Acute in vivo testing of a polymer cuff electrode with integrated microfluidic channels for stimulation, recording, and drug delivery on rat sciatic nerve.

BACKGROUND: 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. NEW METHOD: 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. COMPARISON WITH EXISTING METHODS: While extraneural interfaces prioritize nerve health and intraneural interfaces prioritize functionality, LACE represents a new extraneural approach which could potentially excel at both aims. RESULTS: 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. CONCLUSION: 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.

Techniques and Considerations in the Microfabrication of Parylene C Microelectromechanical Systems.

Parylene C is a promising material for constructing flexible, biocompatible and corrosion-resistant microelectromechanical systems (MEMS) devices. Historically, Parylene C has been employed as an encapsulation material for medical implants, such as stents and pacemakers, due to its strong barrier properties and biocompatibility. In the past few decades, the adaptation of planar microfabrication processes to thin film Parylene C has encouraged its use as an insulator, structural and substrate material for MEMS and other microelectronic devices. However, Parylene C presents unique challenges during microfabrication and during use with liquids, especially for flexible, thin film electronic devices. In particular, the flexibility and low thermal budget of Parylene C require modification of the fabrication techniques inherited from silicon MEMS, and poor adhesion at Parylene-Parylene and Parylene-metal interfaces causes device failure under prolonged use in wet environments. Here, we discuss in detail the promises and challenges inherent to Parylene C and present our experience in developing thin-film Parylene MEMS devices.

A Wireless Implantable Micropump for Chronic Drug Infusion Against Cancer.

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.

Wireless programmable electrochemical drug delivery micropump with fully integrated electrochemical dosing sensors.

We present a fully integrated implantable electrolysis-based micropump with incorporated EI dosing sensors. Wireless powering and data telemetry (through amplitude and frequency modulation) were utilized to achieve variable flow control and a bi-directional data link with the sensors. Wireless infusion rate control (0.14-1.04 µL/min) and dose sensing (bolus resolution of 0.55-2 µL) were each calibrated separately with the final circuit architecture and then simultaneous wireless flow control and dose sensing were demonstrated. Recombination detection using the dosing system, as well as, effects of coil separation distance and misalignment in wireless power and data transfer were studied. A custom-made normally closed spring-loaded ball check valve was designed and incorporated at the reservoir outlet to prevent backflow of fluids as a result of the reverse pressure gradient caused by recombination of electrolysis gases. Successful delivery, infusion rate control, and dose sensing were achieved in simulated brain tissue.

MEMS: Enabled Drug Delivery Systems.

Drug delivery systems play a crucial role in the treatment and management of medical conditions. Microelectromechanical systems (MEMS) technologies have allowed the development of advanced miniaturized devices for medical and biological applications. This Review presents the use of MEMS technologies to produce drug delivery devices detailing the delivery mechanisms, device formats employed, and various biomedical applications. The integration of dosing control systems, examples of commercially available microtechnology-enabled drug delivery devices, remaining challenges, and future outlook are also discussed.