Doctor of Philosophy

dissertationMilitary personnel with amputations face unique challenges due to their short residual limbs and high incidences of multiple limb loss sustained after blast injuries. However, transcutaneous osseointegrated implant (TOI) technology may provide an alternative for individuals with poor socket tolerance by allowing a structural and functional connection between living bone and the surface of a load bearing implant. While TOI has improved activity levels in European patients with limb loss, a lengthy rehabilitation period has limited the expansion of this technology, and may be accelerated with electrical stimulation. The unique advantage of electrically induced TOI is that the exposed exoprosthetic attachment may function as a cathode for regulating electrical current while also serving as the means of prosthetic limb attachment to the host bone. Using this design principle, the goal of this dissertation was to investigate the potential of electrical stimulation for enhancing the rate and magnitude of skeletal fixation at the periprosthetic interface using the implant as a cathode. Although previous studies have examined electrical stimulation for healing atrophic nonunions, inconsistent results have required new predictive measures. Therefore, finite element analysis (FEA) was used as a prerequisite for estimating electric field and current density magnitudes prior to in vivo experimentation. Retrospective computed tomography scans from 11 service members (28.3 ± 5.0 years) demonstrated the feasibility of electrically induced TOI, but variability in residual limb anatomy and the presence of heterotopic ossification confirmed the necessity for patient-specific modeling. Electrically induced osseointegration was also evaluated in vivo in skeletally mature rabbits after establishing design principles based on in vitro cell culturing and FEA. Data from the animal experiment indicated that there were no statistical differences for the appositional bone index (ABI), mineral apposition rate and porosity between the electrically stimulated implants and the unstimulated control implants (UCI). Higher mechanical push-out forces were observed for the UCI group at 6 weeks (p=0.034). In some cases, qualitative backscattered electron images and ABI did indicate that direct current may hold promise for improving suboptimal implant "fit and fill," as bone ongrowth around the cathode was observed despite not having direct contact with the endosteum

Feasibility of simultaneous intracranial EEG-fMRI in humans: a safety study

In epilepsy patients who have electrodes implanted in their brains as part of their pre-surgical assessment, simultaneous intracranial EEG and fMRI (icEEG-fMRI) may provide important localising information and improve understanding of the underlying neuropathology. However, patient safety during icEEG-fMRI has not been addressed. Here the potential health hazards associated with icEEG-fMRI were evaluated theoretically and the main risks identified as: mechanical forces on electrodes from transient magnetic effects, tissue heating due to interaction with the pulsed RF fields and tissue stimulation due to interactions with the switched magnetic gradient fields. These potential hazards were examined experimentally in vitro on a Siemens 3 T Trio, 1.5 T Avanto and a GE 3 T Signa Excite scanner using a Brain Products MR compatible EEG system. No electrode flexion was observed. Temperature measurements demonstrated that heating well above guideline limits can occur. However heating could be kept within safe limits (< 1.0 °C) by using a head transmit RF coil, ensuring EEG cable placement to exit the RF coil along its central z-axis, using specific EEG cable lengths and limiting MRI sequence specific absorption rates (SARs). We found that the risk of tissue damage due to RF-induced heating is low provided implant and scanner specific SAR limits are observed with a safety margin used to account for uncertainties (e.g. in scanner-reported SAR). The observed scanner gradient switching induced current (0.08 mA) and charge density (0.2 μC/cm2) were well within safety limits (0.5 mA and 30 μC/cm2, respectively). Site-specific testing and a conservative approach to safety are required to avoid the risk of adverse events

Safety Aspects, Tolerability and Modeling of Retinofugal Alternating Current Stimulation

Background While alternating current stimulation (ACS) is gaining relevance as a tool in research and approaching clinical applications, its mechanisms of action remain unclear. A review by Schutter and colleagues argues for a retinal origin of transcranial ACS’ neuromodulatory effects. Interestingly, there is an alternative application form of ACS specifically targeting α-oscillations in the visual cortex via periorbital electrodes (retinofugal alternating current stimulation, rACS). To further compare these two methods and investigate retinal effects of ACS, we first aim to establish the safety and tolerability of rACS. ObjectiveThe goal of our research was to evaluate the safety of rACS via finite-element modeling, theoretical safety limits and subjective report. Methods20 healthy subjects were stimulated with rACS as well as photic stimulation and reported adverse events following stimulation. We analyzed stimulation parameters at electrode level as well as distributed metric estimates from an ultra-high spatial resolution magnetic resonance imaging (MRI)-derived finite element human head model and compared them to existing safety limits. ResultsTopographical modeling revealed the highest current densities in the anterior visual pathway, particularly retina and optic nerve. Stimulation parameters and finite element modeling estimates of rACS were found to be well below existing safety limits. No serious adverse events occurred. ConclusionOur findings are in line with existing safety guidelines for retinal and neural damage and establish the tolerability and feasibility of rACS. In comparison to tACS, retinofugal stimulation of the visual cortex provides an anatomically circumscribed model to systematically study the mechanisms of action of ACS

Electrophysiology

The outstanding evolution of recording techniques paved the way for better understanding of electrophysiological phenomena within the human organs, including the cardiovascular, ophthalmologic and neural systems. In the field of cardiac electrophysiology, the development of more and more sophisticated recording and mapping techniques made it possible to elucidate the mechanism of various cardiac arrhythmias. This has even led to the evolution of techniques to ablate and cure most complex cardiac arrhythmias. Nevertheless, there is still a long way ahead and this book can be considered a valuable addition to the current knowledge in subjects related to bioelectricity from plants to the human heart

