|

Received: 8 April 2019    Accepted: 28 April 2019

DOI: 10.1111/srt.12712

ORIGINAL ARTICLE

Comparative “virtual biopsies” of normal skin and skin lesions

using vibrational optical coherence tomography

Frederick H. Silver1,2  | Ruchit G. Shah3 | Michael Richard4 | Dominick Benedetto5

1
Department of Pathology and Laboratory
Medicine, Robert Wood Johnson Medical Abstract
School, Rutgers, the State University of New Background: Increased tissue stiffness (also termed modulus) has been shown to be
Jersey, Piscataway, New Jersey
2 a characteristic of potential tumor metastasis. Measured values of the stiffness of
OptoVibronex, LLC., Mt. Bethel,
Pennsylvania tumors and cancer cells are reported in the literature to increase compared to neigh‐
3
Graduate Program in Biomedical boring normal tissues. Yet the relationship between the mechanical properties of
Engineering, Rutgers, The State University
of New Jersey, Piscataway, New Jersey
cells and the extracellular matrix has yet to be correlated with the histopathology of
4
Neigel Center for Cosmetic and Laser cancerous lesions.
Surgery, Florham Park, New Jersey Materials and Methods: We have developed a technique to do virtual biopsies of skin
5
Center for Advanced Eye Care, Vero Beach,
lesions by combining images made using optical coherence tomography with stiff‐
Florida
ness measurements made simultaneously using vibrational analysis. The technique is
Correspondence
termed vibrational optical coherence tomography (VOCT).
Frederick H. Silver, Department of
Pathology and Laboratory Medicine, Robert Results: In this paper, we report that precancerous and cancerous lesions are charac‐
Wood Johnson Medical School, Rutgers, the
terized by changes in both the morphology and stiffness of the cellular components
State University of New Jersey, Piscataway,
08854 NJ. of the skin. The ratio of the peak heights that correspond to the epidermal (40‐60Hz)
Emails: silverfr@rutgers.edu; fhsilver@
and dermal (140‐160 Hz) resonant frequencies appear to be different for benign and
hotmail.com
cancerous or precancerous lesions compared with normal skin and scar.
Conclusions: Cell‐to‐cell and epidermal‐to‐dermal interactions may be very impor‐
tant in evaluating the potential of skin lesions to become malignant. These interac‐
tions can be evaluated using VOCT, a new technique for performing “virtual biopsies”
of skin lesions.

KEYWORDS
actinic keratosis, basal cell carcinoma, imaging, melanocytic nevus, modulus, optical
coherence tomography, scar, skin, squamous cell carcinoma, stiffness, verrucous carcinoma,
vibrational optical coherence tomography

1 |  I NTRO D U C TI O N
In 2014, an estimated 5 million people were treated for skin cancer
1
at a cost of 8.1 billion dollars. In the United States, the number
of people between 55 and 85 years old is expected to increase to
125 million by 2050 and about 20% of this group will have a skin
1
cancer before the age of 70. Identification of tissue margins and
tissue stiffness non‐invasively in conjunction with enhanced imag‐
ing techniques has the potential to facilitate detection of abnormal
skin lesions and lead to early removal. We have developed at tech‐
nique termed vibrational optical coherence tomography (VOCT) to
image skin in three dimensions and measure the stiffness simulta‐
neously, non‐invasively and non‐destructively to provide a “virtual
biopsy” of skin and skin lesions. 2-9
Increased tissue stiffness (also termed modulus) has been shown
to be a characteristic of potential tumor metastasis.10 Under normal
conditions, the epidermis is thin and the mechanical properties cannot
be measured. However, when a benign or malignant skin lesion forms,

