Early feasibility study with an implantable near-infrared spectroscopy sensor for glucose, ketones, lactate and ethanol.

OBJECTIVE: To evaluate the safety and performance of an implantable near-infrared (NIR) spectroscopy sensor for multi-metabolite monitoring of glucose, ketones, lactate, and ethanol. RESEARCH DESIGN AND METHODS: This is an early feasibility study (GLOW, NCT04782934) including 7 participants (4 with type 1 diabetes (T1D), 3 healthy volunteers) in whom the YANG NIR spectroscopy sensor (Indigo) was implanted for 28 days. Metabolic challenges were used to vary glucose levels (40-400 mg/dL, 2.2-22.2 mmol/L) and/or induce increases in ketones (ketone drink, up to 3.5 mM), lactate (exercise bike, up to 13 mM) and ethanol (4-8 alcoholic beverages, 40-80g). NIR spectra for glucose, ketones, lactate, and ethanol levels analyzed with partial least squares regression were compared with blood values for glucose (Biosen EKF), ketones and lactate (GlucoMen LX Plus), and breath ethanol levels (ACE II Breathalyzer). The effect of potential confounders on glucose measurements (paracetamol, aspartame, acetylsalicylic acid, ibuprofen, sorbitol, caffeine, fructose, vitamin C) was investigated in T1D participants. RESULTS: The implanted YANG sensor was safe and well tolerated and did not cause any infectious or wound healing complications. Six out 7 sensors remained fully operational over the entire study period. Glucose measurements were sufficiently accurate (overall mean absolute (relative) difference MARD of 7.4%, MAD 8.8 mg/dl) without significant impact of confounders. MAD values were 0.12 mM for ketones, 0.16 mM for lactate, and 0.18 mM for ethanol. CONCLUSIONS: The first implantable multi-biomarker sensor was shown to be well tolerated and produce accurate measurements of glucose, ketones, lactate, and ethanol. TRIAL REGISTRATION: Clinical trial identifier: NCT04782934.

Integrity Assessment of a Hybrid DBS Probe that Enables Neurotransmitter Detection Simultaneously to Electrical Stimulation and Recording.

Deep brain stimulation (DBS) is a successful medical therapy for many treatment resistant neuropsychiatric disorders such as movement disorders; e.g., Parkinson's disease, Tremor, and dystonia. Moreover, DBS is becoming more and more appealing for a rapidly growing number of patients with other neuropsychiatric diseases such as depression and obsessive compulsive disorder. In spite of the promising outcomes, the current clinical hardware used in DBS does not match the technological standards of other medical applications and as a result could possibly lead to side effects such as high energy consumption and others. By implementing more advanced DBS devices, in fact, many of these limitations could be overcome. For example, a higher channels count and smaller electrode sites could allow more focal and tailored stimulation. In addition, new materials, like carbon for example, could be incorporated into the probes to enable adaptive stimulation protocols by biosensing neurotransmitters in the brain. Updating the current clinical DBS technology adequately requires combining the most recent technological advances in the field of neural engineering. Here, a novel hybrid multimodal DBS probe with glassy carbon microelectrodes on a polyimide thin-film device assembled on a silicon rubber tubing is introduced. The glassy carbon interface enables neurotransmitter detection using fast scan cyclic voltammetry and electrophysiological recordings while simultaneously performing electrical stimulation. Additionally, the presented DBS technology shows no imaging artefacts in magnetic resonance imaging. Thus, we present a promising new tool that might lead to a better fundamental understanding of the underlying mechanism of DBS while simultaneously paving our way towards better treatments.

PDMS Gasket Underfill for Long-Term Insulation of High-Density Interconnections in Active Implantable Medical Devices.

This work presents reliability investigations of silicone gasket as solid underfill for interconnection interfaces in hybrid implant systems with high channel count flexible electrode arrays and hermetically packed electronics. The gasket is fabricated by laser structuring thin sheet of silicone rubber. The surface activation of silicone sheet ensures mechanical bonds with the mating surfaces thereby improving the mechanical stability of the assembly and the insulation of the interconnects. The gasket samples with $10 \times 10$ openings for interconnect pads, each with diameter of $270 \mu \mathrm {m}$ and a center to center pitch size of $490 \mu \mathrm {m}$, were sandwiched between a polyimide array and a metallized ceramic substrate. The gasket maintained high insulation impedance of $15 \pm 0.30 \mathrm {M}\Omega $ between the adjacent interconnects with markedly capacitive behavior (phase angle, $- 89 ^{\circ})$ after 17 weeks in soaked conditions under accelerated aging at $60 ^{\circ}\mathrm {C}$. The gasket also survived electrical stresses and sustained high impedance $(10.93 \mathrm {M}\Omega $ with phase angle of $- 88 ^{\circ})$ when subjected to constant 3 VDC for 100 days.

