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No statistical methods were used to predetermine sample size. The experiments were not randomized. The investigators were not blinded to allocation during experiments and outcome assessment. Experiments were approved by the Institutional Animal Care and Use Committee of Bordeaux (CE50, France) under the license number 50120102-A and performed in accordance with the European Union directive of 22 September 2010 (2010/63/EU) on the protection of animals used for scientific purposes in an AAALAC-accredited facility (Chinese Academy of Science, Beijing, China). Nine healthy male rhesus monkeys (Macaca mulatta, China; Supplementary Table 1) aged between 4 and 9 years old, and weighing between 4.3 kg and 8.4 kg (6.5 ± 0.5 kg) were housed individually in cages designed according to European guidelines (2 m × 1.6 m × 1.26 m). Environmental enrichment included toys and soothing music. All the monkeys are included in the manuscript. Only two monkeys received a spinal cord injury. All the surgical procedures were performed under full anaesthesia induced with atropine (0.04 mg kg−1) and ketamine (10 mg kg−1, intramuscular injection) and maintained under 1%–3% isofluorane after intubation. A certified functional neurosurgeon (J.B.) supervised all the surgical procedures. Surgical implantations were performed during a single operation lasting approximately 8 h. We implanted a 96-channel microelectrode array (Blackrock Microsystems, of pitch 1.5 mm) into the leg area of the left primary motor cortex1 (F4, Supplementary Table 1). The monkeys also received a wireless system2 (T33F-4, Konigsberg Instruments, USA) to record electromyographic signals from the following leg muscles: gluteus medius (GLU), iliopsoas (IPS), rectus femoris (RF), semitendinosus (ST), gastrocnemius medialis (GM), tibialis anterior (TA), extensor digitorum longus (EDL), and flexor hallucis longus (FHL). A custom-made spinal implant was inserted into the epidural space of the lumbar spinal cord according to previously described methods9. The implant was inserted at the L4–L5 vertebrae and pulled until it reached the T13–L1 vertebrae. Electrophysiological testing was performed intra-operatively to adjust the position of the electrodes. Specifically, we verified that a single pulse of stimulation delivered through the most rostral and most caudal electrodes induced motor responses in the IPS and GM muscles, respectively. The connector of the implant, enclosed into a titanium orthosis, was secured to the vertebral bone using titanium screws (Vis MatrixMIDFACE, of diameter 1.5 mm and length 8 mm, Synthes). The wires were routed subcutaneously to an implantable pulse generator inserted between intercostal muscles (see Supplementary Information). Monkeys Q2 and Q3 received a spinal cord injury. A partial laminectomy was made at the level of the T7/T8 thoracic vertebrae. A micro-blade was used to cut approximately two-thirds of the dorsoventral extent of the spinal cord. The lesion was completed using micro-scissors under microscopic observation. Animals retained bowel, bladder, and autonomic function after the injury. The veterinary team continuously monitored the monkeys during the first hours after surgery, and numerous times daily during the seven subsequent days. A few hours after completion of surgical interventions, the animals were able to move around and feed themselves unaided. Clinical rating and monitoring scales were used to assess post-operative pain. Ketophen (2 mg kg−1; subcutaneous) and Metacam (0.2 mg kg−1; subcutaneous) were administered once daily. Lidocaine cream was also applied to surgical wounds twice per day. The antibiotics ceftriaxone sodium (100 mg kg−1; intramuscular) was given immediately following surgery, and then once daily for 7 days. Monkeys were trained to walk on a treadmill and overground along a corridor (300 cm × 35 cm × 70 cm). Plexiglas enclosures were used to maintain the monkeys within the field of view of the cameras. Food pellets and fruits rewarded appropriate behaviours. Additional food to complete daily dietary requirements was provided after training. Monkeys were lightly sedated with ketamine (3.5 mg kg−1), and suspended in the air using a jacket that did not impede leg movements. Single pulses of cathodic monopolar, charge-balanced stimulation (0.3 ms, 1 Hz) were delivered through the electrodes to elicit compound potentials in leg muscles. We selected the active sites whose corresponding spatial maps of motoneuron activation showed the highest correlation with the hotspots. Brain-controlled stimulation protocols were tested during locomotion on a treadmill at a comfortable speed (Q1, 2.0 km h−1; Q2, 1.6 km h−1). Recording sessions were organized as follows: first, we recorded two to five blocks each of duration 1–2 min during stepping without stimulation. These baseline recordings were used to calibrate the decoders for real-time detection of foot-off and foot-strike gait events. Second, monkeys were recorded during brain-controlled stimulation protocols involving (1) solely the electrode targeting the extensor hotspot, (2) solely the electrode targeting the flexor hotspot, and (3) both electrodes. We tested the effects of stimulation frequency and amplitude over functional ranges (30–80 Hz; 1.5–3.9 V). See Supplementary Table 2. Monkeys Q2 and Q3 were recorded after injury as soon as they were able to sustain independent locomotion on the treadmill, which corresponded to 6 days and 16 days post-injury, respectively. Q3 recovered more slowly than Q2, probably owing to receiving more extensive ventral and lateral spinal cord damage (Extended Data Fig. 9). Therefore, monkey Q3 could only be recorded when appropriate behavioural and physical conditions were reached, which occurred two weeks post-injury. Owing to restrictions on the total duration of the experiments (2 weeks), only one entire session could be conducted with this monkey. Following this experiment, the monkey rapidly recovered, which prevented evaluation of the efficacy of the brain–spine interface. The monkeys were recorded on the treadmill at their most comfortable speed (1.2–1.4 km h−1 for monkey Q2 and 1.0 km h−1 for monkey Q3). Recording sessions were organized as follows. First, we recorded