Skin Res Technol. 2019;00:1–7. wileyonlinelibrary.com/journal/srt   © 2019 John Wiley & Sons A/S. |  1
Published by John Wiley & Sons Ltd
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2       SILVER et al.
it is possible to measure the mechanical properties of the epidermis
since the epidermis thickens and can now be quantitatively analyzed
using VOCT.11 The number of cells, their morphology, the orientation,
and amount of collagen in skin lesions reflects the tissue metabolism
and may be used to characterize skin and skin lesions.11
Measured values of the stiffness of tumors and cancer cells have
12-14
been reported in the literature. For most breast and colorectal
cancer cell types, the stiffness of neoplastic tumors is reported to
increase compared to neighboring normal tissue,12-14 while in con‐
trast, cancer cells, irrespective of the carcinoma, are reported to be
softer than their normal counterparts.15,16 The relationship between
the mechanical properties of individual cells and the properties of
the whole tissue may be a useful relationship to correlate with the
histopathology of different lesions.
Using VOCT to image and analyze the biomechanical proper‐
ties of tissues non‐invasively and non‐destructively, it is possible to
get a “virtual biopsy” of normal skin and abnormal skin lesions. 2-9
Correlating these measurements with in vitro calibration data can be
used to interpret mechanical measurements made in vivo.9-14,17 The
purpose of this paper is to compare a virtual biopsy of normal skin
and a melanocytic nevus to the physical properties of several dif‐
ferent skin lesions in an attempt to define virtual biopsy parameters
that may be useful to differentiate malignant from benign lesions.
2 |  M E TH O DS
In Vitro Calibration Curve Construction Using Measurements on
Extracellular Matrices (ECMs).
Vibrational optical coherence tomography (VOCT) is a new tech‐
nique developed in the Department of Pathology at Robert Wood
Johnson Medical School, Rutgers University. It uses near infrared
light and audible sound applied transversely to the tissue surface to
image and measure the resonant frequency of tissues. 2-9
The reso‐
nant frequency is directly related to the tissue stiffness measured
using conventional uniaxial tensile testing as described previously. 2-9
A calibration curve of modulus values for control ECMs was con‐
structed by comparing moduli measured using conventional uniaxial
tensile testing and vibrational OCT measurements made in vitro as
previously described.2-9 The calibration curve indicated a one‐to‐one
relationship between tensile moduli and vibrational moduli measured
on the same samples including decellularized human dermis, pig fat and
skin, and bovine cartilage.2-9 The resonant frequency was determined
after correction for the resonant frequencies exhibited by the speaker,
sample holders, and any interference due to line fluctuations.2-9
2.1 | Vibrational OCT measurements
2.1.1 | Image collection
OCT cross‐sectional images were obtained using an OQ Labscope
(Lumedica Inc) and a laboratory spectral‐domain optical coherence
tomography device (SD‐OCT) operating in the scanning mode. 2-9
2.1.2 | OCT and vibrational analysis in vivo
Transverse sample displacement was generated by placing a speaker
next to the skin or under the excised lesion to be studied by spec‐
tral‐domain optical coherence tomography (SD‐OCT), a non‐con‐
tact, interferometric technique as discussed previously. 2-9 The
SD‐OCT system uses a fiber‐coupled superluminescent diode light
source with an 810 nm center wavelength and 100 nm bandwidth
(full‐width at half maximum) as described previously. 2-9
In vivo studies on the mechanical properties of skin and healed
scar tissue were conducted by hard wiring a 24 mm × 14 mm rect‐
angular speaker (Digi‐Key) to a Samsung cell phone as described
previously.7 A frequency generating app was downloaded from
the Google Play Store onto the cell phone. This app was capable of
driving the speaker between 10 and 20 000 Hz. The speaker was
applied to the skin using surgical tape, and it was used to generate
a sinusoidal sound wave that vibrated the skin. During in vivo mea‐
surements, no sensation of the light or sound impinging on the skin
was felt. The sound intensity was inaudible unless the speaker was
placed near the subject's ear to make sure it was energized. In vitro
measurements of excised verrucous carcinoma (a SCC subtype), a
nodular basal cell carcinoma (subtype of BCC), an actinic keratosis,
and a melanocytic nevus were made by placing the lesion on a glass
slide and mounting the glass slide on a plastic support under which
a speaker was placed to vibrate the tissue as discussed previously.9
The resonant frequency of each sample was initially estimated
by measuring the transverse displacement resulting from sinusoidal
driving frequencies ranging from 30 Hz to 300 Hz, in steps of 50 Hz.
Once the region where the maximum frequency was identified,
smaller steps of 10 Hz were used to more accurately identify the
peak displacement and the actual resonant frequency, fn. The moduli
of skin and the skin lesions were calculated from measurements of
the resonant frequency and tissue thickness made using VOCT and
images of the tissues as described previously.9 Moduli were obtained
from a calibration curve that relates resonant frequency and thick‐
ness to modulus values (Figure 1).
The original grayscale OCT images of skin, scar, and a melano‐
cytic nevus were pseudo color‐coded based on the pixel intensities
to provide better images of the tissue components. The enhanced
OCT images used darker colored (blue and purple) regions to reflect
lower pixel intensities while the lighter (yellowish) regions reflected
higher pixel intensity regions.
3 | R E S U LT S
OCT images of scar tissue are different than that of normal skin; scar
tissue appears to have a “smoother” surface than normal skin and
lacks the rete pegs that are seen in normal skin (Figure 2) as reported
previously.7,8 The epidermis is quite thin both in normal skin and scar
tissue. The cellular layers are more visible by color coding the image
based on pixel density as shown in Figure 2. The stratum corneum
(C), lucidum (L), germinosum (G), spinosum (C) and basale (B), and
SILVER et al. |
      3

