Examining thein vivofunctionality of the magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI).

Objective. Although neural-enabled prostheses have been used to restore some lost functionality in clinical trials, they have faced difficulty in achieving high degree of freedom, natural use compared to healthy limbs. This study investigated thein vivofunctionality of a flexible and scalable regenerative peripheral-nerve interface suspended within a microchannel-embedded, tissue-engineered hydrogel (the magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI)) as a potential approach to improving current issues in peripheral nerve interfaces.Approach. Assembled MARTEENI devices were implanted in the gaps of severed sciatic nerves in Lewis rats. Both acute and chronic electrophysiology were recorded, and channel-isolated activity was examined. In terminal experiments, evoked activity during paw compression and stimulus response curves generated from proximal nerve stimulation were examined. Electrochemical impedance spectroscopy was performed to assess the complex impedance of recording sites during chronic data collection. Features of the foreign-body response (FBR) in non-functional implants were examined using immunohistological methods.Main results. Channel-isolated activity was observed in acute, chronic, and terminal experiments and showed a typically biphasic morphology with peak-to-peak amplitudes varying between 50 and 500µV. For chronic experiments, electrophysiology was observed for 77 days post-implant. Within the templated hydrogel, regenerating axons formed minifascicles that varied in both size and axon count and were also found to surround device threads. No axons were found to penetrate the FBR. Together these results suggest the MARTEENI is a promising approach for interfacing with peripheral nerves.Significance. Findings demonstrate a high likelihood that observed electrophysiological activity recorded from implanted MARTEENIs originated from neural tissue. The variation in minifascicle size seen histologically suggests that amplitude distributions observed in functional MARTEENIs may be due to a combination of individual axon and mini-compound action potentials. This study provided an assessment of a functional MARTEENI in anin vivoanimal model for the first time.

Microgaskets for High-Channel-Density Reconnectable Implantable Packaging.

Demands for implantable bioelectronic devices to increase the number of channels for greater functional capacity and resolution, shrink implant size to minimize tissue response and patient burden, and support battery changes and electronics upgrades for long-term operational viability, cannot be met with existing implant-connector technology. In this paper we describe our novel approach to develop a rematable high-channel-density implant-connector technology, with a focus on the design, fabrication, and characterization of its microgasket. The microgaskets made of polydimethylsiloxane elastomer (PDMSe) have achieved much better electrical isolation for neural stimulation (~5 MΩ at 10 kHz) compared with conventional implant connectors (50 kΩ at 10 kHz), despite a 200-fold increase in channel density (conventional: ~0.0644 ch/mm2, microgasket: ~12.8 ch/mm2). The microgaskets also achieved high electrical isolation for neural recording (i.e., ~35 MΩ at 1 kHz) at the same high channel density. When mechanically compressed the microscale vias in the PDMSe microgaskets deform laterally, which could damage or enhance gasket-traversing conductive spring elements in each microscale via depending on their design. We have demonstrated that by lowering the height-to-width aspect ratio of the gasket vias, they can maintain their shape under clamping pressures high enough to achieve high isolation.

Proceedings of the Ninth Annual Deep Brain Stimulation Think Tank: Advances in Cutting Edge Technologies, Artificial Intelligence, Neuromodulation, Neuroethics, Pain, Interventional Psychiatry, Epilepsy, and Traumatic Brain Injury.

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury.

Proceedings of the 10th annual deep brain stimulation think tank: Advances in cutting edge technologies, artificial intelligence, neuromodulation, neuroethics, interventional psychiatry, and women in neuromodulation.

The deep brain stimulation (DBS) Think Tank X was held on August 17-19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation. Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the "trough of disillusionment." DBS for depression was considered as "re-emerging" and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS.

The Materials Science Foundation Supporting the Microfabrication of Reliable Polyimide-Metal Neuroelectronic Interfaces.

