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Observing distant objects with a multimode fibre-based holographic endoscope
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Abstract
Holographic wavefront manipulation enables converting hair-thin multimode optical fibres into minimally invasive lensless imaging instruments conveying much higher information densities than conventional endoscopes. Their most prominent applications focus on accessing delicate environments, including deep brain compartments, and recording micrometre-scale resolution images of structures in close proximity to the distal end of the instrument. Here, we introduce an alternative 'farfield' endoscope, capable of imaging macroscopic objects across a large depth of field. The endoscope shaft with dimensions of 0.20.4 mm consists of two parallel optical fibres, one for illumination and the second for signal collection. The system is optimized for speed, power efficiency and signal quality, taking into account specific features of light transport through step-index multimode fibres. The characteristics of imaging quality are studied at distances between 20 and 400 mm. As a proof-of-concept, we provide imaging inside the cavities of a sweet pepper commonly used as a phantom for biomedically relevant conditions. Further, we test the performance on a functioning mechanical clock, thus verifying its applicability in dynamically changing environments. With performance reaching the standard definition of video endoscopes, this work paves the way towards the exploitation of minimally-invasive holographic micro-endoscopes in clinical and diagnostics applications.
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The measurement of the optical transmission matrix (TM) of an opaque material is an advanced form of space-variant aberration correction. Beyond imaging, TM-based methods are emerging in a range of fields, including optical communications, micro-manipulation, and computing. In many cases, the TM is very sensitive to perturbations in the configuration of the scattering medium it represents. Therefore, applications often require an up-to-the-minute characterisation of the fragile TM, typically entailing hundreds to thousands of probe measurements. Here, we explore how these measurement requirements can be relaxed using the framework of compressive sensing, in which the incorporation of prior information enables accurate estimation from fewer measurements than the dimensionality of the TM we aim to reconstruct. Examples of such priors include knowledge of a memory effect linking the input and output fields, an approximate model of the optical system, or a recent but degraded TM measurement. We demonstrate this concept by reconstructing the full-size TM of a multimode fibre supporting 754 modes at compression ratios down to ∼5% with good fidelity. We show that in this case, imaging is still possible using TMs reconstructed at compression ratios down to ∼1% (eight probe measurements). This compressive TM sampling strategy is quite general and may be applied to a variety of other scattering samples, including diffusers, thin layers of tissue, fibre optics of any refractive profile, and reflections from opaque walls. These approaches offer a route towards the measurement of high-dimensional TMs either quickly or with access to limited numbers of measurements.
Multimode fibres have recently been employed as high-resolution ultra-thin endoscopes, capable of imaging biological structures deep inside tissue in vivo. Here, we extend this technique to label-free non-linear microscopy with chemical contrast using coherent anti-Stokes Raman scattering (CARS) through a multimode fibre endoscope, which opens up new avenues for instant and in-situ diagnosis of potentially malignant tissue. We use a commercial 125 µm diameter, 0.29 NA GRIN fibre, and wavefront shaping on an SLM is used to create foci that are scanned behind the fibre facet across the sample. The chemical selectivity is demonstrated by imaging 2 µm polystyrene and 2.5 µm PMMA beads with per pixel integration time as low as 1 ms for epi-detection.
Monitoring and modulating the diversity of signals used by neurons and glia in a closed-loop fashion is necessary to establish causative links between biochemical processes within the nervous system and observed behaviors. As developments in neural-interface hardware strive to keep pace with rapid progress in genetically encoded and synthetic reporters and modulators of neural activity, the integration of multiple functional features becomes a key requirement and a pressing challenge in the field of neural engineering. Electrical, optical and chemical approaches have been used to manipulate and record neuronal activity in vivo, with a recent focus on technologies that both integrate multiple modes of interaction with neurons into a single device and enable bidirectional communication with neural circuits with enhanced spatiotemporal precision. These technologies not only are facilitating a greater understanding of the brain, spinal cord and peripheral circuits in the context of health and disease, but also are informing the development of future closed-loop therapies for neurological, neuro-immune and neuroendocrine conditions. Anikeeva and colleagues review the state of the art in technologies that enable discoveries of brain function and the development of novel therapeutic approaches.
