applied

sciences
Review
Tomographic Diffractive Microscopy: A Review of
Methods and Recent Developments
Ting Zhang 1 , Kan Li 2 , Charankumar Godavarthi 3 and Yi Ruan 2, *
1 Zhejiang Provincial Key Laboratory of Information Processing, Communication and Networking (IPCN),
College of Information Science & Electronic Engineering, Zhejiang University, Hangzhou 310027, China;
[email protected]
2 Collaborative Innovation Center for Bio-Med Physics Information Technology, College of Science, Zhejiang
University of Technology, Hangzhou 310014, China; [email protected]
3 Rue de l’hostellerie-Ville active, 30900 Nimes, France; [email protected]
* Correspondence: [email protected]




Received: 16 August 2019; Accepted: 10 September 2019; Published: 12 September 2019


Abstract: Tomographic diffractive microscopy (TDM) is a label-free, far-field, super-resolution

microscope. The significant difference between TDM and wide-field microscopy is that in TDM
the sample is illuminated from various directions with a coherent collimated beam and the
complex diffracted field is collected from many scattered angles. By utilizing inversion procedures,
the permittivity/refractive index of investigated samples can be retrieved from the measured diffracted
field to reconstruct the geometrical parameters of a sample. TDM opens up new opportunities to
study biological samples and nano-structures and devices, which require resolution beyond the
Rayleigh limit. In this review, we describe the principles and recent advancements of TDM and also
give the perspectives of this fantastic microscopy technique.

Keywords: tomographic diffractive microscopy (TDM); diffracted field; holographic interferometry;

inverse scattering

1. Introduction
Microscopy has revolutionized biological research and promoted the development of human
health. Despite the number of microscopes that have been created and applied for different research
objectives, such as the electron microscope [1,2], the atomic force microscope [3,4], etc., the optical
microscope is still the most used tool in biological research and life science due to its non-invasive
nature [5]. However, the spatial resolution of conventional optical microscopes is limited by Rayleigh
criterion, which is the smallest separation distance between two point sources that can be resolved,
0.61λ/NA (λ is the wavelength of light and NA is the numerical aperture of the objective). For the range
of visible light used in optical microscopes, this limitation is −250 nm. Attracted by the non-contact
mechanical property of optical imaging, enormous efforts have been made to find the way to overcome
this diffraction barrier, collectively termed as optical super-resolution microscopes [5,6].
By placing the light source or an optical probe near the sample at a distance shorter than the
wavelength, the diffraction limit can be bypassed by exploiting the properties of evanescent waves.
This has led to the so-called near-field super-resolution microscopes, such as scanning near-field
optical microscopy (SNOM), whose resolution is limited by the aperture size of the probe (or source),
typically of −25 nm [7]. However, SNOM is operated at near-field distance and in special conditions;
its application is thus limited.
Another common and powerful optical imaging technique is far-field super-resolution
microscopes, including the label (fluorescence) [8,9] and label-free microscopies [10,11], such as the

Appl. Sci. 2019, 9, 3834; doi:10.3390/app9183834 www.mdpi.com/journal/applsci

Appl. Sci. 2019, 9, 3834 2 of 18

stimulated emission depletion microscope [12], the stochastic optical reconstruction microscope [13],
the photo-activated localization microscope [14], and non-label far-field diffractive microscopes [15].
They have successfully overcome the diffraction limit to the level of tens of nanometers resolution.
Moreover, compared to near-field microscopes, these far-field ones greatly simplify the experimental
setup and increase numerous possibilities of practical use in biomedical research. However, in principle,
fluorescence-based methods rely on prior knowledge of the investigated sample, such as molecules and
the availability of specific fluorophores; recognition of antibodies against the specific molecules. In the
bio-medical usage of non-linear microscopies, such as multi-photon excitation (MPE) fluorescence
microscopy [16] and second-harmonic generation microscopy (SHG) [17], the labeling procedure
may also restrict the mobility of the molecules, affecting their functions. Moreover, photobleaching
and phototoxicity of fluorescent microscopy play limiting roles in biology [18]. Optical coherence
topography (OCT) has the ability to visualize the anatomic structures in three-dimensions and in high
resolution [19], but the lateral resolution is not well developed [20]. The coherent anti-stokes Raman
spectroscopy microscope (CARS) is a new imaging technique without sample labeling, but it requires
laser sources with excellent intensity stabilization [21]. Holography microscopes are able to view the
contrast difference, but the quantitative information of intrinsic properties of the sample, like index
of refraction or permittivity, is difficult to retrieve [22,23]. Consequently, tomographic diffractive
microscopy (TDM) is a super-resolution microscopy technique, it is label-free and far-field and works
in a close to physiological environment, one that is non-label, and principally at normal pressure
and room temperature. By illuminating the sample from various directions with coherent collimated
light and detecting the complex diffracted field from many scattered angles [15,24–26], together with
numerical inversion procedures, TDM has emerged to provide quantitative reconstruction of the
opto-geometrical characteristics of the sample [27–32].
The purpose of this review is to give an overview of the tomographic diffractive microscopy
technique. First, following a brief introduction of TDM theory, the accessible spatial frequencies
are analyzed under different TDM configurations. Second, we present the recent development of
TDM, including the optimization of optical setup and the improvement of inversion methods. Finally,
the problems remaining and the perspectives of TDM are discussed.

