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Acquisition of high-resolution images from within internal organs using endoscopic optical imaging has numerous clinical applications. However, difficulties associated with optical aberrations and the trade-off between transverse resolution and depth of focus significantly limit the scope of applications. Here, we integrate a metalens, with the ability to modify the phase of incident light at subwavelength level, into the design of an endoscopic optical coherence tomography catheter (termed nano-optic endoscope) to achieve near diffraction-limited imaging through negating non-chromatic aberrations. Remarkably, the tailored chromatic dispersion of the metalens in the context of spectral interferometry is utilized to maintain high-resolution imaging beyond the input field Rayleigh range, easing the trade-off between transverse resolution and depth of focus. We demonstrate endoscopic imaging in resected human lung specimens and in sheep airways in vivo. The combination of the superior resolution and higher imaging depth of focus of the nano-optic endoscope is likely to increase the clinical utility of endoscopic optical imaging.

Label-free optical imaging employs natural and non-destructive approaches to visualize biomedical samples for both biological assays and clinical diagnosis. At present, this field revolves around multiple technology-oriented communities, each with a specific focus on a particular modality, despite the existence of shared challenges and applications. As a result, biologists or clinical researchers who require label-free imaging are often not aware of the most appropriate modality to use. This Review presents a comprehensive overview of, and comparison among, different label-free imaging modalities and discusses common challenges and applications. We expect this Review to facilitate collaborative interactions between imaging communities, push the field forwards and foster technological advancements and biophysical discoveries, as well as facilitate new avenues in clinical detection, diagnosis and monitoring of diseases.This Review covers a comparison between various label-free biomedical imaging techniques, their advantages over label-based methods and relevant applications.

Optical imaging is crucial to study biological or pathological processes and diagnose diseases. However, poor tissue penetration typically limits conventional optical imaging. Here we report an imaging technique that uses ultrasound to activate luminescent molecules or nanoparticles through two-step intraparticle energy conversion. Ultrasonic activation can convert mechanical fluctuations into chemical energy via the piezoelectric effect and then induce luminescence via the chemiluminescent effect. We demonstrate two modalities for ultrasound-induced luminescence imaging: one achieves delayed imaging after cessation of the ultrasonic excitation, and the other enables real-time imaging during the ultrasonic excitation. Our imaging modality offers an improvement in luminescence intensity of up to 2,000-fold compared with sonoluminescence of H 2 O, a 10-fold improved of signal-to-noise ratio compared with fluorescence imaging, a spatial resolution of 1.46 mm and tissue penetration of up to 2.2 cm. We demonstrate its applicability for imaging subcutaneous and orthotopic tumours, mapping lymph nodes and screening peritoneal metastatic tumours. Furthermore, we design analyte-activatable luminescence probes based on resonance energy transfer, which can assess drug-induced hepatotoxicity and distinguish the responsivity of tumours after drug treatment. We expect that our technique will enable further preclinical and clinical applications, such as the study of histopathological lesions in living animals, the early detection of tumours, the profiling of biological molecules and the monitoring of cancer treatment or prognosis, among others. Ultrasound-induced luminescence enables in vivo molecular imaging of tumours and lymph nodes with spatial resolution of 1.46 mm.

The role and importance of mechanical properties of cells and tissues in cellular function, development and disease has widely been acknowledged, however standard techniques currently used to assess them exhibit intrinsic limitations. Recently, Brillouin microscopy, a type of optical elastography, has emerged as a non-destructive, label- and contact-free method that can probe the viscoelastic properties of biological samples with diffraction-limited resolution in 3D. This led to increased attention amongst the biological and medical research communities, but it also sparked debates about the interpretation and relevance of the measured physical quantities. Here, we review this emerging technology by describing the underlying biophysical principles and discussing the interpretation of Brillouin spectra arising from heterogeneous biological matter. We further elaborate on the technique’s limitations, as well as its potential for gaining insights in biology, in order to guide interested researchers from various fields.

All molecules consist of chemical bonds, and much can be learned from mapping the spatiotemporal dynamics of these bonds. Since its invention a decade ago, stimulated Raman scattering (SRS) microscopy has become a powerful modality for imaging chemical bonds with high sensitivity, resolution, speed and specificity. We introduce the fundamentals of SRS microscopy and review innovations in SRS microscopes and imaging probes. We highlight examples of exciting biological applications, and share our vision for potential future breakthroughs for this technology.

