation causing severe discomfort, etc.), which the therapy parameter adjustment engine 1432 can consider when determining adjusted therapy parameters.

[0212] In some embodiments, the user feedback collection engine 1444 collects clinical observation data 1448 about the clinician's experience working with patients during therapy and / or who have received prescribed therapy. In some instances, the clinical observation data 1448 can include outcome information (e.g., reduction or discontinuation of prescribed medication), diagnostic adjustment information (e.g., severity of condition), and / or progress information (e.g., relative recovery of abilities).

[0213] In some embodiments, the therapy model training engine 1450 accesses user historical treatment parameter data 1436, user historical treatment feedback data 1440, user historical treatment context data 1442, user survey data 1446, and / or clinical observation data 1448 archived from a population of wearers of the neurostimulation system 1404 over a certain period of time (e.g., one month, three months, six months, one year, etc.) to develop one or more trained learning models 1452. For example, the therapy model training engine 1450 can apply machine learning and / or artificial intelligence to obtain promising therapy stimulation parameters and / or routines, such as the therapy stimulation parameters and / or routines 1438. For example, the therapy model training engine 1450 can identify therapy parameters, treatment plans, and / or context parameters (e.g., settings, timing, etc.) that are associated with successful treatment. The trained learning models 1452 may include one or more models for each treatment type (e.g., treatment regimens for treating a particular disease, condition, symptom, etc.), each diagnosis (e.g., comorbidity, such as smoking status, mental health diagnosis, such as depression or PTSD), and / or each user demographic (e.g., age, gender, etc.), and / or each user type (e.g., military personnel, athletes, etc.). For example, the trained learning model 1452 may be designed to predict beneficial therapy stimulation parameters and / or routines 1438 for a particular patient based on user demographics 1424, user medical conditions 1426, and / or user clinical data 1428.

[0214] In some embodiments, after initially training the trained learning model 1452, the therapy model optimization engine 1454 updates the trained learning model 1452 with the new learning data after collecting additional user historical data 1436, 1440, and / or 1442, user survey data 1446, and / or clinical observation data 1448. For example, the therapy model optimization engine 1454 can periodically or continuously optimize the trained learning model 1452 as new data is collected by the sensor data analysis system 1402.

[0215] Although the sensor data analysis system 1402 is shown as being separate from the neurostimulation system 1404, in some embodiments, portions of the sensor data analysis system 1402 are included within the neurostimulation system 1404 and / or are included in a computing device 1406 that is in direct communication (e.g., wired or short-range wireless transmission range, etc.) with the neurostimulation system 1404. For example, in order to quickly adjust ongoing neurostimulation therapy based on sensor feedback, portions of the functionality of the therapy data analysis engine 1420 can be performed in real time or near real time on a device local to the wearer.

[0216] Reference has been made to diagrams illustrating methods and systems according to embodiments of the present disclosure. Various aspects thereof may be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general-purpose computer, a special-purpose computer, or other programmable data processing device to produce a machine, such that execution of the instructions by the processor of the computer or other programmable data processing device creates means for implementing the functions / operations specified in the diagrams.

[0217] One or more processors may be utilized to implement the various functions and / or algorithms described herein. In addition, any functions and / or algorithms described herein may be executed on one or more virtual processors, such as on one or more physical computing systems (e.g., a computer farm or cloud drive).

[0218] Aspects of the present disclosure may be implemented by hardware logic (where the hardware logic naturally also includes any necessary signal lines, memory elements, etc.), and such hardware logic is capable of operating without active software involvement beyond the initial system configuration and any subsequent system reconfiguration. The hardware logic may be synthesized on a reprogrammable computing chip, such as a field programmable gate array (FPGA), a programmable logic device (PLD), or other reconfigurable logic device. In addition, the hardware logic may be hard-coded onto a custom microchip, such as an application specific integrated circuit (ASIC). In other embodiments, software stored as instructions to a non-transitory computer readable medium (such as a memory device, an on-chip integrated memory unit, or other non-transitory computer readable storage) may be used to perform at least part of the functionality described herein.

