High mobility group box 1 protein (HMGB1) is a central mediator of inflammation and pain, but efforts to neutralize it therapeutically have had limited clinical success. This gap suggests that the essential problem is not simply the abundance of extracellular HMGB1, but its accessibility: its availability to assemble into pathogenic complexes, engage receptors such as the receptor for advanced glycation end products (RAGE), enter cells, and deliver inflammatory cargo to the cytosol. Here, a perspective is advanced that integrates HMGB1 biology with the inflammatory reflex and the cholinergic anti-inflammatory pathway. In this framework, HMGB1 promotes inflammatory entry and amplification, whereas acetylcholine, acting through the vagus nerve and alpha7 nicotinic acetylcholine receptors, limits HMGB1 release and uptake of HMGB1-containing complexes. Vagus nerve stimulation therefore emerges as a bioelectronic strategy to restrict upstream access of danger signals to intracellular inflammatory pathways, in addition to suppressing downstream cytokine signaling. This formulation does not alter the established biology of HMGB1; rather, it places existing observations into a unifying model with direct relevance to inflammation and pain.

BackgroundTraumatic or surgical hemorrhage causes substantial morbidity and mortality. Electrical vagus nerve stimulation (VNS) reduces traumatic hemorrhage in animal models. VNS targets acetylcholine-producing T lymphocytes in the spleen to increase intracellular calcium within circulating platelets via α7 nicotinic acetylcholine receptors. Elevated calcium levels facilitate platelet activation (priming) after tissue injury to accelerate and increase clot formation that improves hemostasis. Trigeminal nerve stimulation (TNS) also decreases traumatic hemorrhage in mice, but the mechanism remains unknown. Recently, we showed that transcutaneous auricular neurostimulation (tAN; combined auricular VNS and TNS) reduces blood loss and days of menstruation in women with idiopathic or von Willebrand disease related heavy menstrual bleeding. The ability of tAN or transcutaneous auricular VNS (taVNS) to improve platelet function or laboratory hemostasis remains unknown.MethodsHere we performed a prospective, randomized, double-blind, sham-controlled, single-center, first-in-human exploratory trial to determine the safety and efficacy of taVNS or tAN to prime platelets and augment clot formation. Healthy adult subjects received sham stimulation before taVNS or tAN, followed by serial measurements of platelet and hemostasis markers, including platelet functional analysis, thrombin generation, blood counts, coagulation assays, and thromboelastography. Repeated measures one-way ANOVA followed by Bonferroni’s test was used for comparisons between three or more time points. Two-tailed paired T-test was used for comparisons between two time points.ResultsAdministration of taVNS or tAN was well tolerated without observable adverse events during the study period. taVNS or tAN primed platelets via collagen- or ADP-mediated signaling pathways, respectively. taVNS accelerated clot initiation, propagation, and stabilization as measured by thromboelastography. There were no differences in systemic or local thrombin generation, circulating white or red blood cell counts, platelet counts, prothrombin time, partial thromboplastin time, or INR assays after administration of taVNS or tAN.ConclusionsThese results provide evidence that taVNS or tAN primes human platelets and taVNS accelerates clotting kinetics as quantified by thromboelastography. taVNS and tAN warrant additional clinical study as therapies for traumatic or surgical hemorrhage and congenital or acquired coagulopathies.Trial registrationThis study is registered with the ClinicalTrials.gov database (http://clinicaltrials.gov). The registration number is NCT05977946. The study start is 10–31-2023.Supplementary InformationThe online version contains supplementary material available at 10.1186/s42234-026-00208-w.

In-ear electroencephalography (EEG) has emerged as a promising alternative to traditional in-laboratory sleep studies, offering greater comfort and practicality. Here we present a novel in-ear EEG system, comparing in-ear recordings against scalp EEG channels acquired concurrently as part of polysomnography (PSG). The study enrolled 16 healthy control participants in a single-visit overnight-plus-daytime design, and 8 participants with central disorders of hypersomnolence (CDH) in a randomized crossover daytime design (medication vs. medication-holiday). For overnight sleep recordings, ear-EEG and scalp EEG sleep staging showed substantial agreement (Cohen’s kappa = 0.77). For daytime MWT trials, agreement was moderate (Cohen’s kappa = 0.50), reflecting the predominance of wake epochs in this paradigm. For the primary Maintenance of Wakefulness Test (MWT) endpoint of sleep onset latency (SOL), at the per-subject level (n = 24)—averaging across trials as in standard clinical practice—agreement was good (ICC = 0.71, r = 0.75, MAD = 5.1 min). Among the 37 of 126 trials where both devices detected sleep (approximately 30% of trials), agreement was strong (ICC = 0.82, MAD = 1.9 min), with excellent agreement in healthy controls (ICC = 0.95, MAD = 1.2 min). Overall trial-level agreement across all 126 trials was moderate (ICC = 0.55), reflecting 22 discordant trials in which scalp EEG detected sleep but in-ear EEG did not—predominantly brief, subtle N1 transitions, concentrated in a subset of CDH participants. For overnight sleep architecture (n = 16 healthy controls), total sleep time (r = 0.94, ICC = 0.85), sleep efficiency (r = 0.94), and wake after sleep onset (r = 0.93) showed strong agreement, with small systematic biases consistent with reduced N1 detection sensitivity. These findings support the feasibility of in-ear EEG for sleep staging and daytime sleepiness assessment in laboratory settings, and motivate larger confirmatory studies—including home-based longitudinal monitoring—to establish clinical utility, particularly in populations with altered sleep architecture.

