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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]

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]

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]

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 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]

• 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]