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Imaging of Biological Materials and Cells by X‑ray Scattering and Diffraction Clément Y. J. Hémonnot†,‡,§ and Sarah Köster*,† †

Institute for X-Ray Physics, University of Goettingen, Friedrich-Hund-Platz 1, 37077 Göttingen, Germany Northwestern Argonne Institute of Science and Engineering, Northwestern University, 9700 South Cass Avenue, Argonne, Illinois 60439, United States § Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, United States ‡

ABSTRACT: Cells and biological materials are large objects in comparison to the size of internal components such as organelles and proteins. An understanding of the functions of these nanoscale elements is key to elucidating cellular function. In this review, we describe the advances in X-ray scattering and diffraction techniques for imaging biological systems at the nanoscale. We present a number of principal technological advances in X-ray optics and development of sample environments. We identify radiation damage as one of the most severe challenges in the field, thus rendering the dose an important parameter when putting different X-ray methods in perspective. Furthermore, we describe different successful approaches, including scanning and full-field techniques, along with prominent examples. Finally, we present a few recent studies that combined several techniques in one experiment in order to collect highly complementary data for a multidimensional sample characterization. KEYWORDS: X-ray imaging, X-ray optics, biological materials, biological cells, diffraction, scattering, holography, ptychography, tomography, coherent diffractive imaging

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signal, or be too dim to be visible. Hard X-rays, by contrast, provide a high penetration depth (for example, photons of 10 keV have an attenuation length of 1 mm in water), a small wavelength in the angstrom range, and thereby high resolution, and electron density is directly probed, thus circumventing the need for labeling or staining. Imaging of matter with X-rays began in the 1950s8 and became more prominent about 20 years later with the advent of high-quality zone plates for focusing.9,10 Thus, full-field transmission X-ray microscopes (TXM) employing soft Xrays and exploiting absorption contrast (see Figure 1a for a typical TXM setup) were developed. At about the same time, scanning transmission X-ray microscopes (STXM) were introduced11 with focused beams and the additional option for energy-dispersive detectors to capture X-ray fluorescence (XRF) (see Figure 1b for a typical setup). XRF can be readily combined with other techniques, as the signal is emitted in all directions, hence the detector can be placed at any angle with regard to the sample. The reader is referred to comprehensive reviews such as ref 8 for more details on soft X-ray microscopy.

maging of biological materials and cells began in the late 16th and early 17th century with the advent of the first light microscopes. For centuries, optical resolution remained diffraction-limited as defined by Abbe and Rayleigh. Only recently, nanoscale imaging of biological cells with visible light became possible thanks to recent developments in superresolution techniques.1−3 Electron microscopy (EM) was developed starting in the 1930s and has been improved to nowadays reach a resolution down to a few angstroms4 and is widely and successfully used to image biological samples.5,6 Both fluorescence microscopy and EM have proven to be extremely valuable for studying cellular processes. Fluorescent labels allow for molecule-specific imaging in living cells, thus for dynamic recordings, whereas EM reaches the best spatial resolution available today, that is, a few angstroms in cryo-EM, and a few nanometers for whole hydrated cells.6,7 However, drawbacks remain: Electrons have a small penetration power of only about 100 nm and can only visualize the surface of larger specimens like whole cells. If the interior of a cell shall be studied, the sample has to be sectioned. Furthermore, the fairly involved sample preparation procedures prohibit the study of dynamic or living samples. The advantage in fluorescence microscopy is the ability to visualize molecules in cells and tissues by using optical labels that can target specific molecules. However, the use of labeling can be a disadvantage as the labels may interfere with the function of the molecule, lose their © 2017 American Chemical Society

Received: May 17, 2017 Accepted: August 8, 2017 Published: August 8, 2017 8542

DOI: 10.1021/acsnano.7b03447 ACS Nano 2017, 11, 8542−8559

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Figure 1. Setups for X-ray imaging. (a) Sketch of a full-field transmission X-ray microscope (TXM) with the sample moved out of the focal plane. (b) Sketch of a scanning transmission X-ray microscope (STXM) with an X-ray fluorescence (XRF) detector. (c) Sketch of a scanning nanodiffraction/scanning SAXS setup. (d) Sketch of a coherent diffractive imaging (CDI) setup as used in ptychography. (e) Sketch of an inline holography setup, using waveguides emitting spherical waves. Sketches are not to scale.