[0219] Various aspects of the embodiments disclosed herein are executed on one or more computing devices, such as laptop computers, tablet computers, mobile phones or other handheld computing devices, or one or more servers. Such computing devices include processing circuit systems embedded in one or more processors or logic chips, such as central processing units (CPUs), graphics processing units (GPUs), field programmable gate arrays (FPGAs), application specific integrated circuits (ASICs), or programmable logic devices (PLDs). In addition, the processing circuit system can be implemented as multiple processors working in concert (e.g., in parallel) to execute the instructions of the above-described inventive process.

[0220] The process data and instructions for executing the various methods and algorithms derived herein may be stored in a non-transitory (i.e., non-volatile) computer-readable medium or memory. The claimed advancements are not limited by the form of the computer-readable medium on which the instructions for the processes of the present invention are stored. For example, the instructions may be stored in a CD, DVD, FLASH memory, RAM, ROM, PROM, EPROM, EEPROM, hard disk, or any other information processing device (such as a server or computer) that communicates with a computing device. The processing circuitry and stored instructions may enable Figure 9 Pulse generator 950, Figure 13 System 1360 and / or Figure 14 The sensor data analysis system 1402 is capable of executing the various methods and algorithms described above. In addition, the processing circuit system and the stored instructions can enable Figure 13 The peripheral devices 1354, 1390 are capable of executing the various methods and algorithms described above.

[0221] These computer program instructions can instruct a computing device or other programmable data processing apparatus to operate in a specific manner, so that the instructions stored in the computer-readable medium produce an article of manufacture including instruction means for implementing the functions / operations specified in the illustrated flow.

[0222] The embodiments of this specification rely on network communications. It will be understood that the network can be a public network, such as the Internet, or a private network, such as a local area network (LAN) or a wide area network (WAN), or any combination thereof, and can also include a PSTN or ISDN subnet. The network can also be wired, such as an Ethernet network, and / or can be wireless, such as a cellular network including EDGE, 3G, 4G, and 5G wireless cellular systems. The wireless network can also include Wi-Fi, Bluetooth, Zigbee, or another form of wireless communication.

[0223] Computing devices, such as Figure 13 The peripheral devices 1354 and 1390 of the computing device may, in some embodiments, further include a display controller for interacting with a display (e.g., a built-in display or an LCD monitor). The general I / O interface of the computing device may interact with a keyboard, a manually operated motion tracking I / O device (e.g., a mouse, a virtual reality glove, a trackball, a joystick, etc.), and / or a touch screen panel or touchpad on or separate from the display.

[0224] In some embodiments, a computing device, such as Figure 13 A sound controller is also provided in the peripheral devices 1354, 1390 to interact with the speaker / microphone to provide audio input and output.

[0225] Furthermore, the present disclosure is not limited to the specific circuit components described herein, nor is the present disclosure limited to the specific sizes and types of these components. For example, those skilled in the art will appreciate that the circuit systems described herein may be adapted to accommodate variations in battery size and chemistry, or to accommodate the requirements of the backup load to be powered.

[0226] Certain functions and features described herein may also be performed by various distributed components of the system. For example, one or more processors may perform these system functions, wherein the processors are distributed across multiple components communicating in a network. Distributed components may include one or more client and server machines that can share processing, as well as various human-machine interfaces and communication devices (e.g., display monitors, smartphones, tablet computers, personal digital assistants (PDAs)). The network may be a private network, such as a LAN or WAN, or a public network, such as the Internet. System input may be received through direct user input or remotely in real time or in batch mode.

[0227] Although the context is provided, in other embodiments, the methods and logic flows described herein may be executed on modules or hardware that are not identical to the modules or hardware described. Therefore, other embodiments are also within the scope of what is claimed.

[0228] In some embodiments, a cloud computing environment such as Google Cloud Platform can be used. TM ) to perform at least a portion of the methods or algorithms detailed above. The processes associated with the methods described herein can be executed on a computing processor in a data center. For example, a data center can also include an application processor that can be used as an interface with the system described herein to receive data and output corresponding information. The cloud computing environment can also include one or more databases or other data stores, such as cloud storage and query databases. In some embodiments, a cloud storage database (such as Google Cloud Storage) can store processed and unprocessed data supplied by the system described herein.

[0229] The system described herein can communicate with a cloud computing environment via a secure gateway. In some embodiments, the secure gateway includes a database query interface, such as the Google BigQuery platform.