two to six blocks each of duration 1–2 min without stimulation. These recordings were used to calibrate the decoders. Second, the decoders were used to test brain-controlled stimulation of both the extension and flexion hotspots over a range of stimulation frequencies. The effects of continuous stimulation using the same stimulation features as during brain-controlled stimulation were also tested. Within the functional range of stimulation parameters, brain-controlled stimulation did not trigger undesired movements or spasms that impaired locomotor movements. See Supplementary Table 2. Procedures to record kinematics and muscle activity have been detailed previously25, 31. Whole-body kinematics was measured using the high-speed motion capture system SIMI (Simi Reality Motion Systems, Germany), combining 4 or 6 video cameras (100 Hz). Reflective white paint was directly applied on the shaved skin of the monkey overlying the following body landmarks of the right side: iliac crest, greater trochanter (hip), lateral condyle (knee), lateral malleolus (ankle), 5th metatarsophalangeal (mtp), and the outside tip of the fifth digit (toe). The Simi motion tracking software was used to obtain the three-dimensional spatial coordinates of the markers. Joint angles were computed accordingly. Electromyographic signals were recorded simultaneously (2 kHz, Kronisberg, USA) and synchronized through the Blackrock Cerebrus system (Blackrock Microsystems, USA), which also recorded neural signals. For this, the Cereplex wireless system25 was mounted on the head of the monkeys. Six antennae and a receiver were used to transmit25 broadband neural signals (0.1 Hz to 7.8 kHz band, sampled at 22 kHz). The signals were band-pass filtered (500 Hz to 7.5 kHz) and spiking events were extracted through threshold crossings2, 3, 32, 33, 34. Specifically, a spiking event was defined on each channel (96 in total) if the signal exceeded 3.0–3.5 times its root-mean-square value calculated over a period of 5 s. This procedure resulted in a binary signal from 96 multiunits, each originating from one of the 96 electrodes of the array. Signals from all 96 multiunits were integrated in the decoder. Our aim was to deliver stimulation over the extensor and flexor hotspots around the times at which these hotspots are active during natural locomotion. To this end, we decoded gait-related motor states from neural activity and used those detections to trigger the stimulation protocols at the appropriate times. The control computer was connected to the local network and continuously received Used Datagram Protocol (UDP) packets containing neural recordings. We designed a custom in-house software application running on the control computer (Visual Studio C++ 2010), which analysed the neural signals in real time. Every 20 ms, the application made a decision: whether or not to trigger one of the spinal cord stimulation protocols. The decision was made based on probabilities of observing a foot-off or a foot-strike motor state given the history of neural data (300 ms pre-lesion and 400 ms post-lesion), as calculated by our decoders. Natural activations of the extension and flexion hotspots were time-locked to foot-off and foot-strike gait events, respectively). In turn, we defined the foot-off and foot-strike motor states as the neural activity preceding foot-off and foot-strike gait events by Δt and Δt temporal offsets, respectively. The offsets were derived to maximize the overlap between the stimulation over the hotspots and the natural activation of those hotspots. In effect, the offsets integrated the latencies between the gait events and the hotspot activations, as well as latencies related to wireless communication between our devices, into the design of our decoders. We calibrated the decoders on data from two to seven no-stimulation blocks recorded at the beginning of each session. Gait events were identified from electromyographic recordings (Q1) or from video recordings (Q2 and Q3). Identification of foot-off and foot-strike gait events from electromyographic recordings was performed using signals from the iliopsoas muscle, which was active around the time of swing onset and remained active throughout most of the swing phase of gait. The foot-off and foot-strike gait events were estimated by thresholding the envelope of the rectified electromyographic signal. Identification of foot-off and foot-strike gait events from video recordings was performed visually. After injury and while the monkeys exhibited minimal movements only of the limb ipsilateral to lesion, foot-off and foot-strike gait events were defined according to residual hip or knee oscillations, which correlated with attempts to execute steps. Analysis of the decoding temporal precision in Q1 revealed that decoded foot-off and foot-strike motor states during brain-controlled stimulation differed from the times of the motor states estimated from the foot-off and foot-strike gait events (median difference for foot-off was 68 ms and for foot-strike was −90 ms). We did not observe such a difference when detecting motor states in the absence of stimulation (median difference for foot-off was 11 ms and for foot-strike was 3 ms). A range of factors could have decreased decoding performance, including changes in somatosensory feedback influenced by the stimulation, attempts by a monkey to adapt its gait, changes in stability, and so on. To improve the temporal accuracy of our decoder, we introduced a decoder recalibration process. The initial decoder, trained on data without stimulation, was used to trigger stimulation through the extension hotspot or flexion hotspot independently for 2 to 3 blocks each. The data collected during these blocks was then combined with the blocks of no stimulation to calibrate a new, second decoder. This decoder successfully compensated for stimulation-induced changes in motor cortex activity (Fig. 3. and Extended Data Fig. 5). We sought to stimulate flexion and extension hotspots throughout the duration of their natural activation during locomotion. We determined the duration of the flexion and extension hotspot stimulation protocols by setting this duration to 300 ms. We then recorded a few steps during brain-controlled stimulation, and adjusted the duration of