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A continuously recording, impedimetric thermal liquid flow sensor fabricated on a Parylene C thin film substrate is presented for the first time. The sensing concept, inspired by hot-film anemometry, includes an additional upstream unheated reference electrode pair which enabled attenuation of environmental drift in impedance by more than 5 ×. This sensor design and transduction approach was motivated by the need for an alternative to traditional hot-film anemometers for in vivo applications. An analytical model was developed to describe the axial fluid temperature surrounding the impedimetric sensor and its effect on solution conductivity. The impact of heater power was modeled and matched with experimental data; similar analysis was conducted for other parameters including channel height, ambient temperature, and electrolyte concentration. The sensor achieved a 2σ resolution of 17 μL/min over the range 43–200 μL/min. The models and fabricated device significantly expand our understanding of thermal impedimetric flow sensing. [2020-0357] [ABSTRACT FROM AUTHOR]

Flexible electronics require more compact interconnects for next-generation devices. Polymer devices can be bonded to integrated circuit chips, but combining flexible and rigid substrates poses unique technical challenges. Existing technologies either cannot achieve the density required for modern chips or employ specialized equipment and complex processes to do so. Here, we adapt several approaches to achieve fine-pitch bonding between rigid and flexible substrates including epoxy, ultrasonic wire, and anisotropic conductive film bonding and also introduce a novel technique called polymer ultrasonic on bump (PUB) bonding. Using Parylene C devices and various rigid substrates as our model testbed systems, we investigate these four methods across a range of bond pad size and pitch by measuring yield and resistance and by subjecting devices to thermomechanical reliability tests. We demonstrate that all methods are capable of bonding fine pitch interconnects (100 µm) at low temperature (<100 °C). Additionally, we focus on PUB bonding and join a packaged chip and a bare die to Parylene devices. [ABSTRACT FROM AUTHOR]

A kirigami-based strategy was investigated for strain transduction, using serpentine gold traces embedded in thin-film Parylene C. Multiple kirigami slit designs were evaluated via COMSOL simulation and mechanical force testing; sensors having tightly packed slits stretched up to 17.5 mm (350% strain) before mechanical failure and 9 mm (180% strain) before electrical failure. Strain transduction was achieved by monitoring DC resistance changes during stretching. DC resistance linearly increased with strain, with sensitivities up to 0.16 $\Omega$ /mm (gauge factor = 0.007) and minimal hysteresis. High-frequency trace impedance and inter-trace capacitance were also investigated during strain cycling. Capacitance increased with strain and high-frequency impedance show a nonlinear strain relationship. The biocompatible construction and extremely low profiles (20 $\mu \text{m}$ thick) of these sensors are attractive for minimally invasivein vivostrain sensing applications. [2018-0130] [ABSTRACT FROM AUTHOR]

Closed-loop drug delivery promises autonomous control of pharmacotherapy through the continuous monitoring of biomarker levels. For decades, researchers have strived for portable closed-loop systems capable of treating ambulatory patients with chronic conditions such as diabetes mellitus. After years of development, the first of these systems have left the laboratory and entered commercial use. This long-awaited advance reflects recent development of chronically stable implantable biosensors able to accurately measure biomarker levels in vivo . This review discusses the role of implantable biosensors in closed-loop drug delivery applications, with the intent to provide a resource for engineers and researchers studying such systems. We provide an overview of common biosensor designs and review the principle challenges in implementing long indwelling sensors: namely device sensitivity, selectivity, and lifetime. This review examines novel advances in transducer design, biological interface, and material biocompatibility, with a focus on recent academic and commercial work which provide successful strategies to overcome perennial challenges. This review focuses primarily on the topics of closed-loop glucose control and continuous glucose monitoring biosensors, which make up the overwhelming majority of published research in this area. We conclude with an overview of recent advances in closed-loop systems targeting applications outside blood glucose management. [ABSTRACT FROM AUTHOR]

Recombination of electrolysis gases (oxidation of hydrogen and reduction of oxygen) is an important factor in operation efficiency of devices employing electrolysis such as actuators and also unitized regenerative fuel cells. Several methods of improving recombination speed and repeatability were developed for application to electrolysis microactuators with Nafion ® -coated catalytic electrodes. Decreasing the electrolysis chamber volume increased the speed, consistency, and repeatability of the gas recombination rate. To further improve recombination performance, methods to increase the catalyst surface area, hydrophobicity, and availability were developed and evaluated. Of these, including in the electrolyte pyrolyzed-Nafion ® -coated Pt segments contained in the actuator chamber accelerated recombination by increasing the catalyst surface area and decreasing the gas transport diffusion path. This approach also reduced variability in recombination encountered under varying actuator orientation (resulting in differing catalyst/gas bubble proximity) and increased the rate of recombination by 2.3 times across all actuator orientations. Repeatability of complete recombination for different generated gas volumes was studied through cycling. [ABSTRACT FROM AUTHOR]