Bioelectronic medicine (BEM) is an emerging scientific field that aims to revolutionize the way we understand and treat disease by using electrical impulses for diagnosis and therapy. It is an interdisciplinary endeavour that draws on advances in microelectronics, information technology, materials science, and medicine, and it holds strong promise for addressing currently unmet medical needs. At its core, BEM seeks to develop implantable devices capable of modulating neuronal circuits and biological functions in a precise, targeted, and adaptable manner. Neural interfaces play a pivotal role within this therapeutic paradigm, as they must safely probe and interact with the nervous system while maintaining long‑term stability and biocompatibility. This editorial introduces the papers published in our collection “Neural Interfaces for Bioelectronic Medicine”. The included works present the clinical landscape of neuromodulation, examine mechanisms of device failure and reliability, introduce electrode technologies with improved biocompatibility and selectivity, and explore the therapeutic potential of alternative neuromodulation strategies, such as ultrasound and magnetoelectric nanoparticle‑based approaches, supported by computational models. Together, these contributions highlight both the opportunities and the challenges that must be addressed for bioelectronic medicine to fully flourish. They also identify the key technological advancements that will shape the future of neural interfaces and enable the next generation of bioelectronic therapies. We hope you enjoy this collection as much as we did.

Current imaging assessment for pancreatic cancer resectability demonstrates problematic inter-observer variability, with only fair-to-moderate agreement among experienced raters. Virtual reality technology offers stereoscopic three-dimensional visualization that may improve diagnostic accuracy and agreement. However, optimal visualization strategies for clinical adoption remain unclear. Ten hepatopancreatobiliary surgeons from two high-volume centers were randomized 1:1 to assess twelve contrast-enhanced CT cases using either VR volumetric rendering or CSI. Primary outcomes included inter-rater agreement, diagnostic accuracy against expert reference standard, assessment time, and surgeon confidence. Statistical analysis employed Fleiss’ κ for inter-rater agreement and two-sided Mann–Whitney U tests on surgeon-level summary measures for between-group comparisons. CSI display on 2D screens achieved substantial inter-rater agreement for resectability assessment (κ = 0.609) while VR demonstrated only slight agreement (κ = 0.127). Diagnostic accuracy was superior with CSI (84.7% vs. 79.7%), with the most pronounced difference in resectability determination (83.3% vs. 58.3%, p = 0.033). VR users reported significantly lower confidence (4.85 ± 1.15 vs. 6.32 ± 0.77, p = 0.028). Assessment times were comparable between groups (median 313.5 s vs. 327.5 s, p = 1.00). In this preliminary investigation, our VR visualization strategy demonstrated lower diagnostic accuracy and inter-rater agreement than CSI. However, prior studies suggest that VR systems employing alternative, hybrid visualization approaches may improve inter-rater agreement, indicating that visualization strategy, rather than VR technology per se, is the primary determinant of utility. DRKS00033932 (German Clinical Trials Register), registered prospectively.

Wireless telemetry from fully implanted, millimeter-scale neuromodulation devices is constrained by tight power budgets, inefficient antennas, and in-body attenuation. Standard protocols (e.g., BLE) offer mature ecosystems but exhibit throughput shortfalls and reduced robustness under non-ideal operating conditions. This study introduces the Neural Real-Time Telemetry Protocol (NRTP), a 2.4 GHz, half-duplex protocol designed to address the unmet need for reliable, real-time neural telemetry from miniaturized implants using off-the-shelf hardware, without custom electronics or ASICs. NRTP was implemented on commercial 2.4 GHz hardware with static-length packets, immediate acknowledgments, bounded retransmissions, and single RF channel operation. We evaluated three mitigation strategies—retries, sample-level interleaving, and data overlapping—individually and in combination, and defined a quantitative evaluation metric that prioritizes data quality and power draw. Using identical hardware for NRTP and BLE, we performed controlled sweeps of received signal strength, tested multiple payload lengths and timing configurations, and measured throughput, data loss, and current draw. NRTP sustained zero data loss down to -75 dBm, whereas BLE performance degraded below -55 dBm due to throughput shortfalls under interference and deferred unlimited retries. Interleaving converted contiguous gaps into half-rate segments, delaying score decline at lower received signal strength; overlapping improved robustness but its doubled packet rate requirement was power-prohibitive for implant constraints. Across variants, NRTP delivered higher scores and lower variability over a wider operational range than BLE; BLE’s greater scores at high signal strength were driven by lower current consumption but fell off earlier with attenuation. The observed link-margin advantage for NRTP (up to ~ 23 dB at first loss; ~ 11 dB at 0.5% loss) implies ~ 3.2 × range in air, ~ 2.5 cm greater implant depth in tissue, or equivalently lower TX power for similar performance. NRTP provides robust telemetry for miniaturized implantable devices and is readily adoptable on commodity 2.4 GHz hardware. Its immediate, bounded retries and optional interleaving sustain throughput and minimize true data gaps under attenuation and interference, outperforming BLE across operating conditions relevant to small-animal implants. The resulting link-margin gains translate into practical benefits in coverage, implant depth, and power consumption, lowering barriers to chronic, closed-loop studies.

Peripheral nerve interfaces play a central role in bioelectronic medicine. Since the early foundational experiments of Luigi Galvani in the 1770s, there have been over 250 years of development in electrical neuromodulation. Even so, current clinical approaches to interface with peripheral nerves are limited. Bioelectronic interfaces for small, branched nerves are of increasing interest to unlock new therapies and minimize off-target effects. This is facilitated by our growing understanding of peripheral nervous system physiology and advances in new materials and technologies. Therefore, this review examines historical and recent developments in FDA-approved peripheral nerve interfaces and investigational interfaces with an emphasis on approaches to target smaller nerves. Unmet needs in small nerve peripheral nerve interfaces are highlighted, followed by an examination of new strategies being pursued to address them. To conclude, ongoing challenges are summarized, revealing opportunities and prospects for future advancements.