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The fast-growing field of bioelectronic medicine aims to develop engineered systems that can relieve clinical conditions by stimulating the peripheral nervous system1-5. This type of technology relies largely on electrical stimulation to provide neuromodulation of organ function or pain. One example is sacral nerve stimulation to treat overactive bladder, urinary incontinence and interstitial cystitis (also known as bladder pain syndrome)4,6,7. Conventional, continuous stimulation protocols, however, can cause discomfort and pain, particularly when treating symptoms that can be intermittent (for example, sudden urinary urgency)8. Direct physical coupling of electrodes to the nerve can lead to injury and inflammation9-11. Furthermore, typical therapeutic stimulators target large nerve bundles that innervate multiple structures, resulting in a lack of organ specificity. Here we introduce a miniaturized bio-optoelectronic implant that avoids these limitations by using (1) an optical stimulation interface that exploits microscale inorganic light-emitting diodes to activate opsins; (2) a soft, high-precision biophysical sensor system that allows continuous measurements of organ function; and (3) a control module and data analytics approach that enables coordinated, closed-loop operation of the system to eliminate pathological behaviours as they occur in real-time. In the example reported here, a soft strain gauge yields real-time information on bladder function in a rat model. Data algorithms identify pathological behaviour, and automated, closed-loop optogenetic neuromodulation of bladder sensory afferents normalizes bladder function. This all-optical scheme for neuromodulation offers chronic stability and the potential to stimulate specific cell types.
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Neurônios/fisiologia , Optogenética/instrumentação , Optogenética/métodos , Bexiga Urinária/inervação , Bexiga Urinária/fisiologia , Tecnologia sem Fio/instrumentação , Algoritmos , Animais , Células Cultivadas , Eletrônica , Feminino , Gânglios Espinais/citologia , Humanos , Neurônios/citologia , Ratos , Ratos Sprague-Dawley , Raízes Nervosas Espinhais/citologiaRESUMO
OBJECTIVES: The evolution of neuromodulation devices in order to enter magnetic resonance imaging (MRI) scanners has been one of understanding limitations, engineering modifications, and the development of a consensus within the community in which the FDA could safely administer labeling for the devices. In the initial decades of neuromodulation, it has been contraindicated for MRI use with implanted devices. In this review, we take a comprehensive approach to address all the major products currently on the market in order to provide physicians with the ability to determine when an MRI can be performed for each type of device implant. MATERIALS AND METHODS: We have prepared a narrative review of MRI guidelines for currently marketed implanted neuromodulation devices including spinal cord stimulators, intrathecal drug delivery systems, peripheral nerve stimulators, deep brain stimulators, vagal nerve stimulators, and sacral nerve stimulators. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles, as well as manufacturer-provided information. RESULTS: Guidelines and recommendations for each device and their respective guidelines for use in and around MR environments are presented. CONCLUSIONS: This is the first comprehensive guideline with regards to various devices in the market and MRI compatibility from the American Society of Pain and Neuroscience.
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Terapia por Estimulação Elétrica/instrumentação , Imageamento por Ressonância Magnética , Guias de Prática Clínica como Assunto , Estimulação Encefálica Profunda , Sistemas de Liberação de Medicamentos , Humanos , Injeções Espinhais , Estimulação da Medula Espinal , Estimulação do Nervo VagoRESUMO
PURPOSE OF REVIEW: Our goal is to examine the processes-both central and peripheral-that underlie the development of peripherally-induced neuropathic pain (pNP) and to highlight recent evidence for mechanisms contributing to its maintenance. While many pNP conditions are initiated by damage to the peripheral nervous system (PNS), their persistence appears to rely on maladaptive processes within the central nervous system (CNS). The potential existence of an autonomous pain-generating mechanism in the CNS creates significant implications for the development of new neuropathic pain treatments; thus, work towards its resolution is crucial. Here, we seek to identify evidence for PNS and CNS independently generating neuropathic pain signals. RECENT FINDINGS: Recent preclinical studies in pNP support and provide key details concerning the role of multiple mechanisms leading to fiber hyperexcitability and sustained electrical discharge to the CNS. In studies regarding central mechanisms, new preclinical evidence includes the mapping of novel inhibitory circuitry and identification of the molecular basis of microglia-neuron crosstalk. Recent clinical evidence demonstrates the essential role of peripheral mechanisms, mostly via studies that block the initially damaged peripheral circuitry. Clinical central mechanism studies use imaging to identify potentially self-sustaining infra-slow CNS oscillatory activity that may be unique to pNP patients. While new preclinical evidence supports and expands upon the key role of central mechanisms in neuropathic pain, clinical evidence for an autonomous central mechanism remains relatively limited. Recent findings from both preclinical and clinical studies recapitulate the critical contribution of peripheral input to maintenance of neuropathic pain. Further clinical investigations on the possibility of standalone central contributions to pNP may be assisted by a reconsideration of the agreed terms or criteria for diagnosing the presence of central sensitization in humans.
