Background and Objectives: Tissue response to thermal, electrical, or chemical stimuli are important in the health and survival of tissue. We report experimental results to assess tissue response to various stimuli using a low coherence differential phase interferometer. Study Design/Materials and Methods: The optical system utilized to measure tissue response is a novel fiber-based phase sensitive optical low coherence reflectometer (PS-OLCR). Inasmuch as the PS-OLCR works with back-reflected light, noninvasive sensing of tissue response to stimuli is possible. In addition to high lateral (∼10 μm) and longitudinal (∼10 μm) resolution, PS-OLCR can measure sub-wavelength changes in optical path-length (Angstrom/nanometer range) by extracting the phase difference between interference fringes in two channels corresponding to orthogonal polarization modes. Results: When light spatially splits into two polarization states, precise analysis of surface topography or tissue surface response such as swelling or collapse are possible. Time resolved measurements of nanometer/scale path length changes in response to electrical and thermal stimuli are demonstrated using longitudinally delayed polarization channels. Conclusions: Since PS-OLCR is a useful tool to detect ultra-small path length changes, the system has potential to aid scientists in investigating important phenomena in biomaterials and developing useful diagnostic and therapeutic imaging modalities. Applications include tissue surface profilometry, measurement of tissue, and cell response to various stimuli, high-resolution intensity and phase imaging.