The application of microfabrication to the development of biomedical implants has produced a new generation of miniaturized technology for assisting treatment and research. Microfabricated implantable devices (μID) are an increasingly important tool, and the development of new μIDs is a rapidly growing field that requires new microtechnologies able to safely and accurately function in vivo. Here, we present a review of μID research that examines the critical role of material choice in design and fabrication. Materials commonly used for μID production are identified and presented along with their relevant physical properties and a survey of the state-of-the-art in μID development. The consequence of material choice as it pertains to microfabrication and biocompatibility is discussed in detail with a particular focus on the divide between hard, rigid materials and soft, pliable polymers. [ABSTRACT FROM AUTHOR]

Abstract: Innovation in implantable drug delivery devices is needed for novel pharmaceutical compounds such as certain biologics, gene therapy, and other small molecules that are not suitable for administration by oral, topical, or intravenous routes. This invasive dosing scheme seeks to directly bypass physiological barriers presented by the human body, release the appropriate drug amount at the site of treatment, and maintain the drug bioavailability for the required duration of administration to achieve drug efficacy. Advances in microtechnologies have led to novel MEMS-enabled implantable drug infusion pumps with unique performance and feature sets. In vivo demonstration of micropumps for laboratory animal research and preclinical studies include acute rapid radiolabeling, short-term delivery of nanomedicine for cancer treatment, and chronic ocular drug dosing. Investigation of MEMS actuators, valves, and other microstructures for on-demand dosing control may enable next generation implantable pumps with high performance within a miniaturized form factor for clinical applications. [Copyright &y& Elsevier]

We present high-efficiency Nafion-coated electrochemical actuators having biocompatible construction suitable for biomedical applications such as drug delivery. High flow rates of up to 141.95 \pm 0.46\ \mu\L/min were achieved (at 13 mA). Nafion coating increased efficiency across all current values tested and prevented current-induced damage to electrodes. The effects of coating thickness, electroplating, actuator orientation, and changes in temperature on actuator performance were studied. Electrochemical impedance spectroscopy is introduced as a tool for characterizing electrodes, quality of electrochemical cleaning, determining surface area activity, and also for understanding the impact of electrolyte coatings, electroplating, and substrate changes on actuator performance. Parylene and polyetheretherketone (PEEK) were investigated as flexible substrate substitutes for soda lime glass. The higher surface roughness of the PEEK substrate compared to glass led to actuators with improved flow rates.\hfill[2011-0361] [ABSTRACT FROM AUTHOR]

A novel check valve featuring adhesiveless packaging in heat-shrink tubing and dual regulation of in-plane flow is presented. The modular design enables simple replacement of valve components to modify valve behavior and performance. The specific design is intended for low-profile fluidic applications requiring flow control, such as drug delivery devices. The heat-shrink packaging scheme is extremely robust and can withstand > 2000 mmHg (266.6 kPa) without leakage. Three different valve geometries were investigated and evaluated with theoretical and finite-element modeling analyses. Repeated flow regulation experiments on a fully packaged, hydrated valve demonstrated flow regulation between 25 and 2000 mmHg (3.33–266.6 kPa) and leak-free closure up to 500 mmHg (66.7 kPa) of reverse pressure with no observed stiction. The valve closing time constants were also determined.\hfill[2011-0064] [ABSTRACT FROM AUTHOR]

We report on the use of electrochemical impedance (EI) as the basis for force transduction in Parylene-based microdevices. Electrolyte-filled microstructures were realized for extremely sensitive contact-force detection (10 mN range, \pm0.023 mN resolution) enabled by EI-based transduction and are a promising platform for next-generation biomedical sensing technology. The design, fabrication, and characterization of Parylene-based electrochemical-MEMS (EC-MEMS) devices capable of microNewton contact-mode force measurement are presented and discussed.\hfill[2011-0040] [ABSTRACT FROM AUTHOR]

We report the design, fabrication, and characterization of electrochemical microelectromechanical systems (EC-MEMS) devices featuring encapsulated fluid as the basis for transduction. Parylene microstructures, including discrete chambers (square or circular geometry), are utilized as physical transducers for electrochemically mediated liquid impedance transduction of physical phenomenon such as contact and force. Parylene-based EC-MEMS technologies uniquely leverage advantages in size (<500\ \mu\m diameter), packaging (no hermetic packaging necessary), power (nanowatts to microwatts), and flexibility to address the physical sensing requirements of in vivo applications. Robust EC impedance (EI) sensor responses (up to 20% from base-line) and discrimination of 200-nm chamber deflections were possible using the EI transduction technique. Additional transducer configurations enabling electrolysis-based out-of-plane actuation and biomimetic mechanotransduction in microfluidic channels are also presented. \hfill[2010-0157] [ABSTRACT FROM AUTHOR]

