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com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Received: 31 May 2020 Revised: 28 July 2020 Accepted: 10 August 2020
DOI: 10.1002/tbio.202000013

REVIEW

Optical coherence tomography for tissue classification

of the larynx in an outpatient setting-a translational
challenge on the verge of a resolution?

Lukas Wittig | Christian Betz | Dennis Eggert

Universitätsklinikum Hamburg-
Eppendorf, Otorhinolaryngology, Head
and Neck Surgery, Hamburg, Germany
Correspondence
Lukas Wittig, Universitätsklinikum
Hamburg-Eppendorf,
Otorhinolaryngology, Head and Neck
Surgery, Martinistrasse 52, 20246
Hamburg, Germany.
Email: lu.wittig@uke.de
Abstract
The detection and tissue classifica-
tion of mucosal lesions of the upper
aerodigestive tract (UADT) is crucial for the development of a treatment plan.
Using modern endoscopic examination techniques mucosal changes can be
detected early on in an office-based setting. However, the further classifica-
tion of these lesions requires a surgical procedure with a biopsy taken under
general anesthesia. Optical coherence tomography (OCT) is a noninvasive,
light-based optical tool which can provide high-resolution cross-sectional
images of tissue at near microscopic resolution. Applying it through a single
mode optical fiber allows endoscopic approaches. Routine endoscopic assess-
ment and a thin epithelial layer makes the larynx the perfect organ for
implementing OCT into the clinical endoscopic routine. This review is
focused on summarizing previous and ongoing translational applications of
OCT imaging for tissue classification in the UADT focusing on the larynx,
discussing limitations and benefits and offering an outlook on possible future
applications.

KEYWORDS
cancer, deep learning, larynx, mucosal lesion, optical coherence tomography, upper
aerodigestive tract

1 | INTRODUCTION Tissue analysis is a main aspect in confirming a diag-

1.1 | Laryngeal lesions
Global cancer statistics noted 177.422 new cases of laryn-
geal carcinoma in the year 2018.[1] About 90% of all head
and neck cancers and thus also those of the larynx are
squamous cell carcinomas arising from the epithelial
lining.[2]
nosis in the field of oncology. The early classification of
mucosal lesions in the upper aerodigestive tract (UADT)
and especially its detection of malignant transformation
is crucial for developing a treatment plan.
State-of-the-art in examining the larynx is handheld
flexible or rigid video laryngoscopes. The introduction of
endoscopic tools in the daily practice has improved
the detection rate of premalignant laryngeal lesions.

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Translational Biophotonics. 2021;3:e202000013. www.tbio-journal.org 1 of 9

