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Nitrogen-vacancy centers in diamond for nanoscale magnetic
resonance imaging applications
Alberto Boretti*1,2,§, Lorenzo Rosa3,4, Jonathan Blackledge5,6,7 and Stefania Castelletto8
Review Open Access
Address:
1Department of Mechanical Engineering, College of Engineering,
Prince Mohammad Bin Fahd University, Al Khobar, Saudi Arabia,
2Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh
City, Vietnam, 3Department of Engineering “Enzo Ferrari”, University
of Modena and Reggio Emilia, Modena, Italy, 4Applied Plasmonics
Lab, Centre for Micro-Photonics, Swinburne University of Technology,
Hawthorn, Victoria, Australia, 5School of Electrical and Electronic
Engineering, Technological University Dublin, Ireland, 6Faculty of
Science and Technology, University of Wales, Wrexham, United
Kingdom, 7Department of Computer Science, University of Western
Cape, Cape Town, South Africa and 8School of Engineering, RMIT
University, Bundoora, Victoria, Australia
Email:
Alberto Boretti* - a.a.boretti@gmail.com
* Corresponding author
§ Email: albertoboretti@tdtu.edu.vn
Keywords:
nanodiamonds; nanoscale magnetic resonance imaging (nano-MRI);
nitrogen-vacancy center; optically detected magnetic resonance
Beilstein J. Nanotechnol. 2019, 10, 2128–2151.
doi:10.3762/bjnano.10.207
Received: 04 May 2019
Accepted: 09 October 2019
Published: 04 November 2019
Associate Editor: P. Leiderer
© 2019 Boretti et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The nitrogen-vacancy (NV) center is a point defect in diamond with unique properties for use in ultra-sensitive, high-resolution
magnetometry. One of the most interesting and challenging applications is nanoscale magnetic resonance imaging (nano-MRI).
While many review papers have covered other NV centers in diamond applications, there is no survey targeting the specific devel-
opment of nano-MRI devices based on NV centers in diamond. Several different nano-MRI methods based on NV centers have
been proposed with the goal of improving the spatial and temporal resolution, but without any coordinated effort. After summa-
rizing the main NV magnetic imaging methods, this review presents a survey of the latest advances in NV center nano-MRI.
2128
Review
Introduction
Spin echoes and free induction decays were first detected in
1950 [1] and the first nuclear magnetic resonance (NMR) spec-
trum was reported in 1952 [2]. The first NMR image followed
about two decades later, in 1973 [3]. It was not until 1977 that
the first human magnetic resonance (MR) images were
published [4]. The last few decades have seen the consolidation
of MRI as a medical technique, with the purpose of imaging
soft body tissues and organs through the excitation of their
Beilstein J. Nanotechnol. 2019, 10, 2128–2151.
2129
atomic nuclei with high-frequency radio pulses and the mea-
surement of the response in a strong magnetic field. Recent
research has included using MRI for nanoscale imaging,
enabling image resolution on the molecular or even the atomic
scale. This has given rise to the investigation of nanoscale mag-
netic resonance imaging (nano-MRI) [5].
Different nano-MRI technologies have been proposed that are
based on different sensors. Some of these technologies use the
nitrogen-vacancy (NV) centers in diamond as sensors. The NV
centers in diamond are one example of a sensor for nano-MRI.
Optical measurements with NV centers combined with electron
paramagnetic resonance (EPR) were established at the end of
the 1970s [6], although it was only in 1991 that EPR was also
observed without illumination [7]. The characterization of
single NV centers became popular at the end of the 1990s. It
was demonstrated that the fluorescence of single NV centers
can be detected by room-temperature fluorescence microscopy
and that the defect shows perfect photostability [8]. Room-tem-
perature optically detected MR (ODMR) with NV centers was
also demonstrated [8].
Conventional MRI makes uses of contrast agents to enhance
sensitivity and resolution. In principle, the combination of mag-
netic and radio-frequency excitation in MRI techniques allows
for resolution enhancement both spatially and temporally, while
producing deep tissue imaging with outstanding contrast,
enabling anatomical and functional observation at the same
time. Contrast agents are chemical substances used to enhance
and improve the quality of the MRI images. The ferromagnetic
or paramagnetic nature of a contrast agent determines the posi-
tive or negative imaging contrast for resolution as fine as cell
clusters. The more precise the imaging that is required, the
higher is the dose of the contrast medium that is necessary. This
poses a question of possible toxicity that must be adequately
considered and ultimately constitutes a key limitation to the
deployment of this technique in clinical practice [9].
Nanoscale MRI or nano-MRI is a novel technique aiming to
improve MRI resolution to the nanometer scale (from current
values of tens of micrometers), which would enable the mea-
surement of the MR of a single biomolecule. MRI imaging can
visualize internal tissues in vivo, and functional MRI (fMRI)
can map brain activity with millimeter-scale resolution, which
is a significant improvement for clinical diagnosis [10]. This
application of nano-MRI is being actively developed with the
aim of reaching nanometer-scale resolution, which would allow
for single-molecule resolution and extend the imaging tech-
niques to molecular biology. Magnetic imaging is fundamental
for exploring chemical–physical magnetic processes and
expanding the capacity of magnetic data storage units, enabling
high-resolution, real-time imaging beyond the limitations of
current approaches based on the magneto-optic Kerr effect in
X-ray and electron microscopy [11].
Nano-MRI techniques studied in current research endeavors
include several quantum mechanical and nanotechnological ap-
proaches, such as optically detected MR (ODMR) using NV
centers and MR force microscopy (MRFM). Among the other
approaches, magnetic dipole interaction is a new way to replace
magnetic induction to allow for nanoscale MRI detection and
has delivered promising results in the employment of spin
sensors based on atomic-scale diamond impurities. The use of
diamond NV centers with nano-MRI has allowed for in vivo
imaging on the single-biomolecular scale at room temperature
[12].
Other approaches not based on NV centers are evolving at the
same pace as methods based on NV centers. For example, a
new method for high-resolution nano-MRI coupling high spin
sensitivity of nanowire-based MR detection with high-spectral-
resolution NMR spectroscopy is presented in [13]. In terms of
future commercial products that permit nano-MRI to be under-
taken at hospitals and for medical research, it will inevitably be
required that they be produced in a way that secures the best
trade-off between cost and performance.
Nano-MRI employing nuclear spins is limited by the
spin–lattice relaxation time. This time is longer in singlet states.
It affects the chance of using weak spin–spin interactions and
hyperpolarized media. The symmetry mismatch between singlet
and triplet states prevents interaction so that singlet relaxation
can only be mediated by higher-order weak processes, making
use of adjacent spins which give the same difference bars as
radio frequency (RF) access to singlet states. M2S and spin-
lock induced crossing (SLIC) [14] are examples of pulse se-
quences to circumvent this limitation, transferring the polariza-
tion of the triplet state by coupling near-equivalent spins
depending on spectroscopic features, namely, the J coupling pa-
rameter and the chemical shift differences. J coupling measure-
ments as low as 10 MHz difference have been experimentally
shown [15], reflecting the syn- to anti-geometry discrimination
ability to resolve protein structures. Since protonic spin life-
times are on the scale of seconds, long-range detection is
limited by the coupling resolution (on the order of 100 MHz),
when long-range (up to five or more bonds away) weaker
couplings can be detected by transferring to the singlet state.
Magnetic nanoparticles (MNPs) can act as contrast agents [16]
to improve the imaging of tumors in specific cancer MRI.
Multimodal imaging has been recently made possible by func-
tionalizing the particle surface with biocompatible chemicals,
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where surface coverings (such as the coronas of proteins) are
fundamental to making nanoprobes biocompatible. However,
this promising field still needs to overcome challenges to
deliver its full potential.
Solid chemical shifts have been measured in 2D with 1 µm
accuracy by MR force microscopy [17], a technique that is
readily extendable to 3D imaging by exploiting several spectral
lines. Fourier/Hadamard transform techniques allow
frequency–space multiplexing for faster measurement, where
spatial information is recovered through Hadamard encoding
and quadrature detection.
Hyperpolarization is a novel functional medical imaging tech-
nique that can dramatically increase the signal-to-noise ratio
(SNR) in traditional MRI. The method is being applied to small
injectable endogenous molecules, which can be used to monitor
transient in vivo metabolic events in real time. Among all meth-
odologies, the emergence of hyperpolarized 13C-labeled probes
(such as 13C pyruvate) has best enabled the monitoring of core
cellular metabolic events. Hyperpolarized molecular com-
pounds are obtained, for example, from carbon-13-containing
molecules. This is done by transferring the electron spin polari-
zation to the 13C nuclei at cryogenic temperatures using
dynamic nuclear polarization (DNP). This process is followed
by rapid dissolution to create an injectable solution in the
human body. This procedure can provide up to a 10,000-fold
increase in the signal compared to typical thermal polarization
conditions. The 13C-labeled probes must be well-suited for
medical applications and must undergo the hyperpolarization
process.
Some methods are proposed in [18], albeit not yet applied in
biomedical samples, using nanodiamonds (NDs) as a contrast
agent to improve the SNR in conventional MRI. While NDs
have been recently applied as theranostic platforms, due to their
biocompatibility and low toxicity compared to other nanomate-
rials, the concentration of 13C nuclear spins is diluted (1.1%) in
the diamond unless they are enriched with an 13C isotope
during growth, which is an expensive process. Used in bulk, a
high-purity diamond can exhibit 13C T1 (spin–lattice relaxa-
tion) times of many hours. This is an advantage compared to
other liquid-phase compounds as hyperpolarized 13C spins
usually relax on timescales of T1 ≈60 s to thermal equilibrium.
In [18], synthetic, inexpensive, commercial ND with a diame-
ter ranging from a micrometer to 25 nm were hyperpolarized.
The large-sized particles were hyperpolarized at 25 mK using
the brute force polarization method based on the application of
a high magnetic field (4T) to increase the Boltzmann popula-
tion difference in the nuclear spins. In this case, the spin system
thermalizes (loses polarization) on timescales of 53 min. DNP
was also used at 4 K and a nuclear polarization of 8% was
achieved in larger micrometer-sized diamonds. However, the
spin relaxation time was not increased. Hyperpolarization at
room temperature for 350 nm NDs in water provided an en-
hanced 13C nuclear spin resonance signal, with relaxation times
of several minutes. In terms of relaxation times, these results
are not enough for polarization transfer, which is necessary to
enable the application of NDs in standard MRI technology.
In this context, in [19], another approach for the hyperpolariza-
tion of NDs was pursued. The Overhauser effect is used which
is a proton–electron polarization transfer technique. The process
transfers the spin polarization from paramagnetic impurities
within NDs and the surfaces to 1H spins in the surrounding
water solution (cross-polarization sequences). This is known as
Overhauser-enhanced MRI (OMRI) and the presence of NDs in
the solution permits the enhancement of the 1H MRI signal that
is readily dependent on the ND concentration. NDs are a source
of polarized electron spins attributed mostly to a P1 center
(nitrogen substitutional) and unpaired electrons at the nanoparti-
cle surface, which are detectable by conventional EPR methods.