Table 1. Characteristics of X-ray Focusing Opticsa category

optics

beam diameter (energy)

efficiency

ref

refracting

spherical compound refractive lenses parabolic compound refractive lenses Kinoform lenses Kirkpatrick−Baez mirrors capillaries waveguides Fresnel zone plates multilayer zone plates multilayer Laue lenses pinholes/slits

1 μm (8 keV) 50 nm (21 keV) 100 nm (8 keV) 7 nm (20 keV) 50 nm (8 keV) 10 nm (15 keV) 35 nm (8 keV) 5 nm (13.8 keV) 20 nm (14.6 keV) 1 μm (11 keV)

several 10% >60% >50% >50% 80% 80 Å in the central part of the fiber. Scanning SAXS. As compared to XRD, in case of scanning SAXS, the sample does not need to have periodicity and the signal is diffuse. The particle size can be resolved between the smallest and the highest scattering angles, or q values, corresponding to length scales from 1 to 100 nm.111 Data treatment follows SAXS theory, taking advantage of Guinier or Porod analysis, and fitting procedures to obtain form and structure factors.111 However, it has to be taken into account that beam size and the size of the scatterer are on the same order of magnitude.64,102,104,117 Thus, the extended theory available for solution SAXS, where a large beam is used to ensemble average over many scatterers112,118 is not directly applicable. Bone is a prime example of a composite material, where the hierarchical structure is perfectly well adapted to the mechanical requirements. Pioneering work by Fratzel et al.83 could resolve the size and orientation of hydroxy apatite particles embedded in the collagen matrix in a spatially resolved manner. The eccentricity of the scattering patterns was used as a quantitative measure of the degree of orientation as well as principle direction of the oriented structures. The experiment was performed in the late 1990s using an X-ray tube delivering a comparatively large beam (diameter 100 μm). In recent years, the technique has been transferred to synchrotron setups,119 where beam sizes have been reduced to a few hundreds of nm. Taking advantage of these developments in X-ray optics, one can now image internal structures of whole, unsliced mammalian cells at nanometer resolution. In an early example of such work, we studied bundles and networks of cytoskeletal keratin intermediate filament proteins (see Figure 4b).100 By fitting a model to these data that takes into account the beam diameter and shape and organization of the bundles, we quantified bundle diameters and orientations as well as their inner structure including filament diameter and arrangement,104 and correlated the results to visible light fluorescence micrographs of the same samples. The key characteristic of the method is that nanofocused X-ray beams provide a realspace resolution on the order of 100 to 400 nm while in

made75 or commercial64 microfluidic chambers increase the viability of living cells by constant inflow of nutrients, outflow of wastes and free radicals, as well as probably a slight cooling effect. Although to our knowledge all microfluidics studies using X-rays on cells have been performed on adherent cells, in principle, the devices are also suitable for suspension cells. For diffractive tomographic imaging, the sample has to be rotated and data have to be taken at multiple angles. Depending on the specimen size and beam dimension, silicon nitride windows may be used and offer an angular opening greater than 160°. A good alternative is glass capillaries made of borosilicate or quartz to collect data from all angles. In order to reduce absorption and background scattering, the capillaries should have thin walls, typically from 0.01 to 0.1 mm.78−81 Finally, solid samples, such as bone, hair, or teeth can be directly mounted on the acquisition stage.

SCANNING X-RAY SCATTERING AND DIFFRACTION Scanning X-ray scattering and diffraction are similar techniques and use a similar setup. Diffraction is a specific case of scattering by well ordered and crystalline samples which diffract the incident beam in a few specific directions, determined by Bragg’s law. Whereas in small-angle scattering (SAXS) data are recorded between 0.1 and 10°, in diffraction (XRD or wideangle X-ray diffraction, WAXD) data are recorded up to 90°. Scanning diffraction was first introduced in 1995 by Mahendrasingam et al.82 using synchrotron radiation and applied to polymer samples. Scanning SAXS was independently developed in 1997 by Fratzl et al.83 on laboratory sources and used to study bone samples (see Figure 4a). By scanning the sample through a focused beam and recording a scattering or diffraction signal in each position, spatially resolved reciprocal space data are obtained. Thus, heterogeneity in the sample is captured rather than just average values as known from solution scattering. Biological matter displaying some degree of (hierarchical) order particularly benefits from scanning diffraction. Prominent examples, some of which are discussed in more detail below, are bone,83−88 plant fibers and wood,89−93 teeth,94−96 hair,97−99 cellular components,59,64,77,100−106 and tissues such as muscle107 and brain.108,109 Recently, the technique was used to image initially living cells,59,64 and it has been extended to three dimensions (3D).86,96,110 XRD and SAXS111−113 are both applications of elastic scattering of Xrays: The electrons in the sample are caused by the X-rays to resonate elastically. They produce secondary X-ray waves which interfere and lead to a scattering signal in reciprocal or Fourier space.111 Notably, only the amplitude of the exit wave field is detected, and the phase is lost. Hence, direct inversion of the scattering signal by an inverse Fourier transform is not possible. In scanning techniques, a raster scanning procedure is exploited to compute pseudo-real-space maps in so-called dark-field contrast: all photons collected on the detector at a certain measurement position are added, and this total intensity value is plotted on a color scale at the respective position (see examples in Figure 4a−c). The real-space resolution is thus limited by the beam size and the scanning step size, whichever of the two is larger. Additionally, however, the actual SAXS signal or diffractograms may be analyzed in reciprocal space, and structural information is retrieved. Scanning XRD/WAXD. An early example of scanning micro-XRD was in resolving the helical architecture of cellulose fibrils in wood cells with a microbeam (2 μm diameter).92 In this study, the X-ray beam was oriented almost in parallel to the 8548