Laser-Induced Carbon Pyrolysis of Electrodes for Neural Interface Systems.

The objective of this work is to produce a laser- fabricated polymer-metal-polymer electrode with the merit of a carbon-based coating as the active site. A 10 µm-thick layer of parylene-C is used serving as the insulation layer in which the active site is locally laser-pyrolyzed. Our preliminary results show that the proposed method is promising in terms of fabrication feasibility and desired electrochemical capabilities.

Concept and Development of an Electronic Framework Intended for Electrode and Surrounding Environment Characterization In Vivo.

There has been substantial progress over the last decade towards miniaturizing implantable microelectrodes for use in Active Implantable Medical Devices (AIMD). Compared to the rapid development and complexity of electrode miniaturization, methods to monitor and assess functional integrity and electrical functionality of these electrodes, particularly during long term stimulation, have not progressed to the same extent. Evaluation methods that form the gold standard, such as stimulus pulse testing, cyclic voltammetry and electrochemical impedance spectroscopy, are either still bound to laboratory infrastructure (impractical for long term in vivo experiments) or deliver no comprehensive insight into the material's behaviour. As there is a lack of cost effective and practical predictive measures to understand long term electrode behaviour in vivo, material investigations need to be performed after explantation of the electrodes. We propose the analysis of the electrode and its environment in situ, to better understand and correlate the effects leading to electrode failure. The derived knowledge shall eventually lead to improved electrode designs, increased electrode functionality and safety in clinical applications. In this paper, the concept, design and prototyping of a sensor framework used to analyse the electrode's behaviour and to monitor diverse electrode failure mechanisms, even during stimulation pulses, is presented. We focused on the electronic circuitry and data acquisition techniques required for a conceptual multi-sensor system. Functionality of single modules and a prototype framework have been demonstrated, but further work is needed to convert the prototype system into an implantable device. In vitro studies will be conducted first to verify sensor performance and reliability.

Development of a multichannel implantable connector.

Further development of active implantable medical devices (AIMDs) coming along with higher channel counts and improved maintainability raises the requirements for implantable connectors in such systems. We developed a concept for an implantable multichannel connector. Contact pads manufactured by laser-structuring that are embedded into a silicone substrate serve as contact partners. Processing features specific to two laser technologies were exploited not only to cut the materials but also to 3D-shape the surfaces of the contact pads. First tests for the long-term behavior show stable contact and isolation properties during 6 weeks of soaking at elevated temperature.

Non-hermetic encapsulation for implantable electronic devices based on epoxy.

Hermetic and non-hermetic implant packaging are the two strategies to protect electronic systems from the humid conditions inside the human body. Within the scope of this work twelve different material combinations for a non-hermetic, high-reliable epoxy based encapsulation technique were characterized. Three EPO-TEK (ET) epoxies and one low budget epoxy were chosen for studies with respect to their processability, water vapor transmission rate (WVTR) and adhesion to two different ceramic-based substrates as well as to one standard FR4-substrate. Setups were built to analyze the mentioned properties for at least 30 days using an aging test in a moist environment. As secondary test subjects, commercially available USB flash drives (UFD) were successfully encapsulated inside the epoxies, soaked in phosphate buffered saline (PBS, pH=7.4), stored in an incubator (37°C) and tested for 256 days without failure. By means of epoxy WVTR (0.0278 g/day/m(2)) and degrease of adhesion (24.59 %) during 30 days in PBS, the combination of the standard FR4-substrate and the epoxy ET 301-2 was found to feature the best encapsulation properties. If a ceramic-based electronic system has to be used, the most promising combination consists of the alumina substrate and the epoxy ET 302-3M (WVTR: 0.0588 g/day/m(2); adhesion drop: 49.58 %).

A polymer-metal two step sealing concept for hermetic neural implant packages.