F I G U R E 1   Calibration curve of tissue modulus times thickness vs resonant frequency for different extracellular matrices. This figure
was modified from reference.5-9 Note the modulus for cellular materials (fat and Staph Aureus) is lower (<0.1 MPa) than for normal dermal
collagen (2 to 3 MPa) and scar tissue (7 MPa). Calibration samples include decellularized human dermis at different values of the external
strain, porcine fat, elastic tissue, and bovine cartilage9-11

collagen of the papillary dermis (P) are labeled in the enhanced OCT
image as discussed previously.7,8 A plot of weighted displacement vs
frequency for normal skin and scar tissue is shown in Figure 3. Note
the resonant frequency of scar tissue is much higher than that of
normal skin in vivo and only the collagen peak is observed.
To calculate the moduli, the resonant frequency values obtained
from in vivo studies were corrected for differences in tissue thick‐
ness using the calibration curve for ECMs shown in Figure 1. Plots of
weighted displacement for skin and scar show peaks at 90 to 100 Hz
(normal skin) and 220 to 230 Hz (scar tissue) (see Figure 3), respec‐
tively, and the calculated moduli are about 2.0 to 3.0 MPa (skin) and
7.0 MPa (scar) (Table 1). Note the resonant frequencies of the epi‐
dermis of skin and scar tissue are not measurable since the epidermis
is too thin to generate a signal in these tissues.
Figure 4 shows an enhanced OCT image of a melanocytic nevus
and the histopathology of this lesion. The increased number of cells
seen in this lesion can be identified by the thick yellow layer seen in the
enhanced OCT image and the large number of dark blue nuclei seen by
F I G U R E 2   Enhanced OCT images of skin and scar. The
histopathology. Note the histopathology shows the normal rete pegs interface between scar tissue and normal skin is marked by a
seen at the interface with the papillary dermis. However, a large num‐ surface depression and a difference in the height of the hills and
ber of melanocytes are seen both in the epidermis and dermis. Note valleys seen by OCT. In normal skin and scar the epidermis is quite
the depression in the surface of the enhanced OCT image as well as thin. The stratum corneum (S) is seen in blue at the top while the
stratum lucidum (L) is a continuous layer of yellow: the stratum
a similar depression present in the histopathological image (Figure 4).
granulosum (G), and spinosum (S) are characterized by yellow dots,
Figure 5 shows a plot of weighted displacement vs frequency for the stratum basale is pink (B) and the papillary dermis (P) is blue.
the melanocytic nevus, verrucous carcinoma, nodular basal cell car‐ Normal skin has more apparent hills and valleys in the surface layer
cinoma, and the actinic keratosis. Note the sharpness and location than scar tissue. The interface between normal and scar tissue is
of the low‐frequency peak for the benign melanocytic nevus (40 Hz) marked in the figure by the arrows
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4       SILVER et al.