The procedure involves an AC RF magnetic field in resonance
with the EPR spin frequency, driving the ND electron spin po-
larization which is then transferred to the interacting 1H nuclei
in the water containing the ND. 1H nuclei resonance is then
detected by using a standard inductive NMR technique. An en-
hancement in the detection of 1H of −4 over the thermal 1H
spectrum is achieved. This enhancement is mostly in 125 nm
NDs rather than in 18 nm, and it is larger for higher concentra-
tions. However, the relaxation time is shorter at higher ND con-
centrations. This is not surprising as spin impurities reduce spin
relaxation times. Furthermore, high-pressure high-temperature
(HPHT) NDs provide a good enhancement while natural
diamonds are not useful with this technique due to the low con-
centration of spin impurities. Vials with deionized water and
NDs in solution were imaged using ultra-low-field MRI and
OMRI sequences. The difference images from the two methods
reveal a higher contrast of the NDs compared to water. More-
over, this method permits a better tracking of NDs in biological
samples using OMRI sequences.
NV-center quantum sensing
There are different concepts associated with NV center sensors
for magnetic imaging applications. An NV center is an atomic
size point defect in diamond. Standard optical techniques are
capable of resolving the photoluminescence signal of a single
NV center, the detection of which is facilitated particularly in
the negative charge state (NV−). Room temperature manipula-
tion of electron spins at the NV centers by means of magnetic
or electric field, microwave or light irradiation, or a combina-
tion thereof, allows the generation of sharp resonances in the in-
Beilstein J. Nanotechnol. 2019, 10, 2128–2151.
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tensity and wavelength of the NV photoluminescence. The
origin of these resonances is interpreted using quantum optics
and spin theory, which describe them in terms of spin–orbit
interactions and Rabi oscillations. To achieve NV color centers
in diamond that are applicable to magnetometry, the reader
should refer to the technical information in [20] on the diamond
material preparation. Specifically, NV forms in both bulk and
ND – this option introduces more opportunity in terms of appli-
cations, even if the ND NV magnetic sensing technology is less
developed. A review of the superior properties of diamond
nanomaterials and the NV centers, as well as their uses in bio-
medical applications, is given in [21], which includes details on
biosensing, bioimaging and drug delivery as well as biocompat-
ibility. The toxicity of diamond nanostructures is also dis-
cussed.
Electron spin resonance (ESR) of the NVs themselves is
exploited in [22] to achieve single-spin subwavelength resolu-
tion in the optical region. Diamond NV centers are used to
improve the low SNR and resolution for single-spin images
beyond the usual methods of increasing acquisition times and
lowering temperatures. MRI using magnetically equivalent NV
center spins provides a resolution of less than the wavelength of
the readout light, showcasing nanotesla sensitivity and nanome-
ter resolution at room temperature.
The general principles of NV center optical magnetometry are
given in [23]. An NV center based single electron magnetome-
ter in a commercial diamond is built under an ODMR micro-
scope in [24]. The optically detected time window is optimized
to obtain a better SNR and dynamical decoupling sequences are
used to increase the coherence time of the spin sensor by sup-
pressing spin decoherence due to the environment. This in-
creases the sensitivity in the magnetic field amplitude measure-
ments. Dynamical decoupling schemes are based on π pulse
trains which command the spin precession abruptly. Recently,
dynamical sensitivity control (DYSCO) has been proposed,
aiming to provide smooth and analog sensitivity modulation
[25]. In this control method, |2π| ambiguities are removed with-
out sacrificing accuracy. An enhancement of the dynamic range
by a factor of 4 × 103 is achieved for interrogation times
exceeding 2 ms. Optical detection of weak magnetic fields in a
spin bath is undertaken in [26] by sensing external magnetic
dipoles with fluorescent ND due to the charge dynamics of
coupled spins. This provides ultrashort 10 ms acquisition times
in sub-nanomolar amounts of Gd spins.
The photobleaching and blinking issues of NV are addressed in
[27] by use of fluorescent ND (FND), which has an extremely
high NV center concentration. Their lifetimes are longer than
fluorescent biomolecules, and the emission can be modulated
with a magnetic field giving increased sensitivity. As bio-
imaging probes, they are versatile, cost-effective and easily
functionalized, in addition to being easy to coat with silica for
biomedical applications. Background-free imaging, both in vivo
and in vitro, is achieved by applying an alternating magnetic
field in a traditional fluorescence microscope. As NV centers
can be placed much closer to the sample, within a few nanome-
ters of the surface, NV magnetometry has a clear advantage
over conventional methods [28,29].
The interaction between the NV center and the sample can be
carried out in one of three ways: (1) fabricating the sample on
the diamond; (2) placing a nanostructured diamond on the sam-
ple surface; (3) holding the NV center probe on a scanner and
moving it across the sample surface.
The first approach involves the detection of magnetic fields
using near-surface NV centers in bulk diamond. This approach
can be further divided into the use of single or an ensemble of
NVs for the detection of a few nuclear spins near the surface.
The first relies on the longest coherence time of a single NV in
ultrapure 12C-enriched diamond and in methods to extend the
NV coherence time using complex spin manipulation se-
quences. This approach results in the best achievable sensi-
tivity of magnetic field sensing based on this atomic sensor.
Alternatively, a high concentration of NV centers are formed
close to the surface of bulk diamond using delta-doping tech-
niques, and in this case, ensembles of NVs are used to image
cells with subcellular resolution, as demonstrated for example
in [30]. These examples are also known as diamond magnetom-
eters and are often referred to as vector magnetometry [31], as
the orientation and intensity of the magnetic field are extracted.
Currently, an NV ensemble in a single-crystal diamond vector
magnetometer [31] can allow for the retrieval of all Cartesian
components of a dynamic magnetic field with a bandwidth of
5 Hz to 12.5 kHz for a 50 pT/√Hz magnetic field. The best
magnetic field sensitivity currently achievable for a single NV
center is of the order of 1 nT·Hz−1/2. Higher sensitivity is
possible using either NV ensembles <1 pT·Hz−1/2 [32] or ad-
vanced sensing protocols used in a so-called AC magnetometer
[33]. For an ensemble, in bulk experiments, the best broadband
sensitivity is 15 pT Hz−1/2 over 80 Hz to 2 kHz [34]. Using en-
semble AC measurements, the sensitivity of the magnetic field
is 0.9 pT·Hz−1/2 for a 20 kHz magnetic field [35].
Other NV sensors can be made in an array of NVs in bulk
diamond or as nanostructures in bulk diamond, such as nanopil-
lars. This second approach suffers from a lack of scalability in
sensor fabrication, so it is rarely used. Scanning NV center
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probe and scanning magnetic tip magnetic sensing with high
spatial resolution [36] have also been proposed. Recent
advances in diamond fabrication for scanning tip magnetom-
etry have been achieved by a functionalized ND with NV center
magnetic spins scanned by attaching it to the tip of an atomic
force microscope (AFM). This can also be achieved by
mounting a high-purity diamond nanopillar on an AFM with an
NV center placed 10 nm from its end, achieving a sensitivity of
56 nT·Hz−1/2, as reported in [37].
Nanodiamond scanning tips currently suffer from a statistical
process to integrate the NV in the tips. This limits the applica-
tions due to excessive complex and non-scalable fabrication
procedures, based on nanoscale manipulations [38]. A more
promising approach [39] relies on generating an NV center less
than 20 nm below the surface in a diamond nanopillar mounted
on a thin platform, typically of less than 1 μm thickness.
Coupled with the nanopillar, this diamond film makes a scan-
ning probe when mounted to an AFM head. It is expected that
this method can enhance the photoluminescence collected from
the NV by a factor of 10.
Finally, ND embedded in a living cell can be directly used as a
fluorescence probe and temperature sensor. A review on the use
of fluorescent NDs for tracking in living cells is given in [40]
and [41]. Later in this review, we discuss cell temperature
mapping by ND NV spins. Direct magnetic imaging in cells
using NDs has not yet been developed.
Based on the measurements that are performed using NV
sensors, NV nano-MRI can be further distinguished, irrespec-
tive of whether DC or AC probing methods are implemented.
The choice of method is determined by the sensitivity and reso-
lution subject to the required field-of-view. DC methods rely on
the application of a fixed small magnetic field and are used to
measure constant external magnetic fields. They use, as a read-
out, the ODMR of one or more (an ensemble) NVs. DC magne-
tometry, based on ODMR, can be achieved through the applica-
tion of a continuous or a pulsed optical and microwave excita-
tion to increase sensitivity. AC magnetometry permits the mea-
surement of variable magnetic fields when pulsed optical exci-
tation and pulsed microwave excitation are used. Various
microwave sequences are used such as Rabi oscillation, spin-
echo sequences (closer to conventional MRI as it needs a mea-
surement of the spin–spin relaxation T2 time [28]) and
universal dynamic decoupling protocols [12,42]. These pulsed
sequences are used to increase sensitivity to the point of
measuring Larmor frequencies of nuclear spins [12]. Nanoscale
MRI frequency encoding is used for coherent control and the
site-selective addressing (Rabi oscillations) of 1 × 4 arrays of
NV sites separated by ≈15 nm. The order of three NV centers
per site have the same orientation, detected by measuring the
fluorescence count rates in a standard confocal volume [43].
Stimulated emission depletion (STED) microscopy (see a de-
scription of STED in diamond in [44] and [45]) is first obtained
to confirm the nanoscale geometry of the sites. An image of
four sites is reconstructed by using the NV Fourier magnetic
imaging (FMI) technique in k-space [46]. The key ingredient is
to use a micro-coil fabricated on the diamond chip to supply
electrically tunable magnetic field gradients of ≈0.1 G/nm. In
addition, the frequency encoding consists of mapping the posi-
tions of spins at various locations onto their resonance frequen-
cy, using tunable magnetic field gradients. In fact, DC magnet-
ic gradients attribute a difference ODMR to the four NV sites.
By adding to the DC gradient field, frequency-tailored pulse se-
quences, the method addresses and controls the spins at specif-
ic target positions. This technique is derived from conventional
biomedical MRI for image slice-selection with millimeter-scale
resolution.
Upon applying a DC magnetic field gradient, the Zeeman split
between the |±1⟩ states in individual NV centers becomes posi-
tion-dependent and gets a specific microwave resonance fre-
quency, allowing for individual manipulation. To prove site-
selective NV center addressing by frequency encoding, ODMR
measurements are performed with a DC electric current in-
duced through a micro-coil to achieve a DC gradient. Four
ODMR peaks, corresponding to the four NV sites in the array,
are clearly seen. This allows the control of an individual NV
site (which holds three identical NVs) using different ODMR
frequencies. Site-selective coherent Rabi driving is seen when
the frequency is varied to match each site’s ODMR frequency.