Thin-film polyimide-metal neuroelectronic interfaces hold the potential to alleviate many neurological disorders. However, their long-term reliability is challenged by an aggressive implant environment that causes delamination and degradation of critical materials, resulting in a degradation or complete loss of implant function. Herein, a rigorous and in-depth analysis is presented on the fabrication and modification of critical materials in these thin-film neural interfaces. Special attention is given to improving the interfacial adhesion between thin films and processing modifications to maximize device reliability. Fundamental material analyses are performed on the polyimide substrate and adhesion-promotion candidates, including amorphous silicon carbide (a-SiC:H), amorphous carbon, and silane coupling agents. Basic fabrication rules are identified to markedly improve polyimide self-adhesion, including optimizing the polyimide-cure profile and maximizing high-energy surface activation. In general, oxide-forming materials are identified as poor adhesive aids to polyimide without targeted modifications. Methods are identified to incorporate effective a-SiC:H interfacial layers to improve metal adherence to polyimide, in addition to examples of alloying between adjacent material layers that can impact the trace resistivity and long-term reliability of the thin-film interfaces. The provided rationale and consequences of key decisions made should promote more reproducible science using robust and reliable neuroelectronic technology.

Development of a magnetically aligned regenerative tissue-engineered electronic nerve interface for peripheral nerve applications.

Peripheral nerve injuries can be debilitating to motor and sensory function, with severe cases often resulting in complete limb amputation. Over the past two decades, prosthetic limb technology has rapidly advanced to provide users with crude motor control of up to 20° of freedom; however, the nerve-interfacing technology required to provide high movement selectivity has not progressed at the same rate. The work presented here focuses on the development of a magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI) that combines polyimide "threads" encapsulated within a magnetically aligned hydrogel scaffold. The technology exploits tissue-engineered strategies to address concerns over traditional peripheral nerve interfaces including poor axonal sampling through the nerve and rigid substrates. A magnetically templated hydrogel is used to physically support the polyimide threads while also promoting regeneration in close proximity to the electrode sites on the polyimide. This work demonstrates the utility of magnetic templating for use in tuning the mechanical properties of hydrogel scaffolds to match the stiffness of native nerve tissue while providing an aligned substrate for Schwann cell migration in vitro. MARTEENI devices were fabricated and implanted within a 5-mm-long rat sciatic-nerve transection model to assess regeneration at 6 and 12 weeks. MARTEENI devices do not disrupt tissue remodeling and show axon densities equivalent to fresh tissue controls around the polyimide substrates. Devices are observed to have attenuated foreign-body responses around the polyimide threads. It is expected that future studies with functional MARTEENI devices will be able to record and stimulate single axons with high selectivity and low stimulation regimes.

Safety and Tolerability of Burst-Cycling Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease.

Background: Freezing of gait (FOG) is a common symptom in Parkinson's disease (PD) and can be difficult to treat with dopaminergic medications or with deep brain stimulation (DBS). Novel stimulation paradigms have been proposed to address suboptimal responses to conventional DBS programming methods. Burst-cycling deep brain stimulation (BCDBS) delivers current in various frequencies of bursts (e.g., 4, 10, or 15 Hz), while maintaining an intra-burst frequency identical to conventional DBS. Objective: To evaluate the safety and tolerability of BCDBS in PD patients with FOG. Methods: Ten PD subjects with STN or GPi DBS and complaints of FOG were recruited for this single center, single blinded within-subject crossover study. For each subject, we compared 4, 10, and 15 Hz BCDBS to conventional DBS during the PD medication-OFF state. Results: There were no serious adverse events with BCDBS. It was feasible and straightforward to program BCDBS in the clinic setting. The benefit was comparable to conventional DBS in measures of FOG, functional mobility and in PD motor symptoms. BCDBS had lower battery consumption when compared to conventional DBS. Conclusions: BCDBS was feasible, safe and well tolerated and it has potential to be a viable future DBS programming strategy.

Examining the Need to Standardize Implanted Stimulator Connectors: NANS Survey Results.

