Mansik Jeon

Non-invasive multimodal functional imaging of the intestine with frozen micellar naphthalocyanines

Overview There is a need for safer and improved methods for non-invasive imaging of the gastrointestinal tract. Modalities based on X-ray radiation, magnetic resonance and ultrasound suffer from limitations with respect to safety, accessibility or lack of adequate contrast. Functional intestinal imaging of dynamic gut processes has not been practical using existing approaches. Here, we report the development of a family of nanoparticles that can withstand the harsh conditions of the stomach and intestine, avoid systemic absorption, and give rise to good optical contrast for photoacoustic imaging. The hydrophobicity of naphthalocyanine dyes was exploited to generate purified ~20 nm frozen micelles, which we call nanonaps, with tunable and large near-infrared absorption values (>1000). Unlike conventional chromophores, nanonaps exhibited non-shifting spectra at ultrahigh optical densities and, following oral administration in mice, passed safely through the gastrointestinal tract. Non-invasive, non-ionizing photoacoustic techniques were used to visualize nanonap intestinal distribution with low background and remarkable resolution with 0.5 cm depth, and enabled real-time intestinal functional imaging with ultrasound co-registration. Positron emission tomography following seamless nanonap radiolabelling allowed complementary whole body imaging.

Au-Cu2- xSe heterodimer nanoparticles with broad localized surface plasmon resonance as contrast agents for deep tissue imaging

We report a new type of heterogeneous nanoparticles (NPs) composed of a heavily doped semiconductor domain (Cu2-xSe) and a metal domain (Au), which exhibit a broad localized surface plasmon resonance (LSPR) across visible and near-infrared (NIR) wavelengths, arising from interactions between the two nanocrystal domains. We demonstrate both in vivo photoacoustic imaging and in vitro dark field imaging, using the broad LSPR in Cu2-xSe-Au hybrid NPs to achieve contrast at different wavelengths. The high photoacoustic imaging depth achieved, up to 17 mm, shows that these novel contrast agents could be clinically relevant. More broadly, this work demonstrates a new strategy for tuning LSPR absorbance by engineering the density of free charge carriers in two interacting domains.

Handheld Optical Coherence Tomography Scanner for Primary Care Diagnostics

The goal of this study is to develop an advanced point-of-care diagnostic instrument for use in a primary care office using handheld optical coherence tomography (OCT). This system has the potential to enable earlier detection of diseases and accurate image-based diagnostics. Our system was designed to be compact, portable, user-friendly, and fast, making it well suited for the primary care office setting. The unique feature of our system is a versatile handheld OCT imaging scanner which consists of a pair of computer-controlled galvanometer-mounted mirrors, interchangeable lens mounts, and miniaturized video camera. This handheld scanner has the capability to guide the physician in real time for finding suspicious regions to be imaged by OCT. In order to evaluate the performance and use of the handheld OCT scanner, the anterior chamber of a rat eye and in vivo human retina, cornea, skin, and tympanic membrane were imaged. Based on this feasibility study, we believe that this new type of handheld OCT device and system has the potential to be an efficient point-of-care imaging tool in primary care medicine.

Cu2–xSe Nanocrystals with Localized Surface Plasmon Resonance as Sensitive Contrast Agents for In Vivo Photoacoustic Imaging: Demonstration of Sentinel Lymph Node Mapping

Abstract The promise of a new nanomaterial, Cu(2-x) Se nanocrystals, as a contrast agent for photoacoustic imaging is demonstrated. The Cu(2-x) Se nanocrystals exhibit strong optical absorption at near infrared wavelengths that can efficiently penetrate tissue. In vivo photoacoustic tomography using this nanomaterial as the contrast agent provides clear three-dimensional resolution of a sentinel lymph node in a rat model.

Methylene blue microbubbles as a model dual-modality contrast agent for ultrasound and activatable photoacoustic imaging

Abstract. Ultrasound and photoacoustic imaging are highly complementary modalities since both use ultrasonic detection for operation. Increasingly, photoacoustic and ultrasound have been integrated in terms of hardware instrumentation. To generate a broadly accessible dual-modality contrast agent, we generated microbubbles (a standard ultrasound contrast agent) in a solution of methylene blue (a standard photoacoustic dye). This MB2 solution was formed effectively and was optimized as a dual-modality contrast solution. As microbubble concentration increased (with methylene blue concentration constant), photoacoustic signal was attenuated in the MB2 solution. When methylene blue concentration increased (with microbubble concentration held constant), no ultrasonic interference was observed. Using an MB2 solution that strongly attenuated all photoacoustic signal, high powered ultrasound could be used to burst the microbubbles and dramatically enhance photoacoustic contrast (>800-fold increase), providing a new method for spatiotemporal control of photoacoustic signal generation.