Abstract: A concept for reusable, in-plane polymer microfluidic interconnects that are directly integrated into microfluidic systems is reported. Convenient, on-demand world-to-chip interfaces are established by utilizing a pin-and-socket approach in which commercially available non-coring syringe needles are manually inserted through predefined polydimethylsiloxane (PDMS) septa integrated at the inlets/outlets of microchannels. Receptacles for the septa were batch-fabricated in a single layer of SU-8 that also formed microchannels in the microfluidic system. Due to the self-sealing nature of PDMS, the septa were used repeatedly and withstood multiple needle insertions and removals without leakage. Needle pull-out force was modeled as debonding in a fiber/matrix system and evaluated experimentally both in single and multiple pull-out studies. Results were compared with other published interconnects of similar construction. Interconnects were also evaluated under pressurized conditions and tested to failure. The simple format of these interconnects is readily adapted to many microfluidic fabrication processes and thus can be easily incorporated into existing microfluidic systems. [Copyright &y& Elsevier]

Abstract: A microelectromechanical systems (MEMS) thermal flow sensing array constructed of biocompatible materials has been designed, fabricated, and tested. In addition to the construction, the electronic biasing conditions were selected such that sensor operation was compatible with biological fluids. The device comprises several thin film platinum sensing elements sandwiched in a Parylene C membrane. The membrane is suspended over a bulk-micromachined silicon channel for improved thermal isolation. This sensing array layout permits, for the first time, operation in multiple flow sensing modes using a single device. Multi-mode testing was performed in hot-film, calorimetric, and time-of-flight modes at low overheat ratios. Furthermore, constant current (CC) and constant temperature (CT) biasing methods were explored in hot-film mode. The results of the various testing modes were compared and flow sensing down to 0.5μL/min has been demonstrated. [Copyright &y& Elsevier]

• A multi-faceted review of developments in peripheral nerve interface (PNI). • Explored the status of different PNI strategies to improve resolution and stability. • Integrative treatment of anatomy, PNI design, and characterization methods. Informational density and relative accessibility of the peripheral nervous system make it an attractive site for therapeutic intervention. Electrode-based electrophysiological interfaces with peripheral nerves have been under development since the 1960s and, for several applications, have seen widespread clinical implementation. However, many applications require a combination of neural target resolution and stability which has thus far eluded existing peripheral nerve interfaces (PNIs). With the goal of aiding PNI designers in development of devices that meet the demands of next-generation applications, this review seeks to collect and present practical considerations and best practices which emerge from the literature, including both lessons learned during early PNI development and recent ideas. Fundamental and practical principles guiding PNI design are reviewed, followed by an updated and critical account of existing PNI designs and strategies. Finally, a brief survey of in vitro and in vivo PNI characterization methods is presented. [ABSTRACT FROM AUTHOR]

Parylene C is a thin-film polymer used as a biocompatible barrier layer in biomedical implants and implantable MEMS; free-film Parylene C may serve as both the substrate and insulation in polymer-based microdevices, a growing branch of biomedical technology. The adhesion of vapor deposited Parylene C, particularly when exposed to wet, in vivo environments, is a critical determinant of device lifetime for such polymer-based implants. This paper explores several novel strategies for improving the adhesion of multi-layer Parylene structures, including thermal annealing and the use of several chemical interposer layers. Interfacial adhesion of Parylene-Parylene and Parylene-platinum-Parylene films was examined using a standard T-peel test to quantify adhesion and measure film integrity under chronic exposure to saline up to two years. Improved adhesion and barrier properties in Parylene-Parylene films resulted from the inclusion of diamond-like carbon and ethylene glycol diacrylate layers. Thermal annealing improved Parylene film integrity in wet environments but was insufficient for improving the integrity of Parylene-platinum interfaces. A 100-fold increase in adhesive strength at such interfaces was achieved using a commercially available adhesion promoter, and the corresponding improvements in resistance to moisture driven delamination were observed. X-ray diffraction and X-ray photoelectron spectroscopy results are provided to highlight the role of film morphology and surface composition in adhesion integrity. [2018-0076] [ABSTRACT FROM AUTHOR]

