Flexible active electrode arrays with ASICs that fit inside the rat's spinal canal

Epidural spinal cord electrical stimulation (ESCS) has been used as a means to facilitate locomotor recovery in spinal cord injured humans. Electrode arrays, instead of conventional pairs of electrodes, are necessary to investigate the effect of ESCS at different sites. These usually require a large number of implanted wires, which could lead to infections. This paper presents the design, fabrication and evaluation of a novel flexible active array for ESCS in rats. Three small (1.7 mm2) and thin (100 μm) application specific integrated circuits (ASICs) are embedded in the polydimethylsiloxane-based implant. This arrangement limits the number of communication tracks to three, while ensuring maximum testing versatility by providing independent access to all 12 electrodes in any configuration. Laser-patterned platinum-iridium foil forms the implant’s conductive tracks and electrodes. Double rivet bonds were employed for the dice microassembly. The active electrode array can deliver current pulses (up to 1 mA, 100 pulses per second) and supports interleaved stimulation with independent control of the stimulus parameters for each pulse. The stimulation timing and pulse duration are very versatile. The array was electrically characterized through impedance spectroscopy and voltage transient recordings. A prototype was tested for long term mechanical reliability when subjected to continuous bending. The results revealed no track or bond failure. To the best of the authors’ knowledge, this is the first time that flexible active electrode arrays with embedded electronics suitable for implantation inside the rat’s spinal canal have been proposed, developed and tested in vitro

An Implantable Versatile Electrode-Driving ASIC for Chronic Epidural Stimulation in Rats

This paper presents the design and testing of an electrode driving application specific integrated circuit (ASIC) intended for epidural spinal cord electrical stimulation in rats. The ASIC can deliver up to 1 mA fully programmable monophasic or biphasic stimulus current pulses, to 13 electrodes selected in any possible configuration. It also supports interleaved stimulation. Communication is achieved via only 3 wires. The current source and the control of the stimulation timing were kept off-chip to reduce the heat dissipation close to the spinal cord. The ASIC was designed in a 0.18- \mu m high voltage CMOS process. Its output voltage compliance can be up to 25 V. It features a small core area ( {< } 0.36 mm ^{2} ) and consumes a maximum of 114 \mu W during a full stimulation cycle. The layout of the ASIC was developed to be suitable for integration on the epidural electrode array, and two different versions were fabricated and electrically tested. Results from both versions were almost indistinguishable. The performance of the system was verified for different loads and stimulation parameters. Its suitability to drive a passive epidural 12-electrode array in saline has also been demonstrated

Silicone encapsulation of thin-film SiOₓ, SiOₓNy and SiC for modern electronic medical implants: a comparative long-term ageing study

Objective. Ensuring the longevity of implantable devices is critical for their clinical usefulness. This is commonly achieved by hermetically sealing the sensitive electronics in a water impermeable housing, however, this method limits miniaturisation. Alternatively, silicone encapsulation has demonstrated long-term protection of implanted thick-film electronic devices. However, much of the current conformal packaging research is focused on more rigid coatings, such as parylene, liquid crystal polymers and novel inorganic layers. Here, we consider the potential of silicone to protect implants using thin-film technology with features 33 times smaller than thick-film counterparts. Approach. Aluminium interdigitated comb structures under plasma-enhanced chemical vapour deposited passivation (SiOx, SiOxNy, SiOxNy + SiC) were encapsulated in medical grade silicones, with a total of six passivation/silicone combinations. Samples were aged in phosphate-buffered saline at 67‰ for up to 694 days under a continuous ±5 V biphasic waveform. Periodic electrochemical impedance spectroscopy measurements monitored for leakage currents and degradation of the metal traces. Fourier-transform infrared spectroscopy, x-ray photoelectron spectroscopy, focused-ion-beam and scanning-electron- microscopy were employed to determine any encapsulation material changes. Main results. No silicone delamination, passivation dissolution, or metal corrosion was observed during ageing. Impedances greater than 100 G were maintained between the aluminium tracks for silicone encapsulation over SiOxNy and SiC passivations. For these samples the only observed failure mode was open-circuit wire bonds. In contrast, progressive hydration of the SiOx caused its resistance to decrease by an order of magnitude. Significance. These results demonstrate silicone encapsulation offers excellent protection to thin-film conducting tracks when combined with appropriate inorganic thin films. This conclusion corresponds to previous reliability studies of silicone encapsulation in aqueous environments, but with a larger sample size. Therefore, we believe silicone encapsulation to be a realistic means of providing long-term protection for the circuits of implanted electronic medical devices

