Quantitative phase imaging, i.e., measuring the map of pathlength shifts due to the specimen of interest, has been developing rapidly over the past decade. The main methods and exciting applications to biomedicine will be reviewed.

Quantitative phase imaging in biomedicine

Metasurface is a recently developed nanophotonics concept to manipulate the properties of light by replacing conventional bulky optical components with ultrathin (more than 10 4 times thinner) flat optical components. Since the first demonstration of metasurfaces in 2011, they have attracted tremendous interest in the consumer optics and electronics industries. Recently, metasurface-empowered novel bioimaging and biosensing tools have emerged and been reported. Given the recent advances in metasurfaces in biomedical engineering, this review article covers the state of the art for this technology and provides a comprehensive interdisciplinary perspective on this field. The topics that we have covered include metasurfaces for chiral imaging, endoscopic optical coherence tomography, fluorescent imaging, superresolution imaging, magnetic resonance imaging, quantitative phase imaging, sensing of antibodies, proteins, DNAs, cells, and cancer biomarkers. Future directions are discussed in twofold: application-specific biomedical metasurfaces and bioinspired metasurface devices. Perspectives on challenges and opportunities of metasurfaces, biophotonics, and translational biomedical devices are also provided. The objective of this review article is to inform and stimulate interdisciplinary research: firstly, by introducing the metasurface concept to the biomedical community; and secondly by assisting the metasurface community to understand the needs and realize the opportunities in the medical fields. In addition, this article provides two knowledge boxes describing the design process of a metasurface lens and the performance matrix of a biosensor, which serve as a "crash-course" introduction to those new to both fields.

Metasurfaces for biomedical applications: imaging and sensing from a nanophotonics perspective

A THz graphene metasurface for polarization selective virus sensing.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/adpr.202000205

Tunable Metasurfaces: The Path to Fully Active Nanophotonics

Fluorescence microscopy with optical sectioning capabilities is extensively utilized in biological research to obtain three-dimensional structural images of volumetric samples. Tunable lenses have been applied in microscopy for axial scanning to acquire multiplane images. However, images acquired by conventional tunable lenses suffer from spherical aberration and distortions. Here, we design, fabricate, and implement a dielectric Moire metalens for fluorescence imaging. The Moire metalens consists of two complementary phase metasurfaces, with variable focal length, ranging from ∼10 to ∼125 mm at 532 nm by tuning mutual angles. In addition, a telecentric configuration using the Moire metalens is designed for high-contrast multiplane fluorescence imaging. The performance of our system is evaluated by optically sectioned images obtained from HiLo illumination of fluorescently labeled beads, as well as ex vivo mice intestine tissue samples. The compact design of the varifocal metalens may find important applications in fluorescence microscopy and endoscopy for clinical purposes.

Varifocal Metalens for Optical Sectioning Fluorescence Microscopy

Significance: Noninvasive in vivo fast pulsatile blood flow measurement in deep tissue is important because the blood flow waveform is correlated with physiological parameters, such as blood pressure and elasticity of blood vessels. Compromised blood flow may cause diseases, such as stroke, foot ulcer, and myocardial ischemia. There is great clinical demand for a portable and cost-effective device for noninvasive pulsatile blood flow measurement.
Aim: A diffuse-optics-based method, diffuse speckle pulsatile flowmetry (DSPF), was developed for fast measurement (∼300  Hz) of deep tissue blood flow noninvasively. To validate its performance, both a phantom experiment and in vivo demonstration were conducted.
Approach: Over the past two decades, single-mode fibers have been used as detection fibers in most diffuse-optics-based deep tissue blood flow measurement modalities. We used a multimode (MM) detection fiber with a core size of 200  μm for diffused speckle pattern detection. A background intensity correction algorithm was implemented for speckle contrast calculation. The MM detection fiber helped to achieve a level of deep tissue blood flow measurement similar to that of conventional modalities, such as diffuse correlation spectroscopy and diffuse speckle contrast analysis, but it increases the measurement rate of blood flow to 300 Hz.
Results: The design and implementation of the DSPF system were introduced. The theory of the background intensity correction for the diffused speckle pattern detected by the MM fiber was explained. A flow phantom was built for validation of the performance of the DSPF system. An in vivo cuff-induced occlusion experiment was performed to demonstrate the capability of the proposed DSPF system.
Conclusions: An MM detection fiber can help to achieve fast (∼300  Hz) pulsatile blood flow measurement in the proposed DSPF method. The cost-effective device and the fiber-based flexible probe increase the usability of the DSPF system significantly.