We report on a sapphire fiber Raman imaging probe’s use for challenging applications where access is severely restricted. Small-dimension Raman probes have been developed previously for various clinical applications because they show great capability for diagnosing disease states in bodily fluids, cells, and tissues. However, applications of these sub-millimeter diameter Raman probes were constrained by two factors: first, it is difficult to incorporate filters and focusing optics at such small scale; second, the weak Raman signal is often obscured by strong background noise from the fiber probe material, especially the most commonly used silica, which has a strong broad background noise in low wavenumbers (<500-1700 cm⁻¹). Here, we demonstrate the thinnest-known imaging Raman probe with a 60 μm diameter Sapphire multimode fiber in which both excitation and signal collection pass through. This probe takes advantage of the low fluorescence and narrow Raman peaks of Sapphire, its inherent high temperature and corrosion resistance, and large numerical aperture (NA). Raman images of Polystyrene beads, carbon nanotubes, and CaSO4 agglomerations are obtained with a spatial resolution of 1 μm and a field of view of 30 μm. Our imaging results show that single polystyrene bead (~15 µm diameter) can be differentiated from a mixture with CaSO4 agglomerations, which has a close Raman shift.
Achieving intravital optical imaging with diffraction-limited spatial resolution of deep-brain structures represents an important step toward the goal of understanding the mammalian central nervous system1,2,3,4. Advances in wavefront-shaping methods and computational power have recently allowed for a novel approach to high-resolution imaging, utilizing deterministic light propagation through optically complex media and, of particular importance for this work, multimode optical fibers (MMFs)5,6,7. We report a compact and highly optimized approach for minimally invasive in vivo brain imaging applications. The volume of tissue lesion was reduced by more than 100-fold, while preserving diffraction-limited imaging performance utilizing wavefront control of light propagation through a single 50-μm-core MMF. Here, we demonstrated high-resolution fluorescence imaging of subcellular neuronal structures, dendrites and synaptic specializations, in deep-brain regions of living mice, as well as monitored stimulus-driven functional Ca2+ responses. These results represent a major breakthrough in the compromise between high-resolution imaging and tissue damage, heralding new possibilities for deep-brain imaging in vivo.
Progress in neuroscience relies on new techniques for investigating the complex dynamics of neuronal networks. An ongoing challenge is to achieve minimally invasive and high-resolution observations of neuronal activity in vivo inside deep brain areas. Recently introduced methods for holographic control of light propagation in complex media enable the use of a hair-thin multimode optical fibre as an ultranarrow imaging tool. Compared to endoscopes based on graded-index lenses or fibre bundles, this new approach offers a footprint reduction exceeding an order of magnitude, combined with a significant enhancement in resolution. We designed a compact and high-speed system for fluorescent imaging at the tip of a fibre, achieving a resolution of 1.18 ± 0.04 µm across a 50-µm field of view, yielding 7-kilopixel images at a rate of 3.5 frames/s. Furthermore, we demonstrate in vivo observations of cell bodies and processes of inhibitory neurons within deep layers of the visual cortex and hippocampus of anaesthetised mice. This study paves the way for modern microscopy to be applied deep inside tissues of living animal models while exerting a minimal impact on their structural and functional properties.
We propose and experimentally demonstrate a new concept of endo-microscopy: compressive multimode (MM) fiber imaging. We show that the speckle patterns generated in a MM fiber represent an excellent basis for compressive sensing. We demonstrate high-resolution compressive imaging through a fiber probe with the total number of measurements 20 times less than what is required for the standard raster scanning approach to endo-microscopy. Moreover, we show that the inherent optical sectioning of a MM fiber can help to overcome the main problem of compressive sensing and can be used for the imaging of bulk structures. Compressive MM fiber imaging does not require complex wavefront shaping and significantly increases the pre-calibration and imaging speed, creating a new approach to endo-microscopy.
Multimode fibres: Neural network descrambling A convolutional neural network (CNN) can successfully learn the nonlinear transmission characteristics of a multimode fibre thus allowing accurate image transmission and reconstruction. Propagation along a multimode fibre usually scrambles an input image, resulting in a seemingly random speckle pattern at the output. Babak Rahmani and coworkers from the Ecole Polytechnique Fédérale de Lausanne in Switzerland have now shown that a deep neural network(either a 22-layer CNN based on VGG-net technology or a 20-layer CNN based on Res-net technology) can learn the input-output relationship in a 0.75 m long piece of multimode fibre) and thus undo this scrambling. Experiments showed that both neural networks could perform highly accurate image reconstruction with an image fidelity as high as ~98% for image reconstruction and ~94% for image projection in the best case.