INTRODUCTION: Connectors between implanted stimulator electrodes and pulse generators allow revisions, including battery changes or generator upgrades, to proceed without disturbing uninvolved components, such as the electrode. As new devices are introduced, however, connector incompatibility, even with updated hardware from the same manufacturer, can lead to additional procedures, expense, and morbidity. MATERIALS AND METHODS: Following the example of the cardiac pacemaker/defibrillator industry, the Institute of Neuromodulation (IoN) met to explore the possibility of creating connector standards for implanted neurostimulation devices. At a subsequent meeting of the Association for the Advancement of Medical Instrumentation, which coordinates the development of such standards, industry representatives asked for data defining the need for a new standard. Accordingly, IoN prepared an online survey to be sent to the North American Neuromodulation Society mailing list regarding experience with the connectivity of spinal cord stimulation (SCS) generators and electrodes. RESULTS: The 87 respondents of 9657 surveyed included 77 clinicians, who reported a total of 42,572 SCS implants and revisions. More than a quarter of revisions (2741 of 9935) required the interconnection of devices made by separate manufacturers, in most cases (n = 1528) to take advantage of a new feature (e.g., rechargeability, new waveform) or because an original component could not be replaced (n = 642). Connector adapters provided by manufacturers were used in less than half (n = 1246) of these cases. Nearly all (94%) of the clinicians agreed that standardized connectors should be developed for SCS, and 86% opined that standardized connectors should be developed for other neurostimulation therapies. CONCLUSION: Those who responded to our survey support the development of standard connectors for implanted stimulators, with voluntary compliance by manufacturers, to mitigate the need for adapters and facilitate interchanging components when appropriate. Other advantages to patients and manufacturers might accrue from the adoption of standards, as technology evolves and diversifies.

Microtopographical patterns promote different responses in fibroblasts and Schwann cells: A possible feature for neural implants.

The chronic reliability of bioelectronic neural interfaces has been challenged by foreign body reactions (FBRs) resulting in fibrotic encapsulation and poor integration with neural tissue. Engineered microtopographies could alleviate these challenges by manipulating cellular responses to the implanted device. Parallel microchannels have been shown to modulate neuronal cell alignment and axonal growth, and Sharklet™ microtopographies of targeted feature sizes can modulate bio-adhesion of an array of bacteria, marine organisms, and epithelial cells due to their unique geometry. We hypothesized that a Sharklet™ micropattern could be identified that inhibited fibroblasts partially responsible for FBR while promoting Schwann cell proliferation and alignment. in vitro cell assays were used to screen the effect of Sharklet™ and channel micropatterns of varying dimensions from 2 to 20 µm on fibroblast and Schwann cell metrics (e.g., morphology/alignment, nuclei count, metabolic activity), and a hierarchical analysis of variance was used to compare treatments. In general, Schwann cells were found to be more metabolically active and aligned than fibroblasts when compared between the same pattern. 20 µm wide channels spaced 2 µm apart were found to promote Schwann cell attachment and alignment while simultaneously inhibiting fibroblasts and warrant further in vivo study on neural interface devices. No statistically significant trends between cellular responses and geometrical parameters were identified because mammalian cells can change their morphology dependent on their environment in a manner dissimilar to bacteria. Our results showed although surface patterning is a strong physical tool for modulating cell behavior, responses to micropatterns are highly dependent on the cell type.

Integration of flexible polyimide arrays into soft extracellular matrix-based hydrogel materials for a tissue-engineered electronic nerve interface (TEENI).

BACKGROUND: Biomimetic hydrogels used in tissue engineering can improve tissue regeneration and enable targeted cellular behavior; there is growing interest in combining hydrogels with microelectronics to create new neural interface platforms to help patient populations. However, effective processes must be developed to integrate flexible but relatively stiff (e.g., 1-10 GPa) microelectronic arrays within soft (e.g., 1-10 kPa) hydrogels. NEW METHOD: Here, a novel method for integrating polyimide microelectrode arrays within a biomimetic hydrogel scaffold is demonstrated for use as a tissue-engineered electronic nerve interface (TEENI). Tygon tubing and a series of 3D printed molds were used to facilitate hydrogel fabrication and device assembly. COMPARISON WITH EXISTING METHODS: Other comparable regenerative peripheral nerve interface technologies do not utilize the flexible microelectrode array design nor the hydrogel scaffold described here. These methods typically use stiff electrode arrays that are affixed to a similarly stiff implantable tube serving as the nerve guidance conduit. RESULTS: Our results indicate that there is a substantial mechanical mismatch between the flexible microelectronic arrays and the soft hydrogel. However, using the methods described here, there is consistent fabrication of these regenerative peripheral nerve interfaces suitable for implantation. CONCLUSIONS: The assembly process that was developed resulted in repeatable and consistent integration of microelectrode arrays within a soft tissue-engineered hydrogel. As reported elsewhere, these devices have been successfully implanted in a rat sciatic nerve model and yielded neural recordings. This process can be adapted for other applications and hydrogels in which flexible electronic materials are combined with soft regenerative scaffolds.

