TRANSCUTANEOUS AURICULAR VAGAL NERVE STIMULATION FOR PERI-INTERVENTION INFLAMMATORY MODULATION

1 . A method of mitigating inflammatory complications associated with a medical intervention in a patient, the method comprising:

applying transcutaneous auricular vagal nerve stimulation to the patient at one or more times selected from before the medical intervention, during the medical intervention, and after the medical intervention, wherein the transcutaneous auricular vagal nerve stimulation is delivered via one or more stimulation elements positioned on an auricle of the patient; and

wherein the transcutaneous auricular vagal nerve stimulation activates one or more neuroimmune anti-inflammatory pathways to reduce inflammatory complications associated with the medical intervention.

2 . The method of claim 1 , further comprising:

applying a wearable device to an ear of the patient, the wearable device comprising a housing containing electronics and a power source, a first extending structure having a first end at the housing and a second end positioned within the ear when the wearable device is worn, an anchor arm extending laterally from the first extending structure, a second extending structure having a first end at the housing and a second end positioned within the ear when the wearable device is worn, and an adjustment mechanism configured to adjust a distance between the first extending structure and the second extending structure,

wherein the one or more stimulation elements are positioned on at least one of the first extending structure or the second extending structure.

3 . The method of claim 1 , wherein the transcutaneous auricular vagal nerve stimulation is delivered periodically in sessions having a duration in a range of about 30 seconds to about 24 hours.

4 . The method of claim 1 , further comprising: measuring at least one baseline inflammatory biomarker selected from C-reactive protein, interleukin-6, tumor necrosis factor-α, and/or ferritin prior to applying the transcutaneous auricular vagal nerve stimulation.

5 . The method of claim 4 , wherein the at least one baseline inflammatory biomarker further comprises at least one selected from high mobility group box 1 protein (HMGB1), glial fibrillary acidic protein (GFAP), S100B, neutrophil gelatinase-associated lipocalin (NGAL), von Willebrand factor, D-dimer, neurofilament light chain, calprotectin, C3a, C5a, angiopoietin-2, high-sensitivity C-reactive protein, neutrophil-to-lymphocyte ratio, interleukin-8, interleukin-2, donor-specific antibodies (DSA), lipopolysaccharide-binding protein (LBP), intercellular adhesion molecule-1 (ICAM-1), and/or vascular cell adhesion molecule-1 (VCAM-1).

6 . The method of claim 1 , further comprising: monitoring at least one physiologic parameter selected from heart rate variability, blood pressure variability, and/or body temperature during applying the transcutaneous auricular vagal nerve stimulation; and adjusting at least one stimulation parameter selected from current amplitude, pulse width, frequency, and/or duty cycle based on the monitored physiologic parameter.

7 . The method of claim 6 , wherein the adjusting at least one stimulation parameter comprises titrating the current amplitude to achieve at least a threshold increase in heart rate variability relative to a pre-stimulation baseline measurement.

8 . The method of claim 1 , further comprising: measuring at least one inflammatory biomarker selected from interleukin-6, tumor necrosis factor-α, C-reactive protein, and/or ferritin after applying the transcutaneous auricular vagal nerve stimulation; and comparing the measured inflammatory biomarker to a baseline measurement to assess reduction in inflammatory complications.

9 . The method of claim 6 , wherein the at least one stimulation parameter is adjusted to achieve at least a threshold amount of reduction in a measured inflammatory biomarker level relative to a pre-treatment peak measurement.

10 . The method of claim 1 , wherein the transcutaneous auricular vagal nerve stimulation is applied prior to the medical intervention as a preconditioning treatment for a duration in a range of hours to days before the medical intervention.

11 . The method of claim 1 , wherein the medical intervention comprises a tissue-disruptive intervention selected from the group consisting of: cranial surgery, spinal surgery, cardiothoracic surgery, cardiopulmonary bypass, radiation therapy, radiofrequency ablation, ischemia-reperfusion procedures, and organ transplantation.

12 . The method of claim 11 , wherein the ischemia-reperfusion procedure comprises a reperfusion phase, and wherein the transcutaneous auricular vagal nerve stimulation is synchronized with the reperfusion phase.

13 . The method of claim 1 , wherein the medical intervention comprises an immune-activating intervention selected from the group consisting of CAR-T cell therapy, immune checkpoint inhibitor therapy, stem cell infusion, viral vector gene therapy, and organ transplantation.

14 . The method of claim 13 , wherein the immune-activating intervention comprises hematopoietic stem cell transplantation or organ transplantation, and the inflammatory complication comprises graft-versus-host disease or acute rejection, and wherein at least one of interleukin-6, tumor necrosis factor-α, graft-versus-host disease severity score, and/or donor-specific antibodies (DSA) is monitored to assess the reduction in inflammatory complications and to guide post-transplant protocol duration and intensity.

15 . The method of claim 1 , wherein the medical intervention comprises a foreign-material-introducing intervention selected from the group consisting of: neurostimulator implantation, cardiac device implantation, orthopedic hardware placement, vascular stent placement, contrast agent administration, and blood transfusion.

16 . The method of claim 15 , wherein the foreign-material-introducing intervention comprises implantation of a scaffold, bioengineered tissue construct, or synthetic matrix, and the inflammatory complication comprises fibrotic encapsulation or impaired tissue integration, and wherein TGF-β and/or matrix metalloproteinases are monitored as biomarkers of fibrotic remodeling.