[0230] In some embodiments, according to various embodiments described herein, an edge server is used to transmit data between one or more computing devices and a cloud computing environment. For example, an edge server can be a computing device configured to perform processor-intensive operations, which are sometimes involved in performing machine learning processes, such as natural language processing operations. For example, an edge server can include one or more GPUs that can efficiently perform matrix operations, and a large amount of cache or other high-speed memory to provide services for the GPU. The edge server may be an independent physical device. The edge server can be incorporated into other computing devices, such as laptops, tablets, medical devices, or other dedicated computing devices. Alternatively or additionally, the edge server can be located in a portable case of such a computing device. In another example, the edge server can be incorporated into the communication and processing capabilities of a mobile unit (such as a vehicle or drone), or can be located within the mobile unit.

[0231] In some embodiments, the edge server communicates with one or more local devices of the edge server. For example, the edge server can be used to transfer a portion of the computing power that is traditionally transferred to the cloud computing environment to the local environment, so that any computing-intensive data processing and / or analysis required by one or more local devices can be run accurately and efficiently. In some embodiments, the edge server is used to support one or more local devices without a connection to the remote computing environment. The edge server can be configured to communicate with one or more local devices directly or via a network. For example, the edge server may include a dedicated wireless network interface, a public wireless network interface and / or a wired interface, and the edge server can communicate with one or more local devices through the interface. In some embodiments, some local devices can be configured to communicate with the edge server indirectly, for example via another local device. In addition, the edge server can be configured to communicate with the remote computing (e.g., cloud) environment via one or more public or private wireless network interfaces. For example, a device that interacts with the edge server can share processing functions with the edge server via one or more APIs implemented by a process.

[0232] The systems described herein may include one or more artificial intelligence (AI) neural networks for performing automatic analysis of data. In some instances, the AI ​​neural network may include a synaptic neural network, a deep neural network, a transformation neural network, and / or a generative adversarial network (GAN). One or more machine learning techniques and / or classifiers, such as, in some instances, anomaly detection, clustering, and / or supervision and / or association, may be used to train the AI ​​neural network. In one example, the AI ​​neural network may be developed by Google of Mountain View, CA and / or based on a transformer-based bidirectional encoder representation (BERT) model.

[0233] The systems described herein can communicate with one or more underlying model systems (e.g., artificial intelligence neural networks). In some instances, the underlying model systems can be developed, trained, tuned, fine-tuned, and / or rapidly designed to evaluate data inputs, such as by system 1060 and / or Figure 13 Sensor data analysis system 1352 collects sensor input and / or Figure 14 Sensor inputs collected by the sensor data analysis system 1402. In some examples, the base model system can include or be based on a generative pre-trained transformer (GPT) model (e.g., GPT-3, GPT-3.5, and / or GPT-4) available via the OpenAI platform from OpenAI of San Francisco, CA and / or a generative AI model (e.g., PaLM 2) available through Azure OpenAI or Vertex AI from Google Inc. of Mountain View, CA.

[0234] Certain base models can be fine-tuned as AI models trained to perform specific tasks required by the systems described herein. For example, training material can be submitted to certain base models to adjust the training of the base models to perform the types of analysis described herein.

[0235] Depending on the circumstances, the systems and methods described herein can apply multiple base model systems. For example, the context can include the type of data, the type of response output required (e.g., at least one answer, at least one answer plus an explanation of the reasoning behind the answer, etc.). In another example, the context can include user-based context, such as demographic information, entity information, and / or product information. In some embodiments, a single base model system can dynamically adapt to different forms of analysis requested by the systems and methods described herein using rapid design.

[0236] Although certain embodiments have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the present disclosure. Indeed, the novel methods, apparatuses, and systems described herein may be embodied in a variety of other forms; furthermore, various omissions, substitutions, and changes in form may be made to the methods, apparatuses, and systems described herein without departing from the spirit of the present disclosure. The accompanying claims and their equivalents are intended to cover such forms or modifications as fall within the scope and spirit of the present disclosure.