F I G U R E 3   Weighted displacement vs frequency for human skin (left) and scar tissue (right). The resonant frequency of normal skin is
much lower than that of neighboring scar tissue while the interface between normal skin and scar tissue is characterized by the resonant
frequencies of both tissues (data not shown—see reference 7-9). The weighted displacement of a sample was obtained by dividing the
displacement observed at a frequency by the displacement measured in the absence of the sample as described previously7,8

TA B L E 1   Resonant frequencies and

Resonant frequencies
moduli values of normal, skin, scar, fat and
Tissue (Hz) Modulus #1 (MPa) Modulus #2 (MPa)
verrucous carcinoma from refs 14,16 and
Skin 90‐100 None 2.0‐3.0 this study
Scar 220‐230 None 7.0
Fat 40 0.03 None
M. Nevus 40, 140‐180 0.398 3.10
Verrucous C 50, 150‐170 0.686 2.57
Basal Cell C 60,160 0.618 2.66
Actinic Ker 70,140‐180 0.890 3.05

vs the peaks for the verrucous carcinoma (VC), basal cell carcinoma
(BCC), and the actinic keratosis (AK). The other lesions (VC, BCC,
SCC) have low‐frequency peaks that are wider (40‐70 Hz) and are
not as sharp. In comparison, the high‐frequency peaks (140‐180 Hz)
for all the lesions are broad compared to the peaks for normal skin
and scar, the latter (skin and scar) have resonant frequencies that
vary by about 10 Hz. The ratios of the low‐ to high‐frequency peaks
were high for the melanocytic nevus as compared to that of the ver‐
rucous carcinoma, basal cell carcinoma, and actinic keratosis.
4 |  D I S CU S S I O N
While most dermatologists can visually identify many lesion types,
lesion depth or margins cannot be defined without performing his‐
topathology on the excised lesion.8 The preoperative clinical assess‐
ment of the extent of a tumor in three dimensions would facilitate
surgical planning and allow dermatologists to know which tumors
are wide and deep enough to require a referral to a Mohs specialist
or additional plastic procedures.8 With improved preoperative im‐
aging of the margins and depth of the lesions and measurement of
tissue properties and lesion margins, micrographic surgery could be
shortened, made more cost‐effective and less time‐consuming for
patients and surgeons.8
We have developed a non‐invasive and non‐destructive test,
vibrational optical coherence tomography (VOCT), to image and
measure the stiffness of skin lesions. 2-9 This technique can be
used to measure the stiffness of any substance by vibrating the
material and measuring its resonant frequency. 2-9 Since tissue
stiffness has been identified as a marker for cancerous lesions
and as a predictor of metastatic behavior,10 this technique after
further studies may be useful in rapid classification of skin le‐
sions and their margins. In addition, since the resonant fre‐
quency of the epidermis of normal skin and scar tissue cannot be
SILVER et al. |
      5

F I G U R E 4   Enhanced OCT image (left) and histopathology (right) of melanocytic nevus. Note the normal skin morphology of the lesion
superimposed with a melanocytic infiltration throughout the epidermis and dermis in the histopathological image (right). Note the thickened
yellow layer of cells in the enhanced OCT image of the epidermis of the melanocytic nevus compared to that of normal skin (Figure 2). The
surface depression is shown (arrow) in both the OCT and the histopathological images

