We report a technique for generating controllable, time-varying and localizable forces on arrays of cells in a massively parallel fashion. To achieve this, we grow magnetic nanoparticle-dosed cells ...in defined patterns on micromagnetic substrates. By manipulating and coalescing nanoparticles within cells, we apply localized nanoparticle-mediated forces approaching cellular yield tensions on the cortex of HeLa cells. We observed highly coordinated responses in cellular behavior, including the p21-activated kinase-dependent generation of active, leading edge-type filopodia and biasing of the metaphase plate during mitosis. The large sample size and rapid sample generation inherent to this approach allow the analysis of cells at an unprecedented rate: in a single experiment, potentially tens of thousands of cells can be stimulated for high statistical accuracy in measurements. This technique shows promise as a tool for both cell analysis and control.
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 <inline-formula> <tex-math notation="LaTeX">\text{M}\Omega </tex-math></inline-formula> at 10 kHz) compared with conventional implant connectors (50 <inline-formula> <tex-math notation="LaTeX">\text{k}\Omega </tex-math></inline-formula> at 10 kHz), despite a 200-fold increase in channel density (conventional: ~0.0644 ch/mm 2 , microgasket: ~12.8 ch/mm 2 ). The microgaskets also achieved high electrical isolation for neural recording (i.e., ~35 <inline-formula> <tex-math notation="LaTeX">\text{M}\Omega </tex-math></inline-formula> 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. 2021-0024
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.
Peripheral nerve interfaces (PNIs) as part of advanced prosthetic devices allow for communication between the device and nerves by providing motor control and sensory feedback. To improve PNIs, researchers have turned to tissue engineering. 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.
Applications such as brain-machine interfaces require hardware spike sorting in order to 1) obtain single-unit activity and 2) perform data reduction for wireless data transmission. Such systems must ...be low-power, low-area, high-accuracy, automatic, and able to operate in real time. Several detection, feature-extraction, and dimensionality-reduction algorithms for spike sorting are described and evaluated in terms of accuracy versus complexity. The nonlinear energy operator is chosen as the optimal spike-detection algorithm, being most robust over noise and relatively simple. Discrete derivatives is chosen as the optimal feature-extraction method, maintaining high accuracy across signal-to-noise ratios with a complexity orders of magnitude less than that of traditional methods such as principal-component analysis. We introduce the maximum-difference algorithm, which is shown to be the best dimensionality-reduction method for hardware spike sorting.
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•TEENI integrates a flexible electrode array with a soft regenerative hydrogel.•Novel process for integration of flexible electrodes with soft hydrogel developed.•Series of 3D printed ...molds facilitate TEENI device assembly process.
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.
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.
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.
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.
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.
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.
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.
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
. 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 AMIA biomedical informatics (BMI) core competencies have been designed to support and guide graduate education in BMI, the core scientific discipline underlying the breadth of the field's ...research, practice, and education. The core definition of BMI adopted by AMIA specifies that BMI is 'the interdisciplinary field that studies and pursues the effective uses of biomedical data, information, and knowledge for scientific inquiry, problem solving and decision making, motivated by efforts to improve human health.' Application areas range from bioinformatics to clinical and public health informatics and span the spectrum from the molecular to population levels of health and biomedicine. The shared core informatics competencies of BMI draw on the practical experience of many specific informatics sub-disciplines. The AMIA BMI analysis highlights the central shared set of competencies that should guide curriculum design and that graduate students should be expected to master.
•DARPA's programs foster multi-disciplinary collaborations.•DARPA's BCI programs span four major challenges: detect, emulate, restore, & improve.•Aims: restore function after injury; improve ...performance of healthy individuals.
The Defense Advanced Research Projects Agency (DARPA) has funded innovative scientific research and technology developments in the field of brain–computer interfaces (BCI) since the 1970s. This review highlights some of DARPA's major advances in the field of BCI, particularly those made in recent years. Two broad categories of DARPA programs are presented with respect to the ultimate goals of supporting the nation's warfighters: (1) BCI efforts aimed at restoring neural and/or behavioral function, and (2) BCI efforts aimed at improving human training and performance. The programs discussed are synergistic and complementary to one another, and, moreover, promote interdisciplinary collaborations among researchers, engineers, and clinicians. Finally, this review includes a summary of some of the remaining challenges for the field of BCI, as well as the goals of new DARPA efforts in this domain.
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