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174 9 Tissue Viability Imaging
600
400
200
0
0 0.5 1 1.5 2 2.5 3 3.5 4
RBC concentration (%)
TiVi
index
(A.U.)
600
400
200
0
0 0.5 1 1.5 2 2.5 3 3.5 4
RBC concentration
(
%
)
TiVi
index
(A.U.)
(a)
(
b
)
Experiment – HbO
2
Simulation – HbO
2
Simulation – Hb
Experiment – Hb
Experiment – HbO
2
Simulation – HbO
2
Figure 9.10 TiVi output from experiments
with oxygenated and deoxygenated blood,
along with linearized Kubelka–Munk the-
oretical fits from theory. (a) Data from
high-resolution imager. Error bars represent
the average value of five images ± one stan-
dard deviation. (b) Data from high-speed
video imager used for research purposes.
Error bars represent the average of 25
frames ± 1 standard deviation.
RBC fraction from 0 to 4%, as shown in Figure 9.10. For 0 and 100% oxygen
saturation, the correlation coefficient was calculated to 0.998 (n = 4) and 0.997
(n = 20), respectively. The average TiVi
index
-value calculated for the lower oxygen
saturation was on average 91.5% of that calculated for the higher oxygen saturation,
corresponding to a deviation of <3.9% within the physiological range (70–100%
oxygen saturation) well in accordance with theory. TiVi images can therefore be
considered to be virtually independent of the state of tissue oxygen saturation
for both the high-resolution commercial system and the research-based high-peed
system.
9.4
Technology
The principle of subsurface mapping of local RBC concentration has been
implemented in the Tissue Viability Imager (TiVi) TiVi600 brought to mar-
ket by WheelsBridge AB, Linkoping, Sweden (http://www.wheelsbridge.se). The
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9.4 Technology 175
complete TiVi600 system composed of a Canon EOS system camera (Canon Inc.
Lake Success, MA, USA) equipped with polarization filters to generate cross- or
copolarized photos and remotely controlled by a USB-connected interface with a
portable PC. Camera control, photocapturing, further image processing of TiVi
images, and result generation are made via the dedicated TiVi600 system soft-
ware. In many applications, photos are recorded in sequence, thereby allowing
studies of dynamic skin reactions following topical or systemic application of
substances that cause vasodilatation (increased RBC concentration) or vasocon-
striction (reduced RBC concentration) in the skin. By use of the integrated wizards
and statistic measures, erythema (vasodilatation) and blanching (vasoconstriction)
can be visualized and quantified. The entire process of assessing a specific skin
reaction by, for example, naked eye observation thereby becomes increasingly
independent of the individual investigator. To use the integrated wizards effec-
tively, the object in a sequence of photos must appear in the same position in
all photos. When photos are recorded at different points in time, the first photo
can be used as the Reference Photo. When successive photos are to be captured,
actual test photos are displayed superimposed on the Reference Photo and the
object is repositioned until there is an acceptable overlap of the object in the
Reference Photo and that of the actual test photo, where after the next photo in
the sequence is captured. Alignment of the object in successively captured photos
can thus be attained. To further align the objects in the different photos of a
sequence, an integrated preprocessor performs photo alignment automatically as
a first step in the image processing procedure. These arrangements prepare a
sequence of photos to be analyzed by use of the integrated wizards. An example
of such a procedure is demonstrated in Figure 9.11. Following topical application
of methyl nicotinate (50 mmol) in patches on the skin of the back to produce
vasodilatation, photos were captured in sequence for 20 min with a frequency
of 12 photos per min. In the analysis, regions of interests were drawn around
the patches and combined with a set threshold to produce the Erythema Area
Chart and the Erythema Intensity Chart displaying the dynamic development of the
erythema area and intensity as the drug penetrated the top layer of the skin to
produce vasodilatation in the superficial microvascular network. Data reduction is
thereby attained by reducing images to time traces that, in turn, can be reduced
to indexes (e.g., the time at which 50% of the top level is reached) describing
the entire experiment. The maximum resolution of the images is 18 million pix-
els, thereby rendering it possible to zoom in on a small area with still adequate
resolution.
