Florian Solzbacher - US grants

[unreadable] DESCRIPTION (provided by applicant): Obesity is one of the most popular and growing diseases in America. Popular approaches to weight control such as exercise plans or low carbohydrate diets have failed to halt the American obesity epidemic. Obesity occurs when there is a persistent long-term excess in energy intake over energy expenditure, and will only be resolved when the individual makes behavioral changes that correct this energy imbalance. One reason that such behavioral changes fail to occur is that it is currently very difficult to monitor the effects of behavioral changes on the various components of energy balance under typical daily life conditions. Hence we propose the development of an implantable microsensor array that could be used to conveniently monitor biomarkers relevant to carbohydrate and fat utilization without interfering with daily life activities. Fats and carbohydrates are the body's two major sources of fuel, and their relative rates of utilization depend on factors such as age, diet, exercise intensity, and fitness level. The proposed sensor array could be used to continuously monitor systemic levels of glucose, pH, and pCO2/bicarbonate in the body both at rest and during exercise. We hypothesize that such a sensor will be sensitive enough to detect substantial increases (or decreases) in dietary fat consumption both on short term and also long term basis. In the proposed work we will develop, fabricate, and test an implantable sensor platform based on smart hydrogels and micromachined pressure sensors that would continuously measure glucose, pH, and CO2 with high long term stability and biocompatibility. The proposed equilibrium sensor array will consist of four hydrogels, in independent microcavities, that respond by swelling proportionally to the concentrations of glucose, CO2 and to the pH, the fourth hydrogel acts as a reference. The tendency of hydrogels to increase in volume in confined wells is captured by the pressure transducers. This project will be accomplished in three specific aims. The first one focuses on development and long term testing of hydrogels. Second specific aim focuses on developing the SiC platform and the third specific aim on biocompatibility coating tests and long term in vitro tests. This project will be conducted very diligently by the team of experts in the fields necessary to accomplish the goal. This project is designed to develop an implantable microsensor to continuously monitor the body's metabolism for a long term. A person may be implanted with such a sensor through a minor out patient surgery and it will not hinder the daily activities in anyway. Such a sensor would cost $30 to $50 and greatly benefit people fighting obesity and trying to restore energy balance. [unreadable] [unreadable] [unreadable] [unreadable]

The goal of the proposed BRP is to lay the foundation to make wireless neural interface technology a turnkey technology that can be disseminated to the neuroscience and clinical research communities. Within 24 months this project will generate initial de ices and performance data as a nucleus for a first generation of wireless interfaces for research and acute and chronic clinical use. Further >36 months of funding will be sought separately to render these init al devices into robust tools that can be used in the preparation of a later FDA 510 k application. In order 0 achieve this goal, we will) refine our recently developed and demonstrated wireless neural interface technology, focusing on making smaller and failsafe VLSI signal processing and telemetry in real w rid environments, 2) develop next generation system integration and electronic packaging technologies, 3) develop user-friendly software interfaces and external electronic systems, 4) generate longer in vivo data of wireless stimulation and recording systems to validate the integrated systems. This higher interdisciplinary research will be carried out in partnership of expertise in micro and nano systems Standard Integration Technology, Vl51, and neurophysiology at the University of Utah, Stanford University, the Fraunhofer Institute for Reliability and Micro integration laboratory Utah and Ripple.

