A Wireless Implantable Closed-Loop Electrochemical Drug Delivery System

Wireless implantable drug delivery systems (DDSs) enable targeted, on-demand drug release to maximize therapeutic efficacy. Ultrasound has been proposed to wirelessly power and control millimeter-sized deeply implantable DDSs, but initial demonstrations encountered challenges in power transfer and release control reliability in dynamic in vivo environments. In this work, we present a closed-loop implantable DDS using ultrasound wireless power and communication in conjunction with an electrochemical drug release mechanism. The system consists of piezoelectric transducers for wireless power and data transmission, a drug delivery module containing drug-loaded electroresponsive nanoparticles, and a custom CMOS integrated circuit for closed-loop drug release using a programmable potentiostat capable of providing potentials up to $\boldsymbol{\pm}$1.5 V and sensing current up to $\boldsymbol{\pm}$100 $\boldsymbol{\mu}$A. The chip also improves power transfer robustness by enabling ultrasound power combining and rectifier voltage feedback which can be used to adapt the power transmitter and minimize misalignment. Closed-loop release control is tested in vitro using the wirelessly powered DDS at 8 cm depth by adjusting the potentiostat stimulus voltage based on feedback of redox current into fluorescein-loaded nanoparticles, resulting in consistent 2 $\boldsymbol{\mu}$g release across different fluorescein loading concentrations and a 39$\%$ reduction in release amount variation. These results demonstrate the effectiveness of closed-loop release control in enabling precise and reliable drug delivery.