Figure 9.12 displays the result of the same experiment using the integrated
Cross Section Visualizer. This image displays the development of erythema along a
user-selected cross section in the photos as a function of thetime elapsed. The cross
section shows that, during the first 5 min, the vasodilatation occurs mainly within
the individual patches, while toward the end of the experiment, the drug diffuses
laterally to produce vasodilatation also in the skin sites between the individual
patches.
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176 9 Tissue Viability Imaging
(a)
(b)
Figure 9.11 Development of (a) Erythema Intensity and (b) Erythema Area following topical application of metyl nicotinate in eight patches on the
skin of the back.
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9.4 Technology 177
Figure 9.12 Cross section along two patches following
topical application of methyl nicotinate (time along the
dependent axis). After about 2 min following application of
the substance, the erythema appears inside the patches. Af-
ter 7 min, the erythema has spread outside the patches.
9.4.1
Software Toolboxes
To address specificapplications and needs,dedicatedtoolboxes have beendeveloped
that can be integrated with the TiVi system software.
9.4.1.1 Skin Damage Visualizer
In general, the Skin Damage Visualizer toolbox was developed for direct assessment
of skin damage at the work site or in occupational medicine applications. Skin
damage at the work site can occur as a consequence of exposure to aggressive
chemicals (skin irritation causing erythema) or following the use of vibrating tools
(vasospasm causing vasoconstriction). By displaying the fraction of, for example, a
hand that possesses erythema (RBC concentration above a user-selected threshold
value) in redcolor, the healingprocess and/or progressions ofcontact dermatitis can
be evaluated over time, using the integrated library and trend monitor functions.
This is shown in Figure 9.13.
9.4.1.2 Skin Color Tracker
The color of the skin changes over time in many diseases and conditions and can
thus be a useful indicator for assessment of the development and progression of
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178 9 Tissue Viability Imaging
Figure 9.13 Skin areas with erythema above a set thresh-
old level before (left) and after (right) the exposure to a skin
irritating agent.
skin disease or a healing process. What is generally referred to as skin color is
the spectral content of backscattered light following illumination by a broadband
light source. Consequently, the skin color observed is not only dependent on
the optical properties of the skin but also dependent on the spectral signature of
the illuminating light. If a digital camera is used to capture a photo of the skin, the
spectral sensitivity of the photodetector array further influences the color of the
photos recorded. Consequently, skin color can not be regarded as an absolute
quantity. However, changes in spectral content of the diffusely backscattered light
from the skin under illumination by a light source with a fixed spectral signature,
carry useful information about changing skin conditions. The Skin Color Tracker
toolbox makes it possible to follow a preselected color (or a range of colors) and
thereby to track the progressive development of, for example, scaling tissue in
psoriasis. These color changes are minute and cannot be readily verified by naked
eye observation alone.
9.4.1.3 Spot Analyzer
Facial spots including acne appear most frequently during puberty with a varying
degree of severity. About 90% of the adolescent population is believed to be affected
by this skin disease. Numerous skin care products are commercially available for
treatment of spots, and new and more effective products are continuously released
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9.5 Evaluation 179
on the market. To evaluate the performance of these skin care products, the
product candidates are generally tested using a panel of volunteers with spots of
varying severity. The result is assessed by naked eye observation at which both the
intensity and the extension of the spot erythema are evaluated. These evaluations
are generally performed by a skillful dermatologist, and a severity score on a scale
from one to five may be used to quantify the findings. Because of the unavoidable
investigator-dependent element of these naked eye inspection procedures, results
vary among observers and interlaboratory comparison of data may be difficult to
perform. The Spot Analyzer toolbox renders this process fully automatic and investi-
gator independent. Results are delivered in terms of diagrams displaying the inten-
sity and extension of the spot erythema. The results from individual sessions can be
integrated into aproject window that displaysthe overall result ofa test panel project.
9.4.1.4 Wrinkle Analyzer
Wrinkles frequently appear on the parts of the body where there has been extensive
sun exposure. Wrinkles can appear as fine structures or deep furrows. Smoking,
skin type, heredity occupational, and recreational habits are factors that all promote
wrinkling of the skin. Many products have been developed for the reduction of
wrinkles or rather their appearance, but few cost-effective techniques are to date
available for quantitative analysis of wrinkle appearance. The Wrinkle Analyzer
TiVi90 is a software package that analyzes several features of wrinkles based on
photos captured by polarization spectroscopy camera technology.