The NV FMI technique in k-space is then applied to each site
by adding an AC magnetic field gradient to super-resolve each
site. By synchronizing this gradient with a Hahn echo NV
center pulse sequence, the spatial information is encoded on the
NV spin phase for each site in “k-space”. The gradient strength,
and hence the wavenumber k, is gradually increased by step-
ping up the amplitude of the electrical current supplied to the
micro-coil. The four NVs sites are resolved with a spatial reso-
lution ≈30 nm as a single NV site [43]. To improve the spatial
resolution, the main challenge is to generate gradients in the
magnetic field that can be switched rapidly with respect to the
coherence lifetime on the spin that is strong and spatially homo-
geneous.
NDs are the preferred material for magnetic field imaging in bi-
ological samples, but in general, they suffer from a short coher-
ence time T2. This limits their applications in DC and AC
magnetometry. It was understood that high-purity ND can
accommodate record-long NV T2 times of >60 μs, albeit ob-
Beilstein J. Nanotechnol. 2019, 10, 2128–2151.
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served via universal dynamical decoupling [47]. The main
decoherence contribution in these NDs is due to nearby nitrogen
impurities rather than surface states.
Improved ND NV center electron spin properties were obtained
in [48] by a room-temperature near-field etching method. This
is based on application of a He–Cd ultraviolet laser (325 nm),
which has a longer wavelength than the oxygen molecule
absorption edge and can selectively remove the ND surface
defects. A decrease in the FWHM of the ODMR spectra close
to 15% and an increase in the T2 time of almost 25% are ob-
served, with a maximum T2 of 2 µs. This technique is quite
simple and produces better magnetic imaging results using DC
magnetic fields in NDs.
Optically detected magnetic resonance
(ODMR) methods
Wide-field microscopy is the method mostly used to implement
ODMR-based magnetometry. Often referred to as wide-field
magnetometry, it can compare a fluorescence mapping of a
sample with its magnetic field mapping. Wide-field magnetom-
etry with NVs allows a wide field-of-view, albeit sometimes
with reduced resolution. It has been applied successfully in
several fields, mostly in biomedical applications. The
pioneering works in NV magnetometry are concerned with
proving the underlying principles of nanoscale imaging resolu-
tion and magnetic field sensitivity in various contexts. More
recently there has been a focus on the improvement of material
engineering and diamond magnetometry involving superior
designs, as well as applications in a growing variety of fields. In
the following sections, we described some of these latest
advances and their focus.
An important challenge for improving NV magnetometry is the
control of the NV center origin at desired locations in the
diamond. The formation of closely spaced NVs to achieve spin-
entanglement by direct magnetic dipolar coupling is also a quest
for quantum computation and quantum network protocol appli-
cations. Nitrogen implantation through lithography-style mask
apertures allows the creation of NV centers with high spatial
resolution and fine pitch due to the achievable aperture close-
ness. Such a method used to create an array of NV centers in
diamond for magnetometry is discussed in [49], with record
spatial localizations on the order of 10 nm in 3D and an inter-
NV spacing down to 40 nm (20 nm inter-NV spacing length
scale is needed for strong dipolar coupling).
NV center specific ODMR coplanar waveguides (CPWs) are
discussed in [50]. The authors achieve bandwidths up to
15.8 GHz, allowing for NV center spin manipulation with
external magnetic fields up to 5000 G. The CPW conversion
factor is measured by Rabi nutation experiments, ranging from
6.64 to 10.60 G·W−1/2 in a frequency band from 0.76 to
17.3 GHz. Broadband CPWs also minimize control pulse dis-
tortion, increasing their sharpness and manipulation qualities.
ODMR is combined with pulsed MRI in [51] to obtain ODMR
imaging (ODMRI), delivering NV center images at micrometer
and nanometer-scale resolution. ODMRI allows for a great
advantage, namely, the readout of the spin state simultaneously
from the whole sample with high-quality spectroscopic infor-
mation. This method was further improved in [51] by adding
spatially selective spin addressing and manipulation capability,
thus improving the spatial resolution. Specific groups of sam-
ple spins being selectively manipulated and then the imaging of
the entire sample (a fundamental ability for spin-based quan-
tum sensors) are demonstrated in [51].
A key point of NV magnetometry is to set up a correlation with
MRI-contrast methods based on conventional MRI. The com-
parison is achieved only in subcellular imaging due to the scale
associated with NV magnetometry. Magnetic imaging probes
are important for the analysis of biological and physical
systems. Current magnetic imaging techniques make use of
magnetic beads to target and follow cells. Direct magnetic
imaging of cells has a high detection sensitivity requirement
since biological samples have an inherently low natural magnet-
ic background. However, with current magnetic imaging
methods, single-cell sensitivity, concurrent with a millimeter
field-of-view at the same time cannot be achieved. They
either suffer from resolution issues with respect to optical
microscopy, have no imaging capability of sub-cellular struc-
tures, or involve operating conditions not suitable for living bio-
logical samples.
A wide-field NV ensemble magnetometer for optical magnetic
imaging of living cells was first used in [30]. A nanometer-scale
layer of NV was implanted in arrays close to a bulk diamond
chip surface where the magnetotactic bacteria were deposited.
Magnetic imaging of living magnetotactic bacteria under room-
temperature conditions was achieved with a sub-cellular spatial
resolution of 400 nm and a field-of-view of 100 μm. By NV
center spin states, vector images of the magnetic field emitted
by chains of MNPs, produced by the bacteria placed on the
diamond surface, were rapidly reconstructed. These nanoparti-
cle magnetic field maps were correlated with optical images
together in the same apparatus. This result provided a new capa-
bility for imaging bio-magnetic structures in living cells under
room-temperature conditions with high spatial resolution.
Another demonstration of ambient temperature in-cell imaging
of biomagnetic nanostructures with resolution down to 400 nm
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2134
has been given by layering magnetotactic bacteria on diamond
with a superficial array of NV centers. Optical detection of
quantum spin states allows real-time imaging of bacteria
magnetosome chains with a direct correlation to the optical
image. Single magnetosomes were thus resolved by the tech-
nique on a 100 μm wide field [52].
An alternative approach to fluorescence microscopy is magnet-
ic imaging of cells, labeled or targeted, using MNPs. Single-cell
magnetic imaging of immunomagnetically labeled cells was
achieved in [53] using a quantum diamond microscope reaching
a field-of-view of ≈1 mm2, which is a field-of-view two orders
of magnitude larger than earlier results of NV imaging on simi-
lar samples [30].
Neuronal action potential (AP) magnetic fields have been
measured at the macroscale with coarse spatial and/or temporal
resolution, using MRI methods and magnetoencephalography
for example. This does not supply single-neuron spatial resolu-
tion without scalability to functional networks or intact organ-
isms. In [34], AP magnetic sensing has been realized with
single-neuron sensitivity and intact organism applicability with
an NV quantum diamond microscope under ambient conditions.
The method was applied for excised single neurons from marine
worm and squid and then to marine worms for extended
periods. The key element to making the experiment possible
was to bring an NV layer sensor to within ≈10 μm from the
specimens, while all other methods (e.g., sensitive supercon-
ducting quantum interference devices (SQUIDs)) are limited by
distances of millimeters or more from the biological sample.
Even with a sensitivity of fT·Hz−1/2, the distance does not allow
for single-neuron action potential sensitivity.
A key point of NV magnetometry is to set up a correlation with
MRI-contrast methods based on conventional MRI. The com-
parison is typically achieved only in subcellular imaging due to
the scale associated with NV magnetometry. A method was de-
veloped to correlate the 2D magnetic field measurements ob-
tained by an NV diamond magnetometer to 3D magnetic field
images and to finally compare them with conventional MRI
contrast and images [54]. A method is proposed to study the
connection between subcellular magnetic field imaging using an
NV magnetometer and the related MRI contrast. MRI contrast
is thus correlated to submicrometer resolution and nanotesla
sensitivity magnetic field measurements in biological samples.
Molecular-imaging agents such as iron oxide nanoparticles
(IONPs) can strongly influence MRI images with their
microscale magnetic field gradients produced in the cells and
tissues. Macrophage was labeled with 200 nm superparamag-
netic IONPs and was internalized. Three-dimensional magnetic
field images of the cells were achieved by using NV vector
magnetometry. ODMR signals of the four NV orientations in
bulk diamond were measured and converted to the orthogonal
laboratory reference frame. A procedure for dipole localization
in cellular specimens was also developed to reduce the artifact
of overlapping dipole effects in the 3D images. This modifica-
tion of the NV bulk magnetometer was required to reduce photo
and thermal (dissipation) damage to the biological sample. For
a given minimal and microwave probe power, NV photon emis-
sion was enhanced by the optical collection design of the mag-
netometer, achieved through increasing the NV concentration
and by using SiC as a substrate to aid in heat transfer.
After obtaining the 3D maps of the magnetic field in the sam-
ple from the magnetic field images, Monte Carlo simulations of
the nuclear spin T2 decoherence was performed in lattices of
representative cells. This was done to connect micrometer-scale
magnetic field measurements to the MRI contrast. The pre-
dicted bulk MRI T2 relaxation time was 23.6 ms with an accu-
racy of 2.8%. Direct experimental MRI measurements of T2 in
macrophages prepared for the NV experiment was also per-
formed to determine the accuracy of the reconstruction from the
magnetic field images. The distinction between clustered and
diffused IONPs was also performed. The NV-based 3D magnet-
ic imaging method was then applied to diagnostic imaging of
liver specimens (tissue) from a model of hepatic iron overload
in a mouse and of dynamic endocytic uptake of IONPs in live
mammalian cells.
Magnetometry based on the electron spin of NV defects in
diamond is currently appearing as a platform that is excellently
suited for probing condensed matter systems. In addition to
room temperature operation for biomedical applications, it can
also be used at cryogenic temperatures and has a magnetic field
measurement dynamic range from direct current to AC giga-
hertz bandwidth [33]. As such, NV magnetometry supplies
access to static and dynamic magnetic and electronic phenome-
na at the nanoscale. An NV magnetometer has direct applica-
tion to the measurements of stray magnetic fields of magnetic
samples. Magneto-optic sensor arrays can be fabricated from
diamond NV centers and employed to image thin ferromag-
netic films. The accuracy obtained is sub-micrometer over sur-
faces as wide as 100 × 100 µm2 and the imaging speed is fast
enough to obtain a real-time video of the evolution of stray
magnetic patterns. It is not necessary to supply a microwave
signal to detect the spin status, which can be read optically
by spin relaxation contrast. The sensitivity can thus be im-
proved to less than a microtesla with a subwavelength spatial
resolution and sub-millisecond time resolution. This enables
the wide-field microscopy of a domain wall with skyrmion dy-
namics and allows imaging of metal spins via the Hall effect
[55].
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NV center wide-field microscopy was applied in [11] to charac-
terize and image magnetic samples; sample thin ferromagnetic
films were used to map and image their sub-micrometer stray
magnetic field patterns by using an array of NV center spins.