In this paper, we introduce a technique for double-sealed ceramic packages for the long-term protection of implanted electronics against body fluids. A sequential sealing procedure consisting of a first step, during which the package is sealed with epoxy, protecting the implant electronics from aggressive flux fumes. These result from the application of the actual moisture barrier which is a metal seal applied in a second step by soft soldering. Epoxy sealing is carried out in helium atmosphere for later fine leak testing. The solder seal is applied on the laboratory bench. After the first sealing step, a satisfactory barrier for moisture is already achieved with values for helium leakage of usually LHe = 6·10(-8) mbar 1 s(-1). After solder sealing, a very low leakage rate of LHe ≤ 1·10(-12) mbar 1 s(-1) was found, which was the lower detection limit of the measurement setup, suggesting excellent hermeticity and hence moisture barrier. Presuming an implant package volume of V ≥ 0.5 cm(3), the time to reach a critical humidity of p = 5000 ppm H2O inside the package will be longer than any anticipated average life of human patients.

Cuff electrodes for very small diameter nerves -- prototyping and first recordings in vivo.

A fabrication method for cuff electrodes to interface small nerves was developed. Medical grade silicone rubber conforms the body of the cuff and insulation of the wires, platinum was used as metal for the embedded wiring and contacts. Planar electrode arrays where fabricated using a picosecond laser and then positioned into a carrying tube to provide the third dimension with the desired inner diameter (Ø 0.3-0.5 mm). The post preparation of the cuffs after structuring allows the fabrication of a stable self-closing flap that insulates the opening slit of the cuff without the need of extra sutures. Basic for the success of the cuff is the laser-based local thinning of both the silicone rubber and the metal at defined sections. This is critical to permit the PDMS' body to dominate the mechanical properties. Finite element modeling was applied to optimize the displacement ability of the cuff, leading to design capable of withstanding multiple implantation procedures without wire damage. Furthermore, the contact's surface was roughened by laser patterning to increase the charge injection capacity of Pt to 285 µC/cm(2) measured by voltage transient detection during pulse testing. The cuff electrodes were placed on a small sympathetic nerve of an adult female Sprague-Dawley rat for recording of spontaneous and evoked neural activity in vivo.

A 232-channel retinal vision prosthesis with a miniaturized hermetic package.

Miniaturization of implantable devices while drastically increasing the number of stimulation channels is one of the greatest challenges in implant manufacturing because a small but hermetic package is needed that provides reliable protection for the electronics over decades. Retinal vision prostheses are the best example for it. This paper presents a miniaturized 232-channel vision prosthesis, summarizing the studies on the individual technologies that were developed, improved and combined to fabricate a telemetrically powered retinal device sample. The implantable unit, which is made out of a high temperature co-fired alumina ceramic package containing hermetic feedthroughs, electronic circuitry and a radio frequency coil for powering is manufactured through a modified screen-printing/lasering process. The package is sealed with solder glass to provide unaffected inductive coupling to the telemetric transmitter. A 0.05 cc inner volume allows helium leak testing and mathematical lifetime estimations for moisture-induced failure of up to 100 years. The feedthroughs contact a thin-film polyimide electrode array that utilizes DLC and SiC coatings for improved interlayer adhesion of the metallic tracks to the polymer carrier. Two metal layers allow integrated wiring of the electrode array within the very limited space.

Hermetic electronic packaging of an implantable brain-machine-interface with transcutaneous optical data communication.

Future brain-computer-interfaces (BCIs) for severely impaired patients are implanted to electrically contact the brain tissue. Avoiding percutaneous cables requires amplifier and telemetry electronics to be implanted too. We developed a hermetic package that protects the electronic circuitry of a BCI from body moisture while permitting infrared communication through the package wall made from alumina ceramic. The ceramic package is casted in medical grade silicone adhesive, for which we identified MED2-4013 as a promising candidate.

Improved polyimide thin-film electrodes for neural implants.

Thin-film electrode arrays for neural implants are necessary when large integration densities of stimulating or recording channels are required. However, delamination of the metallic layers from the polymer substrate leads to early failure of the device. Based on new adhesion studies of polyimide to SiC and diamond-like carbon (DLC) the authors successfully fabricated a 232-channel electrode array for retinal stimulation with improved adhesion. Layers of SiC and DLC were integrated into the fabrication procedure of polyimide-platinum (Pt) arrays to create fully coated metal wires, which adhere to the polyimide substrate even after 1 year of accelerated aging in saline solution. Studies on the inter-diffusion of Pt and SiC were conducted to establish an optimal thickness for a gold core of the platinum tracks, which is used for reducing the electrical track resistance. Furthermore, the electrochemical behaviour of the stimulating contacts coated with IrOx were studied in a long-term pulse tests over millions of pulses showing no deterioration of the coating.

Ensuring minimal humidity levels in hermetic implant housings.