2. Theoretical Background
In conventional optical microscopes [33], the object is illuminated simultaneously by a sum
of plane waves spatially incoherent with each other. Each plane wave propagates with a different
illumination angle, so that the object is globally illuminated simultaneously with all possible angles,
within a given numerical aperture noted NAinc , which is the sine of the maximum illumination
angle with respect to the optical axis of the microscope. For the detection, the most commonly used
architecture consists in placing the object near the object focal plane of an objective lens; the diffraction
field is detected by the detector, such as a CCD camera, which is placed at the image focal plane of the
objective lens. However, limited by the NAinc of the objective lens, only parts of object diffracted field
information could be collected by the objective lens; this leads to the well-known Rayleigh criterion,
shown in Figure 1a.
To demonstrate the link between NAinc of the objective lens and its achievable spatial resolution,
we introduce the point-spread function (PSF) to describe the response of the imaging system to a
point source, which bridges the original object O and resultant image G as, G = O ∗ PSF. The Fourier
transform of PSF is defined as the optical transfer function (OTF), corresponding to a particular object
in the Fourier transform domain. The direction of light propagation could be defined by the wave
vector k = kx x + ky y + kz z. We define kk = kx x + ky y, where k propagates on the (x, y) plane. As not
all the light propagated through the sample   is detectable in conventional microscopes, only the plane
waves emerging from the sample with kk  ≤ k0 NA are collected, shown in Figure 2, where NA is
the numerical aperture of the microscope objective; Rayleigh criterion is thus introduced limiting the
Appl. Sci. 2019, 9, 3834 3 of 18

resolution as ∆r = 0.61λ/NA. Moreover, by using conventional optical microscopes, one is unable to

quantitatively
Appl. Sci. 2019, 9, xobtain theREVIEW
FOR PEER opto-geometrical characteristics of the sample. 3 of 19

Figure 1. Schemas of the wide-field microscopy and tomographic diffractive microscopy. (a)
Wide-field microscopy. (b) Tomographic diffractive microscopy.

To demonstrate the link between NA inc of the objective lens and its achievable spatial
resolution, we introduce the point-spread function (PSF) to describe the response of the imaging
system to a point source, which bridges the original object O and resultant image G as,
G = O * PSF . The Fourier transform of PSF is defined as the optical transfer function (OTF),
corresponding to a particular object in the Fourier transform domain. The direction of light
propagation could be defined by the wave vector k = kx x + k y y + kz z . We define
k = kx x + k y y , where k propagates on the (x, y) plane. As not all the light propagated through
the sample is detectable in conventional microscopes, only the plane waves emerging from the
sample with k ≤ k 0 NA are collected, shown in Figure 2, where NA is the numerical aperture
of the microscope objective; Rayleigh criterion is thus introduced limiting the resolution as
Δr =Figure
0.61λ1.1./Schemas
NA
Schemas. of
Moreover,
of the
the by microscopy
using
wide-field
wide-field conventional
microscopy optical
and tomographic
and tomographic microscopes,
diffractive
diffractive one is unable
microscopy.
microscopy. (a)
(a) Wide-field to
quantitatively
microscopy. obtain
Wide-field microscopy.the opto-geometrical
(b) Tomographic
(b) Tomographic characteristics
diffractive
diffractive microscopy. of the sample.
microscopy.

To demonstrate the link between NA inc of the objective lens and its achievable spatial
resolution, we introduce the point-spread function (PSF) to describe the response of the imaging
system to a point source, which bridges the original object O and resultant image G as,
G = O * PSF . The Fourier transform of PSF is defined as the optical transfer function (OTF),
corresponding to a particular object in the Fourier transform domain. The direction of light
propagation could be defined by the wave vector k = kx x + k y y + kz z . We define
k = kx x + k y y , where k propagates on the (x, y) plane. As not all the light propagated through
the sample is detectable in conventional microscopes, only the plane waves emerging from the
sample with k ≤ k 0 NA are collected, shown in Figure 2, where NA is the numerical aperture
of the microscope objective; Rayleigh criterion is thus introduced limiting the resolution as
Figure 2. A description of the accessible frequency domain of conventional microscopy. (a) The
Δr =sample
0.61λis/illuminated
NA . Moreover, by usingand
in normal incidence conventional
detected in theoptical microscopes,
same direction. one is unable
(b) The projection of the to
quantitatively
measurableobtain the wave
diffracted opto-geometrical characteristics
vector k onto the of the
transverse (xOy) sample.
in conventional microscopy.

Thus, two questions arise: Can we get the three-dimensional image of the sample and is it possible
to investigate the material properties of the sample? The answer is tomographic diffractive microscopy,
which was introduced by E. Wolf in the year of 1969 [34]. Upon recording complex diffracted fields
(amplitude and phase) by coherently illuminating the sample, the index of refraction or the permittivity
of the sample are retrievable by numerical inversion procedures, shown in Figure 1b [31,35–38].
Appl. Sci. 2019, 9, 3834 4 of 18

2.1. The Principle of Tomographic Diffractive Microscopy

An incident electromagnetic wave of [Einc , Hinc ] interacts with a sample in vacuum that occupies
a bounded region V in three-dimensional space and a relative permittivity ε(r) for r ∈ V, ε(r)= 1 for
r < V. By deducing the Maxwell equations, the total scalar field satisfies:

∇ × ∇ × E(r) − ε(r)k20 E(r) = 0 (1)

where k0 = 2π/λ is the wave number, where λ is the wavelength in vacuum. We transform Equation (1) as:

∇ × ∇ × E(r) − k20 E(r) = k20 χ(r)E(r) (2)

where χ(r) = ε(r) − 1 is the contrast of permittivity. The method for solving Equation (2) is to find the
Green’s function, i.e., to find the solution of the corresponding differential equation with a Dirac delta
inhomogeneity:
0 0 0
∇ × ∇ × G(r, r ) − k20 G(r, r ) = Iδ(r − r ) (3)

where I is the identity matrix. This Green’s function is known as the free-space dyadic Green’s function:
  0
0  1  eik0 |r−r |
G(r, r ) = I + 2 ∇∇  0  (4)
k0 4πr−r 