Using ODMR, wide-field magnetic imaging over an area of
100 × 100 μm2 with sub-micrometer spatial resolution (440 nm)
and a temporal resolution of 20 ms and 1.5 μT·Hz−1/2 sensi-
tivity could be achieved at room temperature. Without using an
applied microwave field, all-optical spin relaxation contrast
imaging has also been proposed to develop a conventional spin-
relaxation time sequence. This method is particularly relevant to
imaging without an external magnetic field, which may nega-
tively affect sample magnetization. NV center spin relaxation
contrast also allows a new all-optical imaging approach, applic-
able in the presence of large off-axis magnetic fields.
Reviews of condensed matter physics applications of the NV
magnetometer are considered in [56], specifically those involv-
ing magnetic fields generated by spins and currents in solids.
The use of an NV magnetometer in solid-state physics is
applied to the study of static and dynamic magnetic textures and
current distributions. As an example, NV magnetometry is used
to probe magnets and superconductors, correlated-electron
physics, as well as to explore the current distribution in low-
dimensional materials. In addition, the study of static magnetic
textures (e.g., domain walls and skyrmions), spin waves in
ferromagnets and superconducting vortices, and electrical noise
currents in metals have been proved feasible with NV magne-
tometry. Probing static magnetic textures (i.e., the static spin
configuration of a magnetic system) is crucial for developing
magnetic devices. This is a challenging task in condensed
matter physics because the magnetic field reconstruction is
based on stray field measurements, which is an example of an
under-constrained inverse problem. The stray magnetic field
generated by a planar magnetic texture is determined by the
spatial derivatives of the local magnetization. The spatial varia-
tions of the magnetization of magnetic materials are related to
domain walls arising from the connection between regions with
different magnetization orientations, having typical widths of
≈10 nm in ferromagnets. This problem is well suited for an NV
magnetometer. In fact, NVs are sensitive to the projection of the
magnetic field B on the NV spin quantization axis (i.e., the
B || NV-axis). This is the quantity typically measured in NV
magnetometry. As such, the full vector field B can be recon-
structed by measuring any of its components in a plane at a dis-
tance, d, from the sample if this part is not parallel to the mea-
surement plane. The measurement of the out-of-plane stray field
part, Bz (x, y; z = d + h), can be easily reconstructed under the
assumption of the evanescent-field analog of Huygens’ prin-
ciple from the measured B || NV (x, y; z = d). An NV magne-
tometer has been applied to measure magnetic domains of mag-
netic skyrmions with nanoscale (10–100 nm) spin textures. This
is a promising candidate for magnetic storage, due to the ultra-
small-scale features and low currents involved [56].
NV centers can extract the magnetic power spectral density of a
system and can be used as a magnetic noise sensor. This
supplies a relationship to be set up between the magnetic noise
spectrum to the spin and current fluctuations in a material. As
such, it could be used to measure the thermal spin noise in low
dimensional materials such as hexagonal BN. Further, its sensi-
tivity is enough to measure stray fields due to, for instance, the
current density in graphene flakes or stray fields generated by a
vortex in a 100 nm thick superconducting film.
Another application of the NV ensemble magnetometer is re-
ported in [57], where the measurement of the lower (first) criti-
cal field of three different superconductors, high-Tc cuprate
YBa2Cu3O7−δ (YBCO), and iron-based superconductors is per-
formed, as the lower critical field is a fundamental parameter to
characterize a type-II superconductor. Sample cooling to a
target temperature below Tc is done under zero magnetic field,
and then a small magnetic field is delivered while recording
ODMR signals in various positions on the sample to evaluate
homogeneity. From the ODMR splitting at various tempera-
tures, the magnetization is obtained. The transition temperature
to superconductors is measured from the ODMR splitting. The
material, in the absence of a magnetic field, is then cooled and
brought to the superconducting phase. The lower critical field is
obtained from the ODMR splitting by varying the magnetic
field applied. In the experiment, the spatial resolution was
diffraction-limited and the integration time was 4–10 minutes
for each data point used to extract the lower critical magnetic
field and the absolute value of the penetration depth. Both can
be improved using other protocols in NV magnetometry. These
are of some of the benefits of linking superconducting material
properties with theoretical models.
An array of NV sensors under the diamond surface were used in
[58] for the spatial mapping of band bending, where the NV
sensors probe the electric field associated with the surface dis-
tribution of space charge density under different diamond sur-
face termination. The technique is useful for applications of
band bending measurements in electronic devices which need
high control of charge distribution, as in engineering of qubit
devices with enhanced quantum coherence, for example.
Other methods
In addition to nuclear spins in proximity to NV centers, it is also
possible to optically detect electron spins, as paramagnetic
centers in the diamond lattice or diamond surface radicals, via
their coupling to the NV center. Due to interactions of the elec-
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2136
tron spins with each other, their detected spectra are often
broadened to supply critical chemical information. Cross-relax-
ation phenomena between NVs and other paramagnetic defects
in diamond was used in [59] to detect the presence of the well-
known electron spin from the N substitutional centers (P1) and
the NV neutral charge state. Both of these paramagnetism
defects cannot be optically detected. Only the negative charge
state of NV, due to its metastable state properties, permits
ODMR. However, due to their low spin state, they have been
clearly demonstrated by EPR in the presence of a magnetic field
and added microwave excitation. In this work, the authors
proved that by using NV ODMR, it is possible to show their
resonances in the NV cross-relaxation ODMR spectrum for low
magnetic fields (a few milliwatts). This technique allows
ODMR to replace EPR methods that require high B-fields to
provide detailed spectra of the detected electron spins for identi-
fication of radicals or relaxation centers, with low concentra-
tion defect resolution. However, this method needs an ensem-
ble of NVs and it is not clear how it is comparable with
other methods that are able to measure dilute electron spin
resonance in solids with microwave signal read-outs. In bio-
medical applications, EPR methods of radicals have sensitivity
limitations that typically restrict the imaging resolution to
≈10 µm.
High resolution of electron spin imaging of a target solution of
hexaaqua Cu2+ complex using an array of NV centers in
diamond and the cross-relaxation method was achieved [60].
This EPR method discriminates between electronic spin species
by accurately setting the magnetic field to make the NV center
resonate with the external target spin. The method has been
tested by imaging a diamond chip with an image mask made up
of a series of gratings of width ≈500 nm and a pitch of 1 μm.
The minimum resolution compares with the microscope diffrac-
tion limit, which is ≈305 nm over a field-of-view of
50 × 50 μm2 with a spin sensitivity of 104 spins per voxel or
≈100 zmol. This method can enable the development of elec-
tron spin resonance with zeptomole sensitivity in chemical
sciences.
Super-resolution imaging beyond the diffraction limit using
spin defects has recently been developed using NV centers by
STED, STED-ODMR, reversible saturable optical fluorescence
transitions (SPIN)-RESOLFT, stochastic optical reconstruction
microscopy (STORM) ODMR and localization microscopy as
reviewed in [45] in both bulk and NDs. Super-resolution spin
microscopy is, however, difficult to implement in NDs due to
the random orientation of the crystal main axis, and as such, of
the magnetization axis of the NVs. Investigations have been
carried out on the environment of the NV centers within the
same ND to study the quantum properties of NV centers.
A method of spin-manipulated nanoscopy has been set up for
nanoscale resolution imaging of collectively blinking NV
centers when they are confined within the diffraction-limited
region [61]. Collective spontaneous emission in nanomaterials
is a common feature and relates to fundamental photophysical
properties. Multiple NV emission in 45 nm or less is often
subject to collective emission. Using wide-field localization
microscopy combined with nanoscale spin manipulation based
on a microwave source tuned to the ODMR frequency, two
collectively blinking NV centers could be resolved within the
diffraction limit. Here, fundamental studies of the coupling of
photoluminescence and spin properties of NV in diffraction-
limited space are carried out by a super-resolution microscope.
In the presence of a single ground state spin transition frequen-
cy for all emitters, the external magnetic field is used to split the
resonant dips to individually resolve each NV center. Using NV
spin properties creating three-level blinking dynamics, two NV
centers in the same ND were localized at 23 nm.
NDs can host several paramagnetic point defects and impurities
along the diamond surface, which are dark and can broaden the
NV spin spectra. These dark defects limit the use of NVs in
NDs for magnetic imaging. The composition and spin dynam-
ics of a particle-hosted spin bath are examined in [62] by
ODMR inside a 45 nm diamond nanocrystal, revealing nitrogen
donors and an unidentified class of paramagnetic centers. Both
show a spin lifetime much shorter than that of the NV center
spin. By dynamical decoupling and double spin resonance, it is
possible to achieve NV center coherence lifetimes comparable
to bulk.
Spin-reversible saturable optical fluorescence transition (spin-
RESOLFT) microscopy is used in [63] for accurate nanoscale
imaging of spatially varying magnetic field patterns with reso-
lution as low as ≈20 nm transverse to the beam (x- and y-axis),
while precision parallel to the beam (z-axis) can be pushed
down to sub-nanometer values by combining spin-RESOLFT
with NV-center NMR measurements from proton spins in a
sample facing the diamond. In RESOLFT, the NV center
ground-state spins are initialized by a Gaussian laser beam and
then spin manipulation occurs as in typical confocal systems.
An example of this is the dynamical decoupling of microwave
pulse sequences based on spatially selective repolarization via a
pulsed green doughnut beam which is introduced before reading
out the spin to pinpoint a specific NV center within the sub-
diffraction limited area of the Gaussian beam. Additionally,
shallow NVs have been used for measuring proton NMR
signals that are facing the diamond, with 50 nm transverse reso-
lution and while preserving the proton NMR linewidth. In this
case, a sequence of XY8-4 pulses (see modalities for NMR
using NV centers below) was employed for sensing the Larmor
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frequency in a RESOLFT mode for proton spins in immersion
oil placed on the diamond surface.
Optical probes are attractive for imaging neuronal action poten-
tials (APs) due to high signal-to-noise. Unfortunately, optical
probes can also induce toxicity and can interfere with the
network activity of the system during imaging. As NDs have
been used to image the APs of single neurons, in [64], a study
of the electrophysiological effects of NVs in NDs in primary
cortical neurons is reported. Multielectrode array recordings are
used across five replicate studies where NDs are added at dif-
ferent concentrations up to 20 μg/mL for a period of 12 to 36 h.
No statistically significant difference is seen in neuronal behav-
iors over 25 neuronal network parameter comparisons. This
physiological study motivated the culture of neuronal networks
onto a specific glass coverslip with embedded gold microwave
resonator for ODMR sensing coated with polydimethylsiloxane
using the same culturing procedure as for the physiological
study. The ND suspension was dispersed in cell media and then
applied at a concentration of 6 μg/mL to the primary cultures
while performing a routine change of cell media. ODMR from
NVs within the NDs in the neural networks was used for
sensing the temperature from thousands of NDs, which were
probed simultaneously using a wide-field imaging system. It
was seen that at zero magnetic field, the majority of NDs have a
crystal field splitting of D = 2.87 GHz. By recording ODMR of
the NDs at different temperatures a variation of the zero-field
splitting D was seen, corresponding to a known local tempera-
ture variation. The temperature map was then obtained at each
location by converting the shift in D into temperature, using
dD/dt = −74 kHz/K. This demonstrated the intracellular temper-
ature mapping in primary cortical neurons with a high diffrac-
tion-limited spatial resolution. This approach may be of interest
for optogenetics, which is a traditional and widely used tech-
nique for neuronal stimulation. However, due to NDs strains
that may affect the dip in the ODMR signal, the accuracy of the
mapping is limited. Developing multifunctional sensors is truly
relevant for applications under physiological conditions and for
monitoring intracellular processes relevant in biological and
medical applications. In this context, hybrid systems using NV
sensors with other MRI contrast agents or sensors have been
proposed such as iron oxide nanoparticles and paramagnetic
gadolinium complexes.
