Bringing sensation to prosthetic hands—chronic assessment of implanted thin-film electrodes in humans

Direct stimulation of peripheral nerves with implantable electrodes successfully provided sensory feedback to amputees while using hand prostheses. Longevity of the electrodes is key to success, which we have improved for the polyimide-based transverse intrafascicular multichannel electrode (TIME). The TIMEs were implanted in the median and ulnar nerves of three trans-radial amputees for up to six months. We present a comprehensive assessment of the electrical properties of the thin-film metallization as well as material status post explantationem. The TIMEs stayed within the electrochemical safe limits while enabling consistent and precise amplitude modulation. This lead to a reliable performance in terms of eliciting sensation. No signs of corrosion or morphological change to the thin-film metallization of the probes was observed by means of electrochemical and optical analysis. The presented longevity demonstrates that thin-film electrodes are applicable in permanent implant systems

Electrochemical Safety Studies of Cochlear Implant Electrodes Using the Finite Element Method

Cochlear implants, amongst other neural prostheses, utilise platinum electrodes as an interface between the synthetic implant and the biological tissue environment. If excessive electrical charge is injected via these electrodes, injury to the tissue may result. Empirically derived stimulation limits have been defined to prevent tissue damage, however the injurious mechanisms are still unclear. Evidence suggests that the non-uniform distribution of charge on electrodes influences the electrochemical generation of toxic by-products. However, in vivo and in vitro techniques are limited in their ability to systematically explore the factors and mechanisms that contribute to stimulation-induced tissue injury. To this end, an in silico approach was used to develop a time-domain model of cochlear implant stimulation electrodes. A constant phase angle impedance was used to model the reversible processes on the electrode surface, and Butler-Volmer reaction kinetics were used to define the behaviour of the water window irreversible electrochemical reactions. The resulting model provided time-domain responses of the current density distributions, and net charge consumed by the hydrolysis reactions. This model was then used to perform systematic evaluations of various electrode geometries and stimulation parameters. The modelling results showed the current associated with irreversible reactions was non-uniform and tended towards the periphery of the electrode. A comparison of electrode geometries revealed interactions between electrode size, shape and recess depth. Stimulation mode, electrode position, and electrolyte conductivity were found to impact the shape of the electric field and the extent of irreversible reactions. This emphasised the influence of the physiological environment on the stimulation safety. In vitro experiments were conducted to validate the model. The implications of the results described in this thesis can be used to inform the design of safer electrodes

Diamond/Porous Titanium Nitride Electrodes With Superior Electrochemical Performance for Neural Interfacing

Robust devices for chronic neural stimulation demand electrode materials which exhibit high charge injection (Qinj) capacity and long-term stability. Boron-doped diamond (BDD) electrodes have shown promise for neural stimulation applications, but their practical applications remain limited due to the poor charge transfer capability of diamond. In this work, we present an attractive approach to produce BDD electrodes with exceptionally high surface area using porous titanium nitride (TiN) as interlayer template. The TiN deposition parameters were systematically varied to fabricate a range of porous electrodes, which were subsequently coated by a BDD thin-film. The electrodes were investigated by surface analysis methods and electrochemical techniques before and after BDD deposition. Cyclic voltammetry (CV) measurements showed a wide potential window in saline solution (between −1.3 and 1.2 V vs. Ag/AgCl). Electrodes with the highest thickness and porosity exhibited the lowest impedance magnitude and a charge storage capacity (CSC) of 253 mC/cm2, which largely exceeds the values previously reported for porous BDD electrodes. Electrodes with relatively thinner and less porous coatings displayed the highest pulsing capacitances (Cpulse), which would be more favorable for stimulation applications. Although BDD/TiN electrodes displayed a higher impedance magnitude and a lower Cpulse as compared to the bare TiN electrodes, the wider potential window likely allows for higher Qinj without reaching unsafe potentials. The remarkable reduction in the impedance and improvement in the charge transfer capacity, together with the known properties of BDD films, makes this type of coating as an ideal candidate for development of reliable devices for chronic neural interfacing