DESCRIPTION (provided by applicant): The array technology developed by Normann et.al. two decades ago at the University of Utah is currently being manufactured and marketed to the neuroscience research community by Blackrock Microsystems (formerly known as Cyberkinetics, Inc., CKI). The Utah electrode array (UEA) is the only high- electrode density, penetrating microelectrode array that is FDA and CE approved, for human use. These arrays, both chronic and acute, have been shown to work very well in animal subjects and their commercial availability has met with considerable interest. The 'manufacturing'procedures that are used to fabricate the UEA at present are closely based on those that were used in their initial development in the laboratory, two decades ago. To date the fabrication of the UEA's has been carried out on a single array basis and as a result the manufacturing technique is not only time consuming but also labor intensive. Also, the existing fabrication costs including utilities, manpower, and maintenance are high. More importantly, the current processes used to fabricate the UEAs impose limitations in the tolerances of the electrode array geometry and electrical characteristics. Furthermore, the flat architecture of the UEA and convoluted geometry of the targeted tissue can result in poor coupling between the two "mating" surfaces, leading to active electrode tips that are not in proximity to the target neuronal tissue. Thus for an efficient neural interface and for wide experimental usage both in experimental and clinical applications, the existing UEA fabrication technique provides inadequate quality, repeatability, and throughput. There is a need to develop less costly but higher precision batch fabrication technology. In 2006, the University of Utah proposed and began work on optimizing existing processes, exploring new materials, designing new architecture of electrode array that are compliant with the host-tissue, and last but not the least developing wafer-scale based process flow for the UEA fabrication. The applicants of this application compose of such a team of engineers, scientists that have been working together over the past years on the technology development for the UEA. The goals of this application is to transfer the manufacturing technology developed at the University of Utah to Blackrock Microsystems, making the technology into a turnkey technology that can be disseminated to the neuroscience and clinical research community, by making the existing microelectrode arrays affordable, better, reliable, and customizable for both acute and chronic applications. PUBLIC HEALTH RELEVANCE: Relevance The new technology would allow us to fabricate neural multielectrode arrays with (a) uniformly shaped microelectrodes (b) small and uniformly exposed active tip sites (c) coated with an electrode material that can deliver high charge densities i.e. high charge injection capacity (CIC) (d) deposited with a highly robust encapsulation material for chronic applications and (e) convoluted electrode arrays for better geometrical match with the targeted tissue. Furthermore the technology would provide better quality, repeatability, and higher throughput of electrode arrays at lower cost of manufacturing and faster lead time. All these advantages would help in making the electrode arrays affordable and assessable to the neuroscience community.

Abstract
1205722, Normann

Intellectual Merit
The biennial Neural Interfaces Conference is the most prominent multidisciplinary gathering of the leading engineers, neuroscientists, and clinicians engaged in brain-computer interfaces and neural engineering translational research in the world. The scientific program for the 2012 conference addresses ten immediately relevant themes in neural interfaces. The presentations, discussions and formal debates related to each theme will focus on the most salient problems remaining to be solved, thereby challenging all conference participants to propose and explore transformative concepts. The conference chairs, steering committee and program committee are preeminently qualified to guide the development of the scientific program, as multiple experts in each theme are represented. The Neural Interfaces Conference has a long history (the 2012 conference is the 40th such conference), which attests to the excellent organization and persisting importance of the meeting. In recognition of the central role this conference plays in advancing neurotechnologies, many private companies, as well as state and federal sources have committed to support the 2012 Neural Interfaces Conference, ensuring sufficient resources for this flagship meeting.

Broader Impact
The Neural Interfaces Conference provides ample time for dynamic exchange among engineers, scientists, and clinician-scientists, and actively promotes new, multidisciplinary partnerships for neural interfaces research and education. The conference is an ideal venue for the recruitment and retention of trainees in the rapidly growing field of neural interfaces; because a diverse workforce is essential to advancing and sustaining neurotechnologies, travel scholarships will support the participation of women and underrepresented minorities recruited and selected from graduate and undergraduate institutions from around the country. The conference proceedings will be widely disseminated via a dedicated issue of the Journal of Neural Engineering, the conference website, and a special report written by a science writer for the general public. The conference will seed the development of new neural interface technologies, which will reduce health care costs, provide substantial benefits to individuals with neurological disorders, and result in new industries that will strengthen our economy.

DESCRIPTION (provided by applicant): In the last two decades though the field of neuroprosthetics has gained tremendous momentum through the development of novel architectures for neural interfaces, however, till date there is no device which can be nomenclatured as the gold standard in the field. As a result the research and technology environment at each laboratory is unique and require a high-level of customization and integration. The objective of this application is to devise a one-in-all technology that encompasses the assets (such as ultra high aspect ratio, multi- channels, flexible substrate, interconnection etc.) of the silicon (such as the Utah and Michigan array) and polymer based arrays and mitigates their limitations. Most importantly it provides a highly customized and poor man's solution to research laboratories. In this application we present a platform technology, called Blackrock Micro Molding Arrays (BRMMA), based on micro molding technique, which enables devolvement of highly customizable and affordable micro devices without compromising the characteristics of the neural probe such as electrical and mechanical properties, reliability, and durability. BRMMA offers highly customized design rules which include surface and penetrating electrodes. It allow the end users for the first time to dictate their own electrode design (specified within the design rules of BRMMA) as per their hypothesis, and choose the number of active channels per shaft, location and material used for active sites, shape and size of the shaft etc. BRMMA developed by Blackrock Microsystems would produce relevant statistical number of devices to test in vitro and in vivo functionality for long term use BRMMA would be marketed to the neuroscience research community by Blackrock Microsystems.