9.4.1.5 Surface Analyzer
Most women and some men show signs of cellulite where the skin of the lower
limbs, abdomen, and the pelvic region becomes dimpled. The causes of cellulite
are not fully understood, but hormonal components are thought to play a dominant
role in its formation. Several genetic factors promote the development of cellulite
as do lifestyle factors. A number of therapies for treatment of cellulite are available,
but empirical evidence of the efficacy of these treatment regimes is limited, mainly
due to lack of methods for quantification of cellulite appearance. The Surface
Analyzer TiVi95 is a software package that analyzes important features of cellulite
and associated skin dimples based on photos captured by polarization spectroscopy
camera technology.
Both the basic TiVi system software and all toolboxes are supported by an on-line
and interactive Demo Assistant that guides the user through the different steps of
photocapturing and image analysis.
9.5
Evaluation
The basic operation principles and practical use of many commercially available
instruments for assessment of the skin have been thoroughly evaluated, and Guide-
lines regarding their effective use have been published [15–18]. Standardization
reports regarding assessment of critical performance parameters such as deviation
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180 9 Tissue Viability Imaging
in sensitivity and reproducibility for a batch of presumably identical instruments
are, however, frequently limited or nonexistent. Data recorded in different labora-
tories and/or at different points in time are therefore difficult to compare, which
hampers the use of these instruments on a broader scale. The TiVi600 system has
been evaluated with respect to these performance parameters [19]. The average
systematic drift in TiVi system sensitivity over a three-month time period, while
the systems were moved in between laboratories, is reported to be 0.27% and
discrepancy in sensitivity between different units is limited to 4.1%, due to offset
rather than gain deviation when measurements were performed using a paper
of uniform pink color as a object. Spatial variation in image uniformity is below
3.08 and 1.93% in the corners and the center of an individual image, respectively.
Since the intensity of the flash is generally much higher than that of ambient light,
virtually no influence on the image of ambient light can be demonstrated under
ordinary daylight conditions. The distance dependence was assessed by recording
images alternatively at a distance of 15–25 cm and calculating the TiVi
index
-values
produced by erythema-inducing methyl nicotinate in forearm skin. No significant
difference in the average TiVi
index
-values at the two distances could bedemonstrated
(n = 25). In contrast to what is the case with laser Doppler devises, TiVi is further
not sensitive to movement artifacts because no Doppler components are recorded.
Since all image points are recorded simultaneously, there is no interpretation
ambiguity regarding spatial and temporal variations in skin microcirculation, as
may be the case with raster scan laser Doppler perfusion imaging (LDPI) devices.
On theother hand, since TiVi is based on spectroscopy, it is sensitive to allobjects of
a specific color. Consequently, heavily pigmented skin results in higher TiVi values
than nonpigmented skin due to an offset in the TiVi value. The sensitivity of the
TiVi value parameter is, however, less affected by the degree of skin pigmentation.
Alterations in skin RBC concentration as recorded by TiVi over a short period of
time (in comparison with the timescale under which pigmentation changes) are
therefore comparable also for skin types with different degree of pigmentation.
However, it has been observed that skin freckles may mimic skin erythema [20].
Day-to-day variations of normal values of skin response on the dorsal side of the
hand were estimated at 5–7%, with short-term variation (i.e., within 70 s) of <2%.
Studies into the reproducibility and detection ability of the postocclusive reactive
hyperemia (PORH) test showed up to 60% increase in local RBC concentration,
remaining 18% above preocclusion level 30 min posttesting [20].