https://doi.org/10.1002/tbio.202000013

2 of 9
However, the detection of a laryngeal lesion is limited to
the description of morphological aspects on the tissue's
surface and the nomenclature is not consistent. For
example, the clinical terms leucoplakia, erythroplakia or
chronic laryngitis—to name but a few—merely describe
the outer appearance and cannot differentiate benign
hyperplastic or premalignant dysplastic epithelial
lesions.[3] The risk for malignant transformation or early
invasive growth cannot be determined with certainty.[4]
A meta-analysis of 940 cases of laryngeal dysplasia
found an overall malignant transformation rate of 14%,
with severe dysplasia having an increased rate of malignant
transformation compared to mild dysplasia.[5]
Therefore, the gold standard to further classify
endoscopically detected lesions is invasive biopsies and a
histopathological assessment requiring general anesthe-
sia.[6, 7] Besides the general risks of general anesthesia,
every biopsy may lead to tissue damage and scar forma-
tion. The function of the larynx is especially sensitive to
epithelial changes and scarring, so that even a small tis-
sue biopsy can cause long-term adverse effects such as
dysphonia.[5] Isenberg et al. presented data that biopsies
taken from leucoplakia of the larynx showed no dysplasia
in about 50% of the cases.[4] However, even laryngeal
lesions with no dysplasia in the initial biopsy had
an increased risk for transforming into an invasive
squamous cell cancer in the future.
These findings underline the importance for a better
diagnostic risk stratification of laryngeal lesions without
invasive biopsies under general anesthesia. In this regard,
a tool would be desirable that is on the one hand capable
of detecting early invasive growth or high-grade dysplasia
of the larynx in need of surgical intervention, but that
could—on the other hand—differentiate laryngeal lesions
with no or low-grade dysplasia thus preventing unneces-
sary surgeries. At the same time, it should be a reliable
tool for follow-up examinations of these latter lesions
without performing recurrent invasive biopsies.
For decades, several studies have been published with
different classification systems trying to stratify the risk
for malignant transformation based on histologic find-
ings.[7, 8] Currently used classification systems are the
WHO dysplasia system, the squamous intraepithelial
neoplasia, and the Ljubljana classification.[3] What all
those histopathologic classification systems have in
common is the use of traditional light microscope exami-
nation based on architectural and cytological changes. Rel-
evant aspects are, that is, irregular epithelia stratification
and the loss of polarity of basal cells.
A noninvasive tool that is capable of imaging epithe-
lial surfaces in a vertical fashion with an almost similar
resolution to traditional light microscopy is optical
coherence tomography (OCT).
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WITTIG ET AL.
The focus of this article is the discussion of the
challenges in bringing endoscopic guided OCT of the lar-
ynx into clinical routine and providing possible solutions
how to overcome them.
1.2 | Optical coherence tomography
In the life sciences and especially in medicine, optical tools
have been used for over a century for diagnostic purposes
starting with common light microscopes. Since then, the
technological progress has been enormous and in the last
decades the science of biophotonics has emerged. This
field includes different light-based technologies for the
imaging of biologic matter. One of these technologies, first
described for analyzing biologic tissue in 1991 by Huang
et al., is OCT.[9] The technology of optical coherence-
domain reflectometry was initially used to localize faults
in fiber optic networks before it was introduced and devel-
oped further for biological applications.[10, 11]
OCT is a noninvasive light-based optical tool, which
can provide high-resolution cross-sectional images of tissue
using a near-infrared light beam. In 1997, Tearney et al.
presented in vivo images of human tissues with resolutions
in the order of 10 μm and penetration depths of around
2-3 mm,[12] even though empirically, the imaging quality
significantly deteriorates beyond 1.5 mm in mucosal tissue.
Using low-coherence interferometry, the basic principle
of OCT is the measurement of backscattered near-infrared
light from a tissue probe, similar to the ultrasound technol-
ogy. The main components are a light source, an interfer-
ometer, a detector and an application system.
In 2002, the first commercialized OCT system for oph-
thalmology was Federal Drug Administration (FDA)-
approved.[13] The time-domain technology (TD-OCT) uses
a moving mirror for the reference arm limiting the acquisi-
tion rate to about 400 A-scans/s with axial resolution of
about 10 μm,[14] making it susceptible for motion artifacts
especially in awake patients (Figure 1, left). Since then,
multiple advances in the technology of OCT (ie, improved
optical designs and the development of faster computa-
tional imaging) enabled Fourier-Domain (FD) detection
methods with increased imaging speed and better resolu-
tion (Figure 1, right). FD-OCT achieves axial resolutions
of about 2 μm and image acquisition speeds ranging
between 26 000 and 100 000 A-scans/s [15] .
2 | O C T I N TH E L A R Y N X
The development of higher performance OCT systems
has led to a wide field of clinical applications apart from
ophthalmology. Today, two-dimensional and three-
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WITTIG ET AL. 3 of 9

F I G U R E 1 On the left, a
schematic setup of a TD-OCT
System using a movable mirror
for the reference arm is shown
with a corresponding OCT
image and histologic slide from
the lower lip. On the right, a
schematic setup of a FD-OCT
System using a linear detector is
depicted with a corresponding
OCT image and histologic slide
taken from the same spot from
the lower lip. The epithelial
layer (E), the basement
membrane (BM) and the lamina
propria (LP) are clearly
distinguishable on the OCT
images. The mucosal structure
of the inner lip is very similar to
that of the larynx. (Scale bar
shows 1 mm). OCT, optical
coherence tomography

