Chromatin Laser Imaging Reveals Abnormal Nuclear Changes for Early Cancer Detection

We developed and applied rapid scanning laser-emission microscopy to detect abnormal changes in cell nuclei for early diagnosis of cancer and cancer precursors. Regulation of chromatins is essential for genetic development and normal cell functions, while abnormal nuclear changes may lead to many diseases, in particular, cancer. The capability to detect abnormal changes in apparently normal tissues at a stage earlier than tumor development is critical for cancer prevention. Here we report using LEM to analyze colonic tissues from mice at-risk for colon cancer by detecting prepolyp nuclear abnormality. By imaging the lasing emissions from chromatins, we discovered that, despite the absence of observable lesions, polyps, or tumors under stereoscope, high-fat mice exhibited significantly lower lasing thresholds than low-fat mice. The low lasing threshold is, in fact, very similar to that of adenomas and is caused by abnormal cell proliferation and chromatin deregulation that can potentially lead to cancer. Our findings suggest that conventional methods, such as colonoscopy, may be insufficient to reveal hidden or early tumors under development. We envision that this work will provide new insights into LEM for early tumor detection in clinical diagnosis and fundamental biological and biomedical research of chromatin changes at the biomolecular level of cancer development

Monolithic optofluidic ring resonator lasers created by femtosecond laser nanofabrication

We designed, fabricated, and characterized a monolithically integrated optofluidic ring resonator laser that is mechanically, thermally, and chemically robust. The entire device, including the ring resonator channel and sample delivery microfluidics, was created in a block of fused-silica glass using a 3-dimensional femtosecond laser writing process. The gain medium, composed of Rhodamine 6G (R6G) dissolved in quinoline, was flowed through the ring resonator. Lasing was achieved at a pump threshold of approximately 15 μJ/mm2. Detailed analysis shows that the Q-factor of the optofluidic ring resonator is 3.3 × 104, which is limited by both solvent absorption and scattering loss. In particular, a Q-factor resulting from the scattering loss can be as high as 4.2 × 104, suggesting the feasibility of using a femtosecond laser to create high quality optical cavities

On-chip, High-sensitivity Temperature Sensors Based on Dye-doped Solid-state Polymer Microring Lasers

We developed a chip-scale temperature sensor with a high sensitivity of 228.6 pm/°C based on a rhodamine 6G (R6G)-doped SU-8 whispering-gallery mode microring laser. The optical mode was largely distributed in a polymer core layer with a 30 μm height that provided detection sensitivity, and the chemically robust fused-silica microring resonator host platform guaranteed its versatility for investigating different functional polymer materials with different refractive indices. As a proof of concept, a dye-doped hyperbranched polymer (TZ-001) microring laser-based temperature sensor was simultaneously developed on the same host wafer and characterized using a free-space optics measurement setup. Compared to TZ-001, the SU-8 polymer microring laser had a lower lasing threshold and a better photostability. The R6G-doped SU-8 polymer microring laser demonstrated greater adaptability as a high-performance temperature-sensing element. In addition to the sensitivity, the temperature resolutions for the laser-based sensors were also estimated to be 0.13 °C and 0.35 °C, respectively. The rapid and simple implementation of micrometer-sized temperature sensors that operate in the range of 31 – 43 °C enables their potential application in thermometry

Development of Integrative Optofluidic Laser Systems for Biological/Biochemical Applications

