Bioelectronic medicine最新文献

Background: Reduced heart rate (HR) during vagus nerve stimulation (VNS) is associated with therapy for heart failure, but stimulation frequency and amplitude are limited by patient tolerance. An understanding of physiological responses to parameter adjustments would allow differential control of therapeutic and side effects. To investigate selective modulation of the physiological responses to VNS, we quantified the effects and interactions of parameter selection on two physiological outcomes: one related to therapy (reduced HR) and one related to side effects (laryngeal muscle EMG).

Methods: We applied a broad range of stimulation parameters (mean pulse rates (MPR), intra-burst frequencies, and amplitudes) to the vagus nerve of anesthetized mice. We leveraged the in vivo recordings to parameterize and validate computational models of HR and laryngeal muscle activity across amplitudes and temporal patterns of VNS. We constructed a finite element model of excitation of fibers within the mouse cervical vagus nerve.

Results: HR decreased with increased amplitude, increased MPR, and decreased intra-burst frequency. EMG increased with increased MPR. Preferential HR effects over laryngeal EMG effects required combined adjustments of amplitude and MPR. The model of HR responses highlighted contributions of ganglionic filtering to VNS-evoked changes in HR at high stimulation frequencies. Overlap in activation thresholds between small and large modeled fibers was consistent with the overlap in dynamic ranges of related physiological measures (HR and EMG).

Conclusion: The present study provides insights into physiological responses to VNS required for informed parameter adjustment to modulate selectively therapeutic effects and side effects.

Following a SARS-CoV-2 infection, many individuals suffer from post-COVID-19 syndrome. It makes them unable to proceed with common everyday activities due to weakness, memory lapses, pain, dyspnea and other unspecific physical complaints. Several investigators could demonstrate that the SARS-CoV-2 related spike glycoprotein (SGP) attaches not only to ACE-2 receptors but also shows DNA sections highly affine to nicotinic acetylcholine receptors (nAChRs). The nAChR is the principal structure of cholinergic neuromodulation and is responsible for coordinated neuronal network interaction. Non-intrinsic viral nAChR attachment compromises integrative interneuronal communication substantially. This explains the cognitive, neuromuscular and mood impairment, as well as the vegetative symptoms, characterizing post-COVID-19 syndrome. The agonist ligand nicotine shows an up to 30-fold higher affinity to nACHRs than acetylcholine (ACh). We therefore hypothesize that this molecule could displace the virus from nAChR attachment and pave the way for unimpaired cholinergic signal transmission. Treating several individuals suffering from post-COVID-19 syndrome with a nicotine patch application, we witnessed improvements ranging from immediate and substantial to complete remission in a matter of days.

Chest radiographs (CXRs) are the most widely available radiographic imaging modality used to detect respiratory diseases that result in lung opacities. CXR reports often use non-standardized language that result in subjective, qualitative, and non-reproducible opacity estimates. Our goal was to develop a robust deep transfer learning framework and adapt it to estimate the degree of lung opacity from CXRs. Following CXR data selection based on exclusion criteria, segmentation schemes were used for ROI (Region Of Interest) extraction, and all combinations of segmentation, data balancing, and classification methods were tested to pick the top performing models. Multifold cross validation was used to determine the best model from the initial selected top models, based on appropriate performance metrics, as well as a novel Macro-Averaged Heatmap Concordance Score (MA HCS). Performance of the best model is compared against that of expert physician annotators, and heatmaps were produced. Finally, model performance sensitivity analysis across patient populations of interest was performed. The proposed framework was adapted to the specific use case of estimation of degree of CXR lung opacity using ordinal multiclass classification. Acquired between March 24, 2020, and May 22, 2020, 38,365 prospectively annotated CXRs from 17,418 patients were used. We tested three neural network architectures (ResNet-50, VGG-16, and ChexNet), three segmentation schemes (no segmentation, lung segmentation, and lateral segmentation based on spine detection), and three data balancing strategies (undersampling, double-stage sampling, and synthetic minority oversampling) using 38,079 CXR images for training, and validation with 286 images as the out-of-the-box dataset that underwent expert radiologist adjudication. Based on the results of these experiments, the ResNet-50 model with undersampling and no ROI segmentation is recommended for lung opacity classification, based on optimal values for the MAE metric and HCS (Heatmap Concordance Score). The degree of agreement between the opacity scores predicted by this model with respect to the two sets of radiologist scores (OR or Original Reader and OOBTR or Out Of Box Reader) in terms of performance metrics is superior to the inter-radiologist opacity score agreement.