https://www.spiedigitallibrary.org/journals/Journal-of-Biomedical-Optics/volume-25/issue-5/055003/Fast-pulsatile-blood-flow-measurement-in-deep-tissue-through-a/10.1117/1.JBO.25.5.055003.pdf

Fast pulsatile blood flow measurement in deep tissue through a multimode detection fiber

The flexibile nature of optical fiber enables it to offer remote-access capabilities, which could be used in many biomedical applications. This review focuses on different micro- and nano-structured fiber probes for applications in biosensing, imaging, and stimulations. The modifications to fiber could extend design freedom from waveguide optimization to functional material integration. Fiber probes with optimized waveguide structures or integrated functional materials could achieve enhanced optical mode interaction with biosamples, and hence obtain ultrasensitive biosensors with a remarkably low limit of detection. Furthermore, bioimaging with a high spatial resolution can be obtained by engineering dispersion and nonlinearity of light propagation in the fiber core or designing a metal-coated tapered fiber tip with a sub-wavelength aperture. Flat metasurfaces can be assembled on a fiber tip to achieve a large depth of focus and remove aberrations. Fiber is also a compact solution to realize the precise delivery of light for in vivo applications, such as deep brain stimulation. The optical beam size, shape, and direction could be steered by the probe parameters. Micro- and nano-technologies integrated with fiber contribute to various approaches to further improve detection limit, sensitivity, optical resolution, imaging depth, and stimulation precision.

/pdf/micro-and-nano-fiber-probes-for-optical-sensing-imaging-and-3p5li3xu4p.pdf

Micro- and nano-fiber probes for optical sensing, imaging, and stimulation in biomedical applications

Conventional color imaging provides information in the red, green, and blue (RGB) channels with limited resolution in the spectral domain. This could lead to poor sensitivity in imaging biological samples. In fluorescence imaging, the use of multiple fluorophores is often necessary to label proteins and DNAs for in vivo experiments. Crosstalk between fluorophores can be troublesome because it is challenging to differentiate each fluorophore when their emission spectra are overlapped. To help address these issues, we developed a dual-modality hyperspectral microscopy system that combines hyperspectral imaging and microscopy imaging to provide spatial and spectral information of the samples. The dual-modality feature allows us to study biological samples and fluorescent samples using the same system. We show that applications of the system enable: the identification of different tissue and cell structures; identification of each quantum dot fluorophore, calculation of their relative proportions at each location, and elucidation of their spatial distributions in a mixture sample containing multiple types of quantum dot fluorophores. The results give a brief showcase of how hyperspectral imaging can be useful for biomedical imaging and fluorescence imaging applications. 

Dual-Modality Hyperspectral Microscopy for Transmission and Fluorescence Imaging

Fluorescence imaging has shown great potential in non-invasive plant monitoring and analysis. However, current systems have several limitations, such as bulky size, high cost, contact measurement, and lack of multifunctionality, which may hinder its applications in a wide range of settings including indoor vertical farming. Herein, we developed a compact handheld fluorescence imager enabling multipurpose plant phenotyping, such as continuous photosynthetic activity monitoring and non-destructive anthocyanin quantification. The compact imager comprises of pulse-amplitude-modulated multi-color light emitting diodes (LEDs), optimized light illumination and collection, dedicated driver circuit board, miniaturized charge-coupled device camera, and associated image analytics. Experiments conducted in drought stressed lettuce proved that the novel imager could quantitatively evaluate the plant stress by the non-invasive measurement of photosynthetic activity efficiency. Moreover, a non-invasive and fast quantification of anthocyanins in green and red Batavia lettuce leaves had excellent correlation (>84%) with conventional destructive biochemical analysis. Preliminary experimental results emphasize the high throughput monitoring capability and multifunctionality of our novel handheld fluorescence imager, indicating its tremendous potential in modern agriculture.

Shuyan Zhang

Papers

Metasurfaces for biomedical applications: imaging and sensing from a nanophotonics perspective

Fast pulsatile blood flow measurement in deep tissue through a multimode detection fiber

Micro- and nano-fiber probes for optical sensing, imaging, and stimulation in biomedical applications

Dual-Modality Hyperspectral Microscopy for Transmission and Fluorescence Imaging

Handheld Multifunctional Fluorescence Imager for Non-invasive Plant Phenotyping