Super-resolution structured illumination microscopy: past, present and future
Kirti Prakash, Benedict Diederich, Stefanie Reichelt, Rainer Heintzmann, Lothar Schermelleh
SSuper-resolution structured illumination microscopy: past,present and future
Kirti Prakash , Benedict Diederich , Stefanie Reichelt , Rainer Heintzmann ,Lothar Schermelleh kirtiprakash25, beniroquai, StefanieReiche6, HeintzmannLab,LSchermelleh* [email protected], [email protected],[email protected] Abstract
Structured illumination microscopy (SIM) has emerged as an essential technique for 3Dand live-cell super-resolution imaging. However, to date, there has not been a dedicatedworkshop or journal issue covering the various aspects of SIM, from bespoke hardwareand software development and the use of commercial instruments to biologicalapplications. This special issue aims to recap recent developments as well as outlinefuture trends. In addition to SIM, we cover related topics such as complementarysuper-resolution microscopy techniques, computational imaging, visualisation and imageprocessing methods.
Introduction
Fluorescence light microscopy is a core technique in life sciences that has contributed tocountless major discoveries. However, the diffraction limit, first described by ErnstAbbe in 1873 [1], has restricted the optical resolution to about half the wavelength ofthe light used, i.e. 200-300 nm in the lateral directions (x and y), and to about thewavelength of light, i.e. 500-800 nm along the optical axis (z). In the past two decades,several super-resolution microscopy (SRM) approaches have been developed that allowto overcome this barrier and push the spatial resolution to the 10-100 nm range, thusclosing the gap to electron microscopy [25, 70, 71]. The SRM techniques can be further1/12 a r X i v : . [ phy s i c s . op ti c s ] F e b ivided into single-molecule localisation microscopy (SMLM) [43], that includestechniques like photoactivatable localisation microscopy (PALM) [7, 29] and stochasticoptical reconstruction microscopy (STORM) [67], stimulated emission depletion(STED) [3, 27, 58] microscopy and structured illumination microscopy (SIM) [20, 23]. Inrecognition of these breakthrough developments Eric Betzig, Stefan Hell and William E.Moerner were awarded the Nobel prize for Chemistry in 2014 [6]. Frequently asked questions in super-resolution structured illumination microscopyfield
The following questions have not always been agreed upon in the super-resolution/SIMfield, and with this special issue, we hope to address some of these:1. What is super-resolution microscopy and should diffraction-limited linearSIM be classified as ‘super-resolution’ ?2. Should High-NA TIRF-SIM, which can achieve lateral resolution down to 84nm, be considered as diffraction limited?3. Can non-linear SIM become broadly applicable and live-cell compatible?4. Do you need ‘switching’ of states for non-linear super-resolution?5. How can information about single-molecule detection be best combined withthe knowledge of the illumination structure?6. Do high quality SIM images require reconstruction in Fourier space?7. Can SIM be used for deep tissue imaging?8. How can the fundamental limitation of SIM, i.e. generating sufficient stripecontrast in densely labelled and/or extended biological structures due toout-of-focus light, be addressed?9. Should image scanning microscopy be considered a form of SIM and whatforms of structured illumination could be used other than stripes?10. Can SIM be used to improve the resolution of (Rayleigh scattering) transmis-sion microscopy?11. How does sparse illumination compare to dense illumination in linear andnon-linear SIM?12. Can we generate “true” super-resolution images from simple instrumentsenhanced with machine-learning-based algorithms?13. Can research-grade super-resolution (SIM) microscopes be built cost-efficiently?Recent SRM developments have focussed on combining localisation-based microscopywith modulated illumination to push the resolution (precision) towards a fewnanometers as in MINFLUX and SIMFLUX [5, 13, 62, 64]. However, an increase inresolution requires an increase in local light dosage, which increasesphotobleaching/phototoxicity (SIM, STED, SMLM) or requires the need to introducespatial and temporal sparsity (MINFLUX) making imaging comparably slow. Moreover,most SRM techniques mentioned above rely primarily on chemically fixed (i.e. dead)cells, are restricted in the imaged sample volume (2D, single plane, small field-of-views)or are restricted to imaging sparse single entities such as vesicles or single molecules.2/12uper-resolution linear SIM is a notable exception [24, 59]. By making use offrequency mixing when exciting samples with a patterned illumination followed bycomputational unmixing and reconstruction, SIM achieves a 2-fold resolution increaseover conventional diffraction-limited fluorescence microscopy in 2D or 3D (Figure 1).While the numerical resolution improvement is moderate compared to other SRMtechniques, it pushes SIM into an application sweet spot with most macromolecularstructures and their dynamics falling in the size range of 100-300 nm [69, 73, 77]. By notasking for the highest spatial resolution, SIM is less demanding in terms of photonbudget and therefore more compatible with live-cell imaging [30, 31, 39, 53, 72, 81]. Inaddition, it offers volumetric imaging with relatively large field-of-views and comparablyhigh temporal resolution which makes it suitable for high-content and live-cellimaging [50, 83, 84]. Taken together, the uniquely balanced combination of propertieshave made SIM remarkably successful in a wide range of biological applications andpromoting new discoveries [10, 16, 17, 19, 32, 34, 41, 47–49, 51, 55–57, 76, 77, 79].