In this special section of Journal of Micromechanics and Microengineering are a collection of the best microengineering papers presented at the 7th International Conference on Microtechnologies in Medicine and Biology (MMB 2013) which took place in the seaside town of Marina del Rey, California, USA on 10–12 April, 2013. During the 3-day conference, participants enjoyed talks from 6 invited keynote speakers and 125 flash oral/poster presentations. The MMB conference is a biennial meeting with the primary purpose of fostering interactions between biologists and medical researchers, clinicians, chemists, physicists and engineers to enhance and strengthen the potential microtechnologies that will revolutionize the fields of medicine and biological sciences. The conference possesses a unique format where all poster presenters provide a brief 60 s oral presentation highlighting their research. This format was devised to provide training and exposure for young researchers, especially PhD students and postdocs, in the field and stimulate interdisciplinary exchanges. Therefore, MMB provides an intimate intellectual venue the facilitate discussions and collaborations to advance new research tools and technologies for medicine and biological sciences. The MMB conference series was co-founded by Professor David Beebe (University of Wisconsin—Madison) and Professor André Dittmar (University of Lyon) and was the first international meeting to provide a forum focusing on emerging applications of microtechnologies to unmet needs in medicine and biology. The series was held for the first time in 2000, in Lyon, France and followed by Madison, USA (2002), Oahu Island in Hawaii, USA (2005), Okinawa, Japan (2006), Québec City, Canada (2009), Lucerne, Switzerland (2011), and Marina del Rey, USA (2013). The next conference will be held in Seoul, Korea in 2015. This collection of articles highlights recent progress in microtechnologies with medical and biological applications. We are grateful to the many authors who contributed their research achievements to this exciting issue and to the anonymous reviewers for their invaluable insights and suggestions. We would also like to express our thanks to our colleagues on the international steering committee for their dedicated review of the selected presentations that appears at the conference. Finally, we appreciate the support of the editorial staff of Journal of Micromechanics and Microengineering for this inaugural MMB special issue. We look forward to continued collaboration in future MMB conferences. [ABSTRACT FROM AUTHOR]

A novel electrochemical-thermal flow sensor was developed for use in physiological liquids. The sensor was constructed out of a platinum resistive heater and platinum sensing electrodes on a Parylene C substrate, rendering it flexible and fully biocompatible. During heating, changes in electrochemical impedance across the sensing electrodes were used to detect changes in temperature, and highly sensitive flow measurements were achieved with overheat temperatures of only 1 °C. The sensor’s biocompatibility and low overheat temperature make it an ideal candidate for chronic in vivo applications. [2016-0170] [ABSTRACT FROM PUBLISHER]

A novel pressure transducer concept is introduced in which external pressure variations induce changes in the volume of a trapped microbubble ( \mu \textB ) in an electrolyte solution. These volumetric changes are monitored by electrochemical impedance-based measurements and may be used for pressure tracking applications. Microbubbles are nucleated on-demand by electrolysis within a confinement chamber with high precision (measured size RSD $\sim 1$ %). This pressure transducer concept was developed specifically for operation in liquid environments and features biocompatible construction, small footprint (<0.1 mm2), and low power consumption (<1 nW). This combination of features is ideal for in vivo pressure monitoring applications. [2015-0203] [ABSTRACT FROM PUBLISHER]

To investigate the mechanical interactions between the implanted cortical multielectrode probes and brain tissue, a Parylene C-based electrochemical-microelectromechanical systems force sensor array was developed. The array consists of seven linearly distributed sensor units arranged along the length of a flexible Parylene C microchannel. The seven sensor units are formed by eight fluidically coupled and adjacent platinum electrode pairs enclosed within the microchannel. Deformation of the top surface of the mechanically compliant microchannel changes the volumetric conduction path between the pairs of sensing electrodes, and therefore, the measured electrochemical impedance, which is proportional to the magnitude of the contacting force. Each sensor unit demonstrated a linear response from 0 to 60 mN with a sensitivity of 0.13 ± 0.01 percentage change in impedance/ \mu \textN (%/ \mu \textN ; mean ± SE, n = 6 ). The sensor arrays were mounted onto a ceramic intracortical probe and inserted into the tissue phantoms to verify in situ functionality and assess interfacial probe mechanics. Probe surface force distribution was measured under various insertion speeds and the results indicated that interfacial forces are distributed nonuniformly along the probe shaft length, concentrating within the first 1 mm of the advancing probe tip. Faster insertion speeds were also found to decrease the magnitude of the interfacial forces, suggesting that the tissue strain during cortical implantation may be minimized through appropriate selection of the insertion speed.[2014-0320] [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

High performance strain sensors were achieved featuring simple, low-cost construction involving the screen printing of combinations of multi-walled carbon nanotube and graphene nano-platelet nanocomposites on biocompatible and flexible polymer substrates. Conductivity and thermal coefficients of resistance of different conductive nanocomposite sensor materials were measured. The zero current resistance and gauge factor of printed sensors was characterized. The combination of high strain operation (up to 40%), high gauge factor (GF > 100), and biocompatible construction pave the way for applications such as minimally invasive in vivo strain measurements. [ABSTRACT FROM AUTHOR]