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were able to directly compare chemically fixed and living cellular samples, both immersed in aqueous environments.59 We determined the azimuthally integrated SAXS data of living cells and chemically fixed cells, respectively, and calculated the difference in dependence of the scattering vector q. As q is inversely proportional to the corresponding length scale d, we were able to identify length scales, on which structures either disappear or emerge upon fixation, from about 15 to 60 nm (see Figure 4c). Formaldehyde, as we used it here, is one of the most commonly used fixative agents in biological studies and according to this study, artifacts on length scales resolvable by superresolution microscopy are likely to be created. SAXS and Diffraction Computed Tomography. As mentioned above, one great advantage of X-rays over visible light or electrons is their large penetration depth. Large objects can be imaged without slicing or sectioning. Both diffraction and SAXS have been extended to (computed) tomography (CT) as outlined in the following. SAXS-CT was introduced in the 80s121 and has, with the advent of focused beams, developed into a nondestructive (apart from radiation damage) technique to study the local nanostructure of specimens in 3D.122 For example, SAXS-CT has been used to study the morphology of brain tumors.108 The authors used the intensity of the SAXS signal to reconstruct high-resolution images, making use of the extended q-range, and analyzed the slope of the SAXS signal by applying a generalized Porod power law120 to delineate necrotic regions of the tumor from healthy tissue. The same authors also derived maps of the molecular organization of myelin sheaths in formalin-fixed rat brain as shown in Figure 4d.109 The results are anatomical maps similar to transmission tomography or histology and reconstructed the 3D volumes of the samples. By contrast to conventional CT, not absorption contrast, but the differential scattering cross section at the respective position is exploited. Maps of (i) the myelin concentration, and (ii) periodicity of the lamellar structure were obtained by quantifying the intensity of the second-order Bragg peaks and the Bragg peak positions, respectively. Very recently, Liebi et al.110 have combined scanning SAXS with tensor tomography123 to reveal nanostructure organization of trabecular bone on micrometer length scales using a beam with dimension 25 × 25 μm2 (see Figure 4e). The technique had previously been developed on two-dimensional 20 μm thick sections of bone samples,86 and was extended to threedimensional unsliced bone structures. The authors were able to reconstruct the 3D organization of bone by analyzing over one million diffraction patterns, for a total acquisition time of 22.5 h, corresponding to a dose of about 3 × 107 Gy on the whole bone specimen. The reciprocal space intensities could be determined, providing access to the direction and degree of orientation of each scan position in the whole sample. The authors could retrieve the size and shape of the scatterers owing to the SAXS signal and identify domains with a low degree of orientation, corresponding to random orientation of the collagen fibers, and domains with a high degree of orientation, corresponding to aligned collagen fibers. Schaff et al.96 used the same approach to study the collagen fiber orientation within a tooth. They combined real and reciprocal space data in order to obtain a six-dimension space map of the specimen. The technique is based on the reconstruction of the full 3D scattering information (qx, qy, qz) in every voxel. While the method remains fairly slow, it provides information on length scales from a few nanometers to a few millimeters, which is

reciprocal space the resolution is on the order of few nanometers, defined by the accessible q-range. Some of the most prominent protein structures in mammalian cells consist of actin filaments (microfilaments). By correlating visible light fluorescence microscopy with a scanning SAXS approach, Priebe et al. were able to link actin fiber structure and myosin II concentration from visible light micrographs with the structural data obtained from scanning SAXS.64 The same group showed that differentiated stem cells exhibit a pronounced structural orientation and high intensity diffraction signal, whereas naive human mesenchymal stem cells do not show this particularity.106 This result supports the idea that stem cells gain ordered and oriented structures at the molecular and supramolecular level during the differentiation process. Scanning SAXS studies are typically static as the extensive scan times, which are determined by the exposure times per scan point and the size of the field of view, prevent the recording of “movies”. For example, a scan of 100 × 100 steps with 1 s exposure time takes about 3 h. Continuous scanning modes and higher brilliance sources have helped tremendously to decrease the scan times. Furthermore, the associated radiation damage (e.g., 108 Gy for exposure times of 1 s per scan point and a 100 nm step size) remains a major draw back of the high-resolution method. However, biological processes may be studied in an indirect way, for example, by taking “snap shots” at different stages. We have used this approach to follow packing and unpacking and duplication of DNA in nuclei of mammalian cells during the cell division cycle. Visible light phase contrast movies (1 frame every 5 min) were recorded until chemical fixation and plunge-freezing of the samples to characterize the cell division stage. Subsequently, scanning SAXS “snap shot” data of these samples were taken.105 With a real-space resolution of 250 nm and the largest q-values corresponding to only 6 nm, application of a generalized Porod power law120 enabled a quantitative analysis of the power law exponents from the azimuthally integrated scattering signal. The results gave rise to information about internal structure, packing density and surface properties of the scatterers and the DNA packing and unpacking processes could be followed over time in a spatially resolved manner. Surface properties and packing density were retrieved by computing surface-area-tovolume ratio maps derived from the Porod analysis. The surface-area-to-volume ratio provides information about the size, compactness and density of the specimen, in this case from DNA compaction into chromatin. In the previous examples, only dry samples provided strong enough contrast in the electron density to provide information on the single filament level. In SAXS, the contrast arises from the average excess scattering length density of the sample, that is, the difference between the electron density of the sample and the electron density of the solvent. As cells consist mostly of water, the electron density contrast in aqueous environment is comparatively low. When the solvent is changed from water to air, a gain in contrast greater than a factor 800 may be achieved. However, measurements on hydrated samples, especially in combination with specially designed microfluidic flow chambers64,75 also reveal valuable information on the nanometer scale. Such experiments are more challenging due to the application of wet or microfluidic chambers and radiation damage is of higher concern as free radicals move freely in solution. However, an aqueous environment mimics the physiological situation more closely than dried samples. We 8549