The electronic circuitry of active implantable devices is commonly protected against the risk of water-induced corrosion by using gas-tight (hermetic) packages, preventing moisture from the host body to reach the electronics. However, when closing the package, one has to ensure that the packaged components do not contain moisture that could rise humidity inside the package to critical levels by outgassing. For our miniature metal/ceramic packages, we found a drying procedure of 120 °C at 180 mbar absolute pressure for one hour, followed by a dry helium purge sufficient to keep the relative humidity below 2.5% over a time span of 300 days at 80 °C, corresponding to over 15 years at 37 °C. The additional integration of a desiccant inside the package permits to keep the relative humidity below 0.1%, the detection limit of the integrated sensor. This sensor was selected based on an evaluation of 17 commercially available humidity sensors.

A device for vacuum drying, inert gas backfilling and solder sealing of hermetic implant packages.

Modern implanted devices utilize microelectronics that have to be protected from the body fluids in order to maintain their functionality over decades. Moisture protection of implants is addressed by enclosing the electronic circuits into gas-tight packages. In this paper we describe a device that allows custom-built hermetic implant packages to be vacuum-dried (removing residual moisture from inside the package), backfilled with an inert gas at adjustable pressure and hermetically sealed employing a solder seal. A typical operation procedure of the device is presented.

Fabrication and test of a hermetic miniature implant package with 360 electrical feedthroughs.

A fabrication technology for small hermetic implant packages with large numbers of electrical feedthroughs is presented. First prototypes were fabricated on a ceramic substrate of 25·25 mm area, having a metal cup of 5 mm height soldered to it. These prototypes provide 360 feedthroughs. The electrical properties of the feedthroughs are characterized and the leakage rate of the packages is determined using helium fine leak tests. The amount of water sealed inside the packages is investigated. Based on maximum allowable water vapour concentrations inside hermetic packages reported in literature and applying a commonly accepted mathematical model, we predicted a minimum lifetime to water-induced failure of a few hundred years.

Cytotoxicity of implantable microelectrode arrays produced by laser micromachining.

Implantable high-density microelectrode arrays have been successfully fabricated using laser micromachining of conventional implant materials, polydimethylsiloxane (PDMS) and platinum (Pt) foil. This study investigates the impact of modifying PDMS and Pt with high power laser beams and the possible toxicity of by-products that may remain on the implantable device. Materials were characterised both chemically and biologically through x-ray photoelectron spectroscopy (XPS), cell growth inhibition assays and a direct contact cell proliferation assay. It was found that laser micromachining produces oxides of silicon and platinum on the PDMS and Pt respectively. While the chemical properties of materials were altered, there was negligible change in the biological response to either extracts or cell growth directly on the composite electrode array.

Stretchable tracks for laser-machined neural electrode arrays.

An easy and fast method for fabrication of neural electrode arrays is the patterning of platinum foil and spin-on silicone rubber using a laser. However, the mechanical flexibility of such electrode arrays is limited by the integrated tracks that connect the actual electrode sites and the contacts to which wires are welded. Changing the design from straight lines to meanders, the tracks can be stretched to a certain extend defined by the shape of the meanders. Horse-shoe-like designs described by an opening angle theta = 60 degrees and ratio between curvature radius r and track width w of r/w = 3.6 permitted stretching of 14.4% before track breakage. For r/w = 11.7 a maximum elongation at break of 19.7% was measured. Larger opening angles theta provided even better flexibility but with increasing theta, the tensile strength and the electrical conductance of a single track is compromised and the maximum integration density (tracks per area) decreases.

Interconnection technologies for laser-patterned electrode arrays.

Standard interconnection technologies are reviewed in respect to their applicability to electrically and mechanically connect laser-patterned nerve electrodes made from silicone rubber and platinum foil to wires and screen printed alumina substrates. Laser welding, gap welding, microflex ball bonding, and soldering are evaluated. Corresponding processes were established and evaluated in respect to their mechanical strength. Best results were obtained by soldering. If soldering cannot be used because of regulatory reasons, parallel gap welding and microflex are recommended. Laser welding provides weaker interconnects with only moderate reproducibility.

Scaling limitations of laser-fabricated nerve electrode arrays.

A laser technology for manufacturing implantable electrode arrays, using spin-on polydimethylsiloxane (PDMS) and platinum foil as materials, was investigated in respect to its scaling limitations. The following aspects were analyzed: Minimal width and centre-to-centre distance of platinum tracks, the ability of spin-on PDMS to flow between platinum tracks with very narrow gaps and the electrical insulation properties of thin spin-coated PDMS.