Electrical Isolation Performance of Microgasket Technology for Implant Packaging.

High-channel-count neural interfaces are typically packaged by being permanently bonded to their packaged electronics followed by encapsulation. Such interfaces are often intimately integrated into neural tissue, their removal to replace the battery or upgrade electronics is not undesirable. Gaskets are widely used to provide liquid/electrical isolation and to seal the connection between two or more mating parts. Pressure-driven microgaskets are well established in the field of microfluidics. Although rematable microgaskets for fluidic interconnects exist, the use of microgaskets for electrical isolation have not been demonstrated. Our approach is to electrically isolate 2-D arrays of contact pads using a compressible silicone microgasket. Electrochemical impedance spectroscopy (EIS) was used to quantify the electrical isolation of the microgasket on contact pads, which were formed in a polyimide flex circuit, as a function of frequency after being soaked in saline. Experiments have shown that the compressed sub-millimeter PDMSe microgasket can provide excellent isolation (i.e., >30 MΩ at 1 KHz) that is comparable to the other more conventional packaging methods, such as encapsulation in polydimethylsiloxane elastomer (PDMSe) or parylene-C. Our microgasket-based approach should be scalable to high channel counts and high channel densities enabling much smaller and higher-performance neural implants.

Advances in Translational Nanotechnology: Challenges and Opportunities.

The burgeoning field of nanotechnology aims to create and deploy nanoscale structures, devices, and systems with novel, size-dependent properties and functions. The nanotechnology revolution has sparked radically new technologies and strategies across all scientific disciplines, with nanotechnology now applied to virtually every area of research and development in the US and globally. NanoFlorida was founded to create a forum for scientific exchange, promote networking among nanoscientists, encourage collaborative research efforts across institutions, forge strong industry-academia partnerships in nanoscience, and showcase the contributions of students and trainees in nanotechnology fields. The 2019 NanoFlorida International Conference expanded this vision to emphasize national and international participation, with a focus on advances made in translating nanotechnology. This review highlights notable research in the areas of engineering especially in optics, photonics and plasmonics and electronics; biomedical devices, nano-biotechnology, nanotherapeutics including both experimental nanotherapies and nanovaccines; nano-diagnostics and -theranostics; nano-enabled drug discovery platforms; tissue engineering, bioprinting, and environmental nanotechnology, as well as challenges and directions for future research.

In Vitro Reactive-Accelerated-Aging Assessment of Anisotropic Conductive Adhesive and Back-End Packaging for Electronic Neural Interfaces.

Bioelectronic neural interfaces can fail in vivo due to water penetration and corrosion of the packaging technology used to protect sensitive portions of the device. Although anisotropic conductive adhesive (ACA) is gaining popularity in the neural interface community to connect fabricated electrode arrays with back-end packages, the durability of ACA in chronic implants is largely unknown. We have designed a platform that uses an aggressive reactive-accelerated aging (RAA) environment to rapidly assess the ability of ACA and silicone-rubber encapsulation to maintain electrical integrity in vitro. All RAA experiments were performed at 77°C, for 24 days, and with 10 to 20 mM H2O2, which approximates a 1 year implantation. Results from these experiments showed that ACA rapidly fails (i.e., 2 to 4 days RAA) due to water absorption through the silicone encapsulant. Electrical impedance spectroscopy (EIS) confirmed water penetration through the package and the resulting corrosion of the sensitive metallic components.

Freezing-of-Gait Detection Using Wearable Sensor Technology and Possibilistic K-Nearest-Neighbor Algorithm.

Freezing of Gait (FoG) is an episodic motor disturbance in Parkinson disease (PD) that causes patients to be unable to initiate or maintain their locomotion. Prior work that used simple and easy-to-learn algorithms based on a singular feature and rule-based classifiers are not sufficient to learn variations in patient walking styles and freezing patterns. Efforts to use machine-learning algorithms suffer from challenges caused by imbalanced datasets. Here, we propose a new approach for FoG detection using a wide set of online calculable features and an instance-based and non-parametric Possibilistic K-Nearest-Neighbor (KNN) classifier. The issue of imbalanced datasets is addressed using the Self-Organizing-Map (SOM) algorithm.

in vitro Reactive-Accelerated-Aging (RAA) Assessment of Tissue-Engineered Electronic Nerve Interfaces (TEENI).