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Figure 5. Coherent diffractive imaging. (a) Early example of CDI of whole Escherichia coli bacteria. Left: diffraction pattern. Right: corresponding image reconstruction. Reproduced with permission from ref 130. Copyright 2003 National Academy of Sciences, U.S.A. (b) Typical speckle pattern collected by CDI (top) and the corresponding 2D electron density reconstruction of a Staphylococcus aureus cell. Reproduced with permission from ref 137. Copyright 2016 Nature Publishing. (c) Amplitude (left) and phase (right) reconstructions of an insect wing measured by ptychography. Reproduced with permission from ref 136. Copyright 2009 Elsevier B.V. (d) Three-dimensional subcellular structure of a frozen-hydrated Neospora caninum cell. Reproduced with permission from ref 138. Copyright 2015 International Union of Crystallography. (e) Ptychographic X-ray nanotomography of frozen-hydrated Chlamydomonas cells and zoom of one cell. Reproduced with permission from ref 81. Copyright 2015 Science Direct.

with the sample. Speckle patterns due to interference of the phase-modulated exit wave-fields from the specimen are recorded on an area detector (see Figure 5a,b). The positions and intensities of the speckles reflect the structure of the material and the phase and amplitude of the real-space image of the specimen can be retrieved by iterative algorithms. Briefly, the detector reading is proportional to the square modulus of the amplitude. The image reconstruction starts by allocating random phases to the measured amplitudes. The result is then Fourier transformed into real space as a first guess. Constraints about the finite-size support of the specimen are introduced, that is, the electron density outside the support and any negative electron density inside the support are set to zero,129−131 and the newly determined electron density (amplitude and phase) is then Fourier transformed into reciprocal space. The phase is kept, while the new amplitudes are replaced by the measured ones. This procedure is iteratively repeated until the result converges.132 The phase of the specimen can be retrieved by oversampling the object and by using iterative phase-retrieval algorithms.133−136 Here, we focus on those CDI methods, which have been extensively applied to

particularly attractive for composite materials with highly ordered hierarchical structural features and for mesoscopic materials. This technique is now not only available at synchrotron sources, but also for laboratory setups.124 Diffraction tomography was applied to resolve components in a highly biomineralized holdfast organ from Anomia simplex mussels.125,126 The authors were able to investigate aragonite and calcite (CaCO3 polymorphs), which were not detectable in the more conventional absorption tomography, directly by the respective diffraction peaks. Finally, they were able to determine the local degree of Mg substitution in the calcite phase as the calcite lattice constants change in the presence of Mg, whereas Mg does not substitute into aragonite.

COHERENT DIFFRACTIVE IMAGING (CDI) CDI was first suggested theoretically in 1952 by Sayre.127 However, due to technical challenges such as the need for highly coherent beams and area detectors with high dynamic range and quantum efficiency128 experimental demonstration was achieved only in 1999.129 The physical principle is valid for coherent beams of (X-ray) photons or electrons, which interact 8550