By solving Equation (2), we obtain the integral equation as:

Z
0 0 0
E(r) = Eref (r) + k20 G(r, r )χ(r )E(r )dV (5)
V

where the reference field Eref (r) consists of the field without a research object and is a special solution
to the homogeneous equation obtained by setting ε(r) to the homogeneous background, i.e., ε(r) − 1.
The scattered field Esca (r) is the difference between the total field and the reference field:
Z
0 0 0
Esca (r) = k20 G(r, r )χ(r )E(r )dV (6)
V

Notice that the conventional tomographic diffractive microscopy approach neglects the polarization
effects induced by the object and the setup, so that the scalar approximation used for the field and
Equation (6) can be rewritten as a scalar propagation equation in an inhomogeneous medium.

2.2. Born Approximation with Linear Inversion

In far-field cases, if the observation position r is sufficiently far away from the sample, or if the
sample is weakly scattered enough, typically the sample with small permittivity contrasts, i.e., ∆ε < 0.1;
the amplitude of the scattered field is tiny compared to that of the reference field; an approximation
termed Born approximation was commonly used in TDM [35,39–43]. The scalar Green function that
approximates the direction given by the wave vector k in far field is:

0 eik0 r ik·r
G(r, r ) = e (7)
4πr

where k = k0 rr . Defining Eref (r) as a plane wave with incident wave vector kinc , we obtain the scattered
field as:
eik0 r
Z
0 0
Esca (r) = k20 χ(r )e−i(k−kinc )·r dV (8)
4πr
V
 e ik0 r
 χ( r ′)e ( inc ) dV
-i k - k ⋅r ′
Esca ( r ) = k 20 (8)
4πr V
Appl.
From Sci. Equation
2019, 9, 3834 (8), in far field and the Born approximation conditions, the field 5scattered
of 18

Esca (r ) along the wave vector k for an illuminating wave vector k inc and the 3D Fourier
transformFrom Equation
of χ taken (8),
at in
k -fark inc
fieldare the Born approximation conditions, the field scattered Esca (r)
andproportional:
along the wave vector k for an illuminating wave vector kinc and the 3D Fourier transform of χ taken
at k − kinc are proportional: Esca (k - k inc ) ∝ χ(  k - k inc ) (9)
Esca (k − kinc ) ∝ e
χ(k − kinc ) (9)
Hence, thethe
Hence, dielectric
dielectricconstant contrast
constant contrast mapmap of object
of the the object
can becan be retrieved
retrieved by a simplebylinear
a simple linear
inverse
inverse Fourier
Fourier transform
transform of the scattered
of the scattered field recorded
field recorded in the
in the far field. far field.
Simon et al. Simon
reportedetseveral
al. reported several
successful
successful 3D biological sample reconstructions by TDM, shown in Figures
3D biological sample reconstructions by TDM, shown in Figures 3 and 4 [41,44]. 3 and 4 [41,44].

Appl. Sci. Figure

2019, A 3D
x3.FOR view of a Coscinodiscus sp. diatome using tomographic diffractive microscopy (TDM)
Figure 3.9, A 3D PEER
view REVIEW
of a Coscinodiscus sp. diatome using tomographic diffractive microscopy (TDM) 6 of 19
with Born approximation. The pictures depict an 18-step, 0◦ –180◦ rotation of the specimen [41].
with Born approximation. The pictures depict an 18-step, 0°–180° rotation of the specimen [41].

Figure 4. Betula pollen grain image reconstructed by tomographic diffractive microscopy (TDM) under
Figure 4. Betula pollen grain image reconstructed by tomographic diffractive microscopy (TDM)
Born approximation. (a,b) Volumetric cuts of a refraction image and an absorption image, respectively.
under Born
Scale bar:approximation.
10 µm. (c) Outer (a,b) Volumetric
view of the pollen: cuts
Imageofofathe
refraction
absorption image and an(d)absorption
component. Outer view image,
of
respectively.
the pollen:Scale bar:
Image 10 μm.
of the (c) Outer
complex view
index of of the pollen:
refraction. (e) (x-y) Image of the
cut through theabsorption
pollen [44]. component. (d)
Outer view of the pollen: Image of the complex index of refraction. (e) (x-y) cut through the pollen
[44]. The resolution of TDM under the Born approximation is determined by the accessible Fourier
domain, which depends on the configuration of the illumination and detection [45], which we will
discuss in the following
The resolution of TDM section.
under the Born approximation is determined by the accessible Fourier
domain, which depends on the configuration of the illumination and detection [45], which we will
discuss in the following section.

2.3. Rigorous Case with Non-linear Inversion

Born approximation is a scalar approximation restricted to the weakly scattered sample, while,
in the case of high permittivity contrast samples or the need for high quality sample reconstruction
resolution, a more sophisticated inversion procedure is required. The aim of the non-linear inversion
Appl. Sci. 2019, 9, 3834 6 of 18

2.3. Rigorous Case with Non-linear Inversion

Born approximation is a scalar approximation restricted to the weakly scattered sample, while,
in the case of high permittivity contrast samples or the need for high quality sample reconstruction
resolution, a more sophisticated inversion procedure is required. The aim of the non-linear inversion
procedure is stated as finding the permittivity ∆ε of high contrast samples, in which the multiple
scattering inside the sample cannot be neglected [36,46–49]. In rigorous cases, the total field inside
sample E(r), see Equation (6), cannot be simply replaced by Eref (r). We rewrite Equations (5) and (6) as:

E = Eref + AχE
(10)
Esca = BχE

where A denotes a square matrix of size (3N × 3N), contains all the tensors G(ri , rj ); i and j present a
point in the discretized sample bounded investigation domain, i, j = 1, · · · , N; B is a matrix of size (3N ×
3M) and contains the tensors G(ri , rk ); k = 1, · · · , M is an observation point in the observation domain.
Iterative methods are traditionally used for solving Equation (9) [49–51]. Assume the unknown sample
is restricted in a three-dimensional box Ω, the observations are at a far-field surface of Γ, the measured
field is fl , n is the iteration number, and L is the illuminations. The cost function of iterative procedure
can be written as:
L L
(1) 2 (2) 2
X X
Fn (χn , El,n ) = WΓ khl,n k + WΩ khl,n k (11)
Γ Ω
l=1 l=1
(1)
where hl,n and WΓ are the residual error and the weighting coefficient in the far-field, the lower part of
Equation (10):
 L −1
(1) X 
2
hl,n = fl − BχE WΓ =  kfl kΓ  (12)
l=1
(2)
and hl,n and WΩ are the residual error and the weighting coefficient in the near-field, the upper part of
Equation (10):
 L −1
(2) X 
2
hl,n = El,ref − El,n + Aχn El,n WΩ =  kχn−1 El,ref kΩ  (13)
l=1

A simulated scattered field could be obtained from the estimate of the relative permittivity,
like estimation from Born approximation [38]. By minimizing the discrepancy between the measured
scattered field and the simulated one, iterative methods are able to retrieve the distribution of sample
permittivity χ and the total field E in the bounded investigation domain [52]. Traditionally, non-linear
inversion methods are employed to investigate the arbitrarily shaped, anisotropic, and inhomogeneous
samples; however, there are some disadvantages, such as: (i) It is time-consuming, the computational
time is greatly increased with the enlargement of the investigation domain; and (ii) the computational
accuracy is mainly dependent on the number of discretions for the sample. Thus, these efficient
methods are suggested: Compromising the quality of reconstruction and computational time [53],
or incorporating the prior information of the sample [38,53]. For example, prior information of
sample size is helpful to minimize the investigation domain [53], or prior information of sample
permittivity/refractive index is useful to speed up the inversion procedure and also to improve the
resolution of the reconstruction. To the best of our knowledge, the reported resolution of TDM achieves
λ/10 using approximated knowledge of the sample permittivity, see Figure 5 [10].
reconstruction and computational time [53], or incorporating the prior information of the sample
[38,53]. For example, prior information of sample size is helpful to minimize the investigation
domain [53], or prior information of sample permittivity/refractive index is useful to speed up the
inversion procedure and also to improve the resolution of the reconstruction. To the best of our
knowledge, the reported resolution of TDM achieves λ / 10 using approximated knowledge of the
Appl. Sci. 2019, 9, 3834 7 of 18
sample permittivity, see Figure 5 [10].

Figure 5.
Figure Imagesofofa aresin
5. Images resinstar
starsample,
sample, sample
sample information:
information: 97 nm
97 nm wide
wide rodsrods of length
of length 520 and
520 nm nm
and height
height 140 nm140on
nm onsubstrate.
a Si a Si substrate. (a) Image
(a) Image of the sample
of the sample obtained obtained
by SEM. by(b)
SEM.
Image(b)ofImage of the
the sample
sample obtained
obtained by Darkfield
by Darkfield microscopy
microscopy numerical
numerical aperture
aperture (NA)(NA)of of objective0.95.
objective 0.95.(c)
(c) Reconstruction
Reconstruction
obtained with a hybrid inversion method from tomographic diffraction microscopy dataNA
obtained with a hybrid inversion method from tomographic diffraction microscopy data with equals
with NA
to 0.95. (d) Permittivity reconstructed with a bounded inversion method using
equals to 0.95. (d) Permittivity reconstructed with a bounded inversion method using the prior the prior knowledge
of the resin of
knowledge permittivity from the same
the resin permittivity fromdata
the as
same(c).data
(e) Permittivity distribution
as (c). (e) Permittivity z direction
along the along
distribution the z
versus the curvilinear abscissa of the dashed circle in (d) [10].
direction versus the curvilinear abscissa of the dashed circle in (d) [10].
3. The Resolution of Tomographic Diffractive Microscopy
The aim of TDM is to obtain a 3D reconstruction of the investigated sample. The link
between the measured scattered field and the 3D relative permittivity is given in Equation (9);
by merging the measured components as synthetic aperture generation, the permittivity contrast of
the sample is reconstructed through an inverse Fourier transform of the detected field under Born
approximation [54–56]. In principle, for a given angle of illumination (e.g., normal incidence) with
wave vector kinc , the Fourier components of the sample permittivity contrast were on a cap of sphere
of radius 2k0 , truncated by the numerical aperture (NA) of the objective. The sphere was centered on
the extremity of wave vector −kinc , as in Figure 2. In order to increase the amount of detectable Fourier
components, and thus improve the resolution of the object reconstruction, a variety of illumination
angles must be used. Since the accessible frequency domain for each illumination depends on k − kinc ,
we explain the resolution of TDM in three cases, see Figure 6.
 2k 0 , truncated by the numerical aperture ( NA ) of the objective. The sphere was centered on the
extremity of wave vector -k inc , as in Figure 2. In order to increase the amount of detectable Fourier
components, and thus improve the resolution of the object reconstruction, a variety of illumination
angles must be used. Since the accessible frequency domain for each illumination depends on
Appl. Sci. 2019, 9, 3834 8 of 18
k - k inc , we explain the resolution of TDM in three cases, see Figure 6.