SPIONs are single-domain magnetic systems whose features are
used in many technologies, from magnetic information storage
to ferrofluids or nanoscale drug-delivery systems and magneto-
assisted hyperthermia cancer treatments [65]. Single SPION
detection with 10 nm accuracy was shown by bulk diamond NV
center magnetometry combining spin relaxation time (T1) and
spin dephasing time (T2) Hahn-echo measurements. The forma-
tion of hybrid systems between NDs and SPIONs is of growing
interest to enhance NV magnetometry in the local nanoenviron-
ment.
A single NV center was functionalized with a SPION by an
AFM pick-and-place approach in [66]. It is shown that in the
NV-SPION system, the NV spin relaxation time is reduced,
while the T2 coherence dephasing time stays the same. By
configuring the applied AC magnetic fields, the NV electron
spin Rabi oscillation rate decreased, due to a resultant super-
paramagnetic nanoparticle magnetization at the NV center
Larmor frequency. The work shows the effect of coupling
single NV to single SPION systems for magnetic sensing. How-
ever, its applicability to biological samples is difficult in prac-
tice due to the need for multiple NDs coupled to SPIONs.
Paramagnetic gadolinium complexes were attached to NDs with
NV centers by properly engineering the diamond surface in
[67]. A hybrid nanoscale sensor is constructed that can detect
physiological species through a proposed sensing scheme based
on NV spin relaxation time measurements. The Gd3+ com-
plexes are spin labels attached to a polymer shell covering the
ND surface. After activation of a chemical switch due to a local
change, which can be monitored by a change in the T1 relaxa-
tion time of NV centers, Gd3+ complexes are released. The
method consists of measuring spin relaxation rates enabling
time-dependent recordings of changes in pH or redox potential
at a sub-micrometer-length scale. The test was performed in a
microfluidic channel that mimics cellular environments. This
method can be generalized to other ND hybrid systems, where
the release of an attached sensing species on the surface of the
ND due to some chemical reaction can be monitored by the spin
relaxation time of the NV center. Smaller NDs with long spin
relaxation times can be beneficial for this application.
A study of NVs in ND spin properties under a dynamical envi-
ronment is performed in [68]. NVs in NDs are sensitive to the
magnetic, temperature and electric properties of the nanoenvi-
ronment. However, a study of the dynamic conditions of the
nanoenvironment has not been performed to date. This is im-
portant in applications of NV centers in NDs for tracking living
cells. It has been shown that the electron spin resonance
linewidth of the single NV center broadens to match the rota-
tional diffusion constant of the host ND. When NDs gradually
detach from the substrates in an aqueous buffer solution, their
ODMR peaks are broadened by 1.8 MHz, which corresponds to
the rotational diffusion constant of NDs with a diameter of
11.4 nm from the Einstein–Smoluchowski relation [69,70]. This
work can enable the investigation of nanometer-scale fluid
mechanics by the measurement of the rotational Brownian
motion of single nanoparticles.
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Figure 1: Diamond NV center mediated optomagnetic imaging of brain sample neural activity [72]. Image reproduced with permission from [72], an
article licensed under a Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/. (A) Trisynaptic path in
hippocampus sample. Electrical stimulation of the Schaffer collaterals evokes CA1 area activity which is then recorded. (B) 500 × 500 × 300 µm3
simulated CA1 subareas on top of the diamond surface, assuming up to 50 µm distance from the diamond makes neurons dysfunctional. Along x- and
z-axis, the distribution of pyramidal cells is uniform, their soma locations being randomly jittered in a 50 µm wide band along the y-axis. Inverted
microscope with a camera in place of a photodetector is used to detect the photoluminescence change in NV center layer emission due to neural
magnetic fields. (C) Forward modeling scheme pyramidal cell multi-compartment model.
Wide-field ODMR magnetometry was used for strain imaging
of NV centers in [71], resulting in preferentially aligned poly-
crystalline diamond along the grain boundaries with a higher
spin coherence time as with single-crystal samples. This obser-
vation can improve the signal-to-noise of NV sensing applica-
tions and can allow the use of polycrystalline diamond with
large areas as diamond sensors. The method can also be used to
study strain in other materials with optically accessible spin
defects or in strain-engineered devices, as well as for mapping
externally applied strain in specific materials.
NV-center nano-MRI schemes
The latest advances in nano-MRI using NV centers are
reviewed in this section. This includes NV magnetometry de-
velopments to sense external nuclear spins (NV NMR spectros-
copy). More general advances in NV center magnetometry
methods that may help nano-MRI with NV centers of various
systems are also included.
Figure 1 presents the NV center optomagnetic imaging of active
networks of neurons in brain samples [72]; a new way of
achieving wide-field neural dynamics due to the high sensi-
tivity of NV centers. The investigation of neural activity and the
insight in neural information processing mechanisms can thus
be achieved by making use of the established method of in vitro
brain slice observation, overcoming its inherent limitation in
that traditionally it is not possible to detect signals from the
whole of the network at the same time. In fact, NV center
magnetometry makes it possible to detect the spatial and
temporal features of magnetic fields produced by neural activi-
ty across the sample, by use of models extracting the main pa-
rameters of the neural signals and allows the ready comparison
with a single pyramidal cell [72]. This is the new frontier, as
NV center magnetometers are being readily improved to image
full brain slice activity, while the forefront of research is
focusing on the issues of planar cell imaging for single-shot
measurement.
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Figure 2: Experimental set-up and characterization of NV centers and the gradient microcoil of [43]. Image reproduced with permission from [43], an
article licensed under a Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/. (A) Experimental appa-
ratus. A matrix of implantation regions (pink circles) of negative charge NV centers on the diamond is integrated into a scanning confocal microscope.
A green laser (532 nm) is used to initialize and read out NV center spin states in a given region and microwaves emitted by an antenna (orange bar)
manipulate them. A uniform magnetic bias field of B0 = 128 G is applied along one range of NV orientations, causing a Zeeman line splitting among
|±1⟩ NV center spin states; without a magnetic field they would show a 2.87 GHz frequency shift from the |0⟩ state. An added gradient magnetic field
(rainbow-colored arrows) of ≈0.1 G·nm−1 is applied by injecting current along a pair of gold wires (gradient microcoil), inducing the Zeeman shift
depending on the position. (B) Each region (pink circle in a) holds a 1 × 4 array of NV sites with 60 nm diameter and 100 nm spacing, which undergo
interaction that depends on the gradient in the magnetic field. Each site typically holds multiple (≈3 ± 1) NVs of the selected orientation. (C) NV
energy-level diagram. A nonradiative intersystem crossing channel exists between the ground (3A2) and excited (3E) states, and the magnetic field
gradient causes the NV center spin states |±1⟩ Zeeman splitting to be dependent on their position. Each site has a specific resonance that the micro-
wave generator can be tuned to, allowing for selective detection of each site. (D) Gradient microcoil SEM image on the diamond substrate. The micro-
coil, represented by yellow pseudo-color, is 1 µm thick and 2 µm wide. (Inset) E-beam resist apertures on PMMA, SEM image of ion implantation
mask to create a 1 × 4 array of NV sites. (E) Microcoil and NV center matrix image by scanning confocal microscopy. (Inset) STED image of
1 × 4 array of NV sites with 50 nm resolution. Photon count rate (kilo-counts-per-second) is shown by color table.
Among AC magnetometry techniques, NV Fourier magnetic
imaging (FMI) [46] is used besides traditional MRI imaging.
Here an AC gradient in the magnetic field (the pulsed magnetic
field gradient) based on microcoils brings a phase encoding
based on the position in “k-space” of the NV center electronic
spins, which is then converted to a real space image via conven-
tional Fourier inversion.
The key advantages compared to imaging in the real space is
the multiplexed position detection, which enhances the SNR for
characteristic NV center densities, supplying a high data acqui-
sition rate, and the simultaneous readout of all NV center
signals in the field-of-view. The sequence of FMI pulses relies
on a laser initialization pulse, followed by a microwave se-
quence for dynamical-decoupling spin-state manipulation, an
AC magnetic field gradient, and finally, a laser readout pulse.
A key challenge in nanoscale magnetic imaging in NV centers
in diamond is to scale up NV spin control to arrays of NV spins.
A controlling array of spins address the implementation of
nanoscale spin networks and achieve magnetic imaging with a
high spatial dynamic range.
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Figure 3: Single-cell magnetic imaging quantum diamond microscope [53]. Image reprinted with permission from [53], copyright 2015, Springer
Nature Publishing. (a) Wide-field magnetic imaging microscope based on NV centers in diamond. Immunomagnetically labeled cells are positioned on
top of a diamond with a surface layer of NV centers. A 532 nm laser is used to measure the ODMR of the NV electronic spins. An sCMOS camera is
used to image the NV fluorescence. The magnetic field projection along one of the [111] diamond axes is measured over a 1 mm × 0.6 mm field-of-
view for each imaging pixel. The scheme is adapted from [30] where further details are provided. (b) Electron micrograph of an SKBR3 cell labeled
with MNPs conjugated to HER2 antibodies. The black dots on the cell membrane highlighted by the white arrows in the expanded view indicate the
magnetic nanoparticles. The main figure scale bar is 2 μm. The inset scale bar is 500 nm. (c) MNP-labeled diagram of a target and surroundings with
unlabeled normal blood cells. The magnetic bias field B0 externally applied is aligned with the diamond [111] axis. This field is used to magnetize the
MNP labels. These magnetized nanoparticles produce the field then are imaged by the shallow NV center layer that is close to the surface of the
diamond surface to show a dipole-like pattern.
The spatial control of an array of four spin sites at the nano-
scale has been achieved in [43] by combining a microcoil
supplying a DC magnetic field gradient and FMI, as shown in
Figure 2. The microcoil replaces the DC magnetic gradient;
otherwise achieved by a scanning magnetic tip, and has the rela-
tive advantages to improve the bandwidth of gradient switching
and space dynamic range. Nanoscale MR frequency encoding is
applied in [43] to selectively address positions and coherently
control a four-site NV spin array. Positional separation in the
array is 100 nm, and every site is made up of multiple NV
centers with a ≈ 15 nm spacing. Microcoils are built on top of
the diamond to inject electrically tunable magnetic field gradi-
ents of ≈0.1 G/nm. Site-selective NV center spin manipulation
and sensing become possible as the gradient fields and resonant
microwave pulses are suitably arranged, allowing for applica-
tions such as Rabi oscillations, imaging, and NMR spectrosco-
py with nanoscale resolution.