17 . The method of claim 1 , wherein the inflammatory complication is selected from the group consisting of: cytokine release syndrome, cerebral edema, systemic inflammatory response syndrome, acute kidney injury, immune effector cell-associated neurotoxicity syndrome, capillary leak syndrome, and ischemia-reperfusion injury.

18 . The method of claim 1 , wherein the one or more neuroimmune anti-inflammatory pathways are selected from the group consisting of: cholinergic anti-inflammatory pathway activation, central network suppression, reduced cerebral metabolism, autonomic stabilization, sympathetic withdrawal, endothelial stabilization, thromboinflammation modulation, HPA-axis modulation, microglial phenotype shifting, gut-immune axis modulation, and/or pain-inflammation feedback loop interruption.

19 . The method of claim 18 , wherein the cholinergic anti-inflammatory pathway activation comprises binding of acetylcholine to alpha-7 nicotinic acetylcholine receptors (α7 nAChR) on macrophages, microglia, or both, thereby suppressing nuclear factor-κB (NF-κB) activation through JAK2-STAT3 intracellular signaling and reducing production of pro-inflammatory cytokines.

20 . The method of claim 1 , wherein the transcutaneous auricular vagal nerve stimulation is delivered via electrodes as electrical stimulation at: a current amplitude in a range of 0.05 milliamps (mA) to 10 mA; a pulse width in a range of 50 microseconds to 2000 microseconds; and a frequency in a range of 0.1 Hertz (Hz) to 100 Hz.

21 . The method of claim 1 , wherein the transcutaneous auricular vagal nerve stimulation is adaptively modulated based on real-time physiologic feedback selected from heart rate variability, blood pressure variability, and/or measured cytokine levels.

22 . The method of claim 1 , wherein the transcutaneous auricular vagal nerve stimulation is delivered at a sub-perceptive current amplitude that suppresses high-gamma neural activity in the insular cortex, the orbitofrontal cortex, or both, to reduce centrally-mediated inflammatory drive through a central autonomic/limbic gateway mechanism that operates independently of conscious sensory perception and is active during general anesthesia or sedation.

23 . The method of claim 1 , wherein the stimulation is delivered via electrodes positioned within the external auditory canal, or via one or more percutaneous electrodes introduced through the skin of the auricle to a depth sufficient to reduce impedance and increase selectivity for activation of auricular branch of vagus nerve fibers relative to surface electrode delivery.

24 . The method of claim 1 , wherein the stimulation comprises a combination of transcutaneous auricular vagal nerve stimulation and at least one additional modality selected from transcutaneous cervical vagal nerve stimulation, intranasal vagal nerve stimulation delivered via electrodes positioned within the nasal cavity to access trigeminal-vagal convergent pathways, transcranial direct current stimulation, transcranial magnetic stimulation, pulsed electromagnetic field stimulation delivered via a micro-coil positioned over a cervical vagus nerve location, and/or low-intensity focused ultrasound.

25 . The method of claim 1 , wherein the transcutaneous auricular vagal nerve stimulation comprises a combination of electrical stimulation and at least one additional modality selected from vibratory stimulation at a frequency in a range of about 1 Hertz (Hz) to about 1000 Hz, thermal stimulation to a target tissue temperature in a range of about 10 degrees Celsius (° C.) to about 45° C., and/or low-intensity focused ultrasound at a frequency in a range of about 200 kilohertz (kHz) to about 5 megahertz (MHz), delivered simultaneously or in a time-staggered sequence.

26 . The method of claim 1 , wherein the transcutaneous auricular vagal nerve stimulation is delivered using a stochastically modulated waveform in which at least one stimulation parameter selected from current amplitude, pulse width, frequency, and/or inter-pulse interval is varied in a pseudo-random or noise-modulated manner within a therapeutically effective range, to reduce neural habituation and accommodation to repetitive stimulation during extended-duration protocols.

27 . A transcutaneous auricular vagal nerve stimulation device configured for peri-intervention inflammatory modulation, comprising:

a housing adapted for placement relative to an ear of a patient;

one or more stimulation elements positioned to contact auricular tissue when the housing is placed relative to the ear;

a controller coupled to a memory storing instructions; and

output circuitry coupled to the controller and the one or more stimulation elements;

wherein the instructions, when executed by the controller, cause the output circuitry to deliver stimulation via the one or more stimulation elements according to a peri-intervention protocol selected based on an intervention category, wherein the intervention category is selected from tissue-disruptive intervention, immune-activating intervention, and/or foreign-material-introducing intervention.

28 . The device of claim 27 , wherein the instructions further cause the controller to adaptively adjust at least one stimulation parameter based on a measured physiologic parameter selected from heart rate variability, blood pressure variability, and/or temperature.

29 . A non-transitory computer-readable medium storing instructions that, when executed by a controller of a transcutaneous auricular vagal nerve stimulation device, cause the device to:

receive at least one input selected from: (i) a medical intervention type, (ii) a patient risk stratification parameter, or (iii) both the medical intervention type and the patient risk stratification parameter;

select a peri-intervention stimulation protocol based on the at least one input; and

deliver stimulation via one or more stimulation elements positioned on an auricle of a patient according to the selected peri-intervention stimulation protocol to mitigate inflammatory complications associated with a medical intervention.

30 . The non-transitory computer-readable medium of claim 29 , wherein the instructions further cause the device to:

monitor a physiologic parameter selected from heart rate variability or blood pressure variability during delivery of the stimulation; and

adaptively adjust at least one stimulation parameter selected from current amplitude, pulse width, frequency, and/or duty cycle based on the monitored physiologic parameter.