dimensional live OCT images of tissue at near histopath-
ologic resolution can be derived from different anatomi-
cal sites.[16–18] A major focus is the differentiation and
classification of tissue in the different fields of oncology
and a vast amount of studies have been published ex vivo
and in vivo.
By developing single mode optical fibers, the range of
OCT applications has been extended to all endoscopically
accessible areas as well. The combination of OCT and a
flexible endoscope was first described by Sergeev et al. in
1997.[19] The optical fiber of the endoscope could be con-
veniently inserted through the working channel of the
endoscope. In the same year, Tearney et al. published
cross-sectional images of the rabbit gastrointestinal and
respiratory tracts at 10 μm resolution using a catheter
endoscope.[12]
In 2005, Tsuboi et al. showed that endobronchial
OCT can be used to identify abnormal areas of the bron-
chial wall[20] in resected lung-specimen of the human.
Two-years later, Chen et al. demonstrated the feasibility
of real-time OCT imaging to differentiate Barrett's
esophagus, dysplasia, and esophageal adenocarcinoma
during a regular endoscopic examination in humans.[21]
In spite of the good accessibility of the larynx for
endoscopic examinations and the clinical dilemma of
differentiating laryngeal lesions as described above, only
few studies have been published using OCT imaging of
the larynx, and even fewer trials have investigated
laryngeal OCT in an office-based setting. This is even
more unfortunate, as this organ seems better suited for
OCT examinations than any other due to the fact that
the regular epithelium is constantly thin, whereas
mucosal pathologies (such as premalignant changes)
regularly show a thickening of the epithelial layer. This
was shown in a detailed histopathologic assessment by
Arens et al., where the group showed that a progressive
thickening of the epithelial layer of the vocal folds—
which has a “normal” thickness of 110 to 186 μm—
directly correlates with the grade of epithelial dysplasia
(ED), carcinoma in situ (CIS) to early invasive carci-
noma (EIC) (ED I-258 μm; ED II-301 μm; CIS-445 μm;
EIC-974 μm).[22]

4 of 9
An important early study on the usage of OCT solely
in the larynx was published in 2005 by Wong et al. In
their trial, they performed OCT imaging of the larynx in
82 patients during endoscopic surgery under general
anesthesia, using a handheld probe in near contact to the
target site and showed that the mean epithelial thickness
of vocal cords, aryepiglottic fold und epiglottis ranges in
between 129 and 185 μm, thus correlating closely to
the histologically assessed data by Arens et al. Further
did Wong et al. show that OCT is able to provide infor-
mation on the integrity of the basement membrane and
the structure of the lamina propria as additional key
factors in distinguishing between microinvasive cancer,
premalignant lesions and benign disorders.[23] The largest
study to date investigating laryngeal lesions with
OCT was published by Kraft et al. in 2008, examining
217 laryngeal lesions in patients undergoing elective
microlaryngoscopy. Similar to the study cited before, the
authors also stated the penetration of the basement mem-
brane to be the most important criterion in OCT for inva-
sion; they were thereby able to correctly predict the grade
of dysplasia in 71% and malignancy in 93% of their cases.
This notion was repeatedly confirmed, for example in
two case series using an operating microscope with an
integrated OCT system published by Just et al.[24] and
Englhard et al.,[17] where it was shown that it is possible
to differentiate various laryngeal lesions via OCT imag-
ing. In addition, Volgger et al. described the application
of a TD-OCT System under general anesthesia for laryn-
geal lesions and again stated a good correlation of OCT
images and histopathologic slides.[25] Wong et al. were
further able to improve the OCT acquisition rate and
reconstruct virtual 3D models of the subglottis in chil-
dren using a FD-OCT-System with a rotational probe
inside a transparent fluorinated ethylenepropylene (FEP)
sheath for imaging.[26]
Thus, the studies cited above as well as several others
have sufficiently proven the general ability of OCT to
depict the microstructure of the epithelial layer in the lar-
ynx with contact and noncontact systems, either inte-
grated into a microscope or with an handheld probe
under general anesthesia.[17, 23, 27–30] All of them state
the diagnostic potential of OCT in the larynx in differen-
tiating premalignant from early malignant changes.
However, an office-based approach seems to be espe-
cially suitable for OCT. For this reason, we searched the
Medline database for appropriate and relevant publica-
tions in May 2020, focusing on endoscopic OCT imaging
of the larynx in awake patients. Thereby, only a very lim-
ited number of studies was found.
In 2006 Klein et al., presented a first study with an
outpatient-based scenario. They used a flexible trans-
nasal endoscope with an operating channel for
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WITTIG ET AL.
introducing the OCT probe. The OCT probe was placed
in direct contact to the vocal folds under local anesthesia
successfully obtaining OCT images, as well as
polarization-sensitive OCT (PS-OCT) images. Through
PS-OCT, the collagen fiber orientation and density could
be detected, thus better revealing characteristics within
the lamina propria. However, in this proof of concept sce-
nario no histopathological correlation was performed.[31]
In 2008 Sepehr et al. confirmed the proof of concept and
clearly identified laryngeal mucosal microstructure using
an OCT fiber introduced through a vertebrate tube glued
to the flexible endoscope. They stated that fibreoptic
trans-nasal OCT of the larynx has “the potential to aid in
diagnosing laryngeal lesions, to provide more targeted
biopsy of suspicious lesions, and to allow more objective
noninvasive monitoring of disease progression and
response to therapeutic interventions.”[32] One major
weakness of the above-mentioned setups was the image
acquisition in direct contact to the tissue using an image
plane orthogonal to the long axis of the probe requiring
large amounts of local anesthesia. Although when in
direct contact to the tissue there is only little risk of pro-
ducing movement artifacts, acceptance by the patient
might be limited. Further, a tubing for the rotating OCT
fiber was necessary being a limiting factor in the quality
and speed of data acquisition.
Possibly because of these weaknesses, studies with
rigid laryngoscopes have been published as well. Guo
et al. presented a first approach in 2006 using a prototype
rigid 90 laryngoscope. They presented high-resolution
OCT images depicting the epithelium, basement layer,
and lamina propria. Two major challenges pointed out
were motion artifacts and focusing.[33] The individual
anatomy of every patient changes the necessary working
distance, asking for manual adjustment of the laryngo-
scope by the physician. In 2009 Guo et al., presented a
similar setup with a gradient-index lens rod probe all-
owing capturing in vivo images with 8 fps reducing
motion artifacts and improving the handling for the phy-
sician.[34] Within the same year the group presented a
swept-source OCT system integrated into a 90 rigid
laryngoscope with video-rate imaging.[35] A similar setup
with an automated and fast adjusting focusing system
was presented in 2015 by Donner et al further improving
OCT imaging of the larynx. The presented OCT laryngo-
scope combines video laryngoscopic imaging and OCT in
one endoscope providing standard handling ergonomics
for the physician and a fixed lateral position reference of
the OCT-scan-line within the camera images.[36] The
measured mean epithelial thickness of 109.5 μm in
female test persons and 135.4 μm in male test persons
was in good agreement with previously published data by
Wong et al.[23] They further stated their confidence, “that