the stimulation protocols for each monkey when necessary in order to obtain a clear modulation of leg kinematics. This procedure was performed only once for all pre-injury sessions and was repeated for each post-injury session. Data analyses, except for identification of the steps and the marking of foot-off and foot-strike gait events from video recordings, were performed by automatic computer routines. When analyses required involvement of investigators, these were blind to the experimental conditions. To visualize spatiotemporal maps of motoneuron activation, electromyographic signals were mapped onto the rostrocaudal distribution of the motoneurons reconstructed from histological analyses. This approach provides an interpretation of the motoneuron activation at a segmental level rather than at the individual muscle level. Flexion and extension hotspots were identified from the mean spatiotemporal map of motoneuron activation for each monkey independently (n = 3 for Q1, P2 and P3). Single maps computed between two consecutive foot-strike events were time-interpolated to a 1,000-point map and averaged to obtain the mean spatiotemporal map of motoneuron activation. Flexion and extension hotspots were then identified by time-averaging the mean map around the foot-off event (−10% + 20% of the gait cycle) for the flexion hotspot and around the foot strike event (−10% + 30% of the gait cycle) for the extension hotspot. The compound potentials recorded in leg muscles were rectified and integrated for each muscle and stimulation amplitude, and represented in colour-coded spatial maps of motoneuron activation. Instead of measuring specific flexor and extensor muscle selectivity we selected the electrodes that elicited spatial maps similar to those extracted during activation of the flexion and extension hotspots, regardless of muscle specificity. The correlation between the resulting map and the maps recorded during locomotion was calculated for each monkey to identify the voltage range over which the correlation was maximal. The derived voltage range was then used during behavioural experiments (Extended Data Fig. 3c). We quantified the performance of our asynchronous decoders using confusion matrices and normalized mutual information, as described in ref. 35. To evaluate the efficacy of the brain-spine interface and assess the importance of the timing of stimulation in correcting gait deficits, we conducted a post-hoc classification of the steps based on the temporal accuracy of the decoder to reproduce the desired hotspot activation timings. We defined optimal and sub-optimal steps according to the initiation of flexion and extension hotspot stimulation. All the gait cycles that contained only one correct extension activation (stimulation occurring at foot-strike ±125 ms) and only one correct flexion activation (stimulation occurring between foot-off −200 ms and foot-off +50 ms) were defined as optimal steps (Extended Data Fig. 10). After the spinal cord lesion, the monkeys typically walked using their three intact limbs while the leg ipsilateral to the lesion was either dragging along the walking surface or maintained in a flexed posture. Occasionally, monkeys hopped to move both legs forward and avoid bumping against the back of the treadmill enclosure, owing to their inability to move at the selected treadmill belt speed. We counted the numbers of these ‘hop’ and ‘bump’ steps as well as the numbers of normal steps. Experimenters were blinded to stimulation conditions during this analysis. To quantify the functional improvement mediated by the brain–spine interface, we calculated the proportion of normal steps over all recorded blocks on a given day. To quantify the ability of the monkeys to sustain locomotion, we extracted all the events marked as steps, and measured the relative number of steps that were not performed while bumping into the back of the treadmill enclosure. A total of 26 parameters quantifying kinematics (Supplementary Table 3) were computed for each step according to methods described previously in refs 8, 9 and 31. We used principal component analysis to visualize the changes in gait over time and for different conditions (Fig. 4, and Extended Data Figs 7 and 8). To quantify locomotor performance, we calculated the mean Euclidean distance between steps corresponding to a given experimental condition and the mean of steps recorded before the lesion in the same monkey in the entire 26-dimensional space of kinematic parameters. Monkeys were deeply anesthetized and perfused transcardially with a 4% solution of paraformaldehyde. The spinal cord dura was removed and the spinal cord was removed by cutting 40-μm-thick sections using a cryostat microtome, before storage at 4 °C in 0.1 M phosphate-buffered saline azide (0.03%). Monkeys Q2 and Q3 underwent anterograde tracing of corticospinal projections from the leg and trunk area of the left motor cortex using anatomical tracers. All animals were anesthetized as described above. Biotinylated dextran amine (BDA; 10% solution in water; 10,000 Da; Molecular Probes, TSA PLUS Biotin KIT PerkinElmer, catalogue number NEL749A001KT) was injected at 300 nl per site into 40 sites spanning the leg and trunk regions of the left motor cortex. Camera lucida reconstructions of the lesion (Neurolucida 11.0, MBF Biosciences, USA) were performed using evenly spaced horizontal sections (1:4) throughout the whole dorsoventral axis on sections labelled for astrocytic (GFAP; 1:1000, Dako, USA, catalogue number Z0334), NeuN (anti-NeuN; 1:300, Millipore, catalogue number MAB377) and BDA reactivity. Immunoreactions were visualized with secondary antibodies labelled with AlexaFluor 488 (1:400, Invitrogen, catalogue number A-11034) and 647 (1:300, Invitrogen, catalogue number A-21235). All the computed parameters were quantified and compared within each monkey. All data are reported as mean values ± standard error of the mean (s.e.m.). Significance was analysed using the non-parametric Wilcoxon rank-sum test, bootstrapping or a Monte Carlo approach. Data that support the findings and software routines developed for the data analysis are available from the corresponding author upon reasonable request.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 222.05K | Year: 2014