Deep neural networks (DNNs) are used to classify and reconstruct the input images from the intensity of the speckle patterns that result after the inputs are propagated through multimode fiber (MMF). We were able to demonstrate this result for fibers up to 1 km long by training the DNNs with a database of 16,000 handwritten digits. Better recognition accuracy was obtained when the DNNs were trained to first reconstruct the input and then classify based on the recovered image. We observed remarkable robustness against environmental instabilities and tolerance to deviations of the input pattern from the patterns with which the DNN was originally trained.
Digital holography (DH) has emerged as one of the most effective coherent imaging technologies. The technological developments of digital sensors and optical elements have made DH the primary approach in several research fields, from quantitative phase imaging to optical metrology and 3D display technologies, to name a few. Like many other digital imaging techniques, DH must cope with the issue of speckle artifacts, due to the coherent nature of the required light sources. Despite the complexity of the recently proposed de-speckling methods, many have not yet attained the required level of effectiveness. That is, a universal denoising strategy for completely suppressing holographic noise has not yet been established. Thus the removal of speckle noise from holographic images represents a bottleneck for the entire optics and photonics scientific community. This review article provides a broad discussion about the noise issue in DH, with the aim of covering the best-performing noise reduction approaches that have been proposed so far. Quantitative comparisons among these approaches will be presented.
A major open challenge in neuroscience is the ability to measure and perturb neural activity in vivo from well defined neural sub-populations at cellular resolution anywhere in the brain. However, limitations posed by scattering and absorption prohibit non-invasive multi-photon approaches for deep (>2mm) structures, while gradient refractive index (GRIN) endoscopes are relatively thick and can cause significant damage upon insertion. Here, we present a novel micro-endoscope design to image neural activity at arbitrary depths via an ultra-thin multi-mode optical fiber (MMF) probe that has 5–10X thinner diameter than commercially available micro-endoscopes. We demonstrate micron-scale resolution, multi-spectral and volumetric imaging. In contrast to previous approaches, we show that this method has an improved acquisition speed that is sufficient to capture rapid neuronal dynamics in-vivo in rodents expressing a genetically encoded calcium indicator (GCaMP). Our results emphasize the potential of this technology in neuroscience applications and open up possibilities for cellular resolution imaging in previously unreachable brain regions.
Holographic optical tweezers (HOT) hold great promise for many applications in biophotonics, allowing the creation and measurement of minuscule forces on biomolecules, molecular motors and cells. Geometries used in HOT currently rely on bulk optics, and their exploitation in vivo is compromised by the optically turbid nature of tissues. We present an alternative HOT approach in which multiple three-dimensional (3D) traps are introduced through a high-numerical-aperture multimode optical fibre, thus enabling an equally versatile means of manipulation through channels having cross-section comparable to the size of a single cell. Our work demonstrates real-time manipulation of 3D arrangements of micro-objects, as well as manipulation inside otherwise inaccessible cavities. We show that the traps can be formed over fibre lengths exceeding 100 mm and positioned with nanometric resolution. The results provide the basis for holographic manipulation and other high-numerical-aperture techniques, including advanced microscopy, through single-core-fibre endoscopes deep inside living tissues and other complex environments.
Vibrational spectroscopy is a widespread, powerful method of recording the molecular spectra of constituent molecules within a sample in a label-free manner. As an example, Raman spectroscopy has major applications in materials science, biomedical analysis and clinical studies. The need to access deep tissues and organs in vivo has triggered major advances in fibre Raman probes that are compatible with endoscopic settings. However, imaging in confined geometries still remains out of reach for the current state of art fibre Raman systems without compromising the compactness and flexibility. Here we demonstrate Raman spectroscopic imaging via complex correction in single multimode fibre without using any additional optics and filters in the probe design. Our approach retains the information content typical to traditional fibre bundle imaging, yet within an ultra-thin footprint of diameter 125 μm which is the thinnest Raman imaging probe realised to date. We are able to acquire Raman images, including for bacteria samples, with fields of view exceeding 200 μm in diameter.