This paper presents an embedded chip integration technology that incorporates silicon housings and flexible Parylene-based microelectromechanical systems (MEMS) devices. Accelerated-lifetime soak testing is performed in saline at elevated temperatures to study the packaging performance of Parylene C thin films. Experimental results show that the silicon chip under test is well protected by Parylene, and the lifetime of Parylene-coated metal at body temperature (37 °C) is more than 60 years, indicating that Parylene C is an excellent structural and packaging material for biomedical applications. To demonstrate the proposed packaging technology, a flexible MEMS radio-frequency (RF) coil has been integrated with an RF identification (RFID) circuit die. The coil has an inductance of 16 µH with two layers of metal completely encapsulated in Parylene C, which is microfabricated using a Parylene-metal-Parylene thin-film technology. The chip is a commercially available read-only RFID chip with a typical operating frequency of 125 kHz. The functionality of the embedded chip has been tested using an RFID reader module in both air and saline, demonstrating successful power and data transmission through the MEMS coil. [ABSTRACT FROM AUTHOR]

This paper presents the world's first surface-micro-machined parylene dual-valved microfluidic system for on-chip unpowered microflow regulation. Incorporating a normally closed and a normally open passive check valve in a back-to-back configuration inside a microchannel, the dual-valved system has successfully regulated the pressure/flow rate of air and liquid without power consumption or electronic/magnetic/thermal transduction. By exclusively using parylene C (poly-paraxylylene C) as the structural material, the fabricated valves have higher flexibility to shunt flows in comparison to other conventional thin-film valves. A state-of-the-art multilayer polymer surface-micromachining technology is applied here to fabricate parylene microvalves of various designs. The parylene-based devices are completely biocompatible/implantable and provide an economical paradigm for fluidic control in integrated lab-on-a-chip systems. Design, fabrication, and characterization of the parylene dual valves are discussed in this paper. Testing results have successfully demonstrated that the microflow regulation of the on-chip dual-valved system can achieve a bandpass profile in which the pressure control range is 0-50 mmHg with corresponding flow rates up to 2 mL/min for air flow and 1 µL/min flow rate for water flow. This regulation range is suitable for controlling biological conditions in human health care, with potential applications including drug delivery and regulation of elevated intraocular pressure (lOP) in glaucoma patients. [ABSTRACT FROM AUTHOR]

We present for the first time the design, fabrication, and preliminary bench-top characterization of a high-density, polymer-based penetrating microelectrode array, developed for chronic, large-scale recording in the cortices and hippocampi of behaving rats. We present two architectures for these targeted brain regions, both featuring 512 Pt recording electrodes patterned front-and-back on micromachined eight-shank arrays of thin-film Parylene C. These devices represent an order of magnitude improvement in both number and density of recording electrodes compared with prior work on polymer-based microelectrode arrays. We present enabling advances in polymer micro-machining related to lithographic resolution and a new method for back-side patterning of electrodes. In vitro electrochemical data verifies suitable electrode function and surface properties. Finally, we describe next steps toward the implementation of these arrays in chronic, large-scale recording studies in free-moving animal models. [2020-0109] [ABSTRACT FROM AUTHOR]

A Parylene C polymer neural probe array with 64 electrodes purposefully positioned across 8 individual shanks to anatomically match specific regions of the hippocampus was designed, fabricated, characterized, and implemented in vivo for enabling recording in deep brain regions in freely moving rats. Thin film polymer arrays were fabricated using surface micromachining techniques and mechanically braced to prevent buckling during surgical implantation. Importantly, the mechanical bracing technique developed in this work involves a novel biodegradable polymer brace that temporarily reduces shank length and consequently, increases its stiffness during implantation, therefore enabling access to deeper brain regions while preserving a low original cross-sectional area of the shanks. The resulting mechanical properties of braced shanks were evaluated at the benchtop. Arrays were then implemented in vivo in freely moving rats, achieving both acute and chronic recordings from the pyramidal cells in the cornu ammonis (CA) 1 and CA3 regions of the hippocampus which are responsible for memory encoding. This work demonstrated the potential for minimally invasive polymer-based neural probe arrays for multi-region recording in deep brain structures. [2020-0018] [ABSTRACT FROM AUTHOR]

A novel temperature transduction method using the high-frequency electrochemical impedance between a pair of microelectrodes exposed to aqueous solution is reported. The solution resistance of an aqueous ionic solution is highly temperature dependent, and the electrochemical impedance between two microelectrodes is dominated by solution resistance when measured at the appropriate frequency. Therefore, precise measurements of electrochemical impedance at the proper frequency in a two-electrode system can be used to transduce solution temperature. To demonstrate this method, a temperature sensor composed of two thin-film platinum electrodes on a freestanding Parylene C substrate was designed and fabricated. A platinum resistance temperature detector was co-fabricated to provide a simple means of benchmarking against an existing standard. Transduction via electrochemical impedance was achieved by measuring the real part of impedance at the frequency where phase was minimized. Fluid temperature was transduced between 15°C and 50°C with high sensitivity (−1.21%/°C) and resolution (0.02°C). A $4\times $ improvement in sensitivity and resolution over the conventional platinum resistance temperature detector was achieved. The sensor design described here features flexible construction with inert materials which facilitates future use in biomedical or microfluidic applications. [2019-0190] [ABSTRACT FROM AUTHOR]