Flexible Active Electrode Arrays For Epidural Spinal Cord Stimulation

In spinal cord injured (SCI) individuals the neural pathway between the brain and the extremities is damaged. However, there is still the capacity to elicit muscle activation despite the absence of any supraspinal input. Recent studies have proposed epidural spinal cord electrical stimulation (ESCS) as a means to facilitate locomotor recovery in SCI humans. In epidural stimulation a number of electrodes are placed in the spine, outside the dura, and stimulus current pulses are used to ‘tune’ the spinal circuitries. Some rat studies have supported this concept, but further testing is required to increase our understanding and optimise the stimulation parameters. Testing protocols are currently limited by the available technology. More specifically, the number of electrodes one can use seriously limits the paradigms that could be investigated. For this reason, electrode arrays, as opposed to the conventional pairs of electrodes, can be used to investigate the effect of ESCS at different sites. The development of epidural electrode arrays for chronic testing in rats is a challenging task due to their small size. The difficulties increase radically when a large number of electrodes need to be independently controlled. It has been well documented in the literature that a large number of connections (wires) is highly undesirable because it either makes the implantation procedure more challenging, or, if the device is successfully placed in the body, it could imperil perfusion, result in infections, tissue damage, or simply cause the device to fail. The development of a flexible epidural electrode array suitable for chronic implantation in rats was the main goal of this work. For the first generation of the system, flexible passive 12-electrode arrays, using silicone rubber and annealed platinum foil, were designed and fabricated—suitable for use with an external stimulator. In vivo evaluation of these devices showed that they failed quickly, 87.5% of the connections after a week inside the spine of a rat. The failure analysis performed highlighted the need to reduce the number of connections to avoid inflammation and improve the mechanical stability of the implants. To overcome the connections ‘bottleneck’ without compromising the number of electrodes (which was necessary for the planned paradigm), our approach was to develop application-specific integrated circuits (ASICs) to be embedded on the arrays, acting as electrode drivers. The ASICs reduce the number of connections to 3, feature a very small silicon footprint (less than 0.36 mm2 core area), consume very low power (up to 114 μW during a full stimulation cycle), and allow for the necessary versatility for the testing with a real-time control system, developed by our collaborators (in the FP7 NEUWalk project). A custom designed ‘hub’, designed by Dr. Clemens Eder, is used to electronically – rather than manually – manage the stimulus parameters and the operation of the ASICs. It can be programmed via a graphical user interface (GUI) or the real-time controller. Moving to the second generation of the system, active (with embedded ASICs) epidural arrays were designed, developed and evaluated. For this version, platinum iridium foil, was preferred, due to its superior mechanical strength. The next part of the work focused on the the different aspects of the fabrication and assembly processes. More specifically, size restrictions related to the implantation site dictated the need to use thinned ASICs. To post-process the already fabricated chips, a method for purely mechanical silicon thinning at individual die level was developed and characterised. For the integration of the ASICs on the arrays an evaluation study was conducted to examine the mechanical reliability of the bonds produced by electrical rivet bonding. Combining all the above, a new fabrication process was developed for the active arrays. Despite the fact that, so far, chronic in vivo testing has not been yet implemented, the produced prototypes were electrically and mechanically evaluated in vitro, and results are satisfactory, as no failed tracks were observed during the chronic tests in the lab. The current setup allows power and data to be transferred to the implant real-time through a connector fixed on the rat’s head, while the animal is on a treadmill or on a runway. This implies that there is no need for a wireless system at this stage. However, more complex experiments where the rats would be able to move freely and interact with other rats unrestricted, developing a behaviour that is closer to their natural, could provide significant new knowledge in the future. Although there are still many things to understand regarding epidural stimulation and its effect before planning an experiment like this, this was kept in mind throughout the whole design and development phases of this system. On this basis, the developed subcomponents are compatible with a system level design of a fully implantable platform to be used in freely moving rats, stimulated for 3 – 4 hours per day. This system comprises the active electrode array, which is the focus of this thesis, together with a miniaturised, battery-powered implantable version of the previously mentioned hub (which is on-going work, and is not presented here)