Light-sheet fluorescence microscopy has emerged as a powerful platform for 3-D volumetric imaging in the life sciences. Here, we introduce an important step towards its use deep inside biological tissue. Our new technique, based on digital holography, enables delivery of the light-sheet through a multimode optical fibre - an optical element with extremely small footprint, yet permitting complex control of light transport processes within. We show that this approach supports some of the most advanced methods in light-sheet microscopy: by taking advantage of the cylindrical symmetry of the fibre, we facilitate the wavefront engineering methods for generation of both Bessel and structured Bessel beam plane illumination. Finally, we assess the quality of imaging on a sample of fluorescent beads fixed in agarose gel and we conclude with a proof-of-principle imaging of a biological sample, namely the regenerating operculum prongs of Spirobranchus lamarcki.
In complex media such as white paint and biological tissue, light
encounters nanoscale refractive-index inhomogeneities that cause
multiple scattering. Such scattering is usually seen as an impediment to
focusing and imaging. However, scientists have recently used strongly
scattering materials to focus, shape and compress waves by controlling
the many degrees of freedom in the incident waves. This was first
demonstrated in the acoustic and microwave domains using time reversal,
and is now being performed in the optical realm using spatial light
modulators to address the many thousands of spatial degrees of freedom
of light. This approach is being used to investigate phenomena such as
optical super-resolution and the time reversal of light, thus opening
many new avenues for imaging and focusing in turbid media.
The imaging properties of an optical system can be in many cases completely specified by a function of a single variable. A convenient function is the response to a sine wave test pattern as a function of “frequency,” i.e., lines/mm. The difficulty of experimentally providing such a test pattern can be avoided by measuring the response to a square wave (bar pattern) and calculating by a simple formula the corresponding sine wave response factor. The convenience of the sine wave response factor in calculating system performance is illustrated by application to a fluoroscopic imaging system.
A single multimode fiber is considered an ideal optical element for endoscopic imaging due to the possibility of direct image transmission via multiple spatial modes. However, the wave distortion induced by the mode dispersion has been a fundamental limitation. In this Letter, we propose a method for eliminating the effect of mode dispersion and therefore realize wide-field endoscopic imaging by using only a single multimode fiber with no scanner attached to the fiber. Our method will potentially revolutionize endoscopy in various fields encompassing medicine and industry.
There has been an immense drive in modern microscopy towards miniaturization and fibre-based technology. This has been necessitated by the need to access hostile or difficult environments in situ and in vivo. Strategies to date have included the use of specialist fibres and miniaturized scanning systems accompanied by ingenious microfabricated lenses. Here we present a novel approach for this field by utilizing disordered light within a standard multimode optical fibre for lensless microscopy and optical mode conversion. We demonstrate the modalities of bright- and dark-field imaging and scanning fluorescence microscopy at acquisition rates that allow observation of dynamic processes such as Brownian motion of mesoscopic particles. Furthermore, we show how such control can realize a new form of mode converter and generate various types of advanced light fields such as propagation-invariant beams and optical vortices. These may be useful for future fibre-based implementations of super-resolution or light-sheet microscopy.
We demonstrate for the first time to our knowledge a digital phase conjugation technique for generating a sharp focus point at the end of a multimode optical fiber. A sharp focus with a contrast of 1800 is experimentally obtained at the tip of a 105μm core multimode fiber. Scanning of the focal point is also demonstrated by digital means. Effects from illumination and fiber bending are addressed.
We introduce a phase-control holographic technique to characterize scattering media with the purpose of focusing light through it. The system generates computer-generated holograms implemented via a deformable mirror device (DMD) based on micro-electro-mechanical technology. The DMD can be updated at high data rates, enabling high speed wavefront measurements using the transmission matrix method. The transmission matrix of a scattering material determines the hologram required for focusing through the scatterer. We demonstrate this technique measuring a transmission matrix with 256 input modes and a single output mode in 33.8 ms and creating a focus with a signal to background ratio of 160. We also demonstrate focusing through a temporally dynamic, strongly scattering sample with short speckle decorrelation times.