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Ptychograpy. Ptychography combines CDI and scanning and is also referred to as scanning diffraction microscopy. The method was invented by Hoppe in 1969143 and exploits a sufficiently large overlap (>60%)144 between adjacent scanning positions. The size of the imaged object is not limited in the same way as it is in plane-wave CDI. Owing to the redundant information and by using of an iterative feedback algorithm135,136 as outlined previously, it is possible to retrieve the illumination function, that is, the incoming X-ray wave field, as well as the object exit wave field. Due to the phase information, real-space images can be computed. The larger beam and scan step size renders ptychography a more doseefficient (on the order of 103−106 Gy) method compared to scanning SAXS (on the order of a few 108 Gy). One of the first examples of a successful application of ptychography to a biological sample was presented by Thibault et al., where the authors imaged an insect’s wing (Figure 5c).136 Shortly later, even more weakly scattering Magnetospirillum gryphiswaldense bacteria were imaged by ptychography.145 Furthermore, ptychography has been applied to the highly ordered actin filament bundles in inner ear hair cell stereocilia, providing direct imaging of actin bundles at a resolution of 130 nm in the reconstructed phase images.102 Giewekemeyer et al. even achieved a resolution of 85 nm at 6.2 keV and a dose of 1.3 × 105 Gy and were able to reveal unique DNA packing in Deinococcus radiodurans bacteria with four subunits.69 Lima and co-authors studied frozen-hydrated yeast cells by ptychography and demonstrated the advantages of using cryogenic temperatures when imaging cells or tissues.146 Tomographic CDI. Plane-wave CDI is well suited for recording 3D data sets by acquiring a series of 2D diffraction patterns at different angles, owing to the comparatively short exposure times and thus the insensitivity to sample vibrations.128 Furthermore, the relatively low dose greatly helps in the extension to tomographic 3D imaging. The study by Rodriguez et al.138 on Neospora caninum cells was performed at cryogenic temperatures and by tilting the sample the authors achieved a 3D reconstruction of the structure of the cell interior (see Figure 5d). In an even earlier study, Nishino and colleagues147 imaged individual human chromosomes purified from mitotic HeLa cells at a spatial resolution of 38 nm for each 2D reconstruction and a resolution of 120 nm for the 3D reconstructions. They reported the presence of axial structures confirming findings from immunoelectron microscopy or fluorescence microscopy, albeit without the use of labels or staining. Dierlof et al. developed a tomographic version of ptychography148 and applied it to the interconnective canalicular network of cortical bone. They attempted to resolve structures on the length scales of 100 nm such as the osteocyte lacunae. This example nicely shows how biological specimen, which only show a weak absorption contrast, benefit greatly from exploiting phase information. In fact, even quantitative electron density contrast maps can be obtained. Whereas the solid bone sample was dehydrated and then resin-embedded, Diaz et al.81 studied Chlamydomonas reinhardtii algae in solution after preparation in a glass capillary, facilitating the rotation during tomographic ptychography (Figure 5e). They achieved a resolution of 180 nm and by averaging several slices, they measured the cell wall to about 100 nm in thickness. By a segmentation procedure, the authors were additionally able to determine the mass density (see eq 2) of different organelles within the algae to 1.4 g/cm3 for lipid droplets and 1.1 g/cm3

biological matter in the past, plane-wave CDI and ptychography. Plane-Wave CDI. Plane-wave CDI is a full-field technique which is particularly dose-efficient (on the order of 106 Gy). A coherent planar X-ray beam illuminates a sample in transmission geometry and the diffraction patterns are collected on an area detector placed in the far-field. In the so-called Fraunhofer far-field, where the diffraction pattern of an object of size a is observed at a distance z far away from the sample

z≫

a2 , λ

plane waves are observed. By contrast, if the detector is a2

placed in the near-field close to the specimen, z ≪ λ , spherical waves are observed and Fresnel theory of diffraction has to be used. A beam stop blocks the direct, unscattered beam. Diffraction patterns are taken to obey the Nyquist frequency criterion such that the diffracted intensity is oversampled (that is, sampled finely enough) and thus the phase information is encoded in the diffracted intensity. Moreover, the area outside the specimen has to be known or transparent, corresponding to surrounding the electron density of the specimen with an “empty” region. Empirically, the linear oversampling criterion O > 5, which must be fulfilled for high quality phase reconstructions, is defined by the wavelength λ, the sample size D, the sample-to-detector distance z and the detector pixel λz size p, O = pD .131,139 Pioneering work in the field was performed by Miao et al. by imaging Escherichia coli bacteria at an energy of 6.2 keV and with a resolution of 30 nm, as shown in Figure 5a.130 More recently, the same level of resolution was achieved for fully hydrated yeast cells,76 providing images of the specimen morphology and internal details at high contrast. A typical example of a speckle pattern is presented in Figure 5b, together with the 2D electron density projection of a Staphylococcus aureus cell (dimensions: 0.5 to 1.5 μm),137 which already provides a detailed cell density map. With the experimental parameters the authors used, they could reconstruct objects up to 2.5 μm. This example will be discussed further in the tomographic CDI section. X-ray free electron lasers attracted a lot of attention owing to the possibility of collecting diffraction patterns from protein crystals, viruses, or even small whole cells using femtosecond pulses and thus faster than radiation damage is occurring (“diffract before destroy”).140 As of now, there are only a few examples of hard X-ray FEL imaging of whole cells and all those examples are particularly small (bacteria) cells. Assuming, for example, a wavelength of 0.1 nm, a sample-to-detector distance of 1 m and a pixel size of 20 μm, the oversampling criterion λz defines a maximum sample size of D = 5p = 1μm. Fan and coauthors 137 recorded single 10 fs pulse exposures of glutaraldehyde fixed Staphylococcus aureus cells as shown in Figure 5b. By labeling the cells with gold nanoparticles (i.e., enhancing the signal), they reached a resolution of 54 nm, which improved the resolution by a factor 2.6 compared to unstained cells. Living Microbacterium lacticum cells have been imaged by Kimura et al. employing FEL diffraction at a resolution of about 37 nm.141 They observed a nonuniform density within the cell and attributed high density regions to materials with a high electron density such as DNA. A recent study by Takayama and Yonekura using FEL radiation showed that CDI at cryogenic temperature leads to images of chloroplasts from C. melorae and minicells from Escherichia coli at a resolution of 192 and 52 nm, respectively.142 8551