WITTIG ET AL.
these cross-sectional images can support the decision-
making to take a biopsy in patients having dysplasia of
the vocal fold epithelium” and further underlined the
need for “correlation of histologic studies and the
cross-sectional OCT images.”[36]
The latest study published in 2016 by Coughlan et al
demonstrated for the first time a cross-sectional view of
laryngeal vibration in vivo during phonation.[37] Besides
offering interesting approaches for phoniatric research,
an irregular vibration of the vocal folds is a known indi-
cator for epithelial malignancies and might add to the
diagnostic purpose of differentiating laryngeal lesions.
In a nutshell, the above-mentioned studies show the
potential of OCT of the larynx in an office-based setting
and have documented the tremendous technical
improvement throughout the years. However, the need
for trials combining the acquisition of high-resolution
OCT images of laryngeal lesions in awake patients and a
thorough histopathologic correlation is still largely
unmet. As well, since no established imaging atlas for
OCT in the laryngeal mucosa is available, the interpreta-
tion is highly dependable on the examiner's knowledge of
vocal fold anatomy and OCT imaging.
Possibly due to these shortcomings, no laryngoscope
with an integrated OCT system is commercially available
to our knowledge until today.
3 | A N A L Y Z I N G O C T DA T A BY
DEEP LEARNING METHODS
Probably the most challenging part in OCT imaging for a
clinician is the interpretation of OCT images. Direct sub-
jective interpretation of OCT images by human observers
requires extensive training.[38] This becomes even more
challenging with modern OCT systems that can acquire
OCT images at video rate with more than 40 images/s. As
mentioned earlier, the interpretation of OCT images is
highly based on the experience of the clinician causing
an interobserver variability. This can lead to delayed
diagnoses and worse outcomes of the patients.[39] For the
everyday practice a tool is needed which can classify the
OCT images with a high rate of sensitivity and specificity.
A promising adjunct is deep learning techniques,
especially neural networks. Neural networks are comput-
ing systems inspired by biological neural networks (eg,
the human brain).[40] They can be trained to perform
tasks based on input examples, generally without being
programmed with task-specific rules. Convolutional neu-
ral networks (CNNs) are superior in image classification
compared to other algorithms.[41, 42] To perform a task
like image classification a CNN is trained with a set of
annotated datasets. The image features that are used for
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5 of 9
classification are chosen and weighted by the algorithm
itself and not predefined by the user. After being trained,
a CNN can perform the classification on new datasets
without annotation. The performance of a CNN is depen-
dent on both the number and quality of the training datasets
and on the image quality of the datasets that are to be classi-
fied. The more training datasets, the better the annotation
of the training datasets and the higher the image quality the
better the CNN will perform the classification. The shortage
of training datasets with good annotations is the main
challenge in applying CNNs in medical imaging.[43]
Deep learning methods have been used for tissue clas-
sification of the UADT with different imaging techniques
in a number of studies so far.[44–48] Only one small study;
however, investigated deep learning methods for tissue
classification of the UADT using OCT imaging.[49]
Gessert et al. stated that automated classification might
add to the expert's decision-making. However, a larger
dataset of high-quality full resolution OCT are needed to
improve the classification performance.
We conclude that several smaller studies state a high
potential for improving the diagnostic quality using deep
learning methods. The open challenge in the transla-
tional process is the combination of optical imaging, the
routine endoscopic examination and automated tissue
classification.
4 | C O N C L U S I O N A N D PR O S P E C T S
The afore-noted studies have pointed out that OCT can
generate high-resolution and (in the case of FF-OCT)
even near-histopathologic images of tissue from different
anatomical sites and computational processing should be
further able to deliver real-time evaluations. Being a non-
invasive, marker-free technique, OCT has the potential to
improve laryngeal cancer detection and become a stan-
dard method in this field. The objective interpretation of
OCT images and videos—independent of the experience
of the clinician—based on deep learning techniques
is a promising approach which should become more
important in the future.
OCT as a diagnostic tool seems especially suitable for
endoscopic tissue classification of the larynx in an outpa-
tient setting. Ideally, a biocompatible OCT probe is either
inserted through the working channel of a flexible laryn-
goscope for this purpose or is directly integrated into the
laryngoscope. In this way, the OCT image can be directly
correlated with the video image. Figure 2A-C shows the
exemplary insertion of a suited OCT probe into a com-
mercial flexible video laryngoscope (Olympus ENF-VT3).
The OCT images can be acquired during a regular endo-
scopic examination of the larynx in awake and upright
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6 of 9 WITTIG ET AL.

