Carbon Nanomaterials for Biological Imaging and Nanomedicinal Therapy

Optical imaging in vivo with molecular specificity is important in biomedicine because of its high spatial resolution and sensitivity compared with magnetic resonance imaging. Stimulated Raman scattering (SRS) microscopy allows highly sensitive optical imaging based on vibrational spectroscopy without adding toxic or perturbative labels. However, SRS imaging in living animals and humans has not been feasible because light cannot be collected through thick tissues, and motion-blur arises from slow imaging based on backscattered light. In this work, we enable in vivo SRS imaging by substantially enhancing the collection of the backscattered signal and increasing the imaging speed by three orders of magnitude to video rate. This approach allows label-free in vivo imaging of water, lipid, and protein in skin and mapping of penetration pathways of topically applied drugs in mice and humans.

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Video-Rate Molecular Imaging in Vivo with Stimulated Raman Scattering

The quest for ultrahigh detection sensitivity with spectroscopic contrasts other than fluorescence has led to various novel approaches to optical microscopy of biological systems. Coherent nonlinear optical imaging, especially the recently developed nonlinear dissipation microscopy (including stimulated Raman scattering and two-photon absorption) and pump-probe microscopy (including excited-state absorption, stimulated emission, and ground-state depletion), provides new image contrasts for nonfluorescent species. Thanks to the high-frequency modulation transfer scheme, these imaging techniques exhibit superb detection sensitivity. By directly interrogating vibrational and/or electronic energy levels of molecules, they offer high molecular specificity. Here we review the underlying principles and excitation and detection schemes, as well as exemplary biomedical applications of this emerging class of molecular imaging techniques.

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Coherent Nonlinear Optical Imaging: Beyond Fluorescence Microscopy

The ability to dynamically image features deep within living organisms, permitting real-time analysis of cellular structure and function, is important for biological science. This Review article discusses multiphoton microscopy capable of such analysis, along with technologies that are pushing the limits of phenomena that can be quantitatively imaged.

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Advances in multiphoton microscopy technology

A brain–computer interface (BCI) gives those suffering from neuromuscular impairments a means to interact and communicate with their surrounding environment. A BCI translates physiological signals, typically electrical, detected from the brain to control an output device. A significant problem with current BCIs is the lengthy training periods involved for proficient usage, which can often lead to frustration and anxiety on the part of the user. Ultimately this can lead to abandonment of the device. The primary reason for this is that relatively indirect measures of cognitive function, as can be gleaned from the electroencephalogram (EEG), are harnessed. A more suitable and usable interface would need to measure cognitive function more directly. In order to do this, new measurement modalities, signal acquisition and processing, and translation algorithms need to be addressed. In this paper, we propose a novel approach, using non-invasive near-infrared imaging technology to develop a user-friendly optical BCI. As an alternative to the traditional EEGbased devices, we have used practical non-invasive optical techniques to detect characteristic haemodynamic responses due to motor imagery and consequently created an accessible BCI that is simple to attach and requires little user training.

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On the suitability of near-infrared (NIR) systems for next-generation brain?computer interfaces

We develop a new approach in imaging nonfluorescent species with two-color two-photon and excited state absorption mi- croscopy. If one of two synchronized mode-locked pulse trains at different colors is intensity modulated, the modulation transfers to the other pulse train when nonlinear absorption takes places in the me- dium. We can easily measure 10 6 absorption changes caused by either two-photon absorption or excited-state absorption with a RF lock-in amplifier. Sepia melanin is studied in detail as a model system. Spectroscopy studies on the instantaneous two-photon absorption TPA and the relatively long-lived excited-state absorption ESA of melanin are carried out in solution, and imaging capability is demon- strated in B16 cells. It is found that sepia melanin exhibits two distinct excited states with different lifetimes one at 3p s, one lasting hun- dreds of nanoseconds when pumped at 775 nm. Its characteristic TPA/ESA enables us to image its distribution in cell samples with high resolution comparable to two-photon fluorescence microscopy TPFM. This new technique could potentially provide valuable infor- mation in diagnosing melanoma. © 2007 Society of Photo-Optical Instrumentation

https://www.spiedigitallibrary.org/journals/Journal-of-Biomedical-Optics/volume-12/issue-05/054004/Two-color-two-photon-and-excited-state-absorption-microscopy/10.1117/1.2780173.pdf

Two-color, two-photon, and excited-state absorption microscopy.