Figure 3 presents the single-cell magnetic imaging quantum
diamond microscope of [53]. A bulk diamond microscope is
employed to covert the readout of immunomagnetically labeled
cells into an image. Correlated magnetic and fluorescence
imaging of the sample can be obtained using the NV centers in
the diamond. The so constructed diamond microscope can
provide single-cell resolution with a field-of-view of ≈1 mm2.
In the sample application, Glenn et al. [53] successfully
measured cancer biomarkers expressed by rare tumor cells
within a large population of healthy cells.
The quantum diamond microscope relies on a bulk diamond
chip with a near-surface layer of a high sensitivity NVs where
wide-field optical images are taken using a complementary
metal-oxide-semiconductor (CMOS) camera. The microwave
signal is delivered by a microwire on the diamond, and optical
excitation is achieved in total reflection mode. Bright-field
images, a confocal image of dye-stained cells together with
magnetic images using NV in the bulk diamond, were com-
pared using the same microscope. Here, the diamond quantum
microscope is highly simplified to allow a wide field-of-view.
To prove the efficacy of the method, it was possible to quantify
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and show cancer biomarkers corresponding to rare tumor cells
within a large population of healthy cells.
NMR spectroscopy using NV centers in diamond consists of
advancing NV magnetometry methods to sense the Larmor fre-
quency of nuclear spins close by to the NV sensors. The
conventional coil-based induction NMR method has a low
detection sensitivity preventing its application to samples at the
nanometer scale, while due to the atomic size of NV sensors,
coupling at the nanometer scale with nuclei is much more
achievable. However, the coupling efficiency depends on the
distance, and NV centers must be 20 nm from the nuclei. A
single NV created in a 12C-enriched diamond layer at 20 nm
from the surface was used in [73] to sense protons in the
PMMA polymer layer on the surface of a bulk diamond used as
a substrate. The proton spins were manipulated by a radiofre-
quency π pulse (RF) with variable frequency in the presence of
a small magnetic field (80 mT), the NV spin being manipulated
using a spin-echo sequence. The NMR proton Larmor frequen-
cy is measured by a dip in the relative NV spin echo response as
a function of the RF frequency. A shift of the measured Larmor
frequency is seen in the spin-echo signal by varying the external
magnetic field as expected, based on the proton’s gyromagnetic
ratio. To improve the spectral resolution, a Fourier transform
technique is used. Here a time-domain free induction decay
(FID) is obtained by changing the RF π pulse into two π/2
pulses with a time delay τn which is incremented. As the pulse
spacing τn is scanned, the NV spin echo amplitude oscillates
with a period that matches the proton Larmor frequency and by
applying a cosine transform to the time domain data, the fre-
quency spectrum is obtained with a peak in the Larmor frequen-
cy.
A different spin sequence is applied in [74] to single NVs in
bulk diamond and an NV ensemble imaging modality to sense
the Larmor frequencies of H, F and P nuclei close to the NV
sensors. In his case, the NV is polarized by the excitation laser
in the ground state spin |0⟩. It is then placed in a superposition
of |1⟩ and |0⟩ spin states. An XY8-k sequence allows the NV
spins to probe the local magnetic environment, and finally, a
microwave π/2 pulse projects the evolved NV spin coherence
onto a |0⟩, |1⟩ state population difference. The XY8-k sequence
serves to extend NV spin coherence times, and as a spectral
filter, to increase the sensitivity to specific nuclear spins. It
consists of a k-times repeated sequence of eight π pulses, with a
delay time of τ between π pulses, which is related to the fre-
quency of the sensitivity that is enhanced. By changing τ, dif-
ferent nuclear spin frequencies are probed.
The first 2D imaging of nuclear spin was reported in [75]. Here
an XY8-96 sequence is applied to a single NV center in
12C-enriched diamond to provide a two-dimensional image of
1H NMR from a polymer test sample with a spatial resolution of
≈12 nm.
Towards NV-NMR imaging, NV-NMR was used in [76] to de-
termine the accurate position of individual 13C nuclear spins
near the NV sensor within the diamond by nuclear resonance
spectroscopy experiments. The three-dimensional spatial coor-
dinates of the nuclear spins are converted in a 3D image with
sub-Ångstrom resolution and for distances beyond 10 Å. Here a
single NV center close to the diamond surface is used to sense
the precession of nuclear spins under a rapidly switching mag-
netic field obtained with a coil on the diamond surface. To
retrieve the azimuth angle of the nuclear spins and reconstruct a
3D image, the authors achieved a dynamic tilt of the quantiza-
tion axes, induced by a transverse variation of the magnetic
field generated by a high-bandwidth microcoil together with
high-resolution correlation spectroscopy. Four 13C atoms were
localized in a 3D map compared to NV. It is accepted that the
prospect of a general single-molecule MRI technique has some
challenges. These include isolating a single molecule in a spin-
free matrix layer, suppressing nuclear dipolar interactions and
reducing line widths and spectral complexity.
A method is proposed in [77] to engineer nuclear spins within
the diamond layer consisting of 13C nuclear spins doped with
NV embedded in a spin-free 12C crystal matrix. In this case, a
few tens of nuclear spins are controlled by using radio frequen-
cy pulses, and it is shown that nuclei spin coherent control such
as Rabi oscillations and Ramsey spectroscopy is possible.
Figure 4 presents the NV center nano-MRI set-up of [73]. This
is one of the first attempts to detect proton NMR in an organic
sample facing the diamond by using an individual NV center
close to the surface. Electron spin echoes and proton spin
manipulation are combined so that the NV center senses the
nanotesla proton field fluctuations, allowing simultaneous nano-
meter scale time-domain and spectroscopic NMR measure-
ments.
NMR spectroscopy of organic/biological material is possible
only for samples of significant size [78]. Single-molecule ubiq-
uitin-protein NMR sensing at room temperature is possible by
connecting them to a diamond surface that has been functionali-
zed with pairs of qubits whose interaction mimics the coupling
of an electronic spin with an ancillary nuclear spin. The sensi-
tivity can thus be improved to the point that single proton spins
become detectable in integration windows as short as 1 s, as the
diamond surface is treated to improve the spin coherence of the
NV centers and detection accuracy benefits from the quantum
logic relationship between the qubits. The spectral fingerprint
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Figure 4: NV-NMR detection system schematic of [73]. Image reprinted with permission from [73], copyright 2013, AAAS. (A) 12C diamond layer with
NV center spin at [111] orientation embedded at 20 nm depth. Proton NMR is detected in a PMMA layer. (B) Sample surface from fluorescence
imaging, with microwire and NV center (circled). (C) Proton detection sensitivity dependence from space along the PMMA layer cross-section. 50% of
the proton signal comes from a (24 nm)3 volume. The NV center axis is 54.7° tilted from surface normal, originating two lobes as shown. (D) Normal-
ized spin echo response vs total echo time.
obtained allows recognition of single proteins and their chemi-
cal composition.
The microwave RF power needed to create a singlet state is
high enough to pose safety issues for in vivo imaging of bioma-
terials. However, recent experiments show that a long lifetime
nuclear spin-singlet state can also be created by RF spin-locking
fields at powers that are two orders of magnitude lower than the
conventional method. These states also receive help from a long
singlet-triplet coherence time that persists even after the excita-
tion is removed [45].
Improving the contrast mechanism is another important
research avenue for MRI and NMR as recently proven.
Suppression of undesired chemicals using the contrast-
enhancing singlet states (SUCCESS) based on long lifetime
nuclear singlet states supplies an enhanced in vitro capability
for resolution of hard to detect peaks in the background noise.
In this mechanism, singlet states are originated in the target
molecule and stabilized by a continuous RF emission to create a
quantum filter. Subsequently, after they have affected the mag-
netic saturation of the undesired molecules, they are trans-
ported back to the earlier state by a specific pulse sequence and
detected [46].
Shallow NV centers have been exploited to effect multiple-
species MRI and bulk NMR spectroscopy at field intensities
two orders of magnitude lower than traditional methods,
achieving room-temperature nanoscale imaging of proton spin
ensembles for fields as low as 20 mT [65].
To improve the imaging resolution, it is important to accurately
measure the NV center depth under the surface of the diamond.
One recently proposed method combines confocal and NMR
imaging of NV centers and modeling the polarization statistics
of proton spin interactions, reaching a resolution of 1 nm and
achieving good matching with ion implantation simulations
[79].
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Figure 5: Experimental setup and magnetometry with repetitive readout [78]. Image reprinted with permission from [78], copyright 2016 AAAS. (A) Ex-
perimental setup. NV center electronic spin and its associated 15 N nuclear spin are used as a proximal quantum sensor to probe ubiquitin proteins
on the surface of the diamond. (B) Quantum circuit diagram and experimental magnetometry pulse sequence. (C) Repetitive readout cycles and
measured fidelity gain. MW – microwave; RF – radiofrequency; APD – avalanche photodiode; B – nuclear spin magnetic field.
Figure 5 shows the layout of a repeated detection magnetom-
etry experiment from [78], aiming for single-protein spectrosco-
py and NMR. A statistically polarized subset of proximal pro-
tein nuclear spins produces a time-varying magnetic field
whose single Fourier component is measured. Precession at the
nuclear Larmor frequency affects the spin ensemble transverse
magnetization, giving stochastic variations in phase and ampli-
tude at each sequence repetition. The MR signal is obtained by
averaging over many iterations, which gives a zero-mean mag-
netization with nonzero variance. NV center sensing is carried
out by manipulating the spin state by a periodic sequence of
microwave pulses separated by free-evolution intervals of
length τ. Narrow band-pass filtering is affected by the periodic
modulation of the NV center spin, which accumulates the phase
when the modulation frequency, defined as 1/τ, is close to twice
the nuclear Larmor frequency. The interval variation between
the π pulses encodes the protein nuclear spin information within
the measured frequency spectrum. High resolution in both space
and time have been looked for with various other setups of NV
center sensors.
NV center magnetometry can measure the tiny magnetic fields
produced by neural action potentials, allowing for in vivo
neuron imaging. Neural complex dynamics measurement
requires imaging at subcellular or synapse-scale resolution in
order to image single neuron dynamics in living tissue. Typical
neural pulse durations are around 2 ms with a magnetic field of
≤10 nT and peaks at 100 nm from the axon, which is chal-
lenging for NV center magnetometry. By considering an ensem-
ble of NV centers in a single-crystal ultrapure diamond mem-
Beilstein J. Nanotechnol. 2019, 10, 2128–2151.
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brane, a model simulating the time dynamics of the axon has
been developed, while also considering a detection system
relying on wide-field NV center photoluminescence imaging in
a confocal microscope. Options for magnetic field detection
include continuous ODMR and free induction decay, with
sensitivity in both cases of 10 μT·Hz−1/2. The specific sequence
repetition and applied sensing volume (1 μm3) necessary to
image a single axon depends on the size of the axon.