Claims

1. A method of increasing the coagulation potential of a subject, the method comprising: positioning at least one electrode on or through the subject's skin at a location such that each of the at least one electrode is in electrical communication with: i) a neural structure of or leading to the auriculotemporal nerve and / or ii) a neural structure of or leading to the auricular branch of the vagus nerve; and Electrical nerve stimulation therapy is delivered through: For each respective electrode of the at least one electrode in electrical communication with a neural structure of or leading to the auriculotemporal nerve, applying a first stimulation pattern having a frequency in the range of 70 to 150 Hz via the respective electrode, and / or for each of the at least one electrode in electrical communication with a neural structure of or leading to the auricular branch of the vagus nerve, applying a second stimulation pattern having a frequency in the range of 5 to 30 Hz via the corresponding electrode; wherein the electrical nerve stimulation therapy increases the coagulation potential of the subject.

2. The method of claim 1, wherein the electrical nerve stimulation therapy is delivered repeatedly on a regular basis to treat a chronic condition.

3. The method of claim 2, wherein the chronic disease is a chronic coagulation defect in the subject.

4. The method of claim 3, wherein the chronic coagulation defect is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

5. The method of claim 1, wherein the electrical nerve stimulation therapy is delivered prior to and / or during a surgical procedure to at least partially counteract the effects of an anticoagulant drug in the subject.

6. The method of claim 1 or 5, wherein the electrical nerve stimulation therapy is delivered prior to and / or during a medical procedure that has a high potential for inducing bleeding.

7. The method of claim 6, wherein the electrical nerve stimulation therapy is delivered to reduce the likelihood of blood transfusion and / or reduce the amount of blood transfusion required.

8. The method of claim 6, wherein the electrical nerve stimulation therapy is delivered to reduce blood loss during postpartum hemorrhage.

9. The method of any of the preceding claims, wherein the electrical nerve stimulation therapy is configured to cause a transient increase in the coagulation potential of the subject.

10. The method of any one of the preceding claims, wherein the electrical nerve stimulation therapy is delivered to treat abnormal uterine bleeding (AUB), heavy menstrual bleeding (HMB), and / or menorrhagia.

11. The method of claim 10, wherein the AUB, the HMB, and / or the menorrhagia are due to a bleeding disorder.

12. The method of any one of the preceding claims, wherein the electrical nerve stimulation therapy is delivered as a preventative or prophylactic treatment.

13. The method of claim 12, wherein the electrical nerve stimulation therapy is configured as a prophylactic treatment to minimize bleeding in an individual with a bleeding disorder.

14. The method of claim 13, wherein the bleeding disorder is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

15. The method of any one of claims 1 to 4, wherein the electrical nerve stimulation therapy is delivered before and / or during military operations.

16. The method of any of the preceding claims, wherein the electrical nerve stimulation therapy increases the rate of thrombin generation at or near the site of injury in the subject.

17. A method for increasing the ratio of procoagulant to anticoagulant activity at or near a site of injury in a subject, the method comprising: for each respective electrode of at least one electrode, contacting the subject's skin with the respective electrode in a respective area of: i) a neural structure of the auriculotemporal nerve (ATN), ii) a neural structure connected to the ATN, iii) a neural structure of the auricular branch of the vagus nerve (ABVN), or iv) a neural structure connected to the ABVN; as well as applying a corresponding stimulation pattern of at least one stimulation pattern within a frequency range of 5 to 150 Hz to each of the at least one electrode, wherein the corresponding stimulation pattern is configured to stimulate a neural pathway that causes spleen weakness; Wherein applying the at least one stimulation pattern for a period of at least one minute increases the ratio of procoagulant to anticoagulant activity at or near the injury site in the subject.

18. The method of claim 17, wherein the injury site comprises at least one of a penetrating injury or a non-compressible injury.

19. The method of claim 18, wherein the non-compressible injury is gastrointestinal bleeding.

20. The method according to any one of claims 17 to 19, wherein the at least one stimulation pattern is applied before and / or during a surgical procedure.

21. The method of claim 20, wherein the at least one stimulation pattern is applied to reduce the likelihood of blood transfusion and / or reduce the amount of blood transfusion required.

22. The method of any one of claims 17 to 21, wherein the at least one stimulation pattern is configured to cause a transient increase in the coagulation potential of the subject.

23. The method of any one of claims 17 to 22, wherein the at least one stimulation pattern is configured to increase the rate of thrombin generation at or near the injury site.