DESCRIPTION (provided by applicant): The goal of the proposed project is to alleviate the enormous public health burden of heart failure. Heart failure leads to significant morbidity and mortality, affects almost five million Americans, and results in morethan 35 billion dollars in annual healthcare costs. Current pharmacological and surgical treatments are only moderately effective and can have substantial side effects. Regardless of cause, heart failure can lead to sustained, decreased cardiac output resulting in failure of the heart to meet the perfusion demands of peripheral tissue. This decrease in cardiac output is accompanied by an imbalance in input to the heart from the autonomic nervous system. A pathological decrease in parasympathetic activity and increase in sympathetic activity further contribute to heart failure through increased oxidative stress and inflammation and predispose patients to malignant arrhythmias and sudden death. Restoration of autonomic balance would remove stress from th


Grant
Agency: National Science Foundation | Branch: | Program: STTR | Phase: Phase I | Award Amount: 224.07K | Year: 2013

This Small Business Technology Transfer (STTR) Phase I Project aims to optimize and test prototypes of continuous, multi-analyte sensors based on stimuli-responsive hydrogels. The proposed sensor array will be capable of monitoring multiple biomarkers relevant to several common human diseases such as diabetes, ketoacidosis, chronic obstructive pulmonary disease (COPD) and even obesity. During this project, the first generation wired sensors will be validated by long-term in vitro and in vivo (mice models) testing. Although the long-term (beyond current project) goal and final application of the device developed here-in will be in humans, in this project we will focus on developing a sensor targeting needs in animal research and the scientific community. This strategy creates a strong foundation and generates confidence in the sensor for clinical studies in few years. The proposed work will be accomplished within three subprojects: 1) Validation of long-term stability of hydrogel-based sensors in plasma, 2) Optimization of first generation wired implantable sensor array, 3) Long term validation of sensors in mouse models and basic histology studies. The team strongly believes they can accomplish these aims and build a product ready to serve the animal research and scientific community by the end of this project. The broader impact/commercial potential of this project stems from the strong demand and an unmet need for continuous multi-analyte sensor in human and in animal-research market. Before attempting to enter the huge and difficult-to-penetrate human-market for continuous metabolic sensors the team will first generate revenue by providing devices for the more accessible animal market while continuously improving the sensor array. There are approximately 50 million research animals in the world. Assuming an average sales price of $250 per/sensor and the proposed technology addresses 1% of the total market, annual sales could exceed $100 million. This technology will provide researchers with a new tool to continuously monitor relevant biomarkers in a given animal over many days, which not only increases the efficiency of studying animal models but also supplies greater detail of their metabolism than is currently allowed by periodic sampling. A continuous monitoring system would save money, speed research, and provide greater insights into the pathogenesis and new potential therapies of diseases.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 774.50K | Year: 2014