Photoacoustic imaging (PAI) can bridge the gap between high resolution optical imaging and deep tissue imaging applications. This Review introduces PAI as well as various implementations for a range of biological applications. The life sciences can benefit greatly from imaging technologies that connect microscopic discoveries with macroscopic observations. One technology uniquely positioned to provide such benefits is photoacoustic tomography (PAT), a sensitive modality for imaging optical absorption contrast over a range of spatial scales at high speed. In PAT, endogenous contrast reveals a tissue's anatomical, functional, metabolic, and histologic properties, and exogenous contrast provides molecular and cellular specificity. The spatial scale of PAT covers organelles, cells, tissues, organs, and small animals. Consequently, PAT is complementary to other imaging modalities in contrast mechanism, penetration, spatial resolution, and temporal resolution. We review the fundamentals of PAT and provide practical guidelines for matching PAT systems with research needs. We also summarize the most promising biomedical applications of PAT, discuss related challenges, and envision PAT's potential to lead to further breakthroughs.

Optical imaging is commonly performed with either a camera and wide-field illumination or with a single detector and a scanning collimated beam; unfortunately, these options do not exist at all wavelengths. Single-pixel imaging offers an alternative that can be performed with a single detector and wide-field illumination, potentially enabling imaging applications in which the detection and illumination technologies are immature. However, single-pixel imaging currently suffers from low imaging rates owing to its reliance on configurable spatial light modulators, generally limited to 22 kHz rates. We develop an approach for rapid single-pixel imaging which relies on cyclic patterns coded onto a spinning mask and demonstrate it for in vivo imaging of C. elegans worms. Spatial modulation rates of up to 2.4 MHz, imaging rates of up to 72 fps, and image-reconstruction times of down to 1.5 ms are reported, enabling real-time visualization of dynamic objects. Imaging rates in single-pixel imaging has been limited by the dependence on configurable spatial light modulators. Here, the authors use cyclic Hadamard patterns coded onto a spinning mask to demonstrate dynamic imaging with rates up to 72 frames per second and real time reconstruction capabilities.

Increased glycolysis is considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during therapeutic resistance development is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we find that cisplatin-resistant cells exhibit increased fatty acids (FA) uptake, accompanied by decreased glucose uptake and lipogenesis, indicating reprogramming from glucose to FA dependent anabolic and energy metabolism. A metabolic index incorporating glucose derived anabolism and FA uptake correlates linearly to the level of cisplatin resistance in ovarian cancer (OC) cell lines and primary cells. The increased FA uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing beta-oxidation. Consequently, blocking beta-oxidation by a small molecule inhibitor combined with cisplatin or carboplatin synergistically suppresses OC proliferation in vitro and growth of patient-derived xenografts in vivo. Collectively, these findings support a rapid detection method of cisplatin-resistance at single cell level and a strategy for treating cisplatin-resistant tumors. Metabolic reprogramming is associated with cancer initiation, progression and resistance to therapy. Here, the authors show that metabolic reprogramming from glycolysis to fatty acid uptake and beta-oxidation is associated with cancer-cell platinum-based chemotherapy resistance.

The majority of the brain’s vasculature is composed of intricate capillary networks lined by capillary pericytes. However, it remains unclear whether capillary pericytes influence blood flow. Using two-photon microscopy to observe and manipulate brain capillary pericytes in vivo, we find that their optogenetic stimulation decreases lumen diameter and blood flow, but with slower kinetics than similar stimulation of mural cells on upstream pial and precapillary arterioles. This slow vasoconstriction was inhibited by the clinically used vasodilator fasudil, a Rho-kinase inhibitor that blocks contractile machinery. Capillary pericytes were also slower to constrict back to baseline following hypercapnia-induced dilation, and slower to dilate towards baseline following optogenetically induced vasoconstriction. Optical ablation of single capillary pericytes led to sustained local dilation and a doubling of blood cell flux selectively in capillaries lacking pericyte contact. These data indicate that capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain. Vast networks of capillaries feed the brain. Hartmann et al. show that pericyte contractility is critical for maintenance of enduring capillary tone, which sets an optimized rate and distribution of blood flow through brain capillary networks.