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BACKGROUND: Satellite glial cells (SGCs) in the dorsal root ganglia (DRG) play a pivotal role in the formation of neuropathic pain (NP). Sciatic nerve stimulation (SNS) neuromodulation was reported to alleviate NP and reduce neuroinflammation. However, the mechanisms underlying SNS in the DRG remain unclear. This study aimed to elucidate the mechanism of electric stimulation in reducing NP, focusing on the DRG. METHODS: L5 nerve root ligation (NRL) NP rat model was studied. Ipsilateral SNS performed 1 day after NRL. Behavioral tests were performed to assess pain phenotypes. NanoString Ncounter technology was used to explore the differentially expressed genes and cellular pathways. Activated SGCs were characterized in vivo and in vitro. The histochemical alterations of SGCs, macrophages, and neurons in DRG were examined in vivo on post-injury day 8. RESULTS: NRL induced NP behaviors including decreased pain threshold and latency on von Frey and Hargreaves tests. We found that following nerve injury, SGCs were hyperactivated, neurotoxic and had increased expression of NP-related ion channels including TRPA1, Cx43, and SGC-neuron gap junctions. Mechanistically, nerve injury induced reciprocal activation of SGCs and M1 macrophages via cytokines including IL-6, CCL3, and TNF-α mediated by the HIF-1α-NF-κB pathways. SNS suppressed SGC hyperactivation, reduced the expression of NP-related ion channels, and induced M2 macrophage polarization, thereby alleviating NP and associated neuroinflammation in the DRG. CONCLUSIONS: NRL induced hyperactivation of SGCs, which had increased expression of NP-related ion channels. Reciprocal activation of SGCs and M1 macrophages surrounding the primary sensory neurons was mediated by the HIF-1α and NF-κB pathways. SNS suppressed SGC hyperactivation and skewed M1 macrophage towards M2. Our findings establish SGC activation as a crucial pathomechanism in the gliopathic alterations in NP, which can be modulated by SNS neuromodulation.
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Modelos Animales de Enfermedad , Ganglios Espinales , Neuralgia , Enfermedades Neuroinflamatorias , Ratas Sprague-Dawley , Nervio Ciático , Animales , Ganglios Espinales/metabolismo , Neuralgia/terapia , Neuralgia/metabolismo , Masculino , Enfermedades Neuroinflamatorias/metabolismo , Nervio Ciático/patología , Macrófagos/metabolismo , Neuroglía/metabolismo , Ratas , Conducta AnimalRESUMEN
BACKGROUND: Neuropathic pain (NP) is characterized by abnormal activation of pain conducting pathways and manifests as mechanical allodynia and thermal hypersensitivity. Peripheral nerve stimulation is used for treatment of medically refractory chronic NP and has been shown to reduce neuroinflammation. However, whether sciatic nerve stimulation (SNS) is of therapeutic benefit to NP remains unclear. Moreover, the optimal frequency for SNS is unknown. To address this research gap, we investigated the effect of SNS in an acute NP rodent model. METHODS: Rats with right L5 nerve root ligation (NRL) or Sham surgery were used. Ipsilateral SNS was performed at 2 Hz, 20 Hz, and 60 Hz frequencies. Behavioral tests were performed to assess pain and thermal hypersensitivity before and after NRL and SNS. Expression of inflammatory proteins in the L5 spinal cord and the immunohistochemical alterations of spinal cord astrocytes and microglia were examined on post-injury day 7 (PID7) following NRL and SNS. The involvement of the descending pain modulatory pathway was also investigated. RESULTS: Following NRL, the rats showed a decreased pain threshold and latency on the von Frey and Hargreaves tests. The immunofluorescence results indicated hyperactivation of superficial spinal cord dorsal horn (SCDH) neurons. Both 2-Hz and 20-Hz SNS alleviated pain behavior and hyperactivation of SCDH neurons. On PID7, NRL resulted in elevated expression of spinal cord inflammatory proteins including NF-κB, TNF-α, IL-1ß, and IL-6, which was mitigated by 2-Hz and 20-Hz SNS. Furthermore, 2-Hz and 20-Hz SNS suppressed the activation of spinal cord astrocytes and microglia following NRL on PID7. Activity of the descending serotoninergic pain modulation pathway showed an increase early on PID1 following 2-Hz and 20-Hz SNS. CONCLUSIONS: Our results support that both 2-Hz and 20-Hz SNS can alleviate NP behaviors and hyperactivation of pain conducting pathways. We showed that SNS regulates neuroinflammation and reduces inflammatory protein expression, astrocytic gliosis, and microglia activation. During the early post-injury period, SNS also facilitates the descending pain modulatory pathway. Taken together, these findings support the therapeutic potential of SNS for acute NP.