F I G U R E 2 Onsite tissue classification of laryngeal lesions by noncontact endoscopic OCT. A, A biocompatible OCT probe, B, can be
inserted into the working channel of a flexible video laryngoscope. C, The endoscope still has its full flexibility. D, Video image of the OCT
probe aimed at vocal folds, E, with the corresponding OCT image. OCT, optical coherence tomography

F I G U R E 3 Deep learning workflow for automated tissue classification in OCT images. An OCT image or video is first preprocessed
and then analyzed by deep learning techniques such as convolutional neural networks. The final output could classify the tissue into
different groups supporting the physician's decision: benign (no further action is needed), malignant (a surgical resection should be
performed soon), unclear (further investigations are needed)

sitting patients. A video image and the corresponding
OCT image of the vocal folds is shown in Figure 2D,E.
By applying an automated tissue classification system
based on deep learning techniques, this approach might
then be used to automatically differentiate benign lesions
and malignant lesions independent of the examiner's
experience in OCT imaging (deep learning workflow
shown in Figure 3).
Apart from these practical issues that require atten-
tion, new technical developments are at the horizon that
have the potential to improve the OCT-based tissue
classification in the larynx. For example, the imaging
depth and the resolution of OCT scans can be improved
by using a vertical-cavity surface emitting laser (VCSEL)
that sweeps through the bandwidth as light source.[50]
Very high-imaging speeds of up to 580 000 axial scans/s
provide a high-axial resolution of 9 to 12 μm in the tissue,
and an imaging depth of up to 38 mm have been reported
using this technology.[51] The clinical utility of this
device, however, is yet to be determined.[50]
Another highly interesting technical development
that might be interesting with regards to laryngeal
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WITTIG ET AL. 7 of 9

