1. Molecular-targeted OCT and OCM for cancer detection
OCT is a powerful tool for assessing tissue architectural morphology. It enables 3D imaging with resolutions approaching standard histopathology (a few microns), and it can be performed in vivo and in real-time without the need to remove and process specimens. OCM combines coherence-gated detection with confocal microscopy in order to achieve high transverse resolutions, thus enabling 3D visualization of cellular features. However, current OCT and OCM imaging technologies have not been able to leverage the recent advances in molecular-targeted contrast agents that are revolutionizing biomedicine. In this project, we will develop and validate techniques that enable molecular contrast for 3D-OCT and OCM. The successful completion of this project will allow both the structure and pathological states of tissue to be imaged in 3D, in vivo, and in real time with micron-level spatial resolutions at multiple scales. This work will lay the foundation for a wide range of fundamental research, small animal imaging, and future clinical applications in humans. This work will also serve as a starting point for the OCT and OCM studies of other pathologies associated with abnormal protein expression levels, such as neurodegenerative and cardiovascular diseases. This work is supported by NIH/NIBIB through the Pathway to Independence Award (K99/R00).
Molecular-targeted OCT and OCM allow both the structure and pathological states of tissue to be imaged in 3D, in vivo, and in real time with micron-level spatial resolutions at multiple scales. Photothermal OCT imaging was demonstrated in highly scattering human breast tissues ex vivo. (A) No photothermal signal is observed from control images in saline-injected specimen. Phase modulation signal (B) and SNR (C) images obtained from the nanoshell (50 ul, 5 ×10^9 / ml) injected specimen at various photothermal modulation frequencies (no modulation, 5 kHz, 10 kHz, and 20 kHz modulation) demonstrate localized photothermal signal. (D and E) Phase modulation time curves and frequency spectra corresponding to pixels marked in (C). Ref: Zhou et al, Opt. Lett., 35(5):700-702, 2010.
2. OCT and OCM Imaging in Developmental Biology and Tissue Engineering
OCT and OCM have several features that make them attractive for applications in the fields of developmental biology and tissue engineering. OCT and OCM provide the spatial and temporal resolutions needed for imaging developing embryos and engineered tissues. The imaging is non-invasive and does not perturb the natural development and growth of the samples. This allows in vivo imaging of the same sample at various developmental stages. OCT and OCM can also provide real-time 3D structural and functional information about the samples, enabling imaging applications of various dynamic processes.
Representative M-mode OCT imaging of cardiac function in 30-day old adult Drosophila. A: Control showed normal HR (250 BPM) and rhythm; B. Overexpression of dPsn led to increased HR (296 BPM) and irregular heartbeats; C: Silencing of dPsn caused reduced HR (167 BPM), small heart chamber and irregular heartbeat. Ref: Li, Zhou et al, Curr. Alzheimer Res., 8(3):313-322, 2011.
3. 3D OCT imaging of Brain Functions
Normal brain function depends on delivery of oxygen and glucose, and on clearance of the byproducts of metabolism. Thus, an understanding of the normal and pathological conditions of oxygen supply and consumption, and measurement of blood flow is important for basic neuroscience and clinical applications. To this end, a variety of tools have been developed to image cerebral hemodynamics. For example, transcranial Doppler is a common clinical tool but is limited to measurement of blood flow within large vessels. Functional (blood oxygen level dependent - BOLD, or arterial spin labeled - ASL) MRI provides 3D tomography of the brain with moderate spatial resolution (a few millimeters). PET measures cerebral blood flow and oxygen metabolism with a decreased spatial resolution compared to MRI. Currently, the laboratory use of MRI and PET based techniques are limited due to high cost, low spatial and temporal resolution, and low mobility. Optical imaging techniques, such as optical intrinsic imaging and LSI, can be used to extract cerebral blood oxygenation and blood flow information at high spatial and temporal resolutions. However, optical intrinsic imaging and LSI are limited to the mapping of brain functions only in 2D.
We will develop novel OCT imaging techniques to image 3D brain functions in animal models. Not only can OCT provide structural information of the animal cortex at micron-scale resolution, but can also be used to extract 3D cerebral hemodynamic information by using Doppler (for blood flow) and spectroscopic (for blood oxygenation) OCT techniques. The 1-2 mm penetration depth of OCT allows imaging through thinned skull rather than opened skull, which makes longitudinal studies possible. The combination of 3D mapping of blood flow and oxygenation will enable for the first time imaging of cerebral oxygen metabolism in 3D at micron-scale resolution. The successful completion of the development of this technique will enable us to investigate 3D brain functions in physiological (e.g. during forepaw, hind paw and whisker stimulations), and pathophysiological (eg. cortical spreading depression, ischemic and traumatic brain injuries) conditions in animal models.