Figure 6. A
Figure 6. A description
description of
of different
different configurations
configurations of
of tomographic
tomographic diffractive
diffractive microscopy
microscopy(TDM)
(TDM) and
and
the
the corresponding accessible frequency domains. (a) The different configurations of TDM. (b)
corresponding accessible frequency domains. (a) The different configurations of TDM. (b) The
The
accessible
accessible frequency
frequency domain
domain forfor complete
complete configuration.
configuration. (c)
(c) The
The accessible
accessible frequency
frequency domain
domain for
for
transmission configuration. (d) The accessible frequency domain for reflection configuration.
transmission configuration. (d) The accessible frequency domain for reflection configuration.
3.1. TDM in Complete Configuration
3.1. TDM in Complete Configuration
Ideally, samples of all directions within 4π radians are illuminated and these directions are detected
Ideally, samples of all directions within 4π radians are illuminated and these directions are
to obtain the maximum amount of Fourier components. Therefore, for a given illumination direction,
detected to obtain the maximum amount of Fourier components. Therefore, for a given illumination
the accessible Fourier component is a sphere with a radius of 2k0 NA, as in Figure 6b. With this
direction,configuration,
complete the accessibleallFourier component
the spatial is a given
frequencies sphere bywith
k − kaincradius
for any 2k0 NA
ofwave , askinand
vectors Figure 6b.
kinc are
accessible.
WithSci.
Appl. this Such
complete
2019, an PEER
9, x FOR OTF provides an
configuration,
REVIEW allisotropic
the spatialresolution
frequencies∆r = 0.61λ/
given k-k
by(NA +inc inc )any
NAfor , which
waveisvectors
nearly
9 of 19
twice the Rayleigh criterion ∆r = 0.61λ/NAinc . In this case, we simulated the OTF, a sphere of radius
k and k inc are accessible. Such an OTF provides an isotropic resolution
case,
2k we with
0 filled simulated the corresponding
one. The OTF, a spherePSF of is
radius 2k 0infilled
isotropic with one.
all directions andThe
givescorresponding PSF is
the same resolution
Δr3D
in = 0.61λ / (NA + see
dimensions, NAFigure) , which
7. is nearly twice the Rayleigh criterion Δr = 0.61λ
inc and gives the same resolution in 3D dimensions, see Figure 7. inc In this
/ NA .
isotropic in all directions

7. Point-spread function (PSF) image of TDM in complete configuration (a) Transverse cut of
Figure 7.
at zz =
the PSF at = 0. (b)
(b) Longitudinal
Longitudinal cut
cut of
of the
the PSF at y ==0.0.
PSF at

3.2. TDM in Transmission Configuration

In the case of the transmission, the optical axis is irradiated along the side of the sample and
detected on the other side. The reachable frequency range is a torus whose axis is symmetrical with
the z-axis, and its cross-section in the longitudinal plane consisting of two circles of radius
k0 NAinc , see Figure 6c. It is worth noting that since the accessible frequency domain of the
 Figure 7. Point-spread function (PSF) image of TDM in complete configuration (a) Transverse cut of
the 2019,
Appl. Sci. PSF at z = 0. (b) Longitudinal cut of the PSF at y = 0.
9, 3834 9 of 18

3.2. TDM in Transmission Configuration

3.2. TDM in Transmission Configuration
In the case of the transmission, the optical axis is irradiated along the side of the sample and
detectedIn theoncase
theofother
the transmission, the optical
side. The reachable axis is irradiated
frequency range is along the
a torus side ofaxis
whose the is
sample and detected
symmetrical with
on the other side. The reachable frequency range is a torus whose axis is symmetrical
the z-axis, and its cross-section in the longitudinal plane consisting of two circles of radius with the z-axis,
and
k0 NA its cross-section in the longitudinal plane consisting of two circles of radius k0 NAinc , see Figure 6c.
inc , see Figure 6c. It is worth noting that since the accessible frequency domain of the
It is worth noting that since the accessible frequency domain of the transmission configuration along the
transmission configuration along the z direction is smaller compared to the transverse direction x-y
z direction is smaller compared to the transverse direction x-y plane, the resolution of this configuration
plane, the resolution of this configuration is anisotropic and the axial resolution is about three times
is anisotropic and the axial resolution is about three times worse than the transverse resolution. In this
worse than the transverse resolution. In this case, we simulated the OTF, a torus filled with one; the
case, we simulated the OTF, a torus filled with one; the corresponding PSF is anisotropic, especially
corresponding PSF is anisotropic, especially along the z direction, shown in Figure 8b. This means
along the z direction, shown in Figure 8b. This means the axial resolution will deteriorate worse than
the transverse
axial resolution will deteriorate
∆r = 0.61λ/worse
(NA than
+ NAthe transverse resolution Δr = 0.61λ / (NA + NAinc ) .
the resolution inc ).

Figure PSFimage
8. PSF
Figure 8. imageofofTDMTDMinintransmission
transmissionconfiguration.
configuration.
(a)(a) Transverse
Transverse cutcut of the
of the at zat= z0.=(b)
PSFPSF 0.
(b) Longitudinal
Longitudinal cut cut of the
of the at yat= y0.= 0.
PSFPSF