The optofluidic laser is an emerging technology that integrates the microcavity, microfluidic channel, and gain medium in liquid. Further integration with biomaterials results in the optofluidic biolaser, which can emit laser light with the modulation from biological/biochemical conditions. Due to the coherent and nonlinear nature of laser emission, optofluidic biolasers are promising in ultra-sensitive biological/biochemical detections. However, the practical significance of biolasers is still under debate and a large gap still exists in the literature in reference to their application in clinical settings. This thesis outlines the development of integrative, optofluidic laser systems that incorporate biological/biochemical materials with different optical microcavity configurations, showing unique laser characteristics and revealing the potential for the use of lasers in practical biological/biochemical analyses. First, optofluidic lasers utilizing Förster resonant energy transfer (FRET) were examined. Optofluidic FRET lasers that incorporated fluorescent proteins, DNA tetrahedra, and polymer-coated aqueous quantum dots in the liquid gain were experimentally demonstrated with capillary-based optofluidic ring resonators. Experiments show that the laser mechanism can provide up to 100-fold enhancement to the FRET signal and that molecular configurations and molecular interactions can significantly tune the laser performance through FRET. Highly sensitive, laser-based detection schemes for molecular interactions and novel bio-controlled lasers are, thus, promising. Second, optofluidic lasers with a single molecular layer of gain were obtained. Through surface functionalization, gain molecules were concentrated at the solid-liquid interface of a ring resonator to form a single molecular layer. A pure laser signal was generated free of fluorescence background. This scheme significantly lowers the analyte concentration required for laser operation and is an analog to surface-based fluorescence detection technologies, pointing to a new direction for laser-based analyses. Finally, integrative optofluidic laser systems that included biological cells as an active component were studied. A FRET laser was investigated with fluorescent protein FRET pairs located inside living cells. For quantitative and statistical cell laser studies, an integrated microwell array platform was developed that features automated and high throughput cell lasing detection, which has been only rarely achieved in any previous cell lasing detection schemes. Using this integrative platform, heterogeneous cell lasing performance was observed among different cell subpopulations within one insect cell line, Sf9, when stained by a DNA-specific dye, SYTO9. This observation suggests the potential of using lasing performance to detect cellular conditions such as nucleus status.PHDBiomedical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/140876/1/qschen_1.pd

Optofluidic Lasers with Aqueous Quantum Dots

We achieved two types of laser emissions from aqueous quantum dots (QDs) using the same high-Q-factor optofluidic ring resonator (OFRR) platform. In the first type, 2 μM QDs were in bulk buffer solution that filled the entire OFRR cavity volume. The lasing threshold was 0.1 μJ/mm², over 3 orders of magnitude lower than the state-of-the-art. In the second type of laser, the QDs were immobilized as a single layer on the interface between the OFRR inner wall and buffer solution with a surface density as low as 3 × 10⁹–10¹⁰ cm^–2. The lasing threshold of 60 μJ/mm² was achieved. In both bulk solution and single-layer lasing cases, the laser emission persisted even under 5–10 min of uninterrupted pulsed optical excitation that was well above the corresponding lasing threshold, indicative of high photostability of the QD laser. This was in sharp contrast to organic-dye-based lasers, which underwent quick photobleaching during the laser operation under similar pumping conditions. Theoretical analysis is also carried out to elucidate the advantages of QD-based optofluidic lasers over those based on dyes. Our work opens the door to a plethora of applications where optofluidic QD lasers can replace dye-based optofluidic lasers in biosensing and on-chip miniaturized laser development

Supplement 1: Lasing in blood

Supplementary material Originally published in Optica on 20 August 2016 (optica-3-8-809

Optofluidic ring cavity lasers fabricated by 3-D femtosecond laser writing technology

We fabricated a 3-D monolithically integrated optofluidic laser in a fused-silica chip using femtosecond laser pulses. Rhodamine 6G dissolved in quinoline was used as the gain medium and lasing was achieved at a pump threshold of 15 µJ/mm2

Ultrasound modulated droplet lasers

We demonstrated the ultrasound modulated droplet lasers, in which the laser intensity from whispering gallery mode (WGM) of oil droplets can be reversibly enhanced up to 20-fold when the ultrasound pressure is beyond a certain threshold. The lasing enhancement was investigated with various ultrasound frequencies and pressures. Furthermore, the ultrasound modulation of the laser output was achieved by controlling the ultrasound pressure, the duty cycle, and the frequency of ultrasound bursts. Its potential application was explored via the study on a human whole blood vessel phantom. A theoretical analysis was also conducted, showing that the laser emission enhancement results from the directional emission from a deformed cavity under ultrasound pressure. Our studies reveal the unique capabilities of ultrasound modulated droplet lasers, which could lead to the development of laser emission-based microscopy for deep tissue imaging with high spatial resolution and detection sensitivity that may overcome the long-standing drawback of traditional fluorescence imaging.Published versio