Embedding Small Electronic Components into Tiny Flexible Implants

Electronic components in the form of application-specific integrated circuits (ASICs) establishing the communication between the body and the implant, such as stimulation and recording, have, nowadays, become essential elements for current and future generations of implantable devices, as medicine is looking into substituting its traditional pharmaceuticals with electroceuticals, or bioelectronic medicines [1].Protection of implant components inside the body is a mandatory important step to ensure longevity and reliable performance of the device. The package of the implant should act as a bidirectional diffusion barrier protecting the electronics of the device from body liquids, and also preventing diffusion of toxic materials from the implant towards the tissue. At the same time the implant’s outer layer should match the tissue’s mechanical properties in order not to cause scar growth around the implant or damage the body.Current implants do not completely fulfill the desired properties mentioned above, either lacking hermeticity or softness.In this work, an embedding process developed at Fraunhofer IZM [2] and used in the semiconductor packaging field for chip encapsulation is proposed to be modified and used for protecting implantable ASICs. Such a method will have a number of advantages, such as miniaturization, in comparison with conventional titanium case packaging. Furthermore, embedding allows to avoid long interconnects, which can be a crucial problem for the device implanted inside a constantly moving body. The other advantage is that the geometry of these interconnects can be well controlled, and the amount of contact pads can be higher than in widely used wire bonding technology, because the distribution of solder bumps during embedding can take place on the whole chip area.In the proposed process, biocompatible polymer materials, such as ParyleneC and Polyurethane, together with thin glass films will be employed to provide the implant with the required hermeticity and at the same time flexibility. The developed embedding process technology will ensure homogeneous distribution of mechanical stresses, resulting in high reliability for uninterrupted long-term use of smart implants.<br/

Design and Custom Fabrication of a Smart Temperature Sensor for an Organ-on-a-chip Platform

Incubators in cell cultures are used to grow and maintain cells under optimal temperature alongside other key variables, such as pH, humidity, atmospheric conditions etc. As enzymatic activity and protein synthesis proceed optimally at 37.5 oC, a temperature rise can cause protein denaturation, whereas a drop in temperature can slow down catalysis and polypeptide initiation [1]. Inside the incubator, the measurements are gauged according to the temperature of the heating element, which is not exactly the same as that of the cells. Time spent outside the incubator can greatly impact cell health. In fact, out-of-incubator temperature and its change over time are unknown variables to clinicians and researchers, while a considerable number of cell culture losses are attributed to this reason. To accurately monitor the temperature of the culture throughout cell growth, an in situ temperature sensor with at least ±0.5 oC of resolution is of paramount importance. This allows the growth of the cultured cells to be optimized. This work reports on the design and fabrication of a time-mode signal-processing in situ temperature sensor customized for an organ-on-a-chip (OOC) application. The circuit was fabricated using an in-house integrated circuit technology that requires only 7 lithographic steps and is compatible with MEMS fabrication process. The proposed circuit is developed to providethe first out-of-incubator temperature monitoring of cell cultures on an OOC platform in a monolithic fabrication. Measurement results on wafer reveal a temperature measurement resolution of less than ±0.2 oC (3σ) and a maximum nonlinearity error of less than 0.3% across a temperature range from 25 oC to 100 oC. To the authors’ best knowledge, no in situ temperature-sensing fully integrated on an OOC platform exists to date. This is the first time such integration is being performed using a custom designed circuit fabricated on the same silicon substrate as that of the OOC. The simple, robust, and custom IC technology used for the sensor fabrication grants a very cost-effective integratedsolution in virtue of the reduced cost per wafer along with the large silicon area available on the platform [2]. Moreover, no further complicated assembly and subsequent protection of the prefabricated components is required. This minimizes the extra processing steps, along with the related handling risks, leading to higher yields. Finally, the freedom enjoyed by the MEMSelectronicsco-design offers a large degree of versatility to accomodate electronics in a range of different OOC shapes and structures

Flexible active electrode arrays with ASICs that fit inside the rat’s spinal canal

Epidural spinal cord electrical stimulation (ESCS) has been used as a means to facilitate locomotor recovery in spinal cord injured humans. Electrode arrays, instead of conventional pairs of electrodes, are necessary to investigate the effect of ESCS at different sites. These usually require a large number of implanted wires, which could lead to infections. This paper presents the design, fabrication and evaluation of a novel flexible active array for ESCS in rats. Three small (1.7 mm2) and thin (100 ?m) application specific integrated circuits (ASICs) are embedded in the polydimethylsiloxane-based implant. This arrangement limits the number of communication tracks to three, while ensuring maximum testing versatility by providing independent access to all 12 electrodes in any configuration. Laser-patterned platinum-iridium foil forms the implant’s conductive tracks and electrodes. Double rivet bonds were employed for the dice microassembly. The active electrode array can deliver current pulses (up to 1 mA, 100 pulses per second) and supports interleaved stimulation with independent control of the stimulus parameters for each pulse. The stimulation timing and pulse duration are very versatile. The array was electrically characterized through impedance spectroscopy and voltage transient recordings. A prototype was tested for long term mechanical reliability when subjected to continuous bending. The results revealed no track or bond failure. To the best of the authors’ knowledge, this is the first time that flexible active electrode arrays with embedded electronics suitable for implantation inside the rat’s spinal canal have been proposed, developed and tested in vitro.MicroelectronicsElectrical Engineering, Mathematics and Computer Scienc