DESCRIPTION provided by applicant A range of neurological diseases are now being researched or treated using fully implantable electronic systems to either record or modulate brain activity in humans These implants are currently being protected using polymer coatings that envelop the implant and help keep body fluids away from the sensitive electronics Brain implants with complex three dimensional geometries like the Utah Electrode Array UEA shown in the figure provide a challenge for current encapsulation techniques Parylene has been the gold standard for encapsulation of neural and biomedical implants in general due to its well suited combination of biocompatibility electrical properties and chemical inertness However recording capabilities of long term neural implants andgt months encapsulated with Parylene show signs of degradation To combat this problem Blackrock Microsystems proposes a novel bi layer encapsulation scheme that combines Plasma Assisted Atomic Layer Deposited PA ALD alumina layer underneath the Parylene layer This encapsulation scheme novel to biomedical field will retain all the advantages of Parylene while utilizing vastly superior dielecric properties of underlying ALD alumina layer to create a much longer lasting and more electrically stable biomedical implants This bi layer encapsulation scheme may be seamlessly incorporated into our existing fabrication process flow for our flagship product the UEA The bi layer The UEA with integrated electronics encapsulation method will work on different surfaces metal semiconductor polymer ceramic and on devices with integrated wireless components making it ideal for coating any complex medical device intended for long term implant The project has specific aims Specific Aim Optimize an ALD alumina Parylene bi layer encapsulation scheme and compare performance with Parylene only encapsulation on test devices Specific Aim Develop etch methods to selectively expose active electrode sites on UEAs coated with optimized ALD alumina Parylene bi layer Specific Aim Evaluate charge injection impedance characteristics of ALD alumina Parylene bi layer coated UEAs Specific Aim Comparison of in vivo performance of ALD alumina Parylene bi layer coated UEAs to Parylene only coated UEAs Our preliminary results with Parylene and alumina coated planar interdigitated electrode IDE test structures are very promising in support of the proposed work We have shown that the bi layer encapsulation yields more stable leakage current and stable impedance with andlt change at C for about months approximately equivalent to months at C This superior performance of bi layer encapsulation suggests its potential usefulness for chronic implants with complex surface geometries At the end of the Phase I andapos Lab to Marketplaceandapos SBIR project Blackrock expects to have developed protocols and standards to transform this research from its current early stage lab setting into a commercial grade manufacture process PUBLIC HEALTH RELEVANCE Neuroprosthetics systems require chronic implantation of neural interfaces able to perform for years or decades to reduce surgical risks from follow up surgeries and generate levels of efficacy that justifies the risks associated with the implants Th device has to be protected from the harsh body environment which allows it to perform its intended use Therefore encapsulation of implantable device is critical to its functionality stability and longevity This project addresses one of the key failure modes of current biomedical devices We are developing a novel encapsulation scheme specifically for neural interfaces with integrated wireless architecture but can be extended to cover other biomedical implants Our encapsulation scheme will be transformed to manufacturing scale and applied to commercially available neural interfaces from Blackrock Microsystems This technology has great potential to outperform the existing Parylene encapsulation methods


