Brian J. Kim

3D Parylene sheath neural probe for chronic recordings

OBJECTIVE Reliable chronic recordings from implanted neural probes remain a significant challenge; current silicon-based and microwire technologies experience a wide range of biotic and abiotic failure modes contributing to loss of signal quality. APPROACH A multi-prong alternative strategy with potential to overcome these hurdles is introduced that combines a novel three dimensional (3D), polymer-based probe structure with coatings. Specifically, the Parylene C sheath-based neural probe is coated with neurotrophic and anti-inflammatory factors loaded onto a Matrigel carrier to encourage the ingrowth of neuronal processes for improved recording quality, reduce the immune response, and promote improved probe integration into brain tissue for reliable, long-term implementation compared to its rigid counterparts. MAIN RESULTS The 3D sheath structure of the probe was formed by thermal molding of a surface micromachined Parylene C microchannel, with electrode sites lining the interior and exterior regions of the lumen. Electrochemical characterization of the probes via cyclic voltammetry and electrochemical impedance spectroscopy was performed and indicated suitable electrode properties for neural recordings (1 kHz electrical impedance of ∼200 kΩ in vitro). A novel introducer tool for the insertion of the compliant polymer probe into neural tissue was developed and validated both in vitro using agarose gel and in vivo in the rat cerebral cortex. In vivo electrical functionality of the Parylene C-based 3D probes and their suitability for recording the neuronal activity over a 28-day period was demonstrated by maintaining the 1 kHz electrical impedance within a functional range (<400 kΩ) and achieving a reasonably high signal-to-noise ratio for detection of resolvable multi-unit neuronal activity on most recording sites in the probe. Immunohistochemical analysis of the implant site indicated strong correlations between the quality of recorded activity and the neuronal/astrocytic density around the probe. SIGNIFICANCE The provided electrophysiological and immunohistochemical data provide strong support to the viability of the developed probe technology. Furthermore, the obtained data provide insights into further optimization of the probe design, including tip geometry, use of neurotrophic and anti-inflammatory drugs in the Matrigel coating, and placement of the recording sites.

Chronically Implanted Pressure Sensors: Challenges and State of the Field

Several conditions and diseases are linked to the elevation or depression of internal pressures from a healthy, normal range, motivating the need for chronic implantable pressure sensors. A simple implantable pressure transduction system consists of a pressure-sensing element with a method to transmit the data to an external unit. The biological environment presents a host of engineering issues that must be considered for long term monitoring. Therefore, the design of such systems must carefully consider interactions between the implanted system and the body, including biocompatibility, surgical placement, and patient comfort. Here we review research developments on implantable sensors for chronic pressure monitoring within the body, focusing on general design requirements for implantable pressure sensors as well as specifications for different medical applications. We also discuss recent efforts to address biocompatibility, efficient telemetry, and drift management, and explore emerging trends.

Review of polymer MEMS micromachining

The development of polymer micromachining technologies that complement traditional silicon approaches has enabled the broadening of microelectromechanical systems (MEMS) applications. Polymeric materials feature a diverse set of properties not present in traditional microfabrication materials. The investigation and development of these materials have opened the door to alternative and potentially more cost effective manufacturing options to produce highly flexible structures and substrates with tailorable bulk and surface properties. As a broad review of the progress of polymers within MEMS, major and recent developments in polymer micromachining are presented here, including deposition, removal, and release techniques for three widely used MEMS polymer materials, namely SU-8, polyimide, and Parylene C. The application of these techniques to create devices having flexible substrates and novel polymer structural elements for biomedical MEMS (bioMEMS) is also reviewed.

Formation of three-dimensional Parylene C structures via thermoforming

The thermoplastic nature of Parylene C is leveraged to enable the formation of three-dimensional structures using a thermal forming (thermoforming) technique. Thermoforming involves the heating of Parylene films above its glass transition temperature while they are physically confined in the final desired conformation. Micro and macro scale three-dimensional structures composed of Parylene thin films were developed using the thermoforming process, and the resulting chemical and mechanical changes to the films were characterized. No large changes to the surface and bulk chemistries of the polymer were observed following the thermoforming process conducted in vacuum. Heat treated structures exhibited increased stiffness by a maximum of 37% depending on the treatment temperature, due to an increase in crystallinity of the Parylene polymer. This study revealed important property changes resulting from the process, namely (1) the development of high strains in thermoformed areas of small radii of curvature (30?90??m) and (2) ?1.5% bulk material shrinkage in thermoformed multilayered Parylene?Parylene and Parylene?metal?Parylene films. Thermoforming is a simple process whereby three-dimensional structures can be achieved from Parylene C-based thin film structures with tunable mechanical properties as a function of treatment temperature.

Matrigel coatings for Parylene sheath neural probes

The biologically derived hydrogel Matrigel (MG) was used to coat a Parylene-based sheath intracortical electrode to act as a mechanical and biological buffer as well as a matrix for delivering bioactive molecules to modulate the cellular response and improve recording quality. MG was loaded with dexamethasone to reduce the immune response together with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) to maintain neuronal density and encourage neuronal ingrowth toward electrodes within the sheath. Coating the Parylene sheath electrode with the loaded MG significantly improved the signal-to-noise ratio for neural events recorded from the motor cortex in rat for more than 3 months. Electron microscopy showed even coverage of both the Parylene substrate and the platinum recording electrodes. Electrochemical impedance spectroscopy (EIS) of coated electrodes in 1× phosphate-buffered saline demonstrated low impedance required for recording neural signals. This result was confirmed by in vivo EIS data, showing significantly decreased impedance during the first week of recording. Dexamethasone, NGF, and BDNF loaded into MG were released within 1 day in 1× phosphate-buffered saline. Although previous studies showed that MG loaded with either the immunosuppressant or the neurotrophic factor cocktail provided modest improvement in recording quality in a 1-month in vivo study, the combination of these bioactive molecules did not improve the signal quality over coating probes with only MG in a 3-month in vivo study. The MG coating may further improve recording quality by optimizing the in vivo release profile for the bioactive molecules.