F I G U R E 5   Weighted displacement vs frequency for different skin lesions. The resonant frequency of the epidermis in normal skin cannot
be measured due to the thinness of this layer (see Figure 3). However, in skin lesions this layer becomes prominent for the melanocytic nevus
and the epidermal resonant frequency peak is sharper than for the precancerous (actinic keratosis) and the cancerous lesions (verrucous and
basal carcinomas). Note the broadening of the collagen peak in all the lesions suggesting that changes in the orientation and organization
of the collagen in the dermis occur compared to that of normal skin and scar (Figure 3). The ratio of the heights of the epidermal‐to‐dermal
peaks (low/high resonant frequencies) was highest for the benign melanocytic nervus (12.5) and was observed to be significantly lower for
the basal cell carcinoma (2.5), the actinic keratosis (1.3), and the verrucous carcinoma (1.1)

accurately measured, due to the thinness of the normal epider‐
mis, this technique would be useful in identifying pathological
changes to both the epidermis and dermis reported in this study.
Any cellular proliferation of the epidermis or fibrosis of the der‐
mis would lead to an increase in the stiffness of each layer that
could be identified using infrared light and audible sound that is
the basis of VOCT.
In this paper, we present data on the use of VOCT for performing
a virtual biopsy on normal skin and a benign lesion, a melanocytic
nevus, as well as a comparison of the stiffness measurements to a
verrucous carcinoma, basal cell carcinoma, and an actinic keratosis
previously reported on.11 Virtual biopsies of normal skin and skin
lesions have progressed to the point that we are able to identify
most of the layers of skin using near infrared light.11 In addition, we
 |
6       SILVER et al.
are able to measure the resonant frequency of the skin components
using audible sound by applying a transverse sinusoidal wave and
determining the frequency at which the maximum skin displacement
is observed. In normal skin and in scar tissue, the epidermis is too
thin to measure the resonant frequency of this layer; however, in
both benign and cancerous lesions the epidermis thickens, based on
the enhanced OCT image, and the resonant frequency of the epider‐
mis can be measured.
Verrucous carcinoma is a relatively uncommon, locally aggres‐
sive lesion, characterized clinically by endo‐ and exophytic growth.
It is a low‐grade, slow‐growing, well‐differentiated SCC with minimal
metastatic potential. The epithelium shows characteristic external
and internal projective growth, with a granular layer showing marked
18
elevation in keratin production with enlarged keratinocytes.
BCC is a cutaneous malignant proliferation of cells that is thought
to derive from the basal layer and outer root sheath of hair follicles.19
The nodular type consists of aggregates of basaloid cells with well‐
20
defined borders, a peripheral palisading of cells, and a typical cleft.
Mitotic activity is not normally present but can be present in aggres‐
sive forms of the lesion. BCC is the most common human cancer, and
it is usually caused by excessive exposure to ultraviolet light. 21
In comparison, actinic keratosis is thought to be an early form
of SCC. It is characterized as a horizontal alteration of parakera‐
totic and/or keratotic hyperkeratosis with an atrophic epidermis. 20
Neoplastic keratinocytes in the basal layer show increased cellu‐
larity, nuclear pleomorphism, and scattered mitoses. Both nodular
basal cell carcinoma and actinic keratosis are characterized by hy‐
percellularity of the epidermis.
After examination of the data in Table 1 and Figure 5, the mela‐
nocytic nevus appears to exhibit a resonant frequency that is lower
and sharper than that of the cancerous and precancerous lesions
(VC, BCC, AK) and closer to the resonant frequency measured for
fat reported previously.7 The higher range of the resonant frequen‐
cies and moduli seen in the cellular layers found in verrucous car‐
cinoma, basal cell carcinoma, and actinic keratosis may be due to
either changes in the attachments between cells or due to the stiff‐
ening of individual cells. Increased tissue stiffness has been shown
to be a characteristic of cancerous tissues and potential tumor
metastasis.10
Measured values of the stiffness of tumors and cancer cells have