Full-range k-domain linearization in spectral-domain optical coherence tomography

A full-bandwidth k-domain linearization method for spectral-domain optical coherence tomography (SD-OCT) is demonstrated. The method uses information of the wavenumber-pixel-position provided by a translating-slit-based wavelength filter. For calibration purposes, the filter is placed either after a broadband source or at the end of the sample path, and the filtered spectrum with a narrowed line width (∼0.5 nm) is incident on a line-scan camera in the detection path. The wavelength-swept spectra are co-registered with the pixel positions according to their central wavelengths, which can be automatically measured with an optical spectrum analyzer. For imaging, the method does not require a filter or a software recalibration algorithm; it simply resamples the OCT signal from the detector array without employing rescaling or interpolation methods. The accuracy of k-linearization is maximized by increasing the k-linearization order, which is known to be a crucial parameter for maintaining a narrow point-spread function (PSF) width at increasing depths. The broadening effect is studied by changing the k-linearization order by undersampling to search for the optimal value. The system provides more position information, surpassing the optimum without compromising the imaging speed. The proposed full-range k-domain linearization method can be applied to SD-OCT systems to simplify their hardware/software, increase their speed, and improve the axial image resolution. The experimentally measured width of PSF in air has an FWHM of 8 μm at the edge of the axial measurement range. At an imaging depth of 2.5 mm, the sensitivity of the full-range calibration case drops less than 10 dB compared with the uncompensated case.

Dual-color photoacoustic lymph node imaging using nanoformulated naphthalocyanines

Demarking lymph node networks is important for cancer staging in clinical practice. Here, we demonstrate in vivo dual-color photoacoustic lymphangiography using all-organic nanoformulated naphthalocyanines (referred to as nanonaps). Nanonap frozen micelles were self-assembled from two different naphthalocyanine dyes with near-infrared absorption at 707 nm or 860 nm. These allowed for noninvasive, nonionizing, high resolution photoacoustic identification of separate lymphatic drainage systems in vivo. With both types of nanonaps, rat lymph nodes buried deeply below an exogenously-placed 10 mm thick layer of chicken breast were clearly visualized in vivo. These results show the potential of multispectral photoacoustic imaging with nanonaps for detailed mapping of lymphatic drainage systems.

Nonionizing photoacoustic cystography in vivo

We demonstrate the feasibility of a novel and nonionizing process for bladder imaging in vivo, called photoacoustic cystography (PAC). Using a photoacoustic imaging system, we have successfully imaged a rat bladder filled with clinically used Methylene Blue (MB) dye. An image contrast of ~8 was achieved. Further, spectroscopic PAC confirmed the accumulation of MB in the bladder. Using a laser pulse energy of less than 1 mJ/cm² (1/20 of the ANSI safety limit), a deeply (1.2 cm) positioned bladder in biological tissues was clearly visible in the PA image. Our results suggest that PAC can potentially provide a nonionizing, relatively cheap, and portable tool for bladder mapping. Among our clinical interests, nonionizing PAC with an injection of MB can potentially monitor vesicoureteral reflux in children.

Multimodal Photoacoustic Tomography

Currently available optical microscopic imaging techniques-confocal microscopy, multi-photon (also referred to as two-photon) microscopy, and optical coherence tomography-have revolutionized biological and medical research, based on strong optical contrast and high spatial resolution. Unfortunately, owing to unavoidable strong light scattering in biological tissues, such methods cannot maintain contrast and spatial resolution beyond one optical transport mean free path ( ~ 1 mm in tissues). Although model-based diffuse optical tomography is able to operate at greater depths, this technique fails to maintain spatial resolution. Photoacoustic tomography overcomes the fundamental penetration depth problem and achieves high-resolution optical imaging in deep tissues by combing light and ultrasound. In this review article, the multimodal imaging capability of photoacoustic tomography, integrated with existing imaging tools, is contemplated and the potential preclinical and clinical impacts of the combined systems are discussed.

Combined photoacoustic and optical coherence tomography using a single near-infrared supercontinuum laser source

We developed an integrated dual-modal photoacoustic and optical coherence tomography (PA-OCT) system using a single near-infrared supercontinuum laser source to simultaneously provide both optical absorption and scattering contrasts. A pulsed broadband supercontinuum source was generated by a pulsed Nd:YAG laser and a photonic-crystal fiber. When we imaged two colored hairs, the black hair was visible in both PA and OCT images, whereas the white hair was only mapped in the OCT image. The single laser source will potentially allow us to implement relatively simple, cheap, and compact dual-modal PA-OCT systems, which are key criteria for fast clinical translation and commercialization.