3.3. TDM in Reflection Configuration

3.3. TDM in Reflection Configuration
For illumination and detection on the same side of the sample, there is a reflective configuration.
For illumination and detection on the same side of the sample, there is a reflective
Upon varying the illumination angles, the accessible frequency domain occupies part of the complete
configuration. Upon varying the illumination angles, the accessible frequency domain occupies part
sphere, see Figure 6d. Such a reflection configuration can significantly improve the axial resolution;
of the complete sphere, see Figure 6d. Such a reflection configuration can significantly improve the
however, the inverse Fourier transform of this accessible frequency domain yields a complex PSF; as a
axial resolution; however, the inverse Fourier transform of this accessible frequency domain yields a
result, if the sample under investigation has a complex permittivity, the complex PSF will mix the real
complex PSF; as a result, if the sample under investigation has a complex permittivity, the complex
and imaginary part of permittivity in the reconstruction. In this case, we simulated the OTF, a half
PSF will mix the real and imaginary part of permittivity in the reconstruction. In this case, we
of the complete sphere of radius 2k0 filled with one. The corresponding PSF is isotropic. However,
simulated to
compared the OTF, a half ofconfigurations,
the complete sphere
the PSFofofradius 2k 0 filled with one. becomes
The corresponding
Appl. Sci. 2019, 9,the above
x FOR PEERtwo
REVIEW the reflection configuration a complex
10 of 19
function, see the longitudinal cut of the imaginary part of the PSF at y = 0 in Figure 9b. This
PSF is isotropic. However, compared to the above two configurations, the PSF of the reflection
implies
configuration
that
at y the becomes
= 0reconstructed
in Figure aThis
complex
9b.real andfunction,
partimplies seepart
imaginary
that the theof
longitudinal cutpart
the permittivity
reconstructed real ofofthe imaginary
the
and sample part
will
imaginary of the
mingle
part ofinPSF
an
the
unpredictable way [57].
permittivity of the sample will mingle in an unpredictable way [57].

Figure 9.9.PSF
Figure PSFimage of TDM
image in reflection
of TDM configuration.
in reflection (a) Longitudinal
configuration. cut of the real
(a) Longitudinal cutpart
ofofthe
thereal
PSF
at y = 0. (b) Longitudinal cut of the imaginary part of the PSF at y = 0.
part of the PSF at y = 0. (b) Longitudinal cut of the imaginary part of the PSF at y = 0.

4. The Optical Setup of Tomographic Diffractive Microscopy

The TDM can be implemented in either transmission configuration or reflection configuration.
The need of quantitative phase measurement is the significant difference between TDM and
conventional wide-field microscopes [15]. The TDM setup consists of illuminating the sample with a
Appl. Sci. 2019, 9, 3834 10 of 18

4. The Optical Setup of Tomographic Diffractive Microscopy

The TDM can be implemented in either transmission configuration or reflection configuration.
The need of quantitative phase measurement is the significant difference between TDM and conventional
wide-field microscopes [15]. The TDM setup consists of illuminating the sample with a collimated
beam from controlled angles of incidence and recording the field diffracted by the sample in phase and
in amplitude. Varying the illumination of TDM: In principle, two methods are available for varying
illumination angles, rotation of the collimated beam [37] and rotation of the sample [58]; the former
is easier to realize. Keeping the sample static is easy to manipulate for a TDM user. A rotating
mirror permits control of the deflection of the collimated beam [37,59]; however, the missing parts of
non-captured frequencies present a strong anisotropic resolution along the optical axis, especially in
transmission configuration of TDM. To obtain an improved and isotropic resolution, Mudry et al. used
a mirror-assisted setup combining the transmission and reflection configuration together [57] or used
an ellipsoidal mirror for expanding the angular coverage of diffracted field detection [60]. Another way
for varying the illumination is rotation of the sample and keeping incident light static. In TDM under
transmission configuration, fixing the setup, the sample along the x-axis was successfully rotated to
give a quasi-isotropic resolution [61]. Using optical tweezers is another promising method [62–66].
To achieve complete configuration, a combination of specimen rotation and illumination rotation
simultaneously is also feasible by adopting an integrated setup [67]. Phase and amplitude detection of
TDM: An interferometric arrangement of setup—phase shift interferometry—is commonly used in
TDM for the detection of complex diffracted fields, see Figure 10a [38,68]; it involves shifting the phase
relative to the reference beam in steps, recording of the interference between the diffracted field and
reference beam for each phase step, and calculation of the phase from four or more detected intensities
on a CCD camera. For example, the intensity measured on the CCD camera can be written as S, adding
the phase shift by phase modulator, see Figure 10a; we could detect four successive intensities on the
camera as: q 
S1 = Isample +Ireference +2 Isample Ireference cos(ϕ+ π2
q
S2 = Isample +Ireference +2 Isample Ireference cos(ϕ)
q  (14)
S3 = Isample +Ireference +2 Isample Ireference cos(ϕ− π2
q
S4 = Isample +Ireference +2 Isample Ireference cos(ϕ − π)

where ϕ is the original phase differences between the diffracted field and the reference. The diffracted
(S 2 −S4 )+i((S 3 −S1 ))
field of the sample Isample could be retrieved as Esample = √ . Such a configuration
4 Ireference
is usually called an on-axis (or inline) system; since the phase information is obtained by making
consecutive image subtractions, it provides a precise measurement of the phase of the diffracted
field [69,70]. However, performing several phase steps is time consuming, especially if a large number
of illumination angles have to be applied successively in TDM. Phase fluctuations due to thermal
and/or mechanical drift during acquisition can interfere with the measurement [71,72]. An off-axis
setup is a simple configuration for measuring the complex diffracted field from a single hologram
and can avoid the image conjugation and enhance the imaging quality, but it is more sophisticated to
calibrate compared to the on-axis system, see Figure 10b [23,73,74]. The main difference of the setup
between on-axis and off-axis is the removal of the phase modulator. In off-axis, the references are
propagated with a carefully chosen angle. For the sake of simplicity, considering the interference in one
dimension, i.e., in x-axis, the intensity on the charge coupled device (CCD) camera could be written as:

S = Isample +Ireference +e−iαx Esample +eiαx Esample ∗ (15)