A novel Parylene C-based peripheral nerve interface that combines both electrodes and microfluidic channels in an adjustable cuff was designed, fabricated, and characterized. This minimally invasive interface incorporates a drug delivery system for targeted delivery of lysing agents and neurotrophic factors to the nerve surface to locally disrupt the epineurium and allow fascicular selectivity. Multiple platinum (Pt) electrodes were embedded in the microfluidic channels for neural stimulation and recording. The lyse-and-attract cuff electrode (LACE) uses a simple locking mechanism that is adjustable for close contact with nerves of varying diameters. Devices were fabricated using standard Parylene microfabrication techniques resulting in low variability and high device yield. A procedure for the implantation of the LACE was developed and successfully demonstrated in vivo around rat sciatic nerves. The adjustable locking mechanism demonstrated adequate holding strength and fit around the nerves. Benchtop electrochemical characterization of the thin-film Pt electrodes showed that the electrodes possessed high charge storage capacity (>1 mC/cm2) and low impedances ($< 2~\text{k}\Omega $ at 1 kHz) suitable for neural stimulation and recording. As expected, embedded electrodes demonstrated higher impedance values. Acute neural recording from the rat sciatic nerve verified the capability of the LACE to record evoked neural activity (compound action potentials). Controlled and localized microfluidic infusions were achieved at low flow rates ($< 1~\mu \text{L}$ /min). Finally, infusion experiments in vivo demonstrated targeted drug delivery to the sciatic nerve fascicles. This multifunctional peripheral nerve interface has the potential to enhance implant-tissue integration in vivo and provide reliable chronic performance not available in the existing extraneural or intraneural interfaces. [2018-0192] [ABSTRACT FROM AUTHOR]

Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 μM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 μg/day), daily bolus IVT topotecan injections with a similar daily dose (6 μg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 μg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here. [ABSTRACT FROM AUTHOR]

We present an implantable micropump with a miniature form factor and completely wireless operation that enables chronic drug administration intended for evaluation and development of cancer therapies in freely moving small research animals such as rodents. The low power electrolysis actuator avoids the need for heavy implantable batteries. The infusion system features a class E inductive powering system that provides on-demand activation of the pump as well as remote adjustment of the delivery regimen without animal handling. Micropump performance was demonstrated using a model anti-cancer application in which daily doses of 30 μL were supplied for several weeks with less than 6% variation in flow rate within a single pump and less than 8% variation across different pumps. Pumping under different back pressure, viscosity, and temperature conditions were investigated; parameters were chosen so as to mimic in vivo conditions. In benchtop tests under simulated in vivo conditions, micropumps provided consistent and reliable performance over a period of 30 days with less than 4% flow rate variation. The demonstrated prototype has potential to provide a practical solution for remote chronic administration of drugs to ambulatory small animals for research as well as drug discovery and development applications. [ABSTRACT FROM AUTHOR]

The electrochemical (EC) properties of microelectrodes on flexible polymer substrates can vary as a result of microfabrication and postfabrication processes. These in turn may impact the chronic recording performance of such electrodes. In this paper, electrochemical techniques were utilized for the preparation and nonbiological evaluation of microfabricated flexible neural probes consisting of platinum electrode recording sites supported and insulated by Parylene C. The polymer substrate mitigates the mechanical mismatch between neural tissue and the probe. In addition, the thermoplastic nature of the polymer enables the probe to be shaped postfabrication using a thermoforming technique to impart a unique 3-D structure that further promotes tissue integration and supports the use of bioactive coatings. The EC techniques provided a simple means to clean electrode surfaces (80.2% decrease in 1-kHz impedance), identify functional devices, and evaluate their EC properties prior to implant. Both electrochemical impedance spectroscopy and cyclic voltammetry measurements were performed on electrode sites following fabrication, cleaning, mechanical manipulation for assembly, thermoforming, and sterilization. The results reveal in some cases changes in EC properties. Although changes following thermoforming did not impact the ability to acquire electrophysiological recordings, further investigation with additional tools is required to elucidate the exact nature of the structural and EC changes resulting in the observed increase in impedance and reduction in electrode surface area following thermoforming. [2014-0378] [ABSTRACT FROM PUBLISHER]

A correction to the article "High strain biocompatible polydimethylsiloxane-based conductive graphene and multiwalled carbon nanotube nanocomposite strain sensors" that was published in the 2013 issue is presented.