Background: The vagus nerve affects innate immune responses by activating spleen-projecting sympathetic neurons, which modulate leukocyte function. Recent basic and clinical research investigating vagus nerve stimulation to engage the cholinergic anti-inflammatory pathway (CAP) has shown promising therapeutic results for a variety of inflammatory diseases. Abundant sympathetic innervation occurs in rodent spleens, and use of these species has dominated mechanistic research investigating the CAP. However, previous neuroanatomical studies of human spleen found a more restricted pattern of innervation compared to rodents. Therefore, our primary goal was to establish the full extent of sympathetic innervation of human spleens using donor tissue with the shortest procurement to fixation time. Parallel studies of porcine spleen, a large animal model, were performed as a positive control and for comparison.

Methods: Human and porcine spleen tissue were fixed immediately after harvest and prepared for immunohistochemistry. Human heart and porcine spleen were stained in conjunction as positive controls. Several immunohistochemical protocols were compared for best results. Tissue was stained for tyrosine hydroxylase (TH), a noradrenergic marker, using VIP purple chromogen. Consecutive tissue slices were stained for neuropeptide Y (NPY), which often co-localizes with TH, or double-labelled for TH and CD3, a T cell marker. High-magnification images and full scans of the tissue were obtained and analyzed for qualitative differences between species.

Results: TH had dominant perivascular localization in human spleen, with negligible innervation of parenchyma, but such nerves were abundant throughout ventricular myocardium. In marked contrast, noradrenergic innervation was abundant in all regions of porcine spleen, with red pulp having more nerves than white pulp. NPY stain results were consistent with this pattern. In human spleen, noradrenergic nerves only ran close to T cells at the boundary of the periarterial lymphatic sheath and arteries. In porcine spleen, noradrenergic nerves were closely associated with T cells in both white and red pulp as well as other leukocytes in red pulp.

Conclusion: Sympathetic innervation of the spleen varies between species in both distribution and abundance, with humans and pigs being at opposite extremes. This has important implications for sympathetic regulation of neuroimmune interactions in the spleen of different species and focused targeting of the CAP in humans.

Approximately 20 years ago it was discovered that the vagus nerve regulates pro-inflammatory cytokine levels and inflammation. Subsequent research using several preclinical models revealed that vagus nerve stimulation evokes a protective decrease in pro-inflammatory cytokines in multiple inflammatory disorders. Consequently, the pro- and anti- inflammatory cytokine balance has become the predominant readout for indicating a positive outcome of vagus nerve stimulation. However, cytokine levels are just a single aspect of an effective immune response. It is conceivable that vagus nerve stimulation regulates inflammation through additional mechanisms. In this letter, I discuss a manuscript that describes how vagus nerve stimulation promotes resolution of inflammation via regulating the balance of specialised pro-resolving mediator levels and neutrophil activity.

Background: Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge.

Methods: Here, we studied the utility of a micro positron emission tomography (microPET) dual tracer ([¹¹C]PBR28 - for microglial activation and [¹⁸F]FDG for energy metabolism) approach to assess brain dysfunction, including neuroinflammation in murine endotoxemia. MicroPET imaging data were subjected to advanced conjunction and individual analyses, followed by post-hoc analysis.