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Sistema Nervoso Central/fisiopatologia , Neuralgia/etiologia , Sistema Nervoso Periférico/fisiopatologia , Humanos , Neuralgia/fisiopatologia , Neurônios/fisiologia , Sistema Nervoso Periférico/lesõesRESUMO
BACKGROUND: Healthcare clinical and even policy decisions are progressively made based on research-based evidence. The process by which the appropriate trials are developed and well-written manuscripts by means of evidence-based medicine recommendations has resulted in unprecedented necessity in evidence-based medicine in neuromodulation. METHODS: The essential considerations in the planning of neuromodulation research are discussed in the light of available scientific literature as well as the authors' scientific expertise regarding research study design and scientific manuscript preparation. CONCLUSION: This article should enable the reader to understand how to appropriately design a clinical research study and prepare scientific manuscripts. The high-quality and well-designed studies, when performed and reported effectively, support evidence-based medicine and foster improved patient outcomes.
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The use of facemasks is proven to mitigate the spread of the coronavirus and other biological agents that cause disease. Various forms of facemasks, made using different materials, are being used extensively, and it is important to determine their performance characteristics. The size-dependent filtration efficiency and breathing resistance of household sterilization wrap fabrics, and isolation media (American Society for Testing and Materials (ASTM)- and non-ASTM-rated), were measured in filter-holder- and mannequin-in-chamber-based systems, focusing on particles sizes between 20 nm and 2 µm. Double-layer MERV-14 (Minimum Efficiency Reporting Values with rating 14) showed the highest filtration efficiency (94.9-73.3%) amongst household filter media, whereas ASTM-rated isolation masks showed the highest filtration efficiencies (95.6-88.7) amongst all the masks considered. Filtration efficiency of 3D-printed masks with replaceable filter media was found to depend on the degree of sealing around the media holder, which depended on the material's compressibility. Filtration efficiencies of triple-layer combinations (95.8-85.3%) follow a profile similar to single layers but with improved filtration efficiencies.
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OBJECTIVES: Intravenous lidocaine can alleviate painful diabetic peripheral neuropathy (DPN) in some patients. Whether quantitative sensory testing (QST) can identify treatment responders has not been prospectively tested. MATERIALS AND METHODS: This was a prospective, randomized, double-blind, crossover, placebo-controlled trial comparing intravenous lidocaine to normal saline (placebo) for painful DPN. Thirty-four participants with painful DPN were enrolled and administered intravenous lidocaine (5 mg/kg ideal body weight) or placebo as a 40-minute infusion, after a battery of QST parameters were tested on the dorsal foot, with a 3-week washout period between infusions. RESULTS: Thirty-one participants completed both study sessions and were included in the final analysis. Lidocaine resulted in a 51% pain reduction 60 to 120 minutes after infusion initiation, as assessed on a 0 to 10 numerical rating scale, while placebo resulted in a 33.5% pain reduction (difference=17.6%, 95% confidence interval [CI], 1.9%-33.3%, P=0.03). Neither mechanical pain threshold, heat pain threshold, or any of the other measured QST parameters predicted the response to treatment. Lidocaine administration reduced mean Neuropathic Pain Symptom Inventory paresthesia/dysesthesia scores when compared with placebo by 1.29 points (95% CI, -2.03 to -0.55, P=0.001), and paroxysmal pain scores by 0.84 points (95% CI, -1.62 to -0.56, P=0.04), without significant changes in burning, pressing or evoked pain subscores. DISCUSSION: While some participants reported therapeutic benefit from lidocaine administration, QST measures alone were not predictive of response to treatment. Further studies, powered to test more complex phenotypic interactions, are required to identify reliable predictors of response to pharmacotherapy in patients with DPN.