Abstract: This paper presents the design, fabrication, and functional testing of a fully implantable, flexible, Parylene-enable neurostimulator that features single-channel wireless stimulation capability . This system comprises a fold-and-bond microelectromechanical systems (MEMS) coil for wireless power and data transmission, a BION 1-3 CMOS stimulator chip, discrete capacitors, as well as a carrier substrate with two platinum stimulating electrodes and interconnections for system assembly. The physical geometries of the devices are designed for use in retinal implantation with the specifications determined from the implantation results in canine eyes. The coil and carrier substrate are separately fabricated using a Parylene–metal skin technology. The unique properties of Parylene C allow these MEMS devices to be flexible and biocompatible, facilitating surgical procedure. The system assembly is achieved by interconnecting individual components together on the carrier substrate with a biocompatible silver epoxy. A 10μm layer of Parylene C is selectively deposited on the integrated system to protect it from corrosive eye environment. The system functionality is verified using a telemetry link setup, and single-phase pulses with amplitudes ranging from 7 to 8.5V are detected. [Copyright &y& Elsevier]

Abstract: A microfluidic platform for precise biochemical control of the extracellular microenvironment was developed. A chemical interface was established with cells or tissues through the precise and focal delivery of soluble chemical agents through a pore addressed by a polymer microchannel. Thermal flow sensors were integrated along the length of the microchannel and monitored internal flow rate. Sensor performance was characterized in anticipation of future studies with real-time feedback control of focal delivery. The microfluidic system was characterized by determining the fluid delivery rates through the pores and concentration profiles of agents delivered. Finally, focal delivery to rat retinal tissue was demonstrated. [Copyright &y& Elsevier]

Purpose: To evaluate the feasibility of developing a novel mini drug pump for ophthalmic use. Methods: Using principles of microelectromechanical systems engineering, a mini drug pump was fabricated. The pumping mechanism is based on electrolysis and the pump includes a drug refill port as well as a check valve to control drug delivery. Drug pumps were tested first on the bench-top and then after implantation in rabbits. For the latter, we implanted 4 elliptical (9.9 × 7.7 × 1.8 mm) non-electrically active pumps into 4 rabbits. The procedure is similar to implantation of a glaucoma aqueous drainage device. To determine the ability to refill and also the patency of the cannula, at intervals of 4–6 weeks after implantation, we accessed the drug reservoir with a transconjunctival needle and delivered approximately as low as 1 µL of trypan blue solution (0.06%) into the anterior chamber. Animals were followed by slit lamp examination, photography, and fluorescein angiography. Results: Bench-top testing showed 2.0 µL/min delivery when using 0.4 mW of power for electrolysis. One-way valves showed reliable opening pressures of 470 mmHg. All implanted devices refilled at 4–6 weeks intervals for 4–6 months. No infection was seen. No devices extruded. No filtering bleb formed over the implant. Conclusions: A prototype ocular mini drug pump was built, implanted, and refilled. Such a platform needs more testing to determine the long term biocompatibility of an electrically-controlled implanted pump. Testing with various pharmacological agents is needed to determine its ultimate potential for ophthalmic use. [ABSTRACT FROM AUTHOR]

We present the first electrochemical actuator with Parylene bellows for large-deflection operation. The bellows diaphragm was fabricated using a polyethylene-glycol-based sacrificial molding technique followed by coating in Parylene C. Bellows were mechanically characterized and integrated with a pair of interdigitated electrodes to form an electrochemical actuator that is suitable for low-power pumping of fluids. Pump performance (gas generation rate and pump efficiency) was optimized through a careful examination of geometrical factors. Overall, a maximum pump efficiency of 90% was achieved in the case of electroplated electrodes, and a deflection of over 1.5 mm was demonstrated. Real-time wireless operation was achieved. The complete fabrication process and the materials used in this actuator are bio-compatible, which makes it suitable for biological and medical applications. [ABSTRACT FROM AUTHOR]

We present a low power, on demand Parylene MEMS electrothermal valve. A novel Ω-shaped thermal resistive element requires low power (∼mW) and enables rapid valve opening (∼ms). Using both finite element analysis and valve opening experiments, a robust resistive element design for improved valve opening performance in water was obtained. In addition, a thermistor, as an inrush current limiter, was added into the valve circuit to provide variable current ramping. Wireless activation of the valve using RF inductive power transfer was demonstrated. [ABSTRACT FROM AUTHOR]

The first microelectromechanical-system normally closed electrothermal valve constructed using Parylene C is described, which enables both low power (in milliwatts) and rapid operation (in milliseconds). This low-power valve is well suited for applications in wirelessly controlled implantable drug-delivery systems. The simple design was analyzed using both theory and modeling and then characterized in benchtop experiments. Operation in air (constant current) and water (current ramping) was demonstrated. Valve-opening powers of 22 mW in air and 33 mW in water were obtained. Following integration of the valve with catheters, our valve was applied in a wirelessly operated microbolus infusion pump, and the in vivo functionality for the appropriateness of use of this pump for future brain mapping applications in small animals was demonstrated [ABSTRACT FROM AUTHOR]