Results: There were significant increases in [¹¹C]PBR28 and [¹⁸F]FDG uptake in the hippocampus of C57BL/6 J mice 6 h following LPS (2 mg/kg) intraperitoneal (i.p.) administration compared with saline administration. These results confirmed previous postmortem observations. In addition, patterns of significant simultaneous activation were demonstrated in the hippocampus, the thalamus, and the hypothalamus in parallel with other tracer-specific and region-specific alterations. These changes were observed in the presence of robust systemic inflammatory responses manifested by significantly increased serum cytokine levels.

Conclusions: Together, these findings demonstrate the applicability of [¹¹C]PBR28 - [¹⁸F]FDG dual tracer microPET imaging for assessing neuroinflammation and brain metabolic alterations in conditions "classically" characterized by peripheral inflammatory and metabolic pathogenesis.

Background: Electric field therapies such as Tumor Treating Fields (TTFields) have emerged as a bioelectronic treatment for isocitrate dehydrogenase wild-type and IDH mutant grade 4 astrocytoma Glioblastoma (GBM). TTFields rely on alternating current (AC) electric fields (EF) leading to the disruption of dipole alignment and induced dielectrophoresis (DEP) during cytokinesis. Although TTFields have a favourable side effect profile, particularly compared to cytotoxic chemotherapy, survival benefits remain limited (~ 4.9 months) after an extensive treatment regime (20 hours/day for 18 months). The cost of the technology also limits its clinical adoption worldwide. Therefore, the discovery of new technology that can enhance both the therapeutic efficiency and efficacy of these TTFields will be of great benefit to cancer treatment and decrease healthcare costs worldwide.

Methods: In this work, we report the role of electrically conductive gold (GNPs), dielectric silica oxide (SiO₂), and semiconductor zinc oxide (ZnO) nanoparticles (NPs) as transducers for enhancing EF mediated anticancer effects on patient derived GBM cells. Physicochemical properties of these NPs were analyzed using spectroscopic, electron microscopy, and light-scattering techniques.

Results: In vitro TTFields studies indicated an enhanced reduction in the metabolic activity of patient-derived Glioma INvasive marginal (GIN 28) and Glioma contrast enhanced core (GCE 28) GBM As per our journal style, article titles should not include capitalised letters unless these are proper nouns/acronyms. We have therefore used the article title "Electric field responsive nanotransducers for glioblastoma" as opposed to "Electric Field Responsive Nanotransducers for Glioblastoma" as given in the submission system. Please check if this is correct.cells in groups treated with NPs vs. control groups, irrespective of NPs dielectric properties. Our results indicate the inorganic NPs used in this work enhance the intracellular EF effects that could be due to the virtue of bipolar dielectrophoretic and electrophoretic effects.

Conclusions: This work presents preliminary evidence which could help to improve future EF applications for bioelectronic medicine. Furthermore, the merits of spherical morphology, excellent colloidal stability, and low toxicity, make these NPs ideal for future studies for elucidating the detailed mechanism and efficacy upon their delivery in GBM preclinical models.

Background: Neuroinflammation is an important driver of acute and chronic pain states. Therefore, targeting molecular mediators of neuroinflammation may present an opportunity for developing novel pain therapies. In preclinical models of neuroinflammatory pain, calcitonin gene-related peptide (CGRP), substance P and high mobility group box 1 protein (HMGB1) are molecules synthesized and released by sensory neurons which activate inflammation and pain. High-frequency electrical nerve stimulation (HFES) has achieved clinical success as an analgesic modality, but the underlying mechanism is unknown. Here, we reasoned that HFES inhibits neuroinflammatory mediator release by sensory neurons to reduce pain.

Methods: Utilizing in vitro and in vivo assays, we assessed the modulating effects of HFES on neuroinflammatory mediator release by activated sensory neurons. Dorsal root ganglia (DRG) neurons harvested from wildtype or transgenic mice expressing channelrhodopsin-2 (ChR2) were cultured on micro-electrode arrays, and effect of HFES on optogenetic- or capsaicin-induced neuroinflammatory mediator release was determined. Additionally, the effects of HFES on local neuroinflammatory mediator release and hyperalgesia was assessed in vivo using optogenetic paw stimulation and the neuropathic pain model of chronic constriction injury (CCI) of the sciatic nerve.