Recent and future developments in SIM
SIM has been available in commercial instruments for more than 10 years and has beensuccessfully established in many labs and core facilities around the world. However,wider dissemination of SIM has been curtailed by the complexity of instruments and itsproneness to reconstruction artefacts when sample properties, system calibration andparameter settings are not carefully matched [15]. Thus, to lower the activation energyfor research labs to venture into super-resolution SIM, many recent developments aim atfurther performance/resolution enhancement and ‘democratising’ SIM by • using non-linear SIM approaches [21, 26, 42, 63] or by combinations withsingle-molecule imaging [5, 13, 18, 37, 65] • exploiting correlative and combinatorial fluorescence imaging approaches withmultifocal [2, 22], 2-photon [33, 45, 75] and light-sheet microscopy [11, 38] • implementing the technique into smaller and more cost-efficient setups [28, 40, 80] • making the method more robust against artefacts using alternative illuminationschemes [4, 52, 68] and/or intelligent data processing [8, 82] • increasing its application range e.g. by the implementation of adaptiveoptics [9, 14, 35], cryo-imaging [60, 79]Important advancements are being made to improve and simplify the instrumentation.For instance, the newly designed optical setups using an open-sources toolbox [80] orwaveguide-based photonic chips [82] or open-source software development [54] mayreduce the cost of SR imaging enabling SIM on smaller and more affordable devices.Moreover, next-generation sCMOS cameras (for example, the new 500 fps sCMOS byPhotometrics) offer increased frame rates and higher sensitivity with reduced noiselevels to enable faster high-quality SIM imaging for observing cellulardynamics [12, 46, 74]. For a maximal imaging speed, the rolling shutter schemes can becombined with SIM data acquisition [78].In parallel, the rapidly evolving field of computational microscopy is paving the wayto circumvent the resolution limit without the necessity of specialised hardware. Suchcomputational techniques not only reduce the complexity of the instrumentation butcan also potentially reduce aberration artefacts [8, 40, 61, 66, 80, 82]. Adaptive optics(AO) works well to correct sample aberrations. However, it does not solve the problemof reduced illumination pattern contrast in the presence of significant out of focus3/12ackground. One solution here is offered by combining SIM with light sheetillumination, 2-photon, or photoswitching methods.Recent advancements in intelligent microscopy and machine learning (ML) assisteddenoising are now being used for improving SIM reconstructions. For example, usingdeep-learning models, the apparent axial resolution of SIM has been improved by afactor of two [8, 36, 44]. By combining physical data acquisition with simple imageprocessing algorithms, one recover previously inaccessible information. At the sametime, this brings up new problems of validation of the results from ML methods. Newstandards have to be developed, where computational scientists and mathematicians canhelp to bring together state-of-the-art algorithms, such as GPU-parallelization for fasterdata processing or machine-learning-based data interpretation. The wider-reaching social implications
SRM has evolved into a highly interdisciplinary field requiring experts from physics,engineering, chemistry, biology and computer sciences to drive innovations for increasingspatial and temporal resolution and ultimately biological applicability. The globaladvances in super-resolution microscopy need to be synchronized to inspire researchersin the field of microscopy to combine their methods with techniques from different areas.SRM and SIM, in particular, have become important tools of basic science discovery.However, there are still considerable activation barriers for the researcher to use SRM,as instruments are not yet ‘turn-key’, and using SIM (or any other SRM method) to itsfull potential requires considerable knowledge. Furthermore, the use of SRM to studyhuman pathologies and for medical diagnosis is still in its infancy, but will foreseeablyplay a considerable role in the future. New SIM modalities, implementation of AO,machine-learning, and the intelligent algorithms will help to democratise SIM andincrease it’s usage in basic research and biomedical application.Super-resolution microscopy is very often an expensive undertaking, thus limiting itsbroader application. In this meeting, we plan to kick-off the idea of an open-source“openSIM” system inspired by its derivatives in the light-sheet community. Opendiscussions where ideas and requirements for a prototype are gathered are a first andsignificant step to make science not only affordable but available. This special issueshows current progress in SIM development and application.
Acknowledgements
The special issue is part of Theo Murphy international scientific meeting organised bythe Royal Society called SIMposium: recent advancements in structured illuminationmicroscopy. We thank Mike Shaw for comments on the manuscript. A Twitter ( )discussion on this topic which can be followed here or with hashtag SIMposium. References
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Nature methods , 9(7):749–754, 2012. 10/12 igure 1. (Caption next page.) 11/12 igure 1. Biological super-resolution imaging with 3D-SIM. (A) Mouse C127mammary epithelial cell nucleus replication labelled with 5-ethenyl-2’-deoxyuridine (EdU,red) for 15 min before fixation with formaldehyde. The thymidine analogue EdU isincorporated into newly synthesized DNA of S-phase cells (here mid-to-late S phase)and detected via click-chemistry with Alexa Fluor 594 azide. DNA is labelled with 4’,6-diamidino-2-phenylindole (DAPI, cyan). Single z-section of an image stack is shownwith conventional wide-field illumination (top, left), structured illumination (1 of 15 rawimages acquired per z-plane with laterally shifted and rotated stripes; bottom, left), andafter 3D-SIM reconstruction (right). Note that 3D-SIM resolves higher-order domainorganisation of chromatin and DNA-free interchromatin regions (inset), as well as thelocation of nuclear pores in the peripheral chromatin layer visible as DAPI void dots inthe central region of the nucleus. Scale bar: 5 µ m and 1 µ m (inset). (B) Correspondingfrequency distribution of the DAPI signal in Fourier (reciprocal) space. Concentric ringsindicate the respective spatial resolution in µµ