24. A system for increasing the rate of thrombin generation at or near a site of injury in a subject, the system comprising: An ear stimulation device comprising at least one therapeutic electrode, each respective therapeutic electrode of the at least one therapeutic electrode configured to be aligned with an area of ​​the subject's skin to place the respective therapeutic electrode in electrical communication with: i) a neural structure of the auriculotemporal nerve or a neural structure leading to the auriculotemporal nerve and / or ii) a neural structure of the auricular branch of the vagus nerve or a neural structure leading to the auricular branch of the vagus nerve; as well as pulse generating circuitry configured to deliver electrical nerve stimulation therapy via the at least one therapeutic electrode by: generating, for each respective electrode of the at least one therapeutic electrode in electrical communication with a neural structure of or leading to the auriculotemporal nerve, a first stimulation pattern within a frequency range of 70 to 150 Hz for stimulating the auriculotemporal nerve via the respective electrode, and / or generating, for each respective electrode of the at least one therapeutic electrode in electrical communication with a neural structure of or leading to the auricular branch of the vagus nerve, a second stimulation pattern within a frequency range of 5 to 30 Hz for stimulating the auricular branch of the vagus nerve via the respective electrode; wherein the electrical nerve stimulation therapy is configured to increase the rate of thrombin generation at or near the injury site in the subject.

25. The system of claim 24, wherein the injury site comprises at least one of a penetrating injury or a non-compressible injury.

26. The system of claim 25, wherein the non-compressible injury is gastrointestinal bleeding.

27. The system of claim 24 or 25, wherein the at least one stimulation pattern is applied before and / or during a surgical procedure.

28. The system of claim 27, wherein the at least one stimulation pattern is applied to reduce the likelihood of blood transfusion and / or reduce the amount of blood transfusion required.

29. The system of any one of claims 24 to 28, wherein the at least one stimulation pattern is configured to cause a transient increase in the coagulation potential of the subject.

30. A system for triggering a higher rate of platelet activation in a subject, the system comprising: A wearable auricular neurostimulator (WANS) configured to be wrapped around the pinna of the subject, the WANS comprising at least one electrode, the at least one electrode comprising one or more auriculotemporal nerve (ATN) electrodes, the one or more ATN electrodes configured to contact corresponding areas of the subject's skin when the subject is wearing the WANS to place the at least one electrode in electrical communication with: i) neural structures of the auriculotemporal nerve or neural structures leading to said auriculotemporal nerve, and / or ii) one or more auricular branch of the vagus nerve (ABVN) electrodes, the one or more ABVN electrodes configured to contact corresponding areas of the subject's skin when the subject is wearing the WANS to place a second therapeutic electrode in electrical communication with a neural structure of or leading to the auricular branch of the vagus nerve; as well as a pulse generating circuit system configured to deliver electrical nerve stimulation via the at least one electrode, wherein delivering the electrical nerve stimulation comprises For each corresponding ATN electrode of the one or more ATN electrodes, the corresponding ATN electrode is caused to output a first stimulation pattern within a frequency range of 70 to 150 Hz, and / or For each corresponding ABVN electrode of the one or more ABVN electrodes, causing the corresponding ABVN electrode to output a second stimulation pattern within a frequency range of 5 to 30 Hz; wherein the electrical nerve stimulation is configured to trigger the higher rate of platelet activation in the subject.

31. The system of claim 30, wherein the electrical nerve stimulation is delivered prior to the subject donating platelets such that the donated platelets include a higher ratio of stimulated platelets.

32. The system of claim 30 or 31, wherein the higher rate of platelet activation is triggered at or near the site of injury in the subject.

33. A method for treating sepsis by reducing systemic inflammation via auris nerve stimulation, the method comprising: A wearable neurostimulation device comprising at least one therapeutic electrode is positioned on at least one ear of the subject, wherein the wearable neurostimulation device is positioned so that a first of the at least one therapeutic electrode contacts an area of ​​the subject's skin having a neural structure of the auricular branch of the vagus nerve or a neural structure leading to the auricular branch of the vagus nerve; and delivering stimulation therapy via a pulse generator in electrical communication with the at least one therapeutic electrode to reduce systemic inflammation in the subject, wherein The stimulation therapy comprises a stimulation pattern for modulating activity in one or more organs of the subject via the vagus nerve to elicit an anti-inflammatory response, and Delivering the stimulation therapy comprises For a first period of time, the stimulation pattern is continuously applied to obtain an anti-inflammatory response, and After the anti-inflammatory response is achieved, the stimulation pattern is applied periodically to reduce the likelihood of further inflammation.