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Figure 6. Holography. (a) Holographic intensity and phase reconstruction from freeze-dried Dictyostelium discoideum cells. Reproduced with permission from ref 156. Copyright 2011 American Physical Society. (b) Holograms from a cardiomyocyte recorded at five different defocus positions and reconstructed phase (projected electron density). Reproduced with permission from ref 154. Copyright 2017 International Union of Crystallography. (c) 3D holographic reconstruction of freeze-dried Deinococcus radiodurans: effective mass density (blue and red), surface rendering (yellow), and combined surface and mass density. Reproduced with permission from ref 157. Copyright 2017 Springer. (d) Holotomography of mesophyll cells and palisade cells from Arabidopsis seeds. Reproduced with permission from ref 160. Copyright 2006 National Academy of Sciences, U.S.A.

for the cytoplasm. Using a similar approach, Wilke et al.101 studied DNA organization in Deinococcus radiodurans. Each projection was reconstructed with a resolution of about 50 nm. In CDI, the electron density is encoded in the quantitative phase information. From the electron density maps of the bacteria, they estimated the mass density of the high-density regions to about 1.6 g/cm3 and attributed this value to DNA. X-ray Holography. The physical principle of holography was first proposed for visible light in 1948 by Gabor149 and adapted to soft X-ray photons in 1965150 and only in 1996 for hard X-rays, due to the lack of coherent radiation sources at shorter X-ray wavelengths151,152 (for review, see ref 153). By recording both the exit wave of the object and an undisturbed coherent reference wave field, both the intensity and the phase of the scattering object can be reconstructed from the interference pattern of the two waves. In holographic imaging, the detector is placed in the near-field, where the diffraction pattern is almost a perfect projection of the specimen and we observe a change in hologram structure at different sample-todetector distances. In CDI, the detector is placed in the far-field and the diffraction pattern does not change in structure but in size. In in-line holography,149 a coherent beam is produced by a FZP or a waveguide, and the sample is placed out of focus at a distance z1 from the X-ray focus in the illumination cone produced by the optics.149 The scattered wave and transmitted wave interfere and are collected on a 2D detector placed at a distance z2 ≫ z1 from the sample. The magnification is then z given by M = 1 + z2 . Example values are M = 130 (z1 = 38.6

shown in Figure 1c. To our knowledge, there are only a few examples of holographic hard X-ray imaging applied to biological cells. Freeze-dried Dictyostelium discoideum cells have been imaged by in-line holography by employing waveguides to produce the coherent beam156 at a resolution of 157 nm, limited by the relatively large distance z1. The authors captured a large field of view of 38 × 38 μm2 and used a low dose of 0.8 × 103 Gy. They demonstrated the use of waveguides to image cells by holography and were able to resolve several subcellular features such as globular particles of several hundred nanometers in size attributed to mitochondria (Figure 6a). With a similar setup and using waveguides, Wilke et al. studied Bacillus thuringiensis and Bacillus subtilis bacterial cells.155 The technique allowed the authors to obtain images with a large field of view (100 × 50 μm2) for studying many cells at the same time or a small field of view for imaging single cells at a resolution down to 65 nm. Thanks to the high resolution and phase information, the authors were able to measure the mass of endospores to 110−190 fg by integrating the mass density in eq 2 over the number of pixels. Bartels et al. studied Deinococcus radiodurans bacteria in 3D, as shown in Figure 6c157 as well as hydrated, living cells.158 In the first study, holograms of freeze-dried samples were imaged in a tomographic fashion by collecting 83 2D holograms in an angular range of 162 degrees and a spatial resolution of 125 nm was obtained.157 Furthermore, the authors were able to retrieve 3D density maps of Deinococcus radiodurans, with values ranging from 0.8 g/cm3 to 1.2 g/cm3 (see Figure 6c). In the second study, they achieved a resolution of 53 nm at a comparatively small dose of 5.2 × 103 Gy for freeze-dried cells. As this dose is much smaller than the lethal dose of these bacteria (about 20 kGy),159 the authors concluded that the

