BME PhD Dissertation Defense: Hao Zang

Title: "Development of Hollow Microneedles and Enzymatic Biosensors for Real-Time Interstitial Fluid Biomarker Monitoring"

Advisory Committee: James Galagan, PhD – BU BME (Research Advisor) Mark Grinstaff, PhD – BU BME (Chair) Catherine Klapperich, PhD – BU BME Karen Allen, PhD – BU Chemistry Douglas Densmore, PhD – BU ECE

Abstract: Wearable biochemical sensing remains challenging due to the lack of minimally invasive biofluid sampling methods and sufficiently sensitive biosensors for continuous, real-time monitoring. Interstitial fluid (ISF) is an attractive target for wearable sensing because it contains clinically relevant biomarkers and can be accessed through the skin using microneedles. In particular, steroid hormones such as cortisol, testosterone, and progesterone are important biomarkers for stress, endocrine disorders, fatigue, and reproductive health, yet current analytical methods remain unsuitable for continuous monitoring. Here we present the development of a wearable biochemical sensing platform through the integration of hollow microneedle (HMN)-based ISF extraction, enzymatic electrochemical biosensors, and electrochemical signal amplification technologies. A scalable fabrication strategy for beveled silicon HMNs was developed to enable reliable dermal penetration, robust mechanical stability, and sustained vacuum-assisted ISF extraction directly from human skin. Ultra-sensitive platinum interdigitated electrodes (IDEs) were engineered to improve electrochemical sensing performance and support low-concentration analyte detection. Building on this platform, ketosteroid dehydrogenase (KSDH)-based biosensors were developed for sensing cortisol, testosterone, and progesterone. A second-generation mediator-assisted sensing strategy using phenazine methosulfate (PMS) significantly improved electron-transfer efficiency and sensor sensitivity, while multiple immobilization strategies were explored for wearable sensing applications. Finally, PEDOT:PSS-based organic electrochemical transistors (OECTs) were developed as an additional signal amplification platform to further enhance biosensor signals. Collectively, this work establishes a pathway toward minimally invasive, real-time biochemical monitoring for applications in stress monitoring, endocrine disease management, and personalized healthcare.