Amy L. Oldenburg

Optical coherence tomography: a review of clinical development from bench to bedside

Since its introduction, optical coherence tomography (OCT) technology has advanced from the laboratory bench to the clinic and back again. Arising from the fields of low coherence interferometry and optical time- and frequency-domain reflectometry, OCT was initially demonstrated for retinal imaging and followed a unique path to commercialization for clinical use. Concurrently, significant technological advances were brought about from within the research community, including improved laser sources, beam delivery instruments, and detection schemes. While many of these technologies improved retinal imaging, they also allowed for the application of OCT to many new clinical areas. As a result, OCT has been clinically demonstrated in a diverse set of medical and surgical specialties, including gastroenterology, dermatology, cardiology, and oncology, among others. The lessons learned in the clinic are currently spurring a new set of advances in the laboratory that will again expand the clinical use of OCT by adding molecular sensitivity, improving image quality, and increasing acquisition speeds. This continuous cycle of laboratory development and clinical application has allowed the OCT technology to grow at a rapid rate and represents a unique model for the translation of biomedical optics to the patient bedside. This work presents a brief history of OCT development, reviews current clinical applications, discusses some clinical translation challenges, and reviews laboratory developments poised for future clinical application.

Engineered microsphere contrast agents for optical coherence tomography.

Contrast agents are utilized in virtually every imaging modality to enhance diagnostic capabilities. We introduce a novel class of optical contrast agent, namely, encapsulating microspheres, that are based not on fluorescence but on scattering nanoparticles within the shell or core. The agents are suitable for reflection- or scattering-based techniques such as optical coherence tomography, light microscopy, and reflectance confocal microscopy. We characterize the optical properties of gold-, melanin-, and carbon-shelled contrast agents and demonstrate enhancement of optical coherence tomography imaging after intravenous injection of such an agent into a mouse.

Optical probes and techniques for molecular contrast enhancement in coherence imaging.

Optics has played a key role in the rapidly developing field of molecular imaging. The spectroscopic nature and high-resolution imaging capabilities of light provide a means for probing biological morphology and function at the cellular and molecular levels. While the use of bioluminescent and fluorescent probes has become a mainstay in optical molecular imaging, a large number of other optical imaging modalities exist that can be included in this emerging field. In vivo imaging technologies such as optical coherence tomography and reflectance confocal microscopy have had limited use of molecular probes. In the last few years, novel nonfluorescent and nonbioluminescent molecular imaging probes have been developed that will initiate new directions in coherent optical molecular imaging. Classes of probes reviewed in this work include those that alter the local optical scattering or absorption properties of the tissue, those that modulate these local optical properties in a predictable manner, and those that are detected utilizing spectroscopic optical coherence tomography (OCT) principles. In addition to spectroscopic OCT, novel nonlinear interferometric imaging techniques have recently been developed to detect endogenous molecules. Probes and techniques designed for coherent molecular imaging are likely to improve the detection and diagnostic capabilities of OCT.

Magnetomotive contrast for in vivo optical coherence tomography

Molecularly-specific contrast can greatly enhance the biomedical utility of optical coherence tomography (OCT). We describe a contrast mechanism, magnetomotive OCT (MMOCT), where a modulated magnetic field induces motion of magnetic nanoparticles. The motion of the nanoparticles modifies the amplitude of the OCT interferogram. High specificity is achieved by subtracting the background fluctuations of the specimen, and sensitivity to 220 microg/g magnetite nanoparticles is demonstrated. Optically and mechanically correct tissue phantoms elucidate the relationships between imaging contrast and nanoparticle concentration, imaging depth, tissue optical scattering, and magnetic field strength. MMOCT is demonstrated in a living Xenopus laevis tadpole where the results were consistent with corresponding histology.

Optical micro-scale mapping of dynamic biomechanical tissue properties

Mechanical forces such as adhesion, shear stress and compression play crucial roles in tissue growth, patterning and development. To understand the role of these mechanical stimuli, it is of great importance to measure biomechanical properties of developing, engineered, and natural tissues. To enable these measurements on the micro-scale, a novel, dynamic, non-invasive, high-speed optical coherence elastography (OCE) system has been developed utilizing spectral-domain optical coherence tomography (OCT) and a mechanical wave driver. Experimental results of OCE on silicone phantoms are in good agreement with those obtained from a standardized indentation method. Using phase-resolved imaging, we demonstrate OCE can map dynamic elastic moduli of normal and neoplastic ex vivo human breast tissue with a sensitivity of 0.08%. Spatial micro-scale mapping of elastic moduli of tissue offers the potential for basic science and clinical investigations into the role biomechanics play in health and disease.

Imaging magnetically labeled cells with magnetomotive optical coherence tomography

We introduce a novel contrast mechanism for optical coherence tomography (OCT) whereby the optical scattering of magnetically labeled cells is modified by means of an externally applied magnetic field. This modification is made through the addition of a small electromagnet to the imaging arm of a conventional OCT interferometer. We measure the magnetomotive OCT signal by differencing pairs of axial scans (A-scans) acquired with the magnetic field on and off. Magnetomotive contrast is demonstrated in bulk three-dimensional cell scaffolds containing macrophages labeled with microparticles of iron oxide, demonstrating magnetic-specific contrast over a dynamic range of 30 dB.