1

mm and z2 = 5.12 m) or M = 2800 (z1 = 1.81 mm and z2 = 5.13 m).154,155 A typical setup of an in-line holography experiment is 8552


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Figure 7. Combination of techniques. (a) Ptychography (gray scale) and scanning SAXS (color) images acquired from the same cell in a serial fashion. Reproduced from ref 104. Copyright 2016 American Chemical Society. (b) Phase map obtained by combined X-ray ptychography and holography of magnetotactic bacteria MO-1. Reproduced with permission from ref 172. Copyright 2016 Nature Publishing Group. (c) Xray fluorescence (S, K, Ca, and P maps) and ptychography phase map of a Chlamydomonas alga. Reproduced with permission from ref 171. Copyright 2017 Nature Publishing Group.

absorption spectroscopy (XAS),162 X-ray absorption nearedge spectroscopy (XANES, NEXAFS),163 or resonant soft X-ray scattering (RSoXS).164 These spectroscopic techniques are, however, mostly applied in the soft X-ray regime. Furthermore, correlative data from complementary methods, such as visible light (fluorescence) microscopy and electron microscopy increase the information available from an experiment. In the following paragraph, we highlight work that combines several X-ray techniques. The mineralization of fin bony rays from zebrafish was studied by XRF, SAXS, and WAXD.165 In order to locate the bone within the tissue, the authors mapped the calcium distribution by XRF. Simultaneously, they acquired SAXS and WAXD data. Owing to the XRF Ca map, they were able to analyze the SAXS and WAXD data at specific calcium-rich positions within the sample, revealing insights on the mineral phase containing amorphous calcium phosphate, octacalcium phosphate, or carbonated hydroxyapatite, including the mineral particle size and shape. SAXS and XRF are easily combinable, as the XRF detector can be placed at any angle from the sample. However, the position of the detector can be optimized to collect XRF spectra. For example, in case of thick samples a detector at 90° to the beam provides the highest signal-to-noise ratio, whereas for thin samples or samples with high concentration of specific elements, a larger detector at 180° (backscatter geometry) leads to the highest signal-to-noise ratio.166 Consequently, there are several more recent examples, such as a study of substantia nigra neurons in the elderly with additional complementary X-ray phase contrast imaging167 and work on Scrippsiella trochoidea microalgae that were manipulated by laser-based optical tweezers.168

viability of the bacteria should not be compromised and applied the method to living samples and reconstructed holograms at a resolution of 100−150 nm. The decrease by a factor of 2 to 3 in resolution (freeze-dried, 53 nm; living, 100−150 nm) is due to minute movements of the samples in the buffer solution. Arabidopsis seeds were studied by holotomography.160 The authors have imaged single mesophyll cells and palisade cells (Figure 6d) and were able to identify previously unobserved air space network in the seeds. They suggested that it serves to provide oxygen at the onset of germination. A recent study used holography for low dose imaging of mammalian cells in combination with scanning SAXS, as discussed further below (Figure 6b).154

COMBINATION OF TECHNIQUES In the previous sections, we have described a number of X-raybased imaging techniques that are sufficiently mature to be applied to cells and biological matter. Each technique has its specific strengths and drawbacks and most importantly they probe different properties of the studied object. For example in scanning SAXS, high-resolution structural information is collected in reciprocal space at the expense of a high dose, however, no real-space images are obtained, except for the pseudo-real-space dark-field representations. By contrast, in ptychography, high-resolution real-space images are acquired, but no internal structural information is revealed. Hard X-ray holography can achieve a similar resolution as ptychography at an even lower dose. A particular strength lies in combining the techniques we discussed above either with each other or with spectroscopic techniques such as X-ray fluorescence (XRF),161 X-ray 8553


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In our view, the most challenging issue in the field of X-ray imaging at the nanoscale remains radiation damage. When comparing the methods described above concerning the dose that needs to be applied, scanning SAXS imposes the highest energy on the sample, with values up to 108 Gy.104 However, in turn, reciprocal space structural information is retrieved with a resolution down to a few nanometers. Ptychography provides highly resolved real-space images with quantitative phase contrast at the expense of 106 Gy.101 Finally, holography only needs on the order of 103 Gy.158 Holography can identify weaker features compared to CDI, but CDI provides better resolution.173 Hagemann and Salditt have compared CDI and holography using a cell phantom.174 They found that in holography the performance is better than in CDI given the same number of photons per pixel and the same phase reconstruction procedure. However, holography in the hard Xray regime only became possible with third generation synchrotrons delivering highly coherent beams and is thus a relatively “young” technique. At the same time, hard X-rays offer the advantage of being applicable to denser and thicker specimens. We thus believe that in the future hard X-ray holography will play a major role in the investigation of biological structures by X-rays. Cellular systems or biological tissues are particular in the way that heterogeneities within the sample typically play an important role for their function. Hierarchical structures, such as in the cytoskeleton, the nucleus, in bone, wood or teeth encode certain mechanical and biological properties and it is thus of high interest to image and study the different levels of hierarchy. Ensemble averaging, as it is often applied to biological matter, such as known from solution SAXS, does not capture such heterogeneities and thus the methods we presented here provide many tremendous possibilities for future discoveries.