Optical coherence tomography (OCT) is a noninvasive, three-dimensional imaging modality with several medical and industrial applications. Integrated photonics has the potential to enable mass production of OCT devices to significantly reduce size and cost, which can increase its use in established fields as well as enable new applications. Using silicon nitride (Si3N4) and silicon dioxide (SiO2) waveguides, we fabricated an integrated interferometer for spectrometer-based OCT. The integrated photonic circuit consists of four splitters and a 190 mm long reference arm with a foot-print of only 10 × 33 mm2. It is used as the core of a spectral domain OCT system consisting of a superluminescent diode centered at 1320 nm with 100 nm bandwidth, a spectrometer with 1024 channels, and an x-y scanner. The sensitivity of the system was measured at 0.25 mm depth to be 65 dB with 0.1 mW on the sample. Using the system, we imaged human skin in vivo. With further optimization in design and fabrication technology, Si3N4/SiO2 waveguides have a potential to serve as a platform for passive photonic integrated circuits for OCT.

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Photonic integrated Mach-Zehnder interferometer with an on-chip reference arm for optical coherence tomography

We demonstrate an ultra-compact silicon integrated photonic interferometer for swept-source optical coherence tomography (SS-OCT). The footprint of the integrated interferometer is only 0.75×5??mm2. The design consists of three 2×2 splitters, a 13 cm physical length (50.4 cm optical length) reference arm, and grating couplers. The photonic integrated circuit was used as the interferometer of an SS-OCT system. The sensitivity of the system was measured to be ?62??dB with 115 ?W power delivered to the sample. Using the system, we demonstrate cross-sectional OCT imaging of a layered tissue phantom. We also discuss potential improvements in passive silicon photonic integrated circuit design and integration with active components.

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Ultra-compact silicon photonic integrated interferometer for swept-source optical coherence tomography

Optical coherence tomography (OCT) is a medical imaging technology capable of producing high-resolution, crosssectional
images through inhomogeneous samples, such as biological tissue. It has been widely adopted in clinical
ophthalmology and a number of other clinical applications are in active research. Other applications of OCT include
material characterization and non-destructive testing. In addition to current uses, OCT has a potential for a much wider
range of applications and further commercialization. One of the reasons for slow penetration of OCT in clinical and
industrial use is probably the cost and the size of the current systems. Current commercial and research OCT systems
are fiber/free space optics based. Although fiber and micro-optical components have made these systems portable,
further significant miniaturization and cost reduction could be achieved through the use of integrated photonic
components. We demonstrate a Michelson interferometer using integrated photonic waveguides on nanophotonic silicon
on insulator platform. The size of the interferometer is 1500 μm x 50 μm. The structure has been tested using a mirror as
a reflector. We can achieve 40 μm axial resolution and 25 dB sensitivity which can be substantially improved.

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Integrated photonic circuit in silicon on insulator for Fourier domain optical coherence tomography

We show that phase-sensitive detection of spectral hole refilling can yield information about self-phase modulation and two-photon absorption coefficients. We expect that, when applied to tissue microscopy, this technique will allow the study of endogenous molecular markers beneath the surface, even if those markers are nonfluorescent.

Gunay Yurtsever

Papers

Two-color, two-photon, and excited-state absorption microscopy.

Photonic integrated Mach-Zehnder interferometer with an on-chip reference arm for optical coherence tomography

Ultra-compact silicon photonic integrated interferometer for swept-source optical coherence tomography

Integrated photonic circuit in silicon on insulator for Fourier domain optical coherence tomography

Two-photon absorption and self-phase modulation measurements with shaped femtosecond laser pulses.