Study of an ultrahigh-numerical-aperture fiber continuum generation source for optical coherence tomography

The axial resolution of optical coherence tomography images is primarily dependent on the bandwidth of the illumination source. Continuum generation is one way to generate the single-mode, high-bandwidth light needed for point illumination. We present an inexpensive and easy-to-implement augmentation to a Ti:sapphire laser that widens the bandwidth from 20 to over 200 nm with commerically available ultrahigh-numerical-aperture fiber. This technique can provide a readily available broad-bandwidth source for researchers and a practical enhancement to a fiber-optic optical coherence tomography system.

Synthesis of Au(Core)/Ag(Shell) Nanoparticles and their Conversion to AuAg Alloy Nanoparticles

Metal nanoparticles (NPs) are of great interest due to their special optical, [ 1–3 ] electronic, [ 4–8 ] and catalytic [ 9,10 ] properties. [ 11 ] Among metal NPs, Au NPs have been investigated most extensively because of their facile preparation, resistance to oxidation, and surface plasmon resonance (SPR) band that can absorb and scatter visible light. [ 3 ] Core/ shell and alloy bimetallic NPs are especially interesting because they provide opportunities to tune the NPs’ optical and catalytic properties [ 12–15 ] and are potentially useful as taggants for security applications. [ 2 ] The AuAg system is of particular interest because the SPR band is tunable between ∼ 520 nm for Au [ 11 ] and ∼ 410 nm for Ag. [ 16 ] Several syntheses for AuAg alloy, [ 15 , 17–37 ] Au(core)/Ag(shell), [ 22 , 25 , 31 , 33 , 35–45 ] and Ag(core)/Au(shell) NPs [ 28 , 31 , 33–35 , 42 , 46–48 ] have already been reported. Here, we report a facile, stoichiometrically controlled synthesis of Au(core)/Ag(shell) and AuAg alloy NPs through digestive ripening, [ 49–51 ] which is a potentially general method for synthesizing alloy NPs. [ 37 , 52,53 ] Au(core)/Ag(shell) NPs were synthesized and annealed to form AuAg alloy NPs, followed by elemental analysis and structural and optical characterization. Methods utilizing Au rather than Ag NPs as the seed particles are advantageous: obtaining monodisperse Ag NPs is signifi cantly more challenging [ 16 ] because it is harder to control the nucleation of Ag NPs and to avoid oxidation. Huang and co-workers recently demonstrated the conversion of Au(core)/Ag(shell) to AuAg alloy NPs as a part of a larger study showing the generality of digestive ripening for synthesizing alloy NPs, but very limited data without quantitative elemental analysis or optical characterization of the AuAg alloy NPs was provided. [ 37 ] In this study, we compare a twostep synthesis of Au(core)/Ag(shell) NPs and their conversion to AuAg alloy NPs through annealing with a one-step, direct conversion of Au NPs to AuAg alloy NPs. The products of

In vivo magnetomotive optical molecular imaging using targeted magnetic nanoprobes

Dynamic magnetomotion of magnetic nanoparticles (MNPs) detected with magnetomotive optical coherence tomography (MM-OCT) represents a new methodology for contrast enhancement and therapeutic interventions in molecular imaging. In this study, we demonstrate in vivo imaging of dynamic functionalized iron oxide MNPs using MM-OCT in a preclinical mammary tumor model. Using targeted MNPs, in vivo MM-OCT images exhibit strong magnetomotive signals in mammary tumor, and no significant signals were measured from tumors of rats injected with nontargeted MNPs or saline. The results of in vivo MM-OCT are validated by MRI, ex vivo MM-OCT, Prussian blue staining of histological sections, and immunohistochemical analysis of excised tumors and internal organs. The MNPs are antibody functionalized to target the human epidermal growth factor receptor 2 (HER2 neu) protein. Fc-directed conjugation of the antibody to the MNPs aids in reducing uptake by macrophages in the reticulo-endothelial system, thereby increasing the circulation time in the blood. These engineered magnetic nanoprobes have multifunctional capabilities enabling them to be used as dynamic contrast agents in MM-OCT and MRI.

Phase-resolved magnetomotive OCT for imaging nanomolar concentrations of magnetic nanoparticles in tissues

Magnetic nanoparticles (MNPs) are increasingly important in magnetic resonance and biomedical optical imaging. We describe a method for imaging MNPs by detecting nanoscale displacements using a phase-resolved spectral-domain optical coherence tomography (OCT) system. Biological tissues and phantoms are exposed to approximately 800 G magnetic fields modulated at 56 and 100 Hz to mechanically actuate embedded iron oxide MNPs (approximately 20 nm diameter). Sensitivity to 27 microg/g (approximately 2 nM) MNPs within tissue phantoms is achieved by filtering paramagnetic from diamagnetic vibrations. We demonstrate biological feasibility by imaging topically applied MNPs during their diffusion into an excised rat tumor over a 2 hour time period.