been reported in the literature.12-14 For most breast and colorectal
cancer cell types, the stiffness of neoplastic tumors is reported to
increase compared to neighboring normal tissue,12-14 while in con‐
trast, cancer cells, irrespective of the carcinoma, are reported to
usually be softer than their normal counterparts.15,16 The increased
resonant frequency and stiffness of the epidermis found in verru‐
cous carcinoma, basal cell carcinoma, and actinic keratosis may re‐
flect differences in cell‐to‐cell attachments as opposed to changes
in the physical properties of individual cells. A recent review22 sug‐
gests that adherens junctions, in neoplastic cells, involved in cell‐to‐
cell attachments, exhibit transformed organization, regulation, and
stability. Increased organization of adherens junctions may offer an
explanation for the increased resonant frequency and stiffness of the
epidermis in precancerous and cancerous lesions observed by VOCT.
In contrast to the epidermis, the resonant frequency peak for
collagen in the papillary dermis in both benign and cancerous lesions
appears to broaden as compared to normal skin and scar (compare
Figures 3 and 5). This broadening suggests that although the aver‐
age modulus may not change in benign and cancerous lesions, the
orientation and amount of collagen may change. The fact that the
two cancerous lesions, the verrucous carcinoma (a SCC) and the
nodular basal cell carcinoma, had approximately equal ratios of their
peak heights for the cellular and collagenous components (Figure 5),
suggests that in the cancerous lesions (SCC and BCC), the cellular
components in the epidermis are actively modifying the collagen in
the papillary dermis. In contrast, in normal skin and the benign me‐
lanocytic lesion, the papillary dermis may not be influenced by the
changes that occur in the basal and squamous cells and their cell‐
to‐cell interactions. These results suggest that cell‐cell interactions
may modify the papillary dermis metabolism in cancerous and pre‐
cancerous lesions. These altered cell‐cell interactions and increased
stiffness may provide a means by which these lesions may ultimately
become metastatic. The changes in stiffness of the epidermis and
the broadening of the collagen peak may be important parameters
to study as a function of lesion type.
The observation that verrucous carcinoma, nodular basal cell
carcinoma, and actinic keratosis are characterized by changes both
in the cellular and collagenous components of the dermis and are
associated with either cancerous or precancerous lesions suggests
that more attention should be paid to epidermal‐to‐dermal cell in‐
teractions when screening patients for potentially cancerous le‐
sions. We are currently evaluating whether this can be done in
a no‐touch measurement using vibrational VOCT and the “virtual
biopsy.”
5 | CO N C LU S I O N S
VOCT is a useful imaging technique that allows the clinician to visu‐
alize and physically characterize the stiffness of lesions. Since tissue
stiffness has been associated with malignant growth of cells as well
as metastatic potential, VOCT is useful in analysis of lesion composi‐
tion. Cellular contributions to the properties of the lesion occur at
resonant frequencies at or below about 60 Hz while collagen con‐
tributes to the resonant frequencies above 90 Hz depending on the
tissue thickness.
In this study, we report that precancerous and cancerous lesions
are characterized by changes in both the morphology and stiffness
of the cellular and collagenous components of the skin. We conclude
that cell‐to‐cell and epidermal‐to‐dermal interactions may be im‐
portant in evaluating the potential of a skin lesion to become cancer‐
ous and metastatic. Further VOCT studies are needed to correlate
images and resonant frequencies of the epidermis and dermis with
the histopathology of different skin lesions.
SILVER et al.
C O N FL I C T S O F I N T E R E S T
One or more of the authors may receive financial remuneration in
the future from the sale of the device used in this research work.
ORCID
Frederick H. Silver  https://orcid.org/0000-0002-2480-9264
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How to cite this article: Silver FH, Shah RG, Richard M,
Benedetto D. Comparative “virtual biopsies” of normal skin
and skin lesions using vibrational optical coherence
tomography. Skin Res Technol. 2019;00:1–7. https​://doi.
org/10.1111/srt.12712​