We demonstrate that a structured light intensity pattern can be produced at the output of a multi-mode optical fiber by shaping the wavefront of the input beam with a spatial light modulator. We also find the useful property that, as in the case for free space propagation, output intensities can be easily superimposed by taking the argument of the complex superposition of corresponding phase-only holograms. An analytical expression is derived, relating output intensities ratios to hologram weights in the superposition.
Binary computer-generated holograms are similar to interferograms with fringe patterns hardclipped by a photographic process. Therefore the fringe locations in the binary hologram can be determined by solving a grating equation. However, there are two difficulties in using this approach to make binary Fourier transform holograms. First the discrete Fourier transform provides only data at discrete sampling locations. Second, the phase angles thus calculated are given in terms of the residues of the original phase angles after multiples of 2π rad are removed. In this paper an accurate numerical method which circumvents these two difficulties is described. Also discussed are three different techniques for storing amplitude information in the binary computer-generated holograms. The different solution methods discussed in this paper are further illustrated by a number of computer-generated holograms and their reconstructed images.
We report focusing of coherent light through opaque scattering materials by control of the incident wavefront. The multiply scattered light forms a focus with a brightness that is up to a factor of 1000 higher than the brightness of the normal diffuse transmission.
The newly emerging field of wave front shaping in complex media has recently seen enormous progress. The driving force behind these advances has been the experimental accessibility of the information stored in the scattering matrix of a disordered medium, which can nowadays routinely be exploited to focus light as well as to image or to transmit information even across highly turbid scattering samples. We will provide an overview of these new techniques, of their experimental implementations as well as of the underlying theoretical concepts following from mesoscopic scattering theory. In particular, we will highlight the intimate connections between quantum transport phenomena and the scattering of light fields in disordered media, which can both be described by the same theoretical concepts. We also put particular emphasis on how the above topics relate to application-oriented research fields such as optical imaging, sensing and communication.
The American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee provides reviews of existing, new, or emerging endoscopic technologies that have an impact on the practice of GI endoscopy. Evidence-based methodology is used, with a MEDLINE literature search to identify pertinent clinical studies on the topic and a MAUDE (U.S. Food and Drug Administration Center for Devices and Radiological Health) database search to identify the reported complications of a given technology. Both are supplemented by accessing the "related articles" feature of PubMed and by scrutinizing pertinent references cited by the identified studies. Controlled clinical trials are emphasized, but, in many cases, data from randomized, controlled trials are lacking. In such cases, large case series, preliminary clinical studies, and expert opinions are used. Technical data are gathered from traditional and Web-based publications, proprietary publications, and informal communications with pertinent vendors. Technology Status Evaluation Reports are drafted by 1 or 2 members of the ASGE Technology Committee, reviewed and edited by the Committee as a whole, and approved by the Governing Board of the ASGE. When financial guidance is indicated, the most recent coding data and list prices at the time of publication are provided. For this review, the MEDLINE database was searched through October 2013 for articles related to endoscopy by using the keywords "highresolution," "high definition," "high magnification," and "magnifying endoscopy." Technology Status Evaluation Reports are scientific reviews provided solely for educational and informational purposes. Technology Status Evaluation Reports are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment or payment for such treatment.
The holy grail of biomedical optical imaging is to perform microscopy deep inside living tissue. Unfortunately, biological tissue scatters light, which prevents the formation of a sharp focus. However, recently it was shown that wavefront shaping can be used to focus light through and inside turbid materials. So far, most experiments used liquid crystal devices, which are too slow to match the dynamics of perfused tissue. Since DMD technology is approximately 1000 times faster, it may bring wavefront shaping to in-vivo applications. We will compare analytically the performance of different methods for focusing light through scattering media with an intensity-only light modulator.
Optical imaging relies on the ability to illuminate an object, collect and analyse the light it scatters or transmits. Propagation through complex media such as biological tissues was so far believed to degrade the attainable depth, as well as the resolution for imaging, because of multiple scattering. This is why such media are usually considered opaque. Recently, we demonstrated that it is possible to measure the complex mesoscopic optical transmission channels that allow light to traverse through such an opaque medium. Here, we show that we can optimally exploit those channels to coherently transmit and recover an arbitrary image with a high fidelity, independently of the complexity of the propagation.
- A W Snyder
- J D Love
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