34. The method of claim 33, wherein eliciting the anti-inflammatory response comprises reducing the amount of circulating proinflammatory cytokines by modulating activity in the subject's spleen.

35. A method for treating hypovolemia via auris nerve stimulation, the method comprising: A wearable neurostimulation device comprising at least one therapeutic electrode is positioned on at least one ear of the subject, wherein The wearable neurostimulation device is positioned so that a first therapeutic electrode of the at least one therapeutic electrode contacts an area of ​​the subject's skin having a neural structure of the auriculotemporal nerve (ATN) or a neural structure leading to the ATN; and delivering stimulation therapy to treat hypovolemia via a pulse generator in electrical communication with the at least one therapeutic electrode, wherein The stimulation therapy comprises a stimulation pattern for modulating activity in the subject's cardiac system and / or vascular system via the ATN to elicit a pressor response.

36. A method for enhancing platelet-mediated coagulation in a subject, the method comprising: implanting at least one electrode into the subject such that each of the at least one electrode is in physical contact with: i) the splenic nerve, ii) the spleen, iii) vagal efferent nerve fibers (VEFs), iv) the vagus nerve, v) the splanchnic nerve, vi) the splenic nerve, and / or vii) the splanchnic DRG; and for each respective electrode of the at least one electrode, delivering electrical nerve stimulation therapy by applying a stimulation pattern via the respective electrode at a frequency within a range of 1 to 30 Hz; wherein the electrical nerve stimulation therapy enhances platelet-mediated coagulation in the subject.

37. The method of claim 36, wherein the platelet-mediated coagulation is enhanced to minimize bleeding in the subject with a bleeding disorder in a prophylactic or preventative manner.

38. The method of claim 37, wherein the bleeding disorder is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

39. The method of any one of claims 36 or 38, wherein enhancing the platelet-mediated coagulation comprises increasing the maximum clot density as measured via thromboelastography analysis (TEG MA) by at least 10%.

40. The method of any one of claims 36 to 39, wherein enhancing the platelet-mediated coagulation comprises increasing maximum clot density as measured via thromboelastography analysis (TEG MA) by at least 20%.

41. The method of any one of claims 36 to 40, wherein the enhancing platelet-mediated coagulation is configured to minimize bleeding in an individual with a bleeding disorder in a preventative or prophylactic manner.

42. The method of claim 41, wherein the bleeding disorder is one of hemophilia A, hemophilia B, hemophilia C, or von Willebrand's disease.

43. A system for assessing the responsiveness of a subject to an implantable neurostimulation therapy configured to increase coagulation potential by directly stimulating vagal efferent fibers (VEFs), the vagus nerve, splanchnic nerves, splanchnic DRGs, splenic nerves, and / or the spleen, the system comprising: An ear stimulation device comprising at least one therapeutic electrode, wherein each respective therapeutic electrode of the at least one therapeutic electrode is configured to be aligned with an area of ​​the subject's skin to place the respective therapeutic electrode in electrical communication with: i) the neural structure of the auriculotemporal nerve or the neural structure leading to said auriculotemporal nerve and / or ii) the neural structure of the auricular branch of the vagus nerve or the neural structure leading to said auricular branch of the vagus nerve; as well as pulse generating circuitry configured to deliver electrical nerve stimulation therapy via the at least one therapeutic electrode by: generating, for each respective electrode of the at least one therapeutic electrode in electrical communication with a neural structure of or leading to the auriculotemporal nerve, a first stimulation pattern within a frequency range of 70 to 150 Hz for stimulating the auriculotemporal nerve via the respective electrode, and / or generating, for each respective electrode of the at least one therapeutic electrode in electrical communication with a neural structure of or leading to the auricular branch of the vagus nerve, a second stimulation pattern within a frequency range of 5 to 30 Hz for stimulating the auricular branch of the vagus nerve via the respective electrode; wherein the electrical nerve stimulation therapy is configured to increase the clotting potential of the subject's platelets.

44. The system of claim 43, wherein the first stimulation pattern comprises a frequency of 100 Hz; and the second stimulation pattern comprises a frequency of 30 Hz.

