Development of an implantable closed-loop system for delivery of naloxone for the prevention of opioid-related overdose deaths

Aim1, Miniaturized implantable systems for use in rats: We propose to develop a fully implantable, wireless pharmacological therapeutic system that combines miniaturized optoelectronic sensors, electrolytic pumps, structures for fluid storage and delivery, and a central control unit. The results will provide capabilities for highly sensitive, localized measurements of rStO2 and drug delivery at sites of interest for use in rat models. More specifically, to achieve the desired closed-loop pharmacological intervention, the entire integrated platform will include five interconnected sub-systems: (1) optoelectronic components (microscale inorganic light-emitting diodes (μ-ILEDs) and a microscale inorganic photodetector (μ-ILEDs)) on the tip of thin flexible probe for measuring rStO2 at a site of interest, (2) a collection of drug reservoirs, microfluidic channels and independently addressable pumping microsystems (total thickness ~4 mm) for fast, triggered deliver of pharmacological agents through a soft probe; (3) a thin, soft base station for bidirectional Bluetooth communication, with capabilities for data extraction and user control to facilitate development; (4) a wireless power harvesting unit and collection of supercapacitors to allow uninterrupted operation, without time limit, for freely moving and behaving rats in standard cage enclosures, and (5) a smartphone or tablet computer with customized graphical user interface software for real-time visualization of rStO2 data, and an automated and/or manual control interface to operate closed-loop and/or open-loop interventions (Figure AA). The miniaturized form factors and biocompatible encapsulation approaches associated with each of the implanted sub-systems will permit stable, chronic operation in direct measurements of rStO2 and delivery of drugs into adjacent tissues, in a manner that minimizes mechanically induced irritation and immune responses. As outlined in the Background section, our recent work separately demonstrates feasibility in wireless, implantable wireless oximeters [1], microfluidic delivery systems [2], and closed-loop control hardware [3]. These technologies will serve as the foundations for the proposed platforms, illustrated in Fig. AA, for use with naloxone delivery in rat models. Additional details appear in the following. Optical Sensing and Pharmacological Delivery: Both optical sensing and pharmacological delivery modules (sub-system 1 and 2) electrically connect to the wireless control and power module (WCP, sub-system 3 and 4). The filament probe in the sensing module exploits optoelectronic designs typical of reflectance-mode, rStO2, oximeters that we published recently[1]. Here, a pair of µ-ILEDs (with dimensions of 270 µm × 220 µm × 50 µm and 240 µm × 240 µm × 100 µm) and one µ-IPD (with dimensions of 100 µm × 100 µm × 5 µm) allow measurement of oxygenated hemoglobin and deoxygenated hemoglobin (Figure BB.A), with quantitative accuracy that compares favorably to gold standards. The interconnection and substrate will exploit ultrathin, photolithographically defined traces of gold/copper (thickness of 700 nm) and a flexible polyimide substrate. The measured rStO2 from such system will serve as a metric of health status, for triggering the release of naloxone during critical events. Specifically, as outlined subsequently, algorithms that identify levels below a threshold value for a prescribed time period will be used to wirelessly trigger the fast delivery of naloxone contained in microreservoirs via activation of an electrochemical micropump (