Abstract: Novel flexible parylene-based high-density electrode arrays have been developed for functional electrical stimulation in retinal and spinal cord prosthetics. These arrays are microfabricated according to a single-metal-layer process and a revolutionary dual-metal-layer process that promises to meet the needs of extremely high-density stimulation applications. While in many cases thin-film platinum electrodes in parylene C would be sufficient, high surface-area platinum electroplating has been shown to extend the lifetime of stimulated electrodes to more than 430 million pulses without failing. Iridium electrode arrays with higher charge delivery capacity have also been fabricated using a new high-temperature stabilized parylene variant, parylene HT. In addition, a new heat molding process has been implemented to conform electrode arrays to approximate the curvature of canine retinas, and a chronic implantation study of the mechanical effects of parylene-based electrode arrays on the retina over a 6-month follow-up period has provided excellent results. Retinal stimulation from these parylene-based electrode arrays in an isolated tiger salamander preparation was shown to be comparable to light stimulation in terms of generation of action potentials in the inner retina. Finally, electrode arrays have also been implanted and tested on the spinal cords of murine models, with the ultimate goal of facilitation of locomotion after spinal cord injury; these arrays provide a higher density and better spatial control of stimulation and recording than is typically possible using traditional fine-wire electrodes. Spinal cord stimulation typically elicited three muscle responses, an early (direct), a middle (monosynaptic), and a late (polysynaptic) response, classified based on latency after stimulation. Stimulation at different rostrocaudal levels of the cord yielded markedly different muscle responses, highlighting the need for such high-density arrays. [Copyright &y& Elsevier]

Abstract: A microelectromechanical systems (MEMS) drug delivery device is investigated for the treatment of incurable ocular diseases. Unlike conventional ocular drug delivery devices, this MEMS device is capable of being refilled, features electronic control of the drug regimen, and enables targeted intraocular drug delivery. The refillable design permits long-term drug therapy and avoids repetitive surgeries. Electronic control of dosing is achieved by using electrolysis-actuated pumping to deliver pharmaceuticals directly to the intraocular space. A flexible Parylene transscleral cannula allows targeted delivery to tissues in both the anterior and posterior segments of the eye. This electrochemically driven drug delivery device was demonstrated to provide flow rates suitable for ocular drug therapy (pL/min to μL/min). Both continuous and bolus drug delivery modes were performed to achieve accurate delivery of a target volume of 250nL. An encapsulation packaging technique was developed for acute surgical studies and preliminary ex vivo drug delivery experiments in porcine eyes were performed. [Copyright &y& Elsevier]

• Design, fabrication and characterization of a polymer-based cuff electrode with microfluidic channels was demonstrated. • Implantation protocol and systematic characterization of the device in vivo were performed. • Stimulation and recordings of neural response from the rat sciatic nerve were performed, which validated the capability of the design. • Drug delivery through microfluidic channels to focally lyse away the epineurium layer was demonstrated. • Correlated results from histology and 2P imaging techniques were obtained illustrating focal lysing of the epineurium at the interface. Extraneural cuffs are among the least invasive peripheral nerve interfaces as they remain outside the nerve. However, compared with more invasive interfaces, these electrodes may suffer from lower selectivity and sensitivity since the targeted nerve fibers are more distanced from the electrodes. A lyse-and-attract cuff electrode (LACE) was enabled by microfabrication and developed to improve selectivity and sensitivity while maintaining a cuff format. Its engineering design was described in previous work. LACE is a hybrid cuff that integrates both microelectrodes and microfluidic channels. The ultimate goal is to increase fascicular selectivity and sensitivity by focal delivery via the microchannels of (1) lysing agent to remove connective tissue separating electrodes from nerve fibers, and (2) neurotrophic factors to promote axonal sprouting of the exposed nerve fibers into microfluidic channels where electrodes are embedded. Here, we focus on demonstrating in vivo function of microfluidics and microelectrodes in an acute preparation in which we evaluate the ability to focally remove connective tissue and record and stimulate with microchannel-embedded microelectrodes neural activity in rat sciatic nerves. While extraneural interfaces prioritize nerve health and intraneural interfaces prioritize functionality, LACE represents a new extraneural approach which could potentially excel at both aims. Surgical implantation demonstrate preservation of LACE function following careful and minimal handling. In vivo electrical evaluation demonstrates the ability of microelectrodes placed within microfluidic channels to successfully stimulate and record compound action potentials from rat sciatic nerve. Furthermore, collagen-rich epineurium was focally removed following infusion of collagenase via microchannels and confirmed via microscopy. The feasibility of using a cuff having integrated microelectrodes and microfluidics to stimulate, record, and deliver drug to focally lyse away the epineurium layer was demonstrated in acute experiments on rat sciatic nerve. [ABSTRACT FROM AUTHOR]