9.5.1
Iontophoresis
The TiVi device has also been used to map changes in cutaneous microvascular
concentrations of RBCs during the iontophoresis of vasoactive substances
(namely, noradrenaline (NA) and phenylephrine (Phe) for vasoconstriction and
acetylcholine (ACh) and sodium nitroprusside (SNP) for vasodilatation). As the
TiVi output variable is only dependent on the concentration of RBCs, studies of
iontophoresis of vasoactive agents using both TiVi and LDPI were shown to be
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9.5 Evaluation 181
Acetylcholine (ACh)
Edge effect
(a)
(b)
Noradrenaline (NOR)
(mm)
Time = 1 min
Time = 5 min
Time = 10 min
150
100
50
150
100
50
Figure 9.14 The effects of the iontophoresis of (a) a
vasodilating and (b) vasoconstricting agent. Both the
increase and decrease in local perfusion can be quantified.
able to separate the concentration and velocity components of the skin response fit
to an experimental model [21]. Example images of the iontophoresis procedure of
such substances are shown in Figure 9.14 with analysis carried out by the method
of ‘‘dose–response’’ curves, as shown in Figure 9.15. The 50% response level (ED
50) variable has been shown to be a reliable method to quantify the physiological
response of the microvasculature to various drugs, and values determined by TiVi
technology are similar to those previously determined by laser Doppler systems.
‘‘Islands’’ of perfusion can be seen in the region, thus displaying the heterogeneous
structure of the skin microcirculation, the effect of which can influence the
transdermal delivery of drugs. The onset of vasoconstriction and vasodilation can
be observed graphically as shown in Figure 9.16. Epidermal thickness, resistance
to charged particle movement [22], and variation in the underlying microvascular
network [23] may also influence the appearance of islands.
Recent work has also independently quantified the effects of topical vasocon-
strictive agents, providing an operator-independent assessment of skin blanching.
Studies were compared to Minolta chromameter CR 200, which was used as
an independent color reference measurement. The application of the corticoid
Desoximetasone gel (0.05%) was assessed after 6 h and showed that the relative
uncertainty in the blanching estimate produced by the TiVi system was about 5%
and similar to that of the chromameter operated by a single user [24].
9.5.2
Lipid Studies
Using the TiVi technology, changes in erythema following application of 0.5%
benzyl nicotinate in formulations with different lipid content were investigated
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182 9 Tissue Viability Imaging
180
160
140
120
100
80
60
40
20
0
10
−2
10
−1
10
0
10
1
10
2
Dose (mC)
ED
50(Ach)
ED
50(NOR)
NOR
Reference area
ACh
RBC
conc
(A.U.)
Figure 9.15 Dose– response curves outlining the reaction presented by vasoactive agents.
[25]. They observed that benzyl nicotinate containing 10% fat had the effect of
inducing erythema more rapidly and with higher intensity than the formulations
with fat content
>
10%. They also investigated the blanching agent betamethasone
valerate, showing that efficacy was increased with lower fat content formulation.
They concluded that the rate of penetration of the active ingredients was inversely
related to the lipid content; thus, simple changes of the cosmetic properties
by modifications of the lipid content may affect the efficacy of a formulation.
These results can be summarized in Figure 9.17, whereby the response of the
TiVi system can be observed for benzyl nicotinate formulations with various lipid
concentrations. Theseresults havean impacton theformulations ofdermatological
treatments, where the physical and dermatopharmacological actions of the active
ingredients may be changed to suit the patient (i.e., for appearance, odor, etc.).
9.5.3
UV-B Studies
Recent research expanded the use of the TiVi technology to study UV-B
(280–320 nm) phototesting, using a radially attenuating beam of characterized
dosimetry [26]. Previously, LDPI was used to give quantitative evaluation to doses
above the minimal erythemal dose (MED – the lowest dose of UV light that
produces an identifiable erythematous reaction). This improves on current practice
for UV-B phototesting whereby single exposures of increasing dose are made over
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9.5 Evaluation 183
200
100
0
500
600
400
200
0
0
400
300
200
100
20
40
60
80
100
Time (s)
Time (s)
Time (s)
Width (pixels)
20
40
60
80
100
Width (pixels)
Width (pixels)
TiVi
index
(A.U.)
200
100
0
TiVi
index
(A.U.)
100
200
300
400
500
Time (s)
100
200
300
400
500
600
10 20 30 40 50 60 70 80 90 100
Width (pixels)
10 20 30 40 50 60 70 80 90 100 110
Ach
NOR
Figure 9.16 Profiles of a cross section of the reacting area undergoing iontophoresis showing the vasodilation and vasoconstriction process. The
area affected can be assessed spatially and temporarily with TiVi technology.
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