Appl. Sci. 2019, 9, 3834 11 of 18
Appl. Sci. 2019, 9, x FOR PEER REVIEW 12 of 19

Figure 10.
10. Schematic
Schematicimages
imagesofofthree
three different
different methods
methods for complex
for complex diffracted
diffracted field detection.
field detection. (a)
(a) Phase
Phase
shiftingshifting interferometry
interferometry setup. setup. (b) Off-axis
(b) Off-axis interferometry
interferometry setup. Compared
setup. Compared to (a),
to (a), the beam thesplitter
beam
splitter at theupper
at the right right corner
upper corner in rotated
in (b) is (b) is rotated
with awith a small
small angleangle so the
so that thatreference
the reference (blue)
(blue) doesdoes
not
not superimpose
superimpose on diffracted
on the the diffracted
fieldfield
(red).(red). (c) Quadri-wave
(c) Quadri-wave lateral
lateral shearing
shearing interferometry,
interferometry, wavewave
front
front sensors
sensors setup.setup.

By applying
By applying2D 2DFourier
Fouriertransform
transformofofSS,, the
theDirac
Diracfunction
function δδ±α introduced by ee±iαx
introduced by ± iαx helps us
helps us
±α
to retrieve the complex field of the sample. Moreover, the benefit from the nature of single-shot
to retrieve the complex field of the sample. Moreover, the benefit from the nature of single-shot
measurement in the off-axis method is that it could significantly reduce the setup sensitivity to external
measurement in the off-axis method is that it could significantly reduce the setup sensitivity to
fluctuations. However, it is worth noting that single-shot characteristics are measured at the cost of
external fluctuations. However, it is worth noting that single-shot characteristics are measured at the
the camera’s available pixels; a minimal off-axis angle to separate the different interference terms in
cost of the camera’s available pixels; a minimal off-axis angle to separate the different interference
the Fourier space and a maximal angle to successfully distinguish the interference fringes must be
terms in the Fourier space and a maximal angle to successfully distinguish the interference fringes
satisfied simultaneously [75]. To the best of our knowledge, the highest resolution of TDM reported as
must be satisfied simultaneously [75]. To the best of our knowledge, the highest resolution of TDM
one-tenth wavelength of the illumination was using off-axis to yield the phase and amplitude of the
reported as one-tenth wavelength of the illumination was using off-axis to yield the phase and
diffracted field [10]. Besides the interferometric setup, a Shack-Hartmann wavefront sensor can be used
amplitude of the diffracted field [10]. Besides the interferometric setup, a Shack-Hartmann
wavefront sensor can be used to measure the complex diffracted field without the reference beam,
see Figure 10c, to eliminate the external influences and minimize the measurement period [76–79]. In
Appl. Sci. 2019, 9, 3834 12 of 18

to measure the complex diffracted field without the reference beam, see Figure 10c, to eliminate the
external influences and minimize the measurement period [76–79]. In this sensor, a modified Hartmann
mask (MHM) was closely set in front of the detector to create replicas of the incident wavefront in several
identical but tilted waterfronts; their mutual interference patterns were then recorded on the detector.
The phase recovered by applying a Fourier transform to the interferogram. Primot et al. reported
the principle of recovering the intensity and phase of a field with multi-wave interferometry [80].
A successful employment of a wavefront sensor based on quadri-wave lateral shearing interferometry
(QWLSI) in TDM measurement has also been presented [37], but the disadvantage of this sensors is the
limitation of resolution compared to charge coupled device (CCD) or CMOS) cameras [37,81]. Notice
that most tomographic diffractive microscopy (TDM) setups have been used with a laser beam that
was polarized in one direction—vertically or horizontally—for both the illumination and the reference
wave if they are present; however, for the resolution of the measured sample, with respect to the TMD
system far beyond the Rayleigh criterion, the diffracted field close to the edge of the NA of the objective
is no longer parallel to the polarization of the illumination, a modified setup developed to retrieve the
full vectorial diffracted field; the resolution was thus significantly improved [82,83].
To conclude the development of the TDM setup, we present the recent remarkable progress of
TDM setups in Table 1.

Table 1. Recent progress of tomographic diffractive microscopy TDM setups.

Optical Illumination Measured Lateral

Inversion Reference
Schema/Configuration Wavelength Sample Resolution
nanofabricated
Off-axis/Reflection 475 nm 50 nm Non-linear [10]
objects
Bellis perennis
pollen grain
Off-axis/Completeness 475 nm 200 nm Linear [25]
Betula pollen
grain
nanofabricated
On-axis/Reflection 633 nm 400 nm Non-linear [38]
objects
prolate
On-axis/Completeness 633 nm ~300 nm Linear [60]
spheroid
Wavefront nanofabricated
633 nm 1 µm Non-linear [37]
sensors/Reflection objects

5. The Advancements of Tomographic Diffractive Microscopy

The purposes of the developments of TDM setup are to collect the diffracted field as much as
possible. In the best case, the complex diffracted field, including the phase and amplitude from all
possible angles of illumination and observation should be recorded for coverage of all frequency
domains in Fourier space to achieve an isotropic resolution. Limited by the size and the precision,
moving objectives and cameras are the challenges in a typical optical setup. Hence, illumination
and sample are the only two moving components in TDM. However, varying illumination while
keeping sample statics, whether in a transmission configuration or a reflection configuration, we only
obtain the sample information from one side, and thus cannot get tomographic images of the sample
with isotropic resolution. Rotation of the sample by optical tweezers seems promising; however,
this approach is limited to certain types of samples and its controllability and measurability should be
further proved [84]. A mirror-assisted method is thus a practical approach that detects the diffracted
field from both sides of the sample simultaneously [57]. It is important to note that it has the similar
principle of placing two opposing objectives as in a typical 4 pi microscope setup, but it provides much
simpler practical implementation [85].
Appl. Sci. 2019, 9, 3834 13 of 18