F I G U R E 4 OCT images of a hyperkeratotic lesion of the left vocal fold. On the left shows the vocal fold before laser ablation with the
corresponding OCT image slides taken from lateral (1) to medial (30) clearly depicting the thickening of the epithelium (17, 25, 30) as
indicated by the red arrow. On the right shows the vocal fold after laser ablation with corresponding OCT image slides, again taken from
lateral (5) to medial (25) depicting a smooth epithelial surface. OCT, optical coherence tomography

OCT-imaging has recently been proposed,[52] where the
additional analysis of the ATP-dependent motion of cel-
lular structures allows for an increase of the resolution
into a submicrometer range. Due to its subcellular resolu-
tion, this development provides for histology-like con-
trasts in OCT images. So far it has only been
implemented in an ex vivo setting and not been applied
clinically. Still, it might be a promising tool for a “histo-
logical analysis” of unstained tissues.
Last but not least, other advanced OCT techniques such
as optical coherence elastography (OCE), polarization-
sensitive OCT (PS-OCT) and full-field OCT (FF-OCT)
might be integrated into the systems in order to provide
additional information such as relative tissue stiffness,
tissue-specific contrast based on polarized light (eg, colla-
gen fibers) or an improved resolution down to a subcellular
level.[53–57] Especially OCE has shown positive results in
the detection of cancer margins.[58, 59] Still, these tech-
niques have not yet been tested in the larynx for clinical
purposes, but they might show some potential for future
applications.
Apart from these promising technical innovations,
there are numerous further possible applications for OCT
within the larynx. For example, it might be useful as
an effective adjunct during therapeutic interventions
within the larynx. Not long ago, it has been shown that
an OCT-based tissue differentiation of oral mucosa—
being similar to laryngeal mucosa—can effectively be
used for an intraoperative delineation of oral cancer
margins after resection.[16] If this could be proven for the
larynx as well, OCT might in the future add to or even sub-
stitute the current gold standard of frozen section pathology
as a means to obtain clear margins during (pre)cancer
resections in the larynx.
Figure 4 provides another example for the thera-
peutic potential of OCT in the larynx. It shows a so far
unpublished OCT image series taken with an OCT-
microscope (OPMedT iOCT-camera, HS Hi-R 1000G-
microscope Haag-Streit Surgical GmbH, Wedel, Ger-
many) during microlaryngoscopy of a benign hyperker-
atotic lesion of the left vocal cord before and after CO2
LASER ablation. The hyperkeratotic layer that is
clearly depicted in the OCT images before the interven-
tion, is completely gone afterwards, but with the epi-
thelial layer being largely intact. This application
might help to predict the healing process after thera-
peutic procedures, which should be very good in the
presented case.

8 of 9
As a further, more visionary outlook into the future,
OCT could in the long run be used for marker-less, real-
time tracking during surgery. This becomes especially
interesting in robot-assisted laser surgery, where a closed
loop setup could guarantee that the robot is automatically
guided based on the OCT signal. In theory, the larynx
might be an ideal candidate for marker-less OCT-tracked,
robot-assisted laser surgery in the future, so in our view
this technique merits further evaluation.
In conclusion, this article has given an overview over
recent publications on OCT-based tissue classification of
the larynx with a focus on its application in an outpatient
setting. OCT can be a valuable tool both for cancer diag-
nosis and for intraoperative guidance, although it has
(unfortunately) not made it into clinical routine yet.
Current and future developments, such as a full integra-
tion of OCT into video laryngoscopes combined with
automated tissue-evaluation based on deep learning
algorithms, have the potential to revolutionize laryngeal
cancer detection and make OCT a standard adjunct
diagnostic tool in this field.
CONFLICT OF INTEREST
The authors declare no financial or commercial conflict
of interest.
ORCID
Christian Betz https://orcid.org/0000-0003-3188-1026
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How to cite this article: Wittig L, Betz C,
Eggert D. Optical coherence tomography for tissue
classification of the larynx in an outpatient setting-
a translational challenge on the verge of a
resolution? Translational Biophotonics. 2021;3:
e202000013. https://doi.org/10.1002/tbio.202000013