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Diabetes Mellitus , Neuropatias Diabéticas , Neuralgia , Analgésicos , Anestésicos Locais , Estudos Cross-Over , Neuropatias Diabéticas/tratamento farmacológico , Método Duplo-Cego , Humanos , Lidocaína , Neuralgia/tratamento farmacológico , Medição da Dor , Estudos Prospectivos , Resultado do TratamentoRESUMO
RATIONALE AND OBJECTIVE: Three-dimensional (3D) printing allows innovative solutions for personal protective equipment, particularly in times of crisis. Our goal was to generate an N95-alternative 3D-printed respirator that passed Occupational Safety and Health Administration (OSHA)-certified quantitative fit testing during the COVID-19 pandemic. MATERIALS AND METHODS: 3D printed prototypes for N95 solutions were created based on the design of commercial N95 respirators. Computed tomography imaging was performed on an anthropomorphic head phantom wearing a commercially available N95 respirator and these facial contour data was used in mask prototyping. Prototypes were generated using rigid and flexible polymers. According to OSHA standards, prototypes underwent subsequent quantitative respirator fit testing on volunteers who passed fit tests on commercial N95 respirators. RESULTS: A total of 10 prototypes were 3D printed using both rigid (nâ¯=â¯5 designs) and flexible materials (nâ¯=â¯5 designs), Prototypes generated with rigid printing materials (nâ¯=â¯5 designs) did not pass quantitative respirator fit testing. Three of the five prototypes with flexible materials failed quantitative fit testing. The final two prototypes designs passed OSHA-certified quantitative fit tests with an overall mean fit factor of 138 (passing is over 100). CONCLUSION: Through rapid prototyping, 3D printed N95 alternative masks were designed with topographical facial computed tomography data to create mask facial contour and passed OSHA-certified quantitative respiratory testing when flexible polymer was used. This mask design may provide an alternative to disposable N95 respirators in case of pandemic-related shortages. Furthermore, this approach may allow customization for those that would otherwise fail fit testing on standard commercial respirators.
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COVID-19 , Pandemias , Desenho de Equipamento , Humanos , Máscaras , Teste de Materiais , Respiradores N95 , Impressão Tridimensional , SARS-CoV-2 , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: The COVID-19 pandemic has precipitated widespread shortages of filtering facepiece respirators (FFRs) and the creation and sharing of proposed substitutes (novel designs, repurposed materials) with limited testing against regulatory standards. We aimed to categorically test the efficacy and fit of potential N95 respirator substitutes using protocols that can be replicated in university laboratories. SETTING: Academic medical centre with occupational health-supervised fit testing along with laboratory studies. PARTICIPANTS: Seven adult volunteers who passed quantitative fit testing for small-sized (n=2) and regular-sized (n=5) commercial N95 respirators. METHODS: Five open-source potential N95 respirator substitutes were evaluated and compared with commercial National Institute for Occupational Safety and Health (NIOSH)-approved N95 respirators as controls. Fit testing using the 7-minute standardised Occupational Safety and Health Administration fit test was performed. In addition, protocols that can be performed in university laboratories for materials testing (filtration efficiency, air resistance and fluid resistance) were developed to evaluate alternate filtration materials. RESULTS: Among five open-source, improvised substitutes evaluated in this study, only one (which included a commercial elastomeric mask and commercial HEPA filter) passed a standard quantitative fit test. The four alternative materials evaluated for filtration efficiency (67%-89%) failed to meet the 95% threshold at a face velocity (7.6 cm/s) equivalent to that of a NIOSH particle filtration test for the control N95 FFR. In addition, for all but one material, the small surface area of two 3D-printed substitutes resulted in air resistance that was above the maximum in the NIOSH standard. CONCLUSIONS: Testing protocols such as those described here are essential to evaluate proposed improvised respiratory protection substitutes, and our testing platform could be replicated by teams with similar cross-disciplinary research capacity. Healthcare professionals should be cautious of claims associated with improvised respirators when suggested as FFR substitutes.
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COVID-19 , Exposição Ocupacional , Dispositivos de Proteção Respiratória , Adulto , Desenho de Equipamento , Humanos , Respiradores N95 , Pandemias/prevenção & controle , SARS-CoV-2 , Estados Unidos , Ventiladores MecânicosRESUMO
Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O2-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation. These features support in vivo, highly localized tissue oximetry at sites of interest, including deep brain regions of mice, on untethered, awake animal models. The results create many opportunities for studying various O2-mediated processes in naturally behaving subjects, with implications in biomedical research and clinical practice.