A reactive-accelerated-aging (RAA) soak-test has been employed to challenge microfabricated neural interface devices against an aggressive environment that mimics worstcase chronic physiological inflammation. The RAA tests were able to determine the ability of different materials to increase the adhesive strength of the polyimide and platinum-goldplatinum metallization thin-film interface. It was found that a 3-day RAA soak-test at 87 °C in phosphate buffered saline with 10 to 20 mM hydrogen peroxide resulted in adhesive failure of the metal-polyimide interface when titanium was used as the primary adhesion promotor. The addition of hydrogenated amorphous silicon carbide was able to eliminate the onset of adhesive failure of the metal-polyimide interface during 7-day RAA soak tests. However, sporadic cracking of the silicon carbide layer resulted in a minority of broken metal interconnects that resulted in failed electrodes. These tests have demonstrated the ability of RAA soak tests to provide rapid in vitro assessment of microfabricated neural interfaces and thereby reduce the time needed to develop synthetic methods to fabricate chronically reliable devices.

Anti-biofouling implantable catheter using thin-film magnetic microactuators.

Here we report on the development of polyimide-based flexible magnetic actuators for actively combating biofouling that occurs in many chronically implanted devices. The thin-film flexible devices are microfabricated and integrated into a single-pore silicone catheter to demonstrate a proof-of-concept for a self-clearing smart catheter. The static and dynamic mechanical responses of the thin-film magnetic microdevices were quantitatively measured and compared to theoretical values. The mechanical fatigue properties of these polyimide-based microdevices were also characterized up to 300 million cycles. Finally, the biofouling removal capabilities of magnetically powered microdevices were demonstrated using bovine serum albumin and bioconjugated microbeads. Our results indicate that these thin-film microdevices are capable of significantly reducing the amount of biofouling. At the same time, we demonstrated that these microdevices are mechanically robust enough to withstand a large number of actuation cycles during its chronic implantation.

Tissue-Engineered Peripheral Nerve Interfaces.

Research on neural interfaces has historically concentrated on development of systems for the brain; however, there is increasing interest in peripheral nerve interfaces (PNIs) that could provide benefit when peripheral nerve function is compromised, such as for amputees. Efforts focus on designing scalable and high-performance sensory and motor peripheral nervous system interfaces. Current PNIs face several design challenges such as undersampling of signals from the thousands of axons, nerve-fiber selectivity, and device-tissue integration. To improve PNIs, several researchers have turned to tissue engineering. Peripheral nerve tissue engineering has focused on designing regeneration scaffolds that mimic normal nerve extracellular matrix composition, provide advanced microarchitecture to stimulate cell migration, and have mechanical properties like the native nerve. By combining PNIs with tissue engineering, the goal is to promote natural axon regeneration into the devices to facilitate close contact with electrodes; in contrast, traditional PNIs rely on insertion or placement of electrodes into or around existing nerves, or do not utilize materials to actively facilitate axon regeneration. This review presents the state-of-the-art of PNIs and nerve tissue engineering, highlights recent approaches to combine neural-interface technology and tissue engineering, and addresses the remaining challenges with foreign-body response.

Freezing-of-Gait detection using temporal, spatial, and physiological features with a support-vector-machine classifier.

Freezing-of-Gait (FoG) is a syndrome of Parkinson's disease defined by episodes when patients show a complete inability to take a step or continue with their locomotion. In order to develop closed-loop therapeutic strategies, including deep brain stimulation, a reliable means of detecting freezing episodes is required. By using wearable accelerometers, freezing episodes can be detected with energy-based algorithms when the ratio of the energy in the freeze band (3 to 8 Hz) to that of the locomotion band (0.5 to 3 Hz) is above a patient-specific threshold. However, due to the great variability in patient activity type, walking style, and freezing pattern, this detection method often does not work. Here we describe a new FoG-detection method that captures temporal, spatial, and physiological features and uses a support-vector-machine to classify freezing episodes. Since our method uses more diverse features, it is able to more robustly detect FoG events. We have shown that when the energy-based method fails (e.g., area under the receiver operator curve is ~0.5), our new method performs well (e.g., area under ROC curve is 0.96).

Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies.

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.

Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity.

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.