Design of a Multi-Functional Smart Optrode for Electrophysiology and Optogenetics

Optogenetics is a neuromodulation method that holds great potential for the realization of advanced neuroprostheses due to its precise spatial-temporal control of neuronal activity [1]. The development of novel optogenetic implants (optrodes) may open new doors to investigate complex brain circuitry and chronical brain disorders, such as epilepsy, migraine, autism, Parkinson's disease, etc [2]. Design challenges for the optrode include interference minimization between the µLED drivers and the recording electrodes, selection of proper materials, structures and dimensions to minimize tissue damage, biocompability, and batch production. In this work, we propose the construction of a multi-functional optrode to be used for physiological studies in group-housed, freely-moving rodents. It comprises commercial blue-light µLEDs for optical stimulation, an active electrode array for recording the local field potentials at different depths in the brain, and a time-domain temperature sensor. To accomplish this, silicon bulk micromachining is the essential technique used for the device manufacturation. Process steps include epitaxial growth, layers deposition, geometrical etching, ionic implantation, oxidation and diffusion. For the interconnection of the µLEDs, flip-chip bonding is used. Light intensity and frequency can be controlled via a microcontroller interface assembled on a flexible PCB mounted on the rodent head-stage. The active microelectrode array (MEA) is constructed from a Ti/TiN layer to both meet the biocompatibility requirements and to reduce the electrode-tissue interface impedance, and by this the associated thermal noise. Using a custom, simple, robust and cost-effective BiFET in-house IC technology, the recording amplifiers are monolithically integrated into the MEA to achieve a high signal-to-noise ratio (SNR) and to minimize potential crosstalk coming from the µLED drivers. Using the same BiFET IC technology, a time-domain temperature sensor is monolithically integrated into the optrode to anticipate possible brain tissue temperature changes of more than 1oC that may come from heat dissipation in the µLEDs or circuit power dissipation. Finally, the optrode is coated with a PDMS film to electrically protect the µLEDs from the tissue and avoid uncontrollable electrical stimulation of the brain tissue

MEMS-Electronics Integration: A Smart Temperature Sensor for an Organ-on-a-chip Platform

Bio-Electronic

Towards a semi-flexible parylene-based platform technology for active implantable medical devices

Active implantable medical devices have been developed for diagnosis, monitoring and treatment of large variety of neural disorders. Since the mechanical properties of these devices need to be matched to the tissue, soft materials, such as polymers are often preferred as a substrate [1]. Parylene is a good candidate, as it is highly biocompatible and it can be deposited/etched using standard Integrated Circuit (IC) fabrication methods/processes. Further, the implantable devices should be smart, a goal that can be accomplished by including ICs. These ICs, often come in the form of additional pre-packaged components that are assembled on the implant in a heterogenous process. Such a hybrid integration, however, does not allow for size minimization, which is so critical in these applications, as otherwise the implants can cause severe damage to the tissue. On the other hand, it is essential that all components are properly packaged to prevent early failure due to moisture penetration [2].In this work we use a previously developed semi-flexible platform technology based on a Parylene substrate and Pt metallization, which allows integration of electronic components with a flexible substrate in a monolithic process. We use an IC fabrication-based platform that allows for the fabrication of several rigid regions including Application-Specific Integrated Circuits (ASICs) and other components connected to each other by means of flexible interconnects. We aim to add more functionality to this technology and thereby extend it to a platform for a variety of medical applications. An example of such functionality is integrating Light Emitting Diodes (LEDs) for optogenetic stimulation or integrating Capacitive Micromachined Ultrasound Transducers (CMUTs) for ultrasound stimulation or ultrasound wireless power transfer. Since the long-term reliability is critical for implantable devices, we intend to reinforce our implant with an extra Polydimethylsiloxane (PDMS) encapsulation layer that relies on the low viscosity of the uncured rubber to flow in every detail of the surface to prevent void formation [3]. Therefore, this work also focuses on enhancing the adhesion of PDMS to Parylene, as it must remain strong for the required lifetime of the device