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 709.16K | Year: 2015

DESCRIPTION provided by applicant The objective of this proposal is to design develop and validate a commercially viable andquot human useandquot smart channel macro andamp micro ECoG microsystem with integrated recording stimulation and impedance measuring capabilities for epilepsy monitoring The microsystem comprises of a state of art microelectronic signal processing component linked to a macro andamp micro integrated ECoG grid via a thin highly flexible bio compatible micro ribbon cable on one end and a single percutaneous flexible cable andquot pigtailandquot on the other end The custom multiplexing ASIC electronics is capable of channel recordings at bit resolution and has fast settle capability for stimulation option and patient safety circuitry The component is contained on a printed circuit board and is encapsulated with Parylene C and Silicone The encapsulated microelectronic component unit is encased in a titanium case and resides subcutaneously between the skin and the skull The integrated microsystem would have unique andquot snow flakeandquot shape grid design containing alternate rows of macro and micro channels The phase I would target a short term goal of developing bench testing and validating in adult sheep model the complete implantable ECoG microsystem that can be translated to research and clinical lab in the shortest time frame PUBLIC HEALTH RELEVANCE The objective of this proposal is to design develop and validate a commercially viable andquot human useandquot thin film polymer based smart channel macro andamp micro integrated ECoG array system for epilepsy monitoring