The Effect of Scalp Tissue on Current Shunting during Anodal Transcranial Direct Current Stimulation (TDCS)

Transcranial Direct Current Stimulation (tDCS) has been used to treat various mental and neurological illnesses. Rodent models have been used to examine physiological changes in the brain after tDCS, as well as to develop safety standards. However, most animal tDCS studies implant an electrode on the brain, potentially altering the path of current during stimulation. Additionally, no studies have been completed specifically examining maximum safe anodal tDCS limits, and a pilot study conducted to determine an electrode montage to examine biological changes of learning and memory from anodal tDCS indicated brain lesion was occurring before a commonly cited lesion threshold of 142.9 A/m2. Therefore, the goal of this study was to examine both the effects of anodal tDCS and the rodent\u27s scalp on current shunting during anodal tDCS in vivo. Anodal tDCS was applied to the skull of 35 anesthetized male Sprague-Dawley rats for 60 minutes after they were divided into groups either receiving stimulation with an electrode on the skull or scalp tissue. Within each skull and scalp electrode placement group, rats were further separated into groups by tDCS current intensity (µA) received, which was: sham (n=4), 150 µA (n=4), 300 µA (n=4), 500 µA (n=3), 1,000 µA (n=4), and 2,500 µA (n=3) for the skull electrode placement group. For the scalp electrode placement groups, only stimulations that induced lesion during the skull electrode stimulation were chosen: sham iv Distribution A: Approved for public release; distribution unlimited. 88ABW Cleared 11/09/2015; 88ABW-2015-5473. (n=2), 500 µA (n=3), 1,000 µA (n=3), and 2,500 µA (n=3). Brain lesion was quantified using an Olympus BX-63 microscope with Q100 Blue Camera and CellSens software, which showed brain lesion during skull electrode placement first occurring at 500 uA, having a lesion volume of 0.168 mm3. At 1,000 µA and 2,500 µA, the average brain lesion within groups was 6.363 mm3 and 13.013 mm3, respectively. Stimulation of the scalp showed no brain lesion at any of the stimulation groups, suggesting the scalp tissue shunts a portion of the current, and as a result, has different physiological effects on brain lesion development

Design and development of an implantable biohybrid device for muscle stimulation following lower motor neuron injury

In the absence of innervation caused by complete lower motor neuron injuries, skeletal muscle undergoes an inexorable course of degeneration and atrophy. The most apparent and debilitating clinical outcome of denervation is the immediate loss of voluntary use of muscle. However, these injuries are associated with secondary complications of bones, skin and cardiovascular system that, if untreated, may be fatal. Electrical stimulation has been implemented as a clinical rehabilitation technique in patients with denervated degenerated muscles offering remarkable improvements in muscle function. Nevertheless, this approach has limitations and side effects triggered by the delivery of high intensity electrical pulses. Combining innovative approaches in the fields of cell therapy and implanted electronics offers the opportunity to develop a biohybrid device to stimulate muscles in patients with lower motor neuron injuries. Incorporation of stem cell-derived motor neurons into implantable electrodes, could allow muscles to be stimulated in a physiological manner and circumvent problems associated with direct stimulation of muscle. The hypothesis underpinning this project is that artificially-grown motor neurons can serve as an intermediate between stimulator and muscle, converting the electrical stimulus into a biological action potential and re-innervating muscle via neuromuscular interaction. Here, a suitable stem cell candidate with therapeutic potential was identified and a differentiation protocol developed to generate motor neuron-like cells. Thick-film technology and laser micromachining were implemented to manufacture electrode arrays with features and dimensions suitable for implantation. Manufactured electrodes were electrochemically characterised, and motor neuron-like cells incorporated to create biohybrid devices. In vitro results indicate manufactured electrodes support motor neuron-like cell growth and neurite extension. Moreover, electrochemical characterisation suggests electrodes are suitable for stimulation. Preliminary in vivo testing explored implantation in a rat muscle denervation model. Overall, this thesis demonstrates initial development of a novel approach for fabricating biohybrid devices that may improve stimulation of denervated muscles