Single-neuron label-free imaging is possible with current
NV-magnetometry techniques at a 10 nm spatial resolution,
30 μs temporal resolution and 1 mm field-of-view without the
invasiveness and toxicity in vivo, allowing for long observation
periods using single-crystal diamonds supporting the sample on
a uniform 13 μm surface layer of high-density (3 × 107 cm−3)
NV centers. The temporal detection of the NV center MR fre-
quency due to the action potential magnetic field is available
with a temporal resolution of 32 µs and a magnetic field sensi-
tivity of 15 pT·Hz−1/2, giving a single-neuron measured the
magnetic field of ≈4 nT peak-to-peak.
In order for biomedical imaging to be applied to processes with
a wide range of length scales (from micrometer to nanometer)
and to be used to investigate biological functionality down to
the electron configuration of single proteins and DNA se-
quences, nano-MRI is required, which should also be capable of
imaging internal dynamics. Strong magnetic pulses are used in
conventional MRI, however, at very small scales greater sensi-
tivity is needed instead. Molecular MRI needs sensors and
optical probes on the scale of a single atomic spin [12].
The application of nano-MRI with diamond NV centers is
possible due to NV spins having magnetic dipole–dipole inter-
actions with other spins close by, which does not need the usual
high MRI magnetic fields and obtains high SNR wideband
signals at nanometer resolution. NMR imaging of groups of
polymer nuclear spins is proposed in optical confocal and wide-
field microscopy by increasing the complexity of microwave
pulse sequences to stabilize (with respect to frequency) the
coherence time of NV center spins, and also using scanned
magnetic probes functionalized with nuclear spins for nanome-
ter resolution 2D proton imaging and even tighter 3D imaging
of dark electronic spins [12].
NDs of less than 10 nm diameter can be employed as NMR
sensors due to the atomic size and photostable fluorescence of
the NV centers, whose electron spins can be managed by micro-
wave pulse sequences and detected by observing luminescence.
Ultrapure bulk diamond grown isotopically at room tempera-
ture allows for millisecond-scale dephasing using Hahn-echo
pulse sequences, while dynamic decoupling pulse sequences at
77 K make it possible to reach a 1 s coherence time. The NV
center excited triplet state is optically pumped via a dark-state
spin-dependent transition and couples to the magnetic field by a
spin-orbit effect that is mediated by transitions triggered
through an external microwave signal. Thus, the fluorescence is
amplitude-modulated by the magnetic field with a positional
accuracy given by the NV center size. The reported sensitivity
is around 40 nT·Hz−1/2 for DC (direct current) magnetometry
and around 10 nT·Hz−1/2 for AC (alternating current) magne-
tometry. MRI of single nuclear spins is limited by the weak-
ness of their interaction with NV center spins, however, single
NV centers can have a resolution down to 12 nm when imaging
1H NMR in polymers [12].
Super-resolution techniques such as stimulated depletion emis-
sion microscopy (STED) and stochastic optical reconstruction
microscopy (STORM) are fully optical methods that can deliver
nanometer spatial NV center resolution, thus giving rise to
methods that combine STED and STORM with spin resonance
methods based on spin-echo sequences. For instance, Fourier
magnetic imaging (FMI) is based on NV center spin Fourier (or
k-space) phase encoding for magnetometry. A 3.5 nm resolu-
tion is achieved by FMI imaging in the k-vector space, and
phase encoding of spatial information on NV center electronic
spins in the “k-space” is obtained by pulsed magnetic field
gradients. After the wavenumber measurement, the image is
inverse transformed in the real space by fast Fourier transform
(FFT), giving a wide-field view at a short computational time.
This has the advantage of space multiplexing with high SNR
and acquisition rate, as the methods work by compressing the
sensing in wavenumber space and simultaneously reads out all
the NV centers within the field-of-view [30,80].
Spin-hosting, NV color centers in diamond, have the sensitivity
in space to detect NMR signals down to single molecules. How-
ever, the resolution in time (frequency) of present schemes is
insufficient to resolve the details of molecular structures.
Recently, an NMR scheme exploiting an NV center ensemble
used a synchronous readout technique which enables the fre-
quency resolution to be set independent of the coherence time
of the sensor. Diffusion effects are mitigated by the wider
volume of sensing and allow the thermal, rather than statistical,
nuclear polarization to be accessed. The technique achieves a
≈3 Hz spectral resolution, allowing chemical shifts and nuclear
spin–spin couplings to be resolved.
The NV centers are atomic-size defects isolated from the
surroundings and act as atomic-scale magnets with optical
photostable emission. As they are embedded in diamond matrix
they are biocompatible and can be regarded as atomic size
probes. These probes can be in close proximity or introduced
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into living cells and tissues. NV center detection of very weak
magnetic fields is done via their light emission modulation by a
local magnetic field. Due to their size they are used as ultrasen-
sitive magnetic probes to monitor the local magnetic field
strength and direction changes over sub-micrometer distances.
NV centers in diamond have already been used to record NMR
signals from samples on the nanometer scale. For example,
enough sensitivity to detect a single protein magnetic field was
shown in [78]. However, the best resolution in frequency for
NMR of molecules has been only about 100 Hz [81]. Applied to
nanometer and micrometer volumes, NV center protocols pro-
duced broad NMR spectral lines of more than 100 Hz. This is
the result of both the short spin state lifetime of the NV center,
of about 3 ms, in addition to the fluctuating statistical spin po-
larization of the sample [82]. This frequency is not enough to
resolve key spectral features of molecular structures that are
critical to many conventional NMR applications. The induc-
tively detected conventional NMR has the necessary high spec-
tral resolution, but it has limited sensitivity in space, necessi-
tating samples on the millimeter scale.
A sensitive magnetometer based on an ensemble of NV centers
can deliver the sought spectral resolution down to about 1 Hz
[82]. The readout protocol is an evolution of the work in
[83,84]. The spin sensor is an ensemble of NV centers in com-
bination with a narrowband synchronized readout protocol to
obtain the NMR spectral resolution of about 1 Hz. The samples
are of micrometer scale and allow for thermal, rather than statis-
tical, nuclear polarization to be obtained at a spectral resolution
of about 3 Hz. This resolution permits chemical shifts and
nuclear spin–spin couplings to be resolved [82].
This protocol is used to sense NMR signals for as long as
103 seconds. By achieving an NMR spectral resolution of about
1 Hz in the sample volume of a typical cell, it is possible to
observe key spectral features that would otherwise not be
detectable.
The measurement technique of [82] is presented in Figure 6.
This NMR scheme [82] enables frequency resolution indepen-
dent of the sensor coherence time [85]. This approach seems su-
perior to alternatives such as in [81,86,87].
The intrinsic nitrogen nuclear spin was used in [86] and [87], as
a longer-term memory for the first phase measured in correla-
tion spectroscopy with extended interrogation times. Repetitive,
non-demolition nuclear state readouts are integrated into this
approach that also allow decoupling of the sensor electron spin
back-action on the target nuclei, thus shortening their correla-
tion time [87]. Sample diffusion here limits the sensing dura-
tion (≈5 ms). However, the nuclear memory approach resolved
ppm-level chemical shifts in liquid-state samples [81].
In the sample application in [82], the technique was used to
observe NMR couplings under ambient conditions in a microm-
eter-scale sample volume of about 10 picolitres. NMR is
applied to thermally polarized nuclear spins of an ensemble of
NV centers to resolve chemical shift spectra from small mole-
cules, allowing full chemical specificity of a single biological
cell. At sampling frequencies down to 1 Hz, the new measure-
ment scheme is 100× the spectral resolution of prior NMR spec-
troscopy based on NV centers.
The scheme presented in [82] has the potential to apply NMR
spectroscopy down to the single-cell scale. Further develop-
ments are still needed to boost the signal from small samples to
make it faster and more applicable to living samples, as well as
to improve the sensitivity of the NV centers to detect faint
signals produced by samples in weak concentrations.
If it were possible to have a certain type of color centers
demonstrating performance comparable to quantum probes for
NV centers in diamond, quantum sensors based on SiC would
be much improved. However, so far, no color centers in SiC
have shown promise as quantum sensors at room temperature.
The optical contrast of the spin signal, divacancy and silicon-
vacancy in SiC is limited to below 10% at room temperature,
and the overall count rate is also lower than that of the NV in
diamond. Thus, solid-state spin sensing MR spectroscopy
continues to progress in diamonds.
The length of time for which phase is accumulated limits preci-
sion in quantum sensing applications and quantum memory has
been employed to increase precision by extending this time to
longer than the coherence lifetime. The use of a quantum
memory allows for increased sensitivity as well [86], employ-
ing entanglement in a hybrid spin system based on a single NV
center linked to sensing and a memory qubit. In this way the
quantum state is preserved beyond the coherence decay,
allowing for coherent interaction with distinct weakly coupled
nuclear spin qubits. The performance is measured by the
stepped increase of entanglement between sensor and memory,
which is compared with the performance of the lone sensing
qubit, looking forward to high-resolution NMR spectroscopy of
single 13C nuclear spins.
Additionally, sensor dissipation limits the measurement perfor-
mance at the nanoscale, reducing the sensitivity and even
causing relaxation or dephasing. At room temperature, weak
NV center dissipation allows individual target nuclear spins to
be detected but limits the spectral resolution to several hundreds
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Figure 6: NV-ensemble sensor for coherently averaged synchronized readout (CASR) NMR. Image reprinted with permission from [82], copyright
2018, Springer Nature Publishing. (a) NV-ensemble sensor based on an NV center surface layer on a diamond chip, probed by a green laser. Ther-
mally polarized nuclear spins are NMR detected from the sample. (b) CASR detection of an NMR FNP signal. Top row: thermally polarized spin
precession at frequency f causes oscillations in the magnetic field. Middle row: CASR protocol made of optical NV spin-state readouts blocks
repeated at the synchronized readout cycle period intertwined with blocks of identical NV AC magnetometry pulse sequences with central frequency.
(c) Probe geometry: a cuvette holds the sample and the diamond chip, above and below are the cylindrical coils driving the nuclear spins, while a wire
antenna drives the NV centers. A light guide collects the spin-state-dependent fluorescence from the NV to bring it to a photodiode, while an electro-
magnet supplies the magnetic bias field.
of Hz, which is too low for molecular recognition. NV intrinsic
nuclear spins can be used as static memory for NMR [87] and
avoid back-action of the sensor on target by controlled decou-
pling of the sensor, memory, and target. This increases the
memory lifetime up to 4 minutes, enough to apply efficient
measurement and decoupling protocols, while achieving a
room-temperature resolution of 13 Hz.
Environmentally mediated resonance (EMR) control of spin
qubits is considered in [88]. Magnetic field sensitivity and
maximum field range are difficult to optimize at the same time.
However, interferometry-based magnetometry, based on quan-
tum two-level systems (which dynamically vary their phase ac-
cording to the magnetic field) works to address the issue [89].
Since the phase is 2π periodic, an increase of the coherent inter-
rogation time to improve sensitivity causes a reduction of the
field range. The measurement of the geometric phase in a quan-
tum two-level system introduces a way to address this, that is,
by employing the diamond NV center electronic spin, which
allows unwrapping of the 2π phase ambiguity with a 400×
increase in range. The nonadiabatic regime affords an added
increase in sensitivity and significantly affects phase decoher-
ence.