The purpose of the inversion algorithm of TDM is to reconstruct the nature and the
three-dimensional geometry of the investigated sample from the detected complex diffracted field
and its corresponding illuminations. Most TDM applications are applied under Born approximation;
the linear relationship between the sample permittivity and the diffracted field permits us to reconstruct
the sample opto-geometry by using a simple inverse Fourier transform. However, to image high
contrast sample, multiple scattering cannot be neglected and non-linear numerical inversion procedures
are necessary. However, the main bottleneck of the non-linear inversion method is computation time.
To overcome this disadvantage, a combination of linear and non-linear methods is helpful; for example,
a fast Born approximation may provide noisy sample localization and reconstruction [10] that are
useful for minimizing the investigation domain of the non-linear inversion procedure. One reported
integrating DORT (décomposition de l’opérateur de retournement temporal) and SVD (single value
decomposition) methods to quickly localize the sample from a noisy environment. This not only
improves the resolution but also ameliorates the reconstruction speed [53,86]. Furthermore, if prior
information of a sample, such as an estimation or range of sample permittivity, is available, the resolution
can be improved [10].
The advantages of TDM are remarkable; while microscopes like the digital holographic microscope
are able to provide a 3D topography of the samples [23,87,88], the ability of quantitative reconstruction
of the sample permittivity/refractive index using TDM is unique; moreover, the lateral resolution
in TDM has been well improved far beyond the Rayleigh criterion [15]. The studies of TDM have
been increasing rapidly in recent years. To our knowledge, the first commercial products of TDM
were released by Nanolive in Switzerland in 2015 [89], and Tomocube KAIST in Korea at 2017 [90].
These work with transmission configuration and provide 3D reconstructions of cells with transverse
resolutions of 200 nm and axial resolutions of 400 nm [91]. Hence, future developments may
focus on the implementation of the reflection configuration and the use of multiple wavelengths of
illumination to improve the axial resolution. Moreover, integrating TDM with other super-resolution
techniques can provide multiple-modal image methods; for example, a combination of TDM with
single molecule fluorescent microscopes is able to perform the structural and functional analysis of a
sample simultaneously; a combination of TDM with scanning probe microscopy permits the structural,
topographic, and chemical (tip-enhanced Raman spectroscopy, TERS) information of a sample. To the
best of our knowledge, TDM has only been applied to investigate the individual structures, such as
isolated cells and nano-fabricated structures, but three-dimensional imaging of unmarked raw tissues
is also possible using TDM.
However, every coin has two sides; it is worth noting here that the main drawbacks of TDM are:
(i) TDM under Born/Rytov approximation is only valid for samples with low permittivity contrast
∆ε < 0.1; (ii) TDM under Born approximation has a resolution limit which is twice as good as the
Rayleigh criterion resolution; (iii) the non-linear inversion procedures improve the resolution but are
time-consuming. Several hours are at least necessary to reconstruct the investigated sample, thus it
is difficult to realize real-time analysis for the samples using non-linear inversion methods. (iv) An
isotropic resolution still remains a challenge, despite several studies reporting TDM with isotropic
resolution [44,57,67], and a combination of sample rotation with illumination rotation not only needs
accurate correction of the angles, but also greatly increases the amount of data collected [44,67].

6. Conclusions
Compared to other microscopies, TDM permits us to study the sample in a label-free condition.
It provides 3D quantitative reconstruction of the investigated sample and breaks the Rayleigh limit.
With the developments of digital holographic techniques [92,93], the phase detection in optics becomes
more and more simple and reliable, the off-axis methods and wave front sensors are able to retrieve
the complex diffracted field from single-shot measurements, and thus provide high-speed detections;
we believe they are the futuristic techniques in favor of TDM applications. Micro-manipulation tools
are promising methods for enlarging the accessible frequency domain, improving the reconstruction
Appl. Sci. 2019, 9, 3834 14 of 18

resolution. Like using optical tweezers [94], the sample can be rotated without any mechanical contact.
Similarly, using electric fields to rotate the sample is another way to achieve micro-rotation of the
sample [95]. Inversion procedures are mandatory in TDM; for low contrast samples, e.g., biological
cells, Born approximation [96] or Rytov approximation [97,98] is sufficient to provide a real-time
reconstruction [97]; however, for high contrast sample, e.g., nano-structural materials, sophisticated
non-linear inversion methods are necessary. To the best of our knowledge, it is still time-consuming to
characterize the sample by iterative methods. Using a priori information of the sample, e.g., estimation
of sample location and estimation of sample permittivity, is a promising approach to greatly reduce the
reconstruction time.
In conclusion, we present this review to give an overview of TDM, including the principle, the setup,
and the inversion methods for different applications; the limitations of TDM are also addressed. From
a sample imaging point of view, the quantitative measurement of the permittivity/refractive index
of a sample using TDM could provide complementary and useful information in association with
other microscopies. As TDM can be used to image both low contrast samples and high contrast ones,
it will play a key role not only in the exploration of biological cells but also in the investigation of
nano-structural devices.

Author Contributions: T.Z., K.L., Y.R.; writing—original draft preparation, C.G. writing—review and editing.
Funding: This work was funded by National Nature Science Foundation of China Grants NSFC [61801423] (T.Z.),
NSFC [61805213] (Y.R.), NSFC [61605171] (K.L.). The Fundamental Research Funds for the Central Universities
2018FZA5006 (T.Z.).
Conflicts of Interest: The authors declare no conflict of interest.

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