Multimodal Investigation of the Efficiency and Stability of Microstimulation using Electrodes Coated with PEDOT/CNT and Iridium Oxide

Electrical microstimulation is an invaluable tool in neuroscience research to dissect neural circuits, relate brain areas, and identify relationships between brain structure and behavior. In the clinic, electrical microstimulation has enabled partial restoration of vision, movement, sensation and autonomic functions. Recently, novel materials and new fabrication techniques of traditional metals have emerged such as iridium oxide and the conducting polymer PEDOT/CNT. These materials have demonstrated particular promise in the improvement in electrical efficiency. However, the in vivo stimulation efficiency and the in vivo stability of these materials have not been thoroughly characterized. In this dissertation, we use a multimodal approach to study the efficiency and stability of electrode-tissue interface using novel materials in microstimulation

Brain-Computer Interfaces using Electrocorticography and Surface Stimulation

The brain connects to, modulates, and receives information from every organ in the body. As such, brain-computer interfaces (BCIs) have vast potential for diagnostics, medical therapies, and even augmentation or enhancement of normal functions. BCIs provide a means to explore the furthest corners of what it means to think, to feel, and to act—to experience the world and to be who you are. This work focuses on the development of a chronic bi-directional BCI for sensorimotor restoration through the use of separable frequency bands for recording motor intent and providing sensory feedback via electrocortical stimulation. Epidural cortical surface electrodes are used to both record electrocorticographic (ECoG) signals and provide stimulation without adverse effects associated with penetration through the protective dural barrier of brain. Chronic changes in electrode properties and signal characteristics are discussed, which inform optimal electrode designs and co-adaptive algorithms for decoding high-dimensional information. Additionally, a multi-layered approach to artifact suppression is presented, which includes a systems-level design of electronics, signal processing, and stimulus waveforms. The results of this work are relevant to a wider range of applications beyond ECoG and BCIs that involve closed-loop recording and stimulation throughout the body. By enabling simultaneous recording and stimulation through the techniques described here, responsive therapies can be developed that are tuned to individual patients and provide precision therapies at exactly the right place and time. This has the potential to improve targeted therapeutic outcomes while reducing undesirable side effects

Enhancement Of Cancer Vaccine Efficacy Via Nanoparticle Or Molecular-Based Adjuvants

Adjuvants are immunomodulators which enhance immune responses to vaccines. However, parenteral administration of unformulated adjuvants fails to reach lymph nodes (LNs), the anatomic organ where the primary functions of immune cells are orchestrated. The LN-targeting delivery plays the key roles in promoting immune activation and has the great potential to transform disease treatment. The main goal of this thesis is to develop efficient vaccine delivery systems to target therapeutics into draining lymph nodes (dLNs) for ensuring their immunostimulatory activity. We introduced therapeutic applications of activating TLR9 with synthetic CpG oligodeoxynucleotide (ODN) agonists in nanoparticle or molecular form to activate immune responses in animal models. As a nanoparticle deliver platform, positively charged silica nanoparticles (SiNPs) were explored to load immunomodulators that are capable of targeting dLNs and mimicking the size, geometry and surface feathers of live viral pathogens. Immunization with nanoparticles showed potent cellular and humoral immunity superior to vaccination with soluble CpG ODNs. We next explored the transdermal delivery platform using dissolving microneedle arrays (MNs), which can penetrate the skin and facilitate the rapid release of vaccine components in epidermis. We combined this strategy with an albumin ‘hitchhiking’ approach that can promote interaction with and uptake across the lymphatic endothelium. Vaccination via MNs generated robust immune responses, showing enhanced T cell and antibody responses. We characterized the morphology and vaccine loading capabilities of MNs, and systematically explored how the transdermal delivery of molecular vaccines impacted cellular and humoral immunogenicity. We expect that the results of our work will contribute to the advancement of vaccine delivery systems and will help to develop more efficient therapeutics for treating disease or cancer