Comparison of Bumetanide- and Metolazone-Based Diuretic Regimens to Furosemide in Acute Heart Failure:

Introduction: Limited data exist comparing the efficacy and safety of bumetanide- or metolazone-based diuretic regimens to furosemide in acute heart failure (HF). Our purpose was to evaluate the comparative effect on urine output (UO) and renal function between these regimens. Methods: A retrospective study of hospitalized HF patients treated with continuous infusion furosemide (CIF), combination furosemide plus metolazone (F + M), or continuous infusion bumetanide (CIB). Primary end points were between regimen comparisons for change in mean hourly UO versus baseline and incidence of worsening renal function. Results: Data on 242 patients with acute HF (age 58 ± 12 years, 63% male, left ventricular ejection fraction 38% ± 17%) were analyzed (160 CIF, 42 F + M, 40 CIB). The mean duration of diuretic regimens was 41 ± 32 hours. Compared to baseline, all regimens increased mean hourly UO (P < .0001 for all), with greater increases with F + M (109 ± 171 mL) and CIB (90 ± 90 mL) compared to CIF (48 ± 103 mL; P = .009). Incidence of worsening renal function was not different between regimens; however, blood urea nitrogen (BUN) tended to increase more with F + M (4.4 ± 9.8 mg/dL) and CIB (4.3 ± 9.7 mg/dL) than CIF (1.8 ± 10.8 mg/dL), P = .09. The incidence of hyponatremia was higher with F + M and CIB. Differences in UO, BUN, and hyponatremia were retained in the subgroup analysis limited to patients with baseline serum creatinine <1.5 mg/dL, where renal function between the groups was not different. Conclusion: Compared to CIF, F + M or CIB was associated with greater increases in UO. No difference in the incidence of worsening renal function was found; however, electrolyte abnormalities may be more prevalent when furosemide is combined with metolazone or when bumetanide is used. These therapeutic differences warrant prospective study.

Parylene-based electrochemical-MEMS force sensor array for assessing neural probe insertion mechanics

We present the first use of a Parylene-based electrochemical-MEMS (EC-MEMS) sensor array for instrumentation of ceramic-based neural electrode probes. The sensor array consists of a liquid-filled Parylene-based microchannel and an array of enclosed electrodes that monitor local variations in impedance during mechanical deformation of the channel. The array provides real time measurement of out-of-plane interfacial forces produced directly on the electrode shank surface (<;5 mm2) during insertion of the probe. We demonstrate the ability to examine the relative force distribution of interfacial forces produced on the shank surface during insertion, thereby providing a clearer understanding of probe insertion mechanics. Our approach enables, for the first time, robust mechanical instrumentation of electrode shanks providing a means for assessing the poorly understood interfacial mechanics between neural probes and tissue.

Pre-implantation electrochemical characterization of a Parylene C sheath microelectrode array probe

We present the preliminary electrochemical characterization of 3D Parylene C sheath microelectrode array probes towards realizing reliable chronic neuroprosthetic recordings. Electrochemical techniques were used to verify electrode integrity after our novel post-fabrication thermoforming process was applied to flat surface micromachined structures to achieve a hollow sheath probe shape. Characterization of subsequent neurotrophic coatings was performed and accelerated life testing was used to simulate six months in vivo. Prior to probe implantation, crosstalk was measured and electrode surface properties were evaluated through the use of electrochemical impedance spectroscopy.

An implantable all-Parylene liquid-impedance based MEMS force sensor

We present a new transducer paradigm based on the electrochemical impedance transduction capability of encapsulated liquids within Parylene-based MEMS structures. We demonstrate the ability to measure forces in the micronewton range with a resolution of 4.56mΩ/µN. These sensors are ideally suited for applications requiring highly sensitive interrogation of soft non-planar surfaces in wet environments. Specifically, in situ and in vivo measurement of interfacial forces exerted on tissue by chronically implanted neural prosthetic devices is presently an unmet engineering challenge. Our approach enables, for the first time, interrogation of such biomechanical phenomena.

Three dimensional transformation of Parylene thin film structures via thermoforming

Non-planar, three dimensional structures, not possible with conventional microfabrication processes, were achieved using post-fabrication thermal annealing of thin film Parylene-C structures facilitated by a mold (“thermoforming”). We demonstrate thermoforming of Parylene-Parylene and Parylene-metal-Parylene (PMP) structures for increased structural and mechanical functionality such as strain relief, formation of open-lumen sheath structures, and conformation-matching of curved surfaces that broaden applications for Parylene MEMS. Characterization of the material and mechanical properties as a function of thermoforming temperature is also presented. Thermoformed Parylene consistently retained bulk/surface chemical material properties following the treatment regardless of temperature, and thermoforming at higher temperatures increased structural stiffness, which is attributed to increased crystallinity of the polymer. By varying the thermoforming process parameters, the final shaped structure can be mechanically and structurally tuned for broad range of applications, most notably, structured implantable neural interfaces with integrated channels for tissue ingrowth and improved integration.