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184 9 Tissue Viability Imaging
110
100
10%
50%
80%
Control
90
80
70
60
50
40
30
20
10
−10
−20
0
0 5 10 15 20 25 30 35 40 45 50 55
Time (min)
TiVi 600-response (AU)
Figure 9.17 Relationship between TiVi output and three
different lipid concentrations of benzyl nicotinate (represent-
ing different formulations). (Source: After Ref. [25], repro-
duced with permission.)
Lamp housing
Electronic
shutter
Filter
holder
Water tank
(heat filter)
Liquid
light guide
Beam
Divergent lens
Figure 9.18 Instrumentation for wide field UV-B provoca