Ptychograpy and XRF are easily combinable as well. For example, they have been used to study the freshwater diatom Cyclotella meneghiniana,169 the green alga Ostreococcus sp.,170 or Chlamydomonas reinhardtii alga.171 Figure 7c shows the XRF maps (with sub-100 nm resolution) of different elements found in Chlamydomonas reinhardtii alga (sulfur, phosphorus, potassium, and calcium). The ptychogram was recorded at a spatial resolution better than 20 nm (Figure 7c central panel). The XRF and ptychography are acquired simultaneously and there is perfect registry between the two modalities. It is possible to closely overlay the chemical maps (from XRF) with the electron density maps (from ptychography). The authors identified electron-dense spherical structures in the ptychogram that are related to polyphosphate bodies (Ph in Figure 7c, right panel) because they contain polyphosphate complexed with calcium. The granule labeled Ca in Figure 7c has a much lower potassium concentration as compared to the other polyphosphate bodies. The authors suggested that this specific granule might undergo degeneration or aging. Ptychography and scanning SAXS were combined on the identical cells in a serial fashion.104 First, ptychography was employed to obtain high-resolution (about 60 nm) real-space images of the keratin network inside the cells (Figure 7a left panel). After identification of regions of interests from the ptychogram (Figure 7a central panel), diffraction data were acquired by scanning nanodiffraction. Thus, dark-field contrast images (Figure 7a right panel), where each pixel respresents the integrated intensity of a full diffraction pattern, were calculated. By analyzing the SAXS signal and fitting it to a bundle model,64 bundle and filament diameters, filament distance and arrangement were determined from whole unsliced and unstained cells. Recently, hard X-ray holography was successfully combined with scanning SAXS on freeze-dried neo-natal rat cardiac muscle cells.154 The full-field holographic (Figure 6b) data were ideal for locating the features of interest before the scanning SAXS acquisition and for controlling structural degradation and beam damage after the scanning SAXS measurement. Further, holography and ptychography were combined to study the magnetotactic bacteria MO-1 (Figure 7b).172 In ptychography (and diffraction in general) of weak-phase objects (such as soft matter), it is difficult experimentally to obtain a large dynamic range of diffraction patterns due to detector limitations. To overcome this challenge, the authors combined ptychography and X-ray in-line holography, named dark-field X-ray ptychography in their work. They were able to collect ptychography data sets with a beam-stop, and complemented the missing low scattering angle information by the holographic information.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Sarah Köster: 0000-0002-0009-1024 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS The authors thank T. Salditt, M. Burghammer, B. Weinhausen, and S.-C. August for fruitful discussions. This work was supported by the Helmholtz Gemeinschaft in the framework of Virtual Institute VH-VI-403 “In-Situ Nano-Imaging of Biological and Chemical Processes”, by the German Research Foundation (DFG) in the framework of SFB 755 “Nanoscale Photonic Imaging” within project C10 and the Cluster of Excellence and DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), and by the German Ministry of Education and Research (BMBF) under Grant No. 05K13OD4.

CONCLUSIONS In summary, we presented recent examples for the successful application of innovative X-ray imaging techniques at the nanoscale to biological cells and materials. X-rays provide a number of advantages over visible light and electrons, such as the high penetration depth, enabling the study of thick objects. Due to the small wavelength of X-rays, resolution limits are in the nm range for all presented techniques and are still being pushed further. Recent years have also clearly shown a lot of potential for combining several X-ray techniques either in series or in parallel, or in complementing the X-ray measurements by, for example, (fluorescence) visible light microscopy or electron microscopy in a correlative way.

VOCABULARY scattering, change of trajectory of a radiation due to interaction with a media, either elastic (no change of frequency) or inelastic (change of frequency); diffraction, special case of scattering by periodic samples satisfying Bragg’s law (2d sin θ = nλ); SAXS, small-angle X-ray scattering, recording of small 8554


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angle (0.1° to 10°) elastic scattering of X-rays by electrons in an object, which resonate with the frequency of the incident X-rays and emit coherent secondary waves interfering with each other; hard X-rays, electromagnetic radiation with an energy of 5 to 100 keV, corresponding to a wavelength of 0.25 nm down to 0.012 nm; soft X-rays, electromagnetic radiation with an energy of 100 eV to 5 keV, corresponding to a wavelength of 12.4 nm down to 0.25 nm; dose, mean energy absorbed by matter per unit mass due to ionizing radiation, expressed in Gray (Gy = J/ kg); radiation damage, physical change of matter due to the energy deposition of an ionizing particle or radiation

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