Nicholas B. Langhals

Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces

Implantable neural microelectrodes that can record extracellular biopotentials from small, targeted groups of neurons are critical for neuroscience research and emerging clinical applications including brain-controlled prosthetic devices. The crucial material-dependent problem is developing microelectrodes that record neural activity from the same neurons for years with high fidelity and reliability. Here, we report the development of an integrated composite electrode consisting of a carbon-fibre core, a poly(p-xylylene)-based thin-film coating that acts as a dielectric barrier and that is functionalized to control intrinsic biological processes, and a poly(thiophene)-based recording pad. The resulting implants are an order of magnitude smaller than traditional recording electrodes, and more mechanically compliant with brain tissue. They were found to elicit much reduced chronic reactive tissue responses and enabled single-neuron recording in acute and early chronic experiments in rats. This technology, taking advantage of new composites, makes possible highly selective and stealthy neural interface devices towards realizing long-lasting implants.

Using a Common Average Reference to Improve Cortical Neuron Recordings From Microelectrode Arrays

In this study, we propose and evaluate a technique known as common average referencing (CAR) to generate a more ideal reference electrode for microelectrode recordings. CAR is a computationally simple technique, and therefore amenable to both on-chip and real-time applications. CAR is commonly used in EEG, where it is necessary to identify small signal sources in very noisy recordings. To study the efficacy of common average referencing, we compared CAR to both referencing with a stainless steel bone-screw and a single microelectrode site. Data consisted of in vivo chronic recordings in anesthetized Sprague-Dawley rats drawn from prior studies, as well as previously unpublished data. By combining the data from multiple studies, we generated and analyzed one of the more comprehensive chronic neural recording datasets to date. Reference types were compared in terms of noise level, signal-to-noise ratio, and number of neurons recorded across days. Common average referencing was found to drastically outperform standard types of electrical referencing, reducing noise by >30%. As a result of the reduced noise floor, arrays referenced to a CAR yielded almost 60% more discernible neural units than traditional methods of electrical referencing. CAR should impart similar benefits to other microelectrode recording technologies-for example, chemical sensing-where similar differential recording concepts apply. In addition, we provide a mathematical justification for CAR using Gauss-Markov theorem and therefore help place the application of CAR into a theoretical context.

Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes.

We investigated using poly(3,4-ethylenedioxythiophene) (PEDOT) to lower the impedance of small, gold recording electrodes with initial impedances outside of the effective recording range. Smaller electrode sites enable more densely packed arrays, increasing the number of input and output channels to and from the brain. Moreover, smaller electrode sizes promote smaller probe designs; decreasing the dimensions of the implanted probe has been demonstrated to decrease the inherent immune response, a known contributor to the failure of long-term implants. As expected, chronically implanted control electrodes were unable to record well-isolated unit activity, primarily as a result of a dramatically increased noise floor. Conversely, electrodes coated with PEDOT consistently recorded high-quality neural activity, and exhibited a much lower noise floor than controls. These results demonstrate that PEDOT coatings enable electrode designs 15 µm in diameter.

Reduction of neurovascular damage resulting from microelectrode insertion into the cerebral cortex using in vivo two-photon mapping

Penetrating neural probe technologies allow investigators to record electrical signals in the brain. The implantation of probes causes acute tissue damage, partially due to vasculature disruption during probe implantation. This trauma can cause abnormal electrophysiological responses and temporary increases in neurotransmitter levels, and perpetuate chronic immune responses. A significant challenge for investigators is to examine neurovascular features below the surface of the brain in vivo. The objective of this study was to investigate localized bleeding resulting from inserting microscale neural probes into the cortex using two-photon microscopy (TPM) and to explore an approach to minimize blood vessel disruption through insertion methods and probe design. 3D TPM images of cortical neurovasculature were obtained from mice and used to select preferred insertion positions for probe insertion to reduce neurovasculature damage. There was an 82.8 +/- 14.3% reduction in neurovascular damage for probes inserted in regions devoid of major (>5 microm) sub-surface vessels. Also, the deviation of surface vessels from the vector normal to the surface as a function of depth and vessel diameter was measured and characterized. 68% of the major vessels were found to deviate less than 49 microm from their surface origin up to a depth of 500 microm. Inserting probes more than 49 microm from major surface vessels can reduce the chances of severing major sub-surface neurovasculature without using TPM.

In vivo performance of a microelectrode neural probe with integrated drug delivery.

OBJECT The availability of sophisticated neural probes is a key prerequisite in the development of future brain-machine interfaces (BMIs). In this study, the authors developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery promises to extend dramatically the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology. METHODS To form the multifunctional neural probe, the authors affixed a 16-channel microfabricated silicon electrode array to a fused silica catheter. Three experiments were conducted in rats to characterize the performance of the device. Experiment 1 examined cellular damage from probe insertion and the drug distribution in tissue. Experiment 2 measured the effects of saline infusions delivered through the probe on concurrent electrophysiological measurements. Experiment 3 demonstrated that a physiologically relevant amount of drug can be delivered in a controlled fashion. For these experiments, Hoechst and propidium iodide stains were used to assess insertion trauma and the tissue distribution of the infusate. Artificial CSF (aCSF) and tetrodotoxin (TTX) were injected to determine the efficacy of drug delivery. RESULTS The newly developed multifunctional neural probes were successfully inserted into rat cortex and were able to deliver fluids and drugs that resulted in the expected electrophysiological and histological responses. The damage from insertion of the device into brain tissue was substantially less than the volume of drug dispersion in tissue. Electrophysiological activity, including both individual spikes as well as local field potentials, was successfully recorded with this device during real-time drug delivery. No significant changes were seen in response to delivery of aCSF as a control experiment, whereas delivery of TTX produced the expected result of suppressing all spiking activity in the vicinity of the catheter outlet. CONCLUSIONS Multifunctional neural probes such as the ones developed and validated within this study have great potential to help further understand the design space and criteria for the next generation of neural probe technology. By incorporating integrated drug delivery functionality into the probes, new treatment options for neurological disorders and regenerative neural interfaces using localized and feedback-controlled delivery of drugs can be realized in the near future.