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Fontes de Energia Elétrica , Oximetria/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação , Animais , Substitutos Sanguíneos/análise , Corpo Estriado/metabolismo , Corpo Estriado/cirurgia , Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Oxigênio/análise , Ratos , Ratos Sprague-Dawley , Materiais InteligentesRESUMO
By electrically stimulating the spinal cord, it is possible to activate functional populations of neurons that modulate motor and sensory function. One method for accessing these neurons is via their associated axons, which project as functionally segregated longitudinal columns of white-matter funiculi (i.e., spinal tracts). To stimulate spinal tracts without penetrating the cord, we have recently developed technology that enables close-proximity, multi-electrode contact with the spinal cord surface. Our stretchable microelectrode arrays (sMEAs) are fabricated using an elastomer polydimethylsiloxane substrate and can be wrapped circumferentially around the spinal cord to optimize electrode contact. Here, sMEAs were used to stimulate the surfaces of rat spinal cords maintained in vitro, and their ability to selectively activate axonal surface tracts was compared to rigid bipolar tungsten microelectrodes pressed firmly onto the cord surface. Along dorsal column tracts, the axonal response to sMEA stimulation was compared to that evoked by rigid microelectrodes through measurement of their evoked axonal compound action potentials (CAPs). Paired t-tests failed to reveal significant differences between the sMEA's and the rigid microelectrode's stimulus resolution, or in their ranges of evoked CAP conduction velocities. Additionally, dual-site stimulation using sMEA electrodes recruited spatially distinct populations of spinal axons. Site-specific stimulation of the ventrolateral funiculus - a tract capable of evoking locomotor-like activity - recruited ventral root efferent activity that spanned several spinal segments. These findings indicate that the sMEA stimulates the spinal cord surface with selectivity similar to that of rigid microelectrodes, while possessing potential advantages concerning circumferential contact and mechanical compatibility with the cord surface.
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A method for fabricating polydimethylsiloxane (PDMS) based microelectrode arrays (MEAs) featuring novel conical-well microelectrodes is described. The fabrication technique is reliable and efficient, and facilitates controllability over both the depth and the slope of the conical wells. Because of the high-PDMS elasticity (as compared to other MEA substrate materials), this type of compliant MEA is promising for acute and chronic implantation in applications that benefit from conformable device contact with biological tissue surfaces and from minimal tissue damage. The primary advantage of the conical-well microelectrodes--when compared to planar electrodes--is that they provide an improved contact on tissue surface, which potentially provides isolation of the electrode microenvironment for better electrical interfacing. The raised wells increase the uniformity of current density distributions at both the electrode and tissue surfaces, and they also protect the electrode material from mechanical damage (e.g., from rubbing against the tissue). Using this technique, electrodes have been fabricated with diameters as small as 10 µm and arrays have been fabricated with center-to-center electrode spacings of 60 µm. Experimental results are presented, describing electrode-profile characterization, electrode-impedance measurement, and MEA-performance evaluation on fiber bundle recruitment in spinal cord white matter.
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Dimetilpolisiloxanos/química , Estimulação Elétrica/instrumentação , Próteses Neurais , Desenho de Prótese , Animais , Impedância Elétrica , Teste de Materiais , Microeletrodos , RatosRESUMO
A new, scalable process for microfabrication of a silicone-based, elastic multi-electrode array (MEA) is presented. The device is constructed by spinning poly(dimethylsiloxane) (PDMS) silicone elastomer onto a glass slide, depositing and patterning gold to construct wires and electrodes, spinning on a second PDMS layer, and then micropatterning the second PDMS layer to expose electrode contacts. The micropatterning of PDMS involves a custom reactive ion etch (RIE) process that preserves the underlying gold thin film. Once completed, the device can be removed from the glass slide for conformal interfacing with neural tissue. Prototype MEAs feature electrodes smaller than those known to be reported on silicone substrate (60 microm diameter exposed electrode area) and were capable of selectively stimulating the surface of the in vitro isolated spinal cord of the juvenile rat. Stretchable serpentine traces were also incorporated into the functional PDMS-based MEA, and their implementation and testing is described.