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 78.33K | Year: 2016

DESCRIPTION provided by applicant Functional magnetic resonance imaging fMRI has become one of the leading research tools to study brain function and is playing a pivotal role in several large scale brain mapping projects worldwide Despite ongoing technical advancements in MRI which have greatly increased its availability and helped improve the resolution for functional brain mapping we still have very limited understanding of what fMRI signals really represent The fact that hemodynamic fMRI does not provide direct measurement of neuronal activities precludes many potential applications involving studies of neuronal circuit function In contrast electrophysiology detects actual electrical signaling with unsurpassed temporal and spatial resolution but generally falls short of providing information in a large scale network levl due to a limited number of recording sites The desire to combine the strengths of both approaches prompted us to develop a high resolution MR compatible microelectrode array permitting examination of electrophysiological signatures during MRI as well as evaluation of deep brain stimulation DBS efficacy using fMRI Our pilot data have demonstrated success in using an advanced micromachining approach to fabricate a miniature electrode array with high density electrodes down to m pitch In contrast to many platinum iridium glass and silicon based electrodes our microelectrode uses a flexible highly biocompatible and MR compatible base substrate polyimide which is known to better match the mechanical impedance of the brain than the other materials commonly used Our previous work has optimized the rigidity of our electrode by experimenting with various thicknesses and layer designs This unique tool is extremely important to accommodate a variety of over head MR coils and gradient inserts with small inner diameters because the majority of the brain coils particularly the ones for preclinical small animal systems are too large to permit the placement of a percutaneous connector on the head Additionally the probe has a built in ribbon cable to the connector which can be placed few centimeters away from the MR radio frequency RF coils reducing the potential for RF induced heating voltage changes and MR related noise during electrophysiological recording In this Phase STTR award we will quantitatively evaluate this novel microelectrode array in vivo using rat subjects with Aim studying ultra high resolution DBS fMRI and Aim developing validating tools for simultaneous fMRI and electrophysiological recording These studies will be crucial for the future success in commercializing the probe as it will generate preliminary data for marketing and also set the foundation for various types of applications to study neural circuits in normal and diseased brains We believe our work will result in a highly unique product opening up a new avenue to explore and validate functional connectivity in the brain with a resolution and scale that cannot be achieved by traditional fMRI or electrophysiology alone PUBLIC HEALTH RELEVANCE Given the increasing use of magnetic resonance imaging MRI in brain research understanding of what MRI signals really represent has become a fundamental yet fully elusive research topic Recent neuroscience neuroimaging research has also emphasized the importance of using multi modal approaches in which the data are acquired by multiple approaches so as to comprehensively interpret a specific neural event Our project aims to bridge two of the most powerful and widely used research clinical tools used in neuroscience MRI and electrophysiology by creating a novel MR compatible channel microelectrode array The unique design of our tool allows the electrode shank to be bent to accommodate various insertion scenarios in the MRI environment while maintaining the stiffness required to penetrate brain tissue This microelectrode array addresses two major applications high resolution electrophysiology and deep brain stimulation Both of which in combination with simultaneous MRI comprise a highly innovative platform which vastly improves our understanding of brain function and neural circuit connectivity


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 101.10K | Year: 2010

DESCRIPTION (provided by applicant): This project addresses the process development and evaluation of an extremely flexible, Parylene C, micro-ribbon cable that is both biocompatible and biostable. Such a cable would be employed to link micro-electrode arrays with percutaneous connectors as well as with other in vivo micro-electronic arrays and modules. The key innovation is the approach utilized to form a monolithic structure with the array and connector directly incorporated into the ribbon cable. Thus there is no need to connect the cable to the array and connector after its synthesis. The primary advantages are extreme flexibility and low modulus resulting in easy placement of the electrode array and minimal to no residual tethering forces exerted on the array in vivo. A third advantage is the wide range of cable designs that can be easily and inexpensively fabricated using MEMs photolithographic processes. After process development validations will focus on designs for enhanced flexibility and stress relief as well as in vitro testing of electrical and mechanical properties. The key criteria for success are to develop a method of manufacturing a monolithic ribbon cable structure followed by evaluation, of the cable in terms of acceptable flexibility (as determined by key neuroscience researchers), mechanical and electrical stability in accelerated in vitro testing and finally feasibility and ease of manufacture at an acceptable cost.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 709.80K | Year: 2011