45. The system of claim 43 or 44, wherein one or more of the at least one therapeutic electrode in electrical communication with the neural structure of or leading to the auricular branch of the vagus nerve is in electrical communication with the Arnold nerve.

46. ​​The system of any one of claims 43 to 45, further comprising control circuitry configured to: receiving a plurality of sensor signals from one or more sensors monitoring the subject during therapy: analyzing the plurality of sensor signals; and In response to the analysis, at least one of the frequency and pulse width of the first stimulation pattern and / or the second stimulation pattern is adjusted.

47. The system of claim 46, wherein the one or more sensors comprises a thrombin concentration measurement sensor.

48. The system of claim 46, wherein a microfluidic chip comprises the one or more sensors.

49. The system of claim 46, wherein: The diagnostic device comprises the one or more sensors; and Receiving the plurality of sensor signals includes receiving the plurality of sensor signals from the diagnostic device.

50. The system of claim 46, wherein the one or more sensors are configured to measure prothrombin time, partial thromboplastin time, activated partial thromboplastin time, and / or activated clotting time.

51. The system of claim 46, wherein the plurality of sensor signals comprises a signal related to pupillometry.

52. A system for increasing the rate of thrombin generation at or near a site of injury in a subject, the system comprising: An ear stimulation device comprising a plurality of electrodes, the plurality of electrodes comprising a first subset of electrodes and a second subset of electrodes, wherein The first subset of electrodes is configured to align with a first tissue portion of the subject to place at least one first electrode of the first subset of electrodes in electrical communication with a neural structure of or leading to the auriculotemporal nerve, and the second subset of electrodes being configured to align with a second tissue portion of the subject to place at least one second electrode of the second subset of electrodes in electrical communication with a neural structure of or leading to an auricular branch of the vagus nerve; and pulse generating circuitry configured to deliver electrical nerve stimulation via the plurality of electrodes by: generating, for the first electrode subset, a first stimulation pattern within a frequency range of 70 to 150 Hz for stimulating the auriculotemporal nerve via the at least one first electrode in the first electrode subset, and / or For the second subset of electrodes, a second stimulation pattern is generated with a frequency in the range of 5 to 30 Hz for stimulating the auricular branch of the vagus nerve via the at least one second electrode in the second subset of electrodes.

53. The system of claim 52, wherein the system further comprises a wearable auricular neurostimulator (WANS), the WANS configured to wrap around an auricle of the subject, the WANS comprising a plurality of electrodes.

54. The system of claim 52 or 53, wherein the pulse generation circuitry is configured to deliver the electrical nerve stimulation repeatedly on a regular basis.

55. The system of claim 54, wherein periodically repeating the delivery of the electrical neural stimulation comprises delivering the electrical neural stimulation according to a duty cycle comprising an active period of at least 1 minute followed by a cessation of delivery of the electrical neural stimulation for at least 10 seconds.

56. The system of claim 54, wherein periodically repeating the delivery of the electrical neural stimulation comprises delivering the electrical neural stimulation according to a duty cycle comprising at least a 90% active period followed by a rest period without stimulation.

57. The system of any one of claims 52 to 56, wherein the pulse generation circuitry is further configured to deliver the first stimulation mode and the second stimulation mode simultaneously while avoiding simultaneous pulse triggering between the first stimulation mode and the second stimulation mode.

58. The system of any one of claims 52 to 57, further comprising control circuitry configured to: receiving a plurality of sensor signals from one or more sensors monitoring the subject during therapy: analyzing the plurality of sensor signals; and In response to the analysis, at least one of the frequency and pulse width of the first stimulation pattern and / or the second stimulation pattern is adjusted.

59. The system of claim 58, wherein the one or more sensors comprises a thrombin concentration measurement sensor.

60. The system of claim 58 or 59, wherein a microfluidic chip comprises the one or more sensors.

61. The system of any one of claims 58 to 60, wherein: The diagnostic device comprises the one or more sensors; and Receiving the plurality of sensor signals includes receiving the plurality of sensor signals from the diagnostic device.

62. The system of any one of claims 58 to 61, wherein the one or more sensors are configured to measure prothrombin time, partial thromboplastin time, activated partial thromboplastin time and / or activated clotting time.

63. The system of any one of claims 58 to 62, wherein the plurality of sensor signals comprises a signal related to pupillometry.

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