Metallized printed microstructures for precision biomedical recording and stimulation

Implantable electrodes are the central tool for many techniques and treatments in biomedical research and medicine. There is a trend in these tools towards arrays of tissue-penetrating microelectrodes with low geometric surface areas for purposes of both increasing the specificity of recording/stimulation and reducing tissue damage due to insertion trauma and reactive immune responses. However, smaller electrode sizes present new constraints – both difficulty in fabrication as well as significant limitations on effective charge storage/injection capacities as well as higher impedances, making smaller electrodes less capable of easily passing charge safely and efficiently. Fabricating structures on the scale of tens of microns and below poses significant challenges compared to well established machining at larger sizes. Established sets of techniques such as classic MEMS processes are limited to relatively specific shapes, with significant limitations in their ability to produce curved surfaces and surfaces which are not composed of highly distinct stepped layers. We developed a method for improvement of impedance and charge storage capacity of flat electrodes without affecting geometric surface area (footprint) using Resonant Direct Laser Writing (rDLW) 3D printing to fabricate high surface area 3D structures, which were then rendered conductive. The ability to perform DLW printing at a range of laser powers on opaque reflective surfaces is demonstrated, previously a known limitation of direct laser writing. This is demonstrated through a variety of example prints. This capability opens the door to many new possibilities in micron resolution polymer printing which were previously inaccessible, with potentially far reaching ramifications for microfabrication

Applications of Nanobiotechnology

This book is dedicated to the applications of nanobiotechnology, i.e. the way that nanotechnology is used to create devices to study biological systems and phenomena. It includes seven chapters, organized in two sections. The first section (Chapters 1–5) covers a large spectrum of issues associated with nanoparticle synthesis, nanoparticle toxicity, and the role of nanotechnology in drug delivery, tissue engineering, agriculture, and biosensing. The second section (Chapters 6 and 7) is devoted to the properties of nanofluids and the medical and biological applications of computational fluid dymanics modeling

Impacts of selected stimulation patterns on the perception threshold in electrocutaneous stimulation

<p>Abstract</p> <p>Background</p> <p>Consistency is one of the most important concerns to convey stable artificially induced sensory feedback. However, the constancy of perceived sensations cannot be guaranteed, as the artificially evoked sensation is a function of the interaction of stimulation parameters. The hypothesis of this study is that the selected stimulation parameters in multi-electrode cutaneous stimulation have significant impacts on the perception threshold.</p> <p>Methods</p> <p>The investigated parameters included the stimulated location, the number of active electrodes, the number of pulses, and the interleaved time between a pair of electrodes. Biphasic, rectangular pulses were applied via five surface electrodes placed on the forearm of 12 healthy subjects.</p> <p>Results</p> <p>Our main findings were: 1) the perception thresholds at the five stimulated locations were significantly different (p < 0.0001), 2) dual-channel simultaneous stimulation lowered the perception thresholds and led to smaller variance in perception thresholds compared to single-channel stimulation, 3) the perception threshold was inversely related to the number of pulses, and 4) the perception threshold increased with increasing interleaved time when the interleaved time between two electrodes was below 500 μs.</p> <p>Conclusions</p> <p>To maintain a consistent perception threshold, our findings indicate that dual-channel simultaneous stimulation with at least five pulses should be used, and that the interleaved time between two electrodes should be longer than 500 μs. We believe that these findings have implications for design of reliable sensory feedback codes.</p

Electrical stimulation to promote osseointegration of bone anchoring implants: a topical review

Electrical stimulation has shown to be a promising approach for promoting osseointegration in bone anchoring implants, where osseointegration defines the biological bonding between the implant surface and bone tissue. Bone-anchored implants are used in the rehabilitation of hearing and limb loss, and extensively in edentulous patients. Inadequate osseointegration is one of the major factors of implant failure that could be prevented by accelerating or enhancing the osseointegration process by artificial means. In this article, we reviewed the efforts to enhance the biofunctionality at the bone-implant interface with electrical stimulation using the implant as an electrode. We reviewed articles describing different electrode configurations, power sources, and waveform-dependent stimulation parameters tested in various in vitro and in vivo models. In total 55 English-language and peer-reviewed publications were identified until April 2020 using PubMed, Google Scholar, and the Chalmers University of Technology Library discovery system using the keywords: osseointegration, electrical stimulation, direct current and titanium implant. Thirteen of those publications were within the scope of this review. We reviewed and compared studies from the last 45\ua0years and found nonuniform protocols with disparities in cell type and animal model, implant location, experimental timeline, implant material, evaluation assays, and type of electrical stimulation. The reporting of stimulation parameters was also found to be inconsistent and incomplete throughout the literature. Studies using in vitro models showed that osteoblasts were sensitive to the magnitude of the electric field and duration of exposure, and such variables similarly affected bone quantity around implants in in vivo investigations. Most studies showed benefits of electrical stimulation in the underlying processes leading to osseointegration, and therefore we found the idea of promoting osseointegration by using electric fields to be supported by the available evidence. However, such an effect has not been demonstrated conclusively nor optimally in humans. We found that optimal stimulation parameters have not been thoroughly investigated and this remains an important step towards the clinical translation of this concept. In addition, there is a need for reporting standards to enable meta-analysis for evidence-based treatments