ABSTRACTActive implantable microscale reservoir-based drug delivery systems enabled novel and effective drug delivery concepts for both systemic and localized drug delivery applications. These systems typically consist of a drug reservoir and an active pumping mechanism for precise delivery of drugs. Here we present a stand-alone, refillable, scalable, and fully implantable microreservoir platform to be integrated with micropumps as a storing component of active implantable drug delivery microsystems. The microreservoir was fabricated with 3D-printing technology, enabling miniature, scalable, and planar structure, optimized for subcutaneous implantation especially in small animals (e.g., mouse), while being readily scalable for larger animals and human translation. Three different capacities of the microreservoir (1 μL, 10 μL, and 100 μL) were fabricated and characterized all with 3 mm thickness. The microreservoir consists of two main parts: a cavity for long-term drug storage with an outlet microtubing (250 μm OD, 125 μm ID), and a refill port for transcutaneous refills through a septum. The cavity membrane is fabricated with thin Parylene-C layers using a polyethylene glycol sacrificial layer, minimizing restoring force and hence backflow, as fluid is discharged. This feature enables integration to normally-open mechanisms and improves pumping efficiency when integrated to normally-closed pumps. The results of in vitro optimization and characterization of the cavity membrane show 95% extraction percentage of the cavity with insignificant (2%) backflow due to restoring force of the membrane. The refill port septum thickness is minimized down to 1 mm by a novel pre-compression concept, while capable of ~65000 injections with 30 Ga non-coring needles without leakage under 100 kPa (4× greater than physiological backpressure). To demonstrate integrability of the microreservoir to an active micropump, the 10 μL microreservoir was integrated to a micropump recently developed in our laboratory, making an implantable drug delivery microsystem. Two different microsystems were subcutaneously implanted in two mice, and the outlet microtubing was implanted into the round window membrane niche for infusion of a known ototoxic compound (sodium salicylate) at 50 nL/min for 20 min. Real-time shifts in distortion product otoacoustic emission thresholds and amplitudes were measured during the infusion. The in vivo results show a mean shift of 22.1 dB after 20 min for the most basal region, matching with syringe pump results. A biocompatibility experiment was performed on the microsystem for six months to assess design and fabrication suitability for chronic subcutaneous implantation and clinical translational development. The results demonstrate very favorable signs of biocompatibility for long-term implantation. Although tested here on mice for a specific inner ear application, this low-cost design and fabrication methodology is scalable for use in larger animals and human for different applications/delivery sites.
Permeability of round window membrane and its role for drug delivery: our own findings and literature review