Results: Light- or capsaicin-evoked neuroinflammatory mediator release from cultured transgenic DRG sensory neurons was significantly reduced by concurrent HFES (10 kHz). In agreement with these findings, elevated levels of neuroinflammatory mediators were detected in the affected paw following optogenetic stimulation or CCI and were significantly attenuated using HFES (20.6 kHz for 10 min) delivered once daily for 3 days.

Conclusion: These studies reveal a previously unidentified mechanism for the pain-modulating effect of HFES in the setting of acute and chronic nerve injury. The results support the mechanistic insight that HFES may reset sensory neurons into a less pro-inflammatory state via inhibiting the release of neuroinflammatory mediators resulting in reduced inflammation and pain.

The concept of Instrumented Smart Implant emerged as a leading research topic that aims to revolutionize the field of orthopaedic implantology. These implants have been designed incorporating biophysical therapeutic actuation, bone-implant interface sensing, implant-clinician communication and self-powering ability. The ultimate goal is to implement revist interface, controlled by clinicians/surgeons without troubling the quotidian activities of patients. Developing such high-performance technologies is of utmost importance, as bone replacements are among the most performed surgeries worldwide and implant failure rates can still exceed 10%. In this review paper, an overview to the major breakthroughs carried out in the scope of multifunctional smart bone implants is provided. One can conclude that many challenges must be overcome to successfully develop them as revision-free implants, but their many strengths highlight a huge potential to effectively establish a new generation of high-sophisticated biodevices.

Background: Osteoarthritis (OA) is a common and debilitating condition characterized by degeneration of hyaline cartilage. Currently, there is no treatment for OA that directly targets degradation of cartilage matrix. Capacitively coupled electric fields (CCEFs) represent a noninvasive and cost-effective treatment modality that can potentially restore articular cartilage homeostasis. Previous studies showed that stimulation of articular cartilage with CCEFs resulted in upregulation of anabolic factors and downregulation of catabolic factors. These studies didn't explain the derivation of the CCEFs or verify their uniformity and field strength, so it's possible that cartilage wasn't exposed to uniform field strength. The present study aims to employ CCEFs with verified uniform field strength in two in-vitro models of OA to investigate its potential to preserve cartilage matrix and validate the results of the aforementioned studies.

Methods: Rabbit hyaline chondrocytes and full-thickness bovine articular cartilage explants were cultured in the absence or presence of CCEF and in the absence or presence of Interleukin1-B (IL-1B). Quantitative polymerase chain reaction (QPCR) was performed on chondrocytes to measure gene expression of ADAM-TS4, MMP3, MMP9, IL-6, TIMP1, and TIMP2. QPCR was performed on explants to measure gene expression of MMP3, Aggrecan, Collagen-2, and TIMP1. Aggrecan concentration in explants was measured with histology. Statistical analysis was performed using one-way analysis of variance and Tukey-Kramer multiple comparison test.

Results: The treatment of chondrocytes with IL-1B resulted in upregulated expression of ADAM-TS4, MMP3, MMP9, and IL-6, while simultaneous administration of IL-1B and CCEF led to a relative decrease in ADAM-TS4, MMP3, MMP9, and IL-6 expression and a relative increase in TIMP1 and TIMP2 expression. Application of IL-1B and CCEF to the explants resulted in decreased expression of MMP3 and increased expression of Aggrecan, Collagen-2, and TIMP1 when compared to application of IL-1B alone.

Conclusion: The data indicate that application of a CCEF with verified uniformity may result in upregulation of cartilage anabolic factors even in the presence of IL-1B while attenuating IL-1B induced upregulation of catabolic factors in both monolayer culture and whole tissue. These results demonstrate the potential of CCEFs to suppress the progression of OA and regenerate articular cartilage matrix.