DESCRIPTION (provided by applicant): In order to successfully use microelectrode arrays for stimulation in chronic implantation, the neural electrode must have longevity and efficacy. Efficacy of stimulation primarily means injecting enough charge to the targeted tissue to elicit action potentials. However, in doing so, the electrode itself must not (1) degrade, (2) generate harmful substances and (3) provoke significant immune response. Attaining the stated requirements remains a challenge as studies have shown loss of discriminable single unit action potentials on the order of weeks, months, or in rare studies, years. Suitable electrode material or strategies that permit prolonged excitation of neurons for long period of time without injuring the tissue or damaging the electrodes are yet to be developed and demonstrated. For the efficacy of the stimulating electrodes, large charge injection capacity (CIC) is desired. CIC depends on the electrode-tissue interface and is characteristic of electrode material used. Though, much of the microelectrode research during the past 30 years has been directed toward the evaluation of various types of materials with regard to individual stimulus charge density limits, till date, in the scientific literature, there is no single material which can avoi over-stimulation i.e. neural damage. In this application, we present a novel surface modification technique that addresses the longevity and efficacy of the microelectrodes in chronic experiments. The three distinct features of our proposed objectives are (1) novel surface modification technique that produces electrochemical characteristics which are by far superior to any material/technology reported in the literature till date. With the surface modified electrodes we were able to achieve electrode impedance of 188 at 1 kHz and CIC of 24 mC/cm2. The high CIC would lower the potential required for stimulation thereby reducing the chances of neural injury and dissolution of electrode material and toxic remnants. Even with the presence of glial sheath, it would not be necessary to go outside the water window thereby reducing the chances of tissue insult at the site of stimulation. (2) Biocompatible electrode-tissue interface. It has been postulated by researchers that by manipulating the surface structure of the electrode at micro scale one can reduce astrocyte adhesion around the microelectrode, including reducing the proliferation of glial cells, reduced macrophages and preferential neuron sparing at the site of implant. (3) Simple and inexpensive method of obtaining desired electrode characteristics as opposed to any current thin film deposition method. The objective of this research is to develop, validate, examine (in-vitro, in-vivo and histology) and commercialize the proposed surface modification technology for microelectrodes in chronic experiments. The specific aim of our proposed research is to demonstrate (1) manufacturability of the proposed surface modification for use in a microelectrode array; (2) superior electrochemical properties; (3) improved physiological efficacy; and (4) biocompatible electrode-tissue interface i.e. reduced glial proliferation and reduction in neuronal loss at the biotic-abiotic interface. It is envisioned that with the availability of proposed superior electrochemical characteristics in the neural microelectrode arrays there would be a paradigm shift in the neuroscience research and applications. The enabling innovation has clear clinical benefits in such applications as cortical stimulation and recording, deep brain stimulation, cardiac pacing and pain management and therefore has a significant commercial potential.

Abstract A range of neurological diseases are now being researched or treated using fully implantable electronic systems to either record or modulate brain activity in humans. These implants are currently being protected using polymer coatings that envelop the implant and help keep body fluids away from the sensitive electronics. Brain implants with complex three-dimensional geometries, like the Utah Electrode Array (UEA) provide a challenge for current encapsulation techniques. Parylene has been the gold standard for encapsulation of neural and biomedical implants in general due to its well-suited combination of biocompatibility, electrical properties and chemical inertness. However recording capabilities of long-term neural implants (>6 months) encapsulated with Parylene show signs of degradation. To address this problem, we propose to develop and evaluate performance and biocompatibility/safety of a new Silicon Carbide (SiC) based encapsulation designed to extend the long term stability and implantable lifetime for a high density Utah Slant Electrode Array (HD-USEA) in line with lifetime expectations for conventional cochlea implant electrodes. The HD-USEA is used as penetrating auditory nerve electrode in a new type of intracranial auditory prosthesis that targets the auditory nerve en route to the brainstem in order to substantially improve hearing performance over the current standard of care, the cochlear implant (CI) (NIH 1UG3NS107688-01). SiC has been studied in the past as encapsulation and electrode material due to its outstanding inherent material properties. This encapsulation layer, novel to biomedical field, will retain all the advantages of Parylene while utilizing vastly superior dielectric properties of silicon carbide layer to create a much longer lasting and more electrically stable biomedical implants. This layer encapsulation scheme may be seamlessly incorporated into our existing fabrication process flow for our flagship product, the UEA. This encapsulation will work on different surfaces (metal, semiconductor, polymer, ceramic) and on devices with integrated wireless components making it ideal for coating any complex medical device intended for long term implant. Our preliminary results with silicon carbide coated UEA are very promising in support of the proposed work. We have shown that silicon carbide yields more stable leakage current, and stable impedance (with <5% change). This superior performance of suggests its potential usefulness for chronic implants with complex surface geometries.

