Optical coherence tomography (OCT) is a rapidly evolving technology with a broad range of applications, including biomedical imaging and diagnosis. Conventional intensity-based OCT provides depth-resolved imaging with a typical resolution and sensitivity to structural alterations of about 5–10 microns. It would be desirable for functional biological imaging to detect smaller features in tissues due to the nature of pathological processes. In this article, we perform the analysis of the spatial frequency content of the OCT signal based on scattering theory. We demonstrate that the OCT signal, even at limited spectral bandwidth, contains information about high spatial frequencies present in the object which relates to the small, sub-wavelength size structures. Experimental single frame imaging of phantoms with well-known sub-micron internal structures confirms the theory. Examples of visualization of the nanoscale structural changes within mesenchymal stem cells (MSC), which are invisible using conventional OCT, are also shown. Presented results provide a theoretical and experimental basis for the extraction of high spatial frequency information to substantially improve the sensitivity of OCT to structural alterations at clinically relevant depths.

Although time-domain optical coherence tomography (TD-OCT) systems are straightforward to realize, the imaging speed, sensitivity, and imaging depth limit their range of applications. Multiple reference optical coherence tomography (MR-OCT) based on TD-OCT increases imaging range by about tenfold while providing sensitivity to image highly scattering biological samples. The multiple path-delays and freespace construction make MR-OCT also interesting for hybrid and compact systems, filling the gap between fibre-based and wafer-level integrated optical systems. We describe an optical configuration using a balanced detection scheme and the resulting signal properties due to the required use of polarizing optical components. We numerically simulate the signal properties using Jones calculus and compare the results with measurements. We discuss the origin of signal degradation due to birefringence of the sample in OCT and show that the quarter-wave plate in the sample arm of the Michelson interferometer can be adjusted to optimize the signal returning from a birefringent sample thereby improving the visibility of structures of interest. The theory discussed will be useful to understand and minimize signal degradation due to birefringence in Time-Domain and Fourier-Domain OCT systems.

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We demonstrate the capability of nsOCT technique to discern MSC pellets labelled with different concentrations of nanostars. Useful to track stem cell differentiation and interpret the mechanism by which stem cells deliver their therapeutic effect.