Back-action in measurements can be addressed by protecting
the spin state through multilevel 14N nuclear-spin memory,
allowing for repeated readouts and making it possible to use
error correction based on the quantum logic of coherent feed-
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back to reverse measurement back-action. This results in a
13-fold enhancement of readout fidelity and a 2-fold improve-
ment in the signal [90].
Robust estimation methods can aid in the measurement of spec-
tral properties in classical and quantum dephasing environ-
ments through filter function orthogonalization, optimal control
filters maximizing the relevant Fisher Information, and multi-
qubit entanglement [91]. Scheme robustness under noise is
considered, looking at effects of finite-precision measurements,
dephasing of the probe, spectral leakage, and slow temporal
fluctuations of the spectrum.
While the above-described approaches using NDs in hyperpo-
larization are not related to the presence of NVs in the NDs, but
simply try to use the material with conventional MRI methods
using paramagnetic electrons spin, other approaches are fol-
lowed by combining efficient DNP with optically polarized NV.
These approaches are more relevant in the context of NV nano-
MRI applications, even if they appear difficult for scale-up
purposes and none of the current realizations of polarization
transfer are simultaneously robust and efficient. In [92], a fast
and robust approach to achieve DNP of NV polarization to 13C
nearby nuclear spins is proposed and experimentally demon-
strated in single NV centers in a diamond. The design of se-
quences of short pulses with longer waiting periods between the
pulses achieves a polarization transfer through many repeti-
tions of the sequence. This method can be applied for the polar-
ization of nuclear spins of molecules external to the diamond
using an ensemble of close-to-surface NV centers or for the
hyperpolarization of ND as MRI biomarkers. This hyperpolar-
ization method is much simpler than the others described above,
mutated from MRI technologies, as it can be achieved at room
temperature.
The application of the above method to NDs is still challenging
as NVs in different NDs have different spin resonance proper-
ties due to the random lattice orientation of the NDs to the mag-
netic field orientation. This problem is similar to the applica-
tion of the ODMR-based magnetometer using NDs rather than
an ensemble of NVs in bulk diamond, as it is hard to collec-
tively polarize the NVs in all NDs at the same time. An attempt
to solve this problem is reported in [93]. Here, to overcome the
challenges to optically hyperpolarize diamond powder, a DNC
sequence has been applied to 200 μm diamond particles. The
polarization transfer is achieved by optically pumping NV
centers to 13C in diamond particles and by a first microwave ir-
radiation at low field values (1 to 30 mT), after which the sam-
ple is subject to rapid bulk inductive readouts at 7 T. The
process occurs at room temperature; however, the relaxation
time appears shorter to that obtained by using brute force in
large diamond crystals. Overall the combination of optical po-
larization of NV seems to improve 13C polarization by orders of
magnitude compared to those obtained using thermally polar-
ized P1 centers under comparable conditions [19]. However, the
transfer to biomedical imaging using conventional MRI with
these particles sizes is a challenge.
Detecting and controlling nuclear spin nano-ensembles is
crucial for the further development of NMR spectroscopy. The
fabrication of mono-atomic layers of nuclear spins and their
control is achieved in diamond NV centers in [77]. Using chem-
ical vapor deposition, a nanometer-thick diamond layer of
13C carbon atoms was grown in between two layers of a
12C-enriched diamond (acting as spin dephasing protecting
caps), on an ultrapure diamond substrate. The 13C layer was
doped with nitrogen via δ-doping during the growth process to
create a single NV near the 13C layer. In another sample, the
NV was implanted at different depths within the 13C layer. In
both samples, single NVs are coupled to a few tens of nuclear
spins, thus enabling polarization and readout of the magnetiza-
tion of these small ensembles. This work has principal applica-
tions in quantum simulation with an engineered quantum
Hamiltonian. A fabrication method is provided, which is a use-
ful tool to improve nuclear spin polarization via optical NV
electron spin polarization.
A new method has been proposed in [94] to hyperpolarize sur-
rounding nuclear spins (hydrogen nuclear spin ensemble in mo-
lecular poly(methyl methacrylate)) on the diamond surface
using NVs in a diamond probe at room temperature without
resorting to any radio-frequency or microwave sequence. An
external low magnetic field is used to tune the ground-state spin
transition frequency of the NV into resonance with target
nuclear spins. The NV is initially optically polarized and
readout is performed via its photoluminescence signal. While an
extended MRI contrast agent hyperpolarization small chamber
is proposed, this method appears challenging for its scale-up
potential in biomedical applications. Considering the many
recent contributions to achieve hyperpolarized NDs for conven-
tional MRI-aided (or otherwise by NV optical polarization and
microwave sequence), this topic appears to be a growing area of
research interest. However, the path to move to the use of NDs
as MRI contrast agents with or without NV centers is still quite
long.
NMR sensors based on optically probed NV defects in diamond
have allowed molecular spectroscopy from sample volumes that
are several orders of magnitude smaller than the most sensitive
inductive detectors. However, NV-NMR spectrometers have
only been able to observe signals from pure, highly concen-
trated samples.
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To advance the applications in mass-limited chemical analysis
and single-cell biology using NV-NMR, it is necessary to
increase the spectral resolution and the concentration sensi-
tivity. For this purpose, the use of diamond quantum sensors as
in-line microfluidic NMR detectors is presented in [95], where
by spatially separating the polarization and detection phases in a
microfluidic platform, picoliter-volume sensitivity is achieved.
Two-dimensional correlation spectroscopy within ≈40 picoliter
detection volume is performed with a spectral resolution of
0.65 ± 0.05 Hz, which is an improvement by an order-of-magni-
tude over the earlier diamond NMR study.
Finally, by combining picoliter-scale NV-NMR that uses a
CASR NMR protocol with 1 Hz resolution with Overhauser
dynamic nuclear polarization (DNP) using electronic spins in
the TEMPOL radicals, high-resolution spectroscopy on a
variety of small molecules in dilute solution was achieved
reaching femtomole sensitivity [96].
Conclusion
This review outlines many of the nano-MRI techniques that are
currently under development. It is arguable that NV centers in
diamond are one of the most promising of these techniques. In
this review, we have summarized several methods that use NV
centers in diamond for nano-MRI involving magnetometry at
the nanoscale. These are based on the NV sensor paramagnetic
resonance properties that provide sensitivities compatible with
nano-MRI for nuclear spins.
The research field presents a variety of material sensors such as
NV in bulk diamond structured from single NV to large ensem-
bles of NVs (layers of many NVs under the diamond surface),
fabricated arrays of NVs below the surface, and in NDs as en-
semble-producing FNDs. The current best sensitivity is
achieved using an ensemble of NVs in a layer in bulk diamond.
However, the use of arrays of high-density NVs is a very desir-
able approach for multichannel magnetic sensing.
The use of NDs for nano-MRI is still extremely limited, mostly
due to the lack of high-quality NDs, and few examples of appli-
cations of NDs as temperature and turbulence fluid sensors have
been shown. The functionalization of NDs with magnetic
contrast agents such as MNPs and Gd is another area of interest
for applications for nano-MRI. Similarly, attempts at hyperpo-
larization of NDs with and without NV centers have been per-
formed with no applications in biomedical studies developed to
date due to the limited contrast.
In terms of methods, we have found many approaches that lead
to different sensitivity and spatial resolution. The highest sensi-
tivity and spatial resolution are not always achieved in the same
experiments due to the excessive complexity associated with
the combination of both in the same setup/protocols.
The simplest approach is NV ODMR magnetometry, which can
reach sensitivities as low as nT·Hz−1/2 in bulk diamond
(100 nT·Hz−1/2 in NDs) and has been demonstrated in many ap-
plications in fields of biomedical imaging and condensed matter
physics. Some remarkable biomedical applications include
imaging magnetotactic bacteria with subcellular resolution
(400 nm) with a micrometer field-of-view, imaging mammalian
cells with nT sensitivity and sub-micrometer resolution, sensing
neuron action potentials with single-neuron sensitivity, opto-
magnetic imaging of neural network activity in brain slices, and
3D magnetic imaging of macrophage labeled with superpara-
magnetic iron oxide nanoparticles for liver tissues specimens.
These last specific applications are currently addressing bio-
medical needs and are likely to achieve further development
due to the similarity to conventional MRI applications with en-
hanced sensitivity and resolution. They are, however, based on
sensing of magnetic contrast agents or magnetic biological
systems rather than nuclear spins within these systems.
ODMR-based magnetometry is also used for solid-state physics
metrology in thin film ferromagnetic materials, current distribu-
tion in 2D layer materials, magnetic noise, and superconductor
critical field applications. Advanced ODMR magnetometry has
been combined with super-resolution microscopy methods, such
as STED and STORM, achieving spin localization with high
spatial resolution of up to 20 nm, even in NDs.
More complex NV magnetometry radiofrequency and micro-
wave sequences have been developed for NMR with a sensi-
tivity of a few pT·Hz−1/2, which is the closest approach to
conventional MRI while using NV as a sensor. Many different
approaches are used for NV NMR. However, small ensembles
of nuclear spins in polymer spectroscopy and single protein
nuclear spectroscopy were achieved by NV centers in bulk
diamond. NMR spectroscopy has been converted to the 2D
imaging of a dilute ensemble of 1H with 12 nm resolution. A
3D image of nuclear spins of NV in near proximity to
13C atoms has been achieved with a sub-nanometer resolution;
however, 3D imaging of single-molecule nuclear spins still
remains a challenge.
High sensitivity AC NV magnetometry has been combined with
super-resolution microscopy methods to increase the imaging
resolution. The frequency resolution of NV center NMR is
limited to 100 Hz, due to the broad nuclear spin resonance
detected from single proteins, while conventional NMR has a
high spectral resolution. This problem has recently been
resolved by implementing a CASR NMR protocol, reaching
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1 Hz frequency resolution and providing the ability to sense
molecular structures critical for conventional inductive NMR.
In general, a great deal of progress has been made using simple
ODMR NV magnetometry which recently has shown great
potential in biomedical applications. However, this method
cannot be applied to any biological system but only to specific
cases.
Regarding NV NMR, which paves the way for a truly nano-
MRI general method, the main challenge is to achieve 3D
imaging of nuclear spins in molecules and develop algorithms
and protocols to achieve this aim. The sensitivity should also be
improved to fT·Hz−1/2. In regard to the development of proto-
cols to achieve the required sensitivity for 3D imaging of
nuclear spins at the single molecular level, a road map should
be generated to fast track outstanding applications. It is under-
stood that one of the main challenges that remains is the isola-
tion of single molecules in the spin-free layer.
Acknowledgements
The authors received no funding and have no conflict of inter-
ests to declare. All the authors equally contributed to the manu-
script. The graphical abstract is reprinted with permission from
[82], copyright 2018 Springer Nature Publishing.
ORCID® iDs
Alberto Boretti - https://orcid.org/0000-0002-3374-0238
Lorenzo Rosa - https://orcid.org/0000-0002-9210-5680
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