ABSTRACT The proposed project will build and evaluate the safety and design needs of a new type of intracranial auditory prosthesis that targets the auditory nerve between the cochlea and the brainstem (auditory nerve implant, ANI) in order to substantially improve hearing performance over the current standard of care, the cochlear implant (CI). Current CIs provide crucial speech information to many recipients, but do not restore normal hearing, and are particularly challenged in noisy or complex acoustic environments. Despite concerted efforts over the past 25 years, little overall improvement in CI performance has been obtained, primarily due to the poor electrode- neural interface in which the CI electrodes are immersed in cochlear fluids and separated from the auditory nerve by the cochlea's bony wall. The new approach will build upon encouraging data from animal studies, well-established human surgical techniques to access the auditory nerve, and high-density electrode and safe stimulation technologies currently available for human use in order to test the safety and efficacy of the ANI that enables direct contact between the electrodes and the auditory nerve. The ANI provides great promise of improved speech and music perception for its prospective recipients, by overcoming the challenge that has limited improvements in CIs for the past quarter century. The first aim is to design and build a full ANI system in accordance with regulatory requirements, including necessary reliability, safety, functional, biocompatibility, and sterilization testing for human use. The ANI system will be built by combining a well-established CI device in the auditory implant field with a novel electrode and cabling technology already being evaluated in human patients for other clinical applications. The second aim is to refine the ANI surgery in human cadaver experiments and acutely during other relevant in vivo operations to consistently position and anchor the electrode array and cabling into the target region. The third aim is to develop and validate critical psychophysical tests to properly evaluate the performance of the ANI during the pilot human study, which can then inform the design of a future clinical ANI device. The fourth aim is to seek regulatory approvals and set up the clinical trial infrastructure and monitoring entities. The fifth and final aim is to perform a pilot ANI study in up to three deaf patients to obtain safety, reliability and functionality data that can properly guide the design of a proceeding clinical device and a feasibility study.

Project Summary The proposed ANI funded by the parent grant (1UG3NS107688-01) is a new central auditory prosthesis that targets the auditory nerve to substantially improve hearing performance (tonal range and resolution) over the current standard cochlear implant by interfacing directly with the auditory nerve. The funded parent grant supports the development and all necessary biocompatibility, safety and functional pre- clinical testing required to obtain an FDA Investigative Device Exemption (IDE) for the first in human demonstration in the UH3 part of the project. Since the start of the project in October 2018 it has become clear through discussions with the surgical team as part of the ongoing cadaver studies and a new FDA guidance on MRI compatibility for implantable devices, that a) having the ability to carry out an MRI in a human subject without the need to surgically remove the electrode would after all be highly desirable if not necessary, given the selected patient group(s) and b) that third party safety testing according to the new guidance is required to satisfy the need for highest possible safety for the study participants. These additional tasks were not anticipated or budgeted for in the original proposal. While the majority of regulatory, GMP and fabrication costs can be absorbed or are not affected by this additional task, the cost for the specific test devices and the third-party MRI testing provider would need to be added to the current budget through an administrative supplement. The third- party cost would be an overhead exempt pass through cost. The supplement project will evaluate potential safety hazards in patients with ANI devices for 1.5 and 3 T MRI systems through simulation and testing. This data will be provided to the FDA as part of the future IDE application and to BfArM for approval for use in the ANI clinical trial in Hannover, Germany. Based on a preliminary assessment, we anticipate that the generated data would support that the device can be considered conditionally MRI safe. If the full system is considered not MRI safe, then we can cut the cable and remove the stimulator module which only requires a superficial surgery and not the more invasive intracranial surgery to remove the electrode and assembly, assuming that the latter is passing the MRI safety testing. It will however stop the ability of patients to continue to participate in the study and to generate data. Only if the system and the electrode assembly are both considered MRI unsafe, would a full removal surgery be required. Beyond the specific need for this project, the supplement project will generate important safety, reliability and functionality data that can properly inform the design of a future clinical ANI devices and products at an early stage in the development cycle. The ability to allow MRI imaging in patients with chronic neuromodulation implants is seen as a critical potential barrier to widespread use.