An Injectable 64 nW ECG Mixed-Signal SoC in 65 nm for Arrhythmia Monitoring

A syringe-implantable electrocardiography (ECG) monitoring system is proposed. The noise optimization and circuit techniques in the analog front-end (AFE) enable 31 nA current consumption while a minimum energy computation approach in the digital back-end reduces digital energy consumption by 40%. The proposed SoC is fabricated in 65 nm CMOS and consumes 64 nW while successfully detecting atrial fibrillation arrhythmia and storing the irregular waveform in memory in experiments using an ECG simulator, a live sheep, and an isolated sheep heart.

Regenerative peripheral nerve interface viability and signal transduction with an implanted electrode

Background: The regenerative peripheral nerve interface is an internal interface for signal transduction with external electronics of prosthetic limbs; it consists of an electrode and a unit of free muscle that is neurotized by a transected residual peripheral nerve. Adding a conductive polymer coating on electrodes improves electrode conductivity. This study examines regenerative peripheral nerve interface tissue viability and signal fidelity in the presence of an implanted electrode coated or uncoated with a conductive polymer. Methods: In a rat model, the extensor digitorum longus muscle was moved as a nonvascularized free tissue transfer and neurotized by the divided peroneal nerve. Either a stainless steel pad electrode (n = 8) or a pad electrode coated with poly(3,4-ethylenedioxythiophene) conductive polymer (PEDOT) (n = 8) was implanted on the muscle transfer and secured with an encircling acellular extracellular matrix. The contralateral muscle served as the control. Results: The free muscle transfers were successfully revascularized and over time reinnervated as evidenced by serial insertional needle electromyography. Compound muscle action potentials were successfully transduced through the regenerative peripheral nerve interface. The conductive polymer coating on the implanted electrode resulted in increased recorded signal amplitude that was observed throughout the course of the study. Histologic examination confirmed axonal sprouting, elongation, and synaptogenesis within regenerative peripheral nerve interface regardless of electrode type. Conclusions: The regenerative peripheral nerve interface remains viable over seven months in the presence of an implanted electrode. Electrodes with and without conductive polymer reliably transduced signals from the regenerative peripheral nerve interface. Electrodes with a conductive polymer coating resulted in recording more of the regenerative peripheral nerve interface signal.

Innovations in prosthetic interfaces for the upper extremity.

Summary: Advancements in modern robotic technology have led to the development of highly sophisticated upper extremity prosthetic limbs. High-fidelity volitional control of these devices is dependent on the critical interface between the patient and the mechanical prosthesis. Recent innovations in prosthetic interfaces have focused on several control strategies. Targeted muscle reinnervation is currently the most immediately applicable prosthetic control strategy and is particularly indicated in proximal upper extremity amputations. Investigation into various brain interfaces has allowed acquisition of neuroelectric signals directly or indirectly from the central nervous system for prosthetic control. Peripheral nerve interfaces permit signal transduction from both motor and sensory nerves with a higher degree of selectivity. This article reviews the current developments in each of these interface systems and discusses the potential of these approaches to facilitate motor control and sensory feedback in upper extremity neuroprosthetic devices.

Providing a sense of touch to prosthetic hands.

Summary: Each year, approximately 185,000 Americans suffer the devastating loss of a limb. The effects of upper limb amputations are profound because a person’s hands are tools for everyday functioning, expressive communication, and other uniquely human attributes. Despite the advancements in prosthetic technology, current upper limb prostheses are still limited in terms of complex motor control and sensory feedback. Sensory feedback is critical to restoring full functionality to amputated patients because it would relieve the cognitive burden of relying solely on visual input to monitor motor commands and provide tremendous psychological benefits. This article reviews the latest innovations in sensory feedback and argues in favor of peripheral nerve interfaces. First, the authors examine the structure of the peripheral nerve and its importance in the development of a sensory interface. Second, the authors discuss advancements in targeted muscle reinnervation and direct neural stimulation by means of intraneural electrodes. The authors then explore the future of prosthetic sensory feedback using innovative technologies for neural signaling, specifically, the sensory regenerative peripheral nerve interface and optogenetics. These breakthroughs pave the way for the development of a prosthetic limb with the ability to feel.

Update in facial nerve paralysis: tissue engineering and new technologies.

Purpose of reviewTo present the recent advances in the treatment of facial paralysis, emphasizing the emerging technologies. This review will summarize the current state of the art in the management of facial paralysis and discuss the advances in nerve regeneration, facial reanimation, and use of novel biomaterials. This review includes surgical innovations in reinnervation and reanimation as well as progress with bioelectrical interfaces. Recent findingsThe last decade has witnessed major advances in the understanding of nerve injury and approaches for management. Key innovations include strategies to accelerate nerve regeneration, provide tissue-engineered constructs that may replace nonfunctional nerves, approaches to influence axonal guidance, limiting of donor-site morbidity, and optimization of functional outcomes. Approaches to muscle transfer continue to evolve, and new technologies allow for electrical nerve stimulation and use of artificial tissues. SummaryThe fields of biomedical engineering and facial reanimation increasingly intersect, with innovative surgical approaches complementing a growing array of tissue engineering tools. The goal of treatment remains the predictable restoration of natural facial movement, with acceptable morbidity and long-term stability. Advances in bioelectrical interfaces and nanotechnology hold promise for widening the window for successful treatment intervention and for restoring both lost neural inputs and muscle function.