DESCRIPTION (provided by applicant): The array technology developed by Normann et.al. two decades ago at the University of Utah is currently being manufactured and marketed to the neuroscience research community by Blackrock Microsystems (formerly known asCyberkinetics, Inc., CKI). The Utah electrode array (UEA) is the only high- electrode density, penetrating microelectrode array that is FDA and CE approved, for human use. These arrays, both chronic and acute, have been shown to work very well in animal subjects and their commercial availability has met with considerable interest. The 'manufacturing' procedures that are used to fabricate the UEA at present are closely based on those that were used in their initial development in the laboratory, two decadesago. To date the fabrication of the UEA's has been carried out on a single array basis and as a result the manufacturing technique is not only time consuming but also labor intensive. Also, the existing fabrication costs including utilities, manpower, andmaintenance are high. More importantly, the current processes used to fabricate the UEAs impose limitations in the tolerances of the electrode array geometry and electrical characteristics. Furthermore, the flat architecture of the UEA and convoluted geometry of the targeted tissue can result in poor coupling between the two mating surfaces, leading to active electrode tips that are not in proximity to the target neuronal tissue. Thus for an efficient neural interface and for wide experimental usage bothin experimental and clinical applications, the existing UEA fabrication technique provides inadequate quality, repeatability, and throughput. There is a need to develop less costly but higher precision batch fabrication technology. In 2006, the University of Utah proposed and began work on optimizing existing processes, exploring new materials, designing new architecture of electrode array that are compliant with the host-tissue, and last but not the least developing wafer-scale based process flow for theUEA fabrication. The applicants of this application compose of such a team of engineers, scientists that have been working together over the past years on the technology development for the UEA. The goals of this application is to transfer the manufacturing technology developed at the University of Utah to Blackrock Microsystems, making the technology into a turnkey technology that can be disseminated to the neuroscience and clinical research community, by making the existing microelectrode arrays affordable, better, reliable, and customizable for both acute and chronic applications. PUBLIC HEALTH RELEVANCE: Relevance The new technology would allow us to fabricate neural multielectrode arrays with (a) uniformly shaped microelectrodes (b) small and uniformly exposed active tip sites (c) coated with an electrode material that can deliver high charge densities i.e. high charge injection capacity (CIC) (d) deposited with a highly robust encapsulation material for chronic applications and (e) convoluted electrode arrays for better geometrical match with the targeted tissue. Furthermore the technology would provide better quality, repeatability, and higher throughput of electrode arrays at lower cost of manufacturing and faster lead time. All these advantages would help in making the electrode arrays affordable and assessable to the neuroscience community.


Patent
Blackrock Microsystems | Date: 2015-01-08

Systems and methods for making and using an electrical connector system for electrically connecting an implantable medical device and a data acquisition system are described. The electrical connector system includes a base connected to the implantable medical device and an adaptor connected to the data acquisition system. The base includes a plurality of base magnets arranged on a base contact surface in a unique non-symmetrical pattern. The base contact surface also includes a plurality of base electrical contacts. The adaptor has an adaptor contact surface with a plurality of adaptor magnets and adaptor electrical contacts configured to match those of the base contact surface. The unique non-symmetrical pattern allows the base contact surface and the adaptor contact surface to self-align and self-engage to electrically connect the implantable medical device and the data acquisition system. Other embodiments are described.


Trademark
Blackrock Microsystems | Date: 2012-11-05

Measuring and recording system primarily for medical diagnostic purposes comprised of apparatus and instruments, namely, computer hardware, software, microelectrode arrays, electrodes, acute and chronic connectors, fiber optic links, metal microelectrodes, silicon probes, grids, and array inserters for the purpose of monitoring, recording, analyzing, and storing of human brain and peripheral nerve electrical activity. Product research and development; and consultation services in the field of neuroscience research, neural engineering and neuroprosthetics.

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