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Neuralgia , Roedores , Animales , Hiperalgesia/metabolismo , Hiperalgesia/terapia , Neuralgia/metabolismo , Neuralgia/terapia , Enfermedades Neuroinflamatorias , Ratas , Nervio Ciático/metabolismo , Médula Espinal/metabolismoRESUMEN
In intact and spinal-injured anesthetized animals, stimulation levels that did not induce any visible muscle twitches were used to elicit motor evoked potentials (MEPs) of varying amplitude, reflecting the temporal and amplitude dynamics of the background excitability of spinal networks. To characterize the physiological excitability states of neuronal networks driving movement, we designed five experiments in awake rats chronically implanted with an epidural stimulating interface, with and without a spinal cord injury (SCI). First, an uninjured rat at rest underwent a series of single electrical pulses at sub-motor threshold intensity, which generated responses that were continuously recorded from flexor and extensor hindlimb muscles, showing an intrinsic patterned modulation of MEPs. Responses were recruited by increasing strengths of stimulation, and the amplitudes were moderately correlated between flexors and extensors. Next, after SCI, four awake rats at rest showed electrically induced MEPs, varying largely in amplitude, of both flexors and extensors that were mainly synchronously modulated. After full anesthesia, MEP amplitudes were largely reduced, although stimulation still generated random baseline changes, unveiling an intrinsic stochastic modulation. The present five cases demonstrate a methodology that can be feasibly replicated in a broader group of awake and behaving rats to further define experimental treatments involving neuroplasticity. Besides validating a new technology for a neural stimulating interface, the present data support the broader message that there is intrinsic patterned and stochastic modulation of baseline excitability reflecting the dynamics of physiological states of spinal networks.NEW & NOTEWORTHY Chronic implants of a new epidural stimulating interface trace dynamics of spinal excitability in awake rats, before and after injury. Motor evoked potentials induced by trains of pulses at sub-motor threshold intensity were continuously modulated in amplitude. Oscillatory patterns of amplitude modulation reduced with increasing strengths of stimulation and were replaced by an intrinsic stochastic tone under anesthesia. Variability of baseline excitability is a fundamental feature of spinal networks, affecting their responses to external input.
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Potenciales Evocados Motores/fisiología , Red Nerviosa/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Estimulación de la Médula Espinal , Médula Espinal/fisiología , Anestesia , Animales , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Electromiografía , RatasRESUMEN
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: A decrease in frontoparietal functional connectivity has been demonstrated with multiple anesthetic agents, and this decrease has been proposed as a final common functional pathway to produce anesthesia.Two alternative measures of long-range cortical interaction are coherence and phase-amplitude coupling. Although phase-amplitude coupling within frontal cortex changes with propofol administration, the effects of propofol on phase-amplitude coupling between different cortical areas have not previously been reported. WHAT THIS ARTICLE TELLS US THAT IS NEW: Using a previously published monkey electrocorticography data set, it was found that propofol induced coherent slow oscillations in visual and oculomotor networks made up of cortical areas with strong anatomic projections.Frontal eye field within-area phase-amplitude coupling increased.Contrary to expectations from previous functional connectivity studies, interareal phase-amplitude coupling also increased with propofol. BACKGROUND: Frontoparietal functional connectivity decreases with multiple anesthetics using electrophysiology and functional imaging. This decrease has been proposed as a final common functional pathway to produce anesthesia. Two alternative measures of long-range cortical interaction are coherence and phase-amplitude coupling. Although phase-amplitude coupling within frontal cortex changes with propofol administration, the effects of propofol on phase-amplitude coupling between different cortical areas have not previously been reported. Based on phase-amplitude coupling observed within frontal lobe during the anesthetized period, it was hypothesized that between-lead phase-amplitude coupling analysis should decrease between frontal and parietal leads during propofol anesthesia. METHODS: A published monkey electrocorticography data set (N = 2 animals) was used to test for interactions in the cortical oculomotor circuit, which is robustly interconnected in primates, and in the visual system during propofol anesthesia using coherence and interarea phase-amplitude coupling. RESULTS: Propofol induces coherent slow oscillations in visual and oculomotor networks made up of cortical areas with strong anatomic projections. Frontal eye field within-area phase-amplitude coupling increases with a time course consistent with a bolus response to intravenous propofol (modulation index increase of 12.6-fold). Contrary to the hypothesis, interareal phase-amplitude coupling also increases with propofol, with the largest increase in phase-amplitude coupling in frontal eye field low-frequency phase modulating lateral intraparietal area ß-power (27-fold increase) and visual area 2 low-frequency phase altering visual area 1 ß-power (19-fold increase). CONCLUSIONS: Propofol anesthesia induces coherent oscillations and increases certain frontoparietal interactions in oculomotor cortices. Frontal eye field and lateral intraparietal area show increased coherence and phase-amplitude coupling. Visual areas 2 and 1, which have similar anatomic projection patterns, show similar increases in phase-amplitude coupling, suggesting higher order feedback increases in influence during propofol anesthesia relative to wakefulness. This suggests that functional connectivity between frontal and parietal areas is not uniformly decreased by anesthetics.
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Anestésicos Intravenosos/administración & dosificación , Lóbulo Frontal/fisiología , Corteza Motora/fisiología , Red Nerviosa/fisiología , Lóbulo Parietal/fisiología , Propofol/administración & dosificación , Animales , Electrocardiografía/efectos de los fármacos , Electrocardiografía/métodos , Lóbulo Frontal/efectos de los fármacos , Macaca fuscata , Corteza Motora/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , Lóbulo Parietal/efectos de los fármacosRESUMEN
BACKGROUND: Pediatric gastrointestinal motility disorders are a large and broad group. Some of these disorders have been effectively treated with electrical stimulation. The goal of our present study is to determine whether the rate of intestinal peristalsis can be increased with electrical stimulation. METHODS: Juvenile mini-Yucatan pigs were placed under general anesthesia and a short segment of the jejunum was transected. Ultrasound gel was placed inside the segment. The segment of the jejunum was first monitored for 20 min under no stimulation, followed by direct electrical stimulation using a planar electrode. The gel extruded out of the intestine via peristalsis was collected and weighed for each 20-min time interval. RESULTS: Effective delivery of the current to the intestine was confirmed via direct measurements. When there was no direct intestinal electrical stimulation, an average of 0.40 g of gel was expelled in 20 min, compared to 1.57 g of gel expelled during direct electrical stimulation (P < 0.01). CONCLUSIONS: Direct intestinal electrical stimulation accelerates the transit of gastrointestinal contents. This approach may be useful in the treatment of a range of pediatric motility disorders.
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Estimulación Eléctrica , Enfermedades Gastrointestinales/terapia , Yeyuno/fisiología , Peristaltismo/fisiología , Animales , Niño , Femenino , Enfermedades Gastrointestinales/fisiopatología , Humanos , Modelos Animales , Porcinos , Porcinos EnanosRESUMEN
Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.
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Traumatismos de la Médula Espinal , Estimulación de la Médula Espinal , Humanos , Potenciales Evocados Motores/fisiología , Estimulación Eléctrica , Interneuronas , Médula Espinal , Tractos Piramidales/fisiologíaRESUMEN
The sympathetic nervous system (SNS) of the bone marrow regulates the regeneration and mobilization of hematopoietic stem cells. Chemotherapy can damage bone marrow SNS, which impairs hematopoietic regeneration and aggravates hematologic toxicities. This leads to long-term bone marrow niche damage and increases mortality in patients undergoing chemotherapy. Electrical neuromodulation has been used to improve functional recovery after peripheral nerve injury. This study demonstrates that electrical sympathetic neuromodulation (ESN) of bone marrow can protect the bone marrow niche from chemotherapy-induced injury. Using carboplatin-treated rats, the SNS via the sciatic nerve innervating the femoral marrow with the effective protocol for bone marrow sympathetic activation is electrically stimulated. ESN can mediate several hematopoietic stem cells maintenance factors and promote hematopoietic regeneration after chemotherapy. It also activates adrenergic signals and reduces the release of pro-inflammatory cytokines, particularly interleukin-1 ß, which contribute to chemotherapy-related nerve injury. Consequently, the severity of chemotherapy-related leukopenia, thrombocytopenia, and mortality can be reduced by ESN. As a result, in contrast to current drug-based treatment, such as granulocyte colony-stimulating factor, ESN can be a disruptive adjuvant treatment by protecting and modulating bone marrow function to reduce hematologic toxicity during chemotherapy.
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Médula Ósea , Células Madre Hematopoyéticas , Ratas , Animales , Células Madre Hematopoyéticas/fisiología , Citocinas/farmacología , Células de la Médula Ósea , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos/uso terapéuticoRESUMEN
Highly varying patterns of electrostimulation (Dynamic Stimulation, DS) delivered to the dorsal cord through an epidural array with 18 independent electrodes transiently facilitate corticospinal motor responses, even after spinal injury. To partly unravel how corticospinal input are affected by DS, we introduced a corticospinal platform that allows selective cortical stimulation during the multisite acquisition of cord dorsum potentials (CDPs) and the simultaneous supply of DS. Firstly, the epidural interface was validated by the acquisition of the classical multisite distribution of CDPs on the dorsal cord and their input-output profile elicited by pulses delivered to peripheral nerves. Apart from increased EMGs, DS selectively increased excitability of the spinal interneurons that first process corticospinal input, without changing the magnitude of commands descending from the motor cortex, suggesting a novel correlation between muscle recruitment and components of cortically-evoked CDPs. Finally, DS increases excitability of post-synaptic spinal interneurons at the stimulation site and their responsiveness to any residual supraspinal control, thus supporting the use of electrical neuromodulation whenever the motor output is jeopardized by a weak volitional input, due to a partial disconnection from supraspinal structures and/or neuronal brain dysfunctions.
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Monitoring of colon activity is currently limited to tethered systems like anorectal manometry. These systems have significant drawbacks, but fundamentally limit the observation time of colon activity, reducing the likelihood of detecting specific clinical events. While significant technological advancement has been directed to mobile sensor capsules, this work describes the development and feasibility of a stationary sensor for describing the coordinated activity between neighboring segments of the colon. Unlike wireless capsules, this device remains in position and measures propagating pressure waves and impedances between colon segments to describe activity and motility. This low-power, flexible, wireless sensor-the colon monitor to capture activity (ColoMOCA) was validated in situ and in vivo over seven days of implantation. The ColoMOCA diameter was similar to common endoscopes to allow for minimally invasive diagnostic placement. The ColoMOCA included two pressure sensors, and three impedance-sensing electrodes arranged to describe the differential pressures and motility between adjacent colon segments. To prevent damage after placement in the colon, the ColoMOCA was fabricated with a flexible polyimide circuit board and a silicone rubber housing. The resulting device was highly flexible and suitable for surgical attachment to the colon wall. In vivo testing performed in eleven animals demonstrated suitability of both short term (less than 3 hours) and 7-day implantations. Data collected wirelessly from animal experiments demonstrated the ColoMOCA described colon activity similarly to wired catheters and allowed untethered, conscious monitoring of organ behavior.
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Colon , Prótesis e Implantes , Animales , Electrodos , Impedancia Eléctrica , CatéteresRESUMEN
Electrical stimulation has been demonstrated as an alternative approach to alleviate intractable colonic motor disorders, whose effectiveness can be evaluated through colonic motility assessment. Various methods have been proposed to monitor the colonic motility and while each has contributed towards better understanding of colon motility, a significant limitation has been the spatial and temporal low-resolution colon motility data acquisition and analysis. This paper presents the study of employing bio-impedance characterization to monitor colonic motor activity. Direct distal colon stimulation was undertaken in anesthetized pigs to validate the bio-impedance scheme simultaneous with luminal manometry monitoring. The results indicated that the significant decreases of bio-impedance corresponded to strong colonic contraction in response to the electrical stimulation in the distal colon. The magnitude/power of the dominant frequencies of phasic colonic contractions identified at baseline (in the range 2-3 cycles per minute (cpm)) were increased after the stimulation. In addition, positive correlations have been found between bio-impedance and manometry. The proposed bio-impedance-based method can be a viable candidate for monitoring colonic motor pattern with high spatial and temporal resolution. The presented technique can be integrated into a closed-loop therapeutic device in order to optimize its stimulation protocol in real-time.
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Enfermedades del Colon , Motilidad Gastrointestinal , Animales , Colon/fisiología , Impedancia Eléctrica , Motilidad Gastrointestinal/fisiología , Manometría/métodos , PorcinosRESUMEN
Novel neural stimulation protocols mimicking biological signals and patterns have demonstrated significant advantages as compared to traditional protocols based on uniform periodic square pulses. At the same time, the treatments for neural disorders which employ such protocols require the stimulator to be integrated into miniaturized wearable devices or implantable neural prostheses. Unfortunately, most miniaturized stimulator designs show none or very limited ability to deliver biomimetic protocols due to the architecture of their control logic, which generates the waveform. Most such designs are integrated into a single System-on-Chip (SoC) for the size reduction and the option to implement them as neural implants. But their on-chip stimulation controllers are fixed and limited in memory and computing power, preventing them from accommodating the amplitude and timing variances, and the waveform data parameters necessary to output biomimetic stimulation. To that end, a new stimulator architecture is proposed, which distributes the control logic over three component tiers - software, microcontroller firmware and digital circuits of the SoC, which is compatible with existing and future biomimetic protocols and with integration into implantable neural prosthetics. A portable prototype with the proposed architecture is designed and demonstrated in a bench-top test with various known biomimetic output waveforms. The prototype is also tested in vivo to deliver a complex, continuous biomimetic stimulation to a rat model of a spinal-cord injury. By delivering this unique biomimetic stimulation, the device is shown to successfully reestablish the connectivity of the spinal cord post-injury and thus restore motor outputs in the rat model.
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Thin-film polymer microelectrode arrays (MEAs) facilitate the high-resolution neural recording with its superior mechanical compliance. However, the densely packed electrodes and interconnects along with the ultra-thin polymeric encapsulation/substrate layers give rise to non-negligible crosstalk, which could result in severe interference in the neural signal recording. Due to the lack of standardized characterization or modeling of crosstalk in neural electrode arrays, to date, crosstalk in polymer MEAs remains poorly understood. In this work, the crosstalk between two adjacent polymer microelectrodes is measured experimentally and modeled using equivalent circuits. Importantly, this study demonstrated a two-well measuring platform and systematically characterized the crosstalk in polymer microelectrodes with true isolation of the victim channel and precise control of its grounding condition. A simple, unified equation from detailed circuit modeling was proposed to calculate the crosstalk in different environments. Finite element analysis (FEA) analysis was conducted further to explore the crosstalk in more aggressively scaled polymer electrode threads. In addition to standardizing neural electrode array crosstalk characterization, this study not only reveals the dependence of the crosstalk in polymer MEAs on a variety of key device parameters but also provides general guidelines for the design of thin polymer MEAs for high-quality neural signal recording.
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Epidural electrical spinal stimulation can facilitate recovery of volitional motor control in individuals that have been completely paralyzed for more than a year. We recently reported a novel neuromodulation method named Dynamic Stimulation (DS), which short-lastingly increased spinal excitability and generated a robust modulation of locomotor networks in fully-anesthetized intact adult rats. In the present study, we applied repetitive DS patterns to four lumbosacral segments acutely after a contusive injury at lumbar level. Repetitive DS delivery restored the spinally-evoked motor EMG responses that were previously suppressed by a calibrated spinal cord contusion. Sham experiments without DS delivery did not allow any spontaneous recovery. Thus, DS uniquely provides the potential for a greater long-term functional recovery after paralysis.
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Potenciales Evocados Motores/fisiología , Traumatismos de la Médula Espinal/terapia , Estimulación de la Médula Espinal/métodos , Médula Espinal/fisiopatología , Animales , Electromiografía , Femenino , Vértebras Lumbares , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
Reliable packaging for implantable neural prosthetic devices in body fluids is a long-standing challenge for devices' chronic applications. This work studied the stability of Parylene C (PA), SiO2, and Si3N4 packages and coating strategies on tungsten wires using accelerated, reactive aging tests in three solutions: pH 7.4 phosphate-buffered saline (PBS), PBS + 30 mM H2O2, and PBS + 150 mM H2O2. Different combinations of coating thicknesses and deposition methods were studied at various testing temperatures. Analysis of the preliminary data shows that the pinholes/defects, cracks, and interface delamination are the main attributes of metal erosion and degradation in reactive aging solutions. Failure at the interface of package and metal is the dominating factor in the wire samples with open tips.
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BACKGROUND: Potentiation of synaptic activity in spinal networks is reflected in the magnitude of modulation of motor responses evoked by spinal and cortical input. After spinal cord injury, motor evoked responses can be facilitated by pairing cortical and peripheral nerve stimuli. OBJECTIVE: To facilitate synaptic potentiation of cortico-spinal input with epidural electrical stimulation, we designed a novel neuromodulation method called dynamic stimulation (DS), using patterns derived from hind limb EMG signal during stepping. METHODS: DS was applied dorsally to the lumbar enlargement through a high-density epidural array composed of independent platinum-based micro-electrodes. RESULTS: In fully anesthetized intact adult rats, at the interface array/spinal cord, the temporal and spatial features of DS neuromodulation affected the entire lumbosacral network, particularly the most rostral and caudal segments covered by the array. DS induced a transient (at least 1â¯min) increase in spinal cord excitability and, compared to tonic stimulation, generated a more robust potentiation of the motor output evoked by single pulses applied to the spinal cord. When sub-threshold pulses were selectively applied to a cortical motor area, EMG responses from the contralateral leg were facilitated by the delivery of DS to the lumbosacral cord. Finally, based on motor-evoked responses, DS was linked to a greater amplitude of motor output shortly after a calibrated spinal cord contusion. CONCLUSION: Compared to traditional tonic waveforms, DS amplifies both spinal and cortico-spinal input aimed at spinal networks, thus significantly increasing the potential and accelerating the rate of functional recovery after a severe spinal lesion.
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Electromiografía/métodos , Vértebras Lumbares/fisiología , Corteza Motora/fisiología , Estimulación de la Médula Espinal/métodos , Médula Espinal/fisiología , Animales , Femenino , Vértebras Lumbares/inervación , Masculino , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Recuperación de la Función/fisiologíaRESUMEN
BACKGROUND: Knowledge on optimal electrical stimulation (ES) modalities and region-specific functional effects of colonic neuromodulation is lacking. We aimed to map the regional colonic motility in response to ES of (a) the colonic tissue and (b) celiac branch of the abdominal vagus nerve (CBVN) in an anesthetized porcine model. METHODS: In male Yucatan pigs, direct ES (10 Hz, 2 ms, 15 mA) of proximal (pC), transverse (tC), or distal (dC) colon was done using planar flexible multi-electrode array panels and CBVN ES (2 Hz, 0.3-4 ms, 5 mA) using pulse train (PT), continuous (10 min), or square-wave (SW) modalities, with or without afferent nerve block (200 Hz, 0.1 ms, 2 mA). The regional luminal manometric changes were quantified as area under the curve of contractions (AUC) and luminal pressure maps generated. Contractions frequency power spectral analysis was performed. Contraction propagation was assessed using video animation of motility changes. KEY RESULTS: Direct colon ES caused visible local circular (pC, tC) or longitudinal (dC) muscle contractions and increased luminal pressure AUC in pC, tC, and dC (143.0 ± 40.7%, 135.8 ± 59.7%, and 142.0 ± 62%, respectively). The colon displayed prominent phasic pressure frequencies ranging from 1 to 12 cpm. Direct pC and tC ES increased the dominant contraction frequency band (1-6 cpm) power locally. Pulse train CBVN ES (2 Hz, 4 ms, 5 mA) triggered pancolonic contractions, reduced by concurrent afferent block. Colon contractions propagated both orally and aborally in short distances. CONCLUSION AND INFERENCES: In anesthetized pigs, the dominant contraction frequency band is 1-6 cpm. Direct colonic ES causes primarily local contractions. The CBVN ES-induced pancolonic contractions involve central neural network.
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Colon/inervación , Estimulación Eléctrica/métodos , Motilidad Gastrointestinal/fisiología , Nervio Vago , Animales , Colon/fisiología , Manometría , Sus scrofa , PorcinosRESUMEN
Bioresorbable electronic stimulators are of rapidly growing interest as unusual therapeutic platforms, i.e., bioelectronic medicines, for treating disease states, accelerating wound healing processes and eliminating infections. Here, we present advanced materials that support operation in these systems over clinically relevant timeframes, ultimately bioresorbing harmlessly to benign products without residues, to eliminate the need for surgical extraction. Our findings overcome key challenges of bioresorbable electronic devices by realizing lifetimes that match clinical needs. The devices exploit a bioresorbable dynamic covalent polymer that facilitates tight bonding to itself and other surfaces, as a soft, elastic substrate and encapsulation coating for wireless electronic components. We describe the underlying features and chemical design considerations for this polymer, and the biocompatibility of its constituent materials. In devices with optimized, wireless designs, these polymers enable stable, long-lived operation as distal stimulators in a rat model of peripheral nerve injuries, thereby demonstrating the potential of programmable long-term electrical stimulation for maintaining muscle receptivity and enhancing functional recovery.
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Implantes Absorbibles , Terapia por Estimulación Eléctrica/instrumentación , Traumatismos de los Nervios Periféricos/terapia , Poliuretanos/química , Tecnología Inalámbrica/instrumentación , Animales , Modelos Animales de Enfermedad , Terapia por Estimulación Eléctrica/métodos , Femenino , Humanos , Ensayo de Materiales , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Ratas , Regeneración , Nervio Ciático/lesiones , Nervio Ciático/fisiologíaRESUMEN
Gastrointestinal (GI) electrical stimulation has been shown in several studies to be a potential treatment option for GI motility disorders. Despite the promising preliminary research progress, however, its clinical applicability and usability are still unknown and limited due to the lack of a miniaturized versatile implantable stimulator supporting the investigation of effective stimulation patterns for facilitating GI dysmotility. In this paper, we present a wireless implantable GI modulation system to fill this technology gap. The system consists of a wireless extraluminal gastrointestinal modulation device (EGMD) performing GI electrical stimulation, and a rendezvous device (RD) and a custom-made graphical user interface (GUI) outside the body to wirelessly power and configure the EGMD to provide the desired stimuli for modulating GI smooth muscle activities. The system prototype was validated in bench-top and in vivo tests. The GI modulation system demonstrated its potential for facilitating intestinal transit in the preliminary in vivo chronic study using porcine models.
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Electrical stimulation using non-periodic biomimetic stimulation pattern has been shown to be effective in various critical biomedical applications. However, the existing programmable stimulators that support this protocol are non-portable and have architectures that are not translatable to wearable or implantable applications. In this work, we present a 32-channel neural stimulator system based on an implantable System-On-Chip (SoC) that addresses these technological challenges. The system is designed to be portable, powered by a single battery, wirelessly controlled, and versatile to perform concurrent multi-channel stimulation with independent arbitrary waveforms. The experimental results demonstrate multi-channel stimulation mimicking electromyography (EMG) waveforms and randomly-spaced stimulation pulses mimicking neuronal firing patterns. This compact and highly flexible prototype can support various neuromodulation researches and animal studies and serves as a precursor for the development of the next generation implantable biomimetic stimulator.
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Translational research may lead to development of micro-electromechanical system-based devices to treat muscle and nerve dysfunctions whose current treatments are inadequate and, at best, palliative. This paper discusses the development of engineered microsystems as a treatment option for palsies of the seventh cranial nerve and the potential application of these devices as a platform technology for treatment of other nervous dysfunctions. The engineering techniques for electrical and chemical stimulation of denervated muscle are discussed along with current caveats from clinical and engineering standpoints. As opposed to current treatments, miniaturized implants offer the possibility of the reduced toxicity and increased specificity of direct drug delivery. As with the increased miniaturization of other technologies, engineering of these increasingly small implantable microsystems holds great promise for the future development of yet smaller, even nanoscale, implantable devices.