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This paper presents a flexible multi-functional physiological sensing system that provides multiple noise-immune readout architectures and hybrid-sensing capability with an analog pre-processing scheme. The proposed multi-functional system is designed to support five physiological detection methodologies of piezo-resistive, pyro-resistive, electro-metric, opto-metric and their hybrid, utilizing an in-house multi-functional e-skin device, in-house flexible electrodes and a LED-photodiode pair. For their functional verification, eight representative physiological detection capabilities were demonstrated using wearable device prototypes. Especially, the hybrid detection method includes an innovative continuous measurement of blood pressure (BP) while most previous wearable devices are not ready for it. Moreover, for effective implementation in the form of the wearable device, post-processing burden of the hybrid method was much reduced by integrating a proposed analog pre-processing scheme, where only simple counting process and calibration remain to estimate the BP. This multi-functional sensor readout circuits and their hybrid-sensing interface are fully integrated into a single readout integrated circuit (ROIC), which is designed to implement three readout paths: two electrometric readout paths and one impedometric readout path. For noise-immune detection of the e-skin sensor, a pseudo-differential front-end with a ripple reduction loop is proposed in the impedometric readout path, and also state-of-the-art body-oriented noise reduction techniques are adopted for the electrometric readout path. The ROIC is fabricated in a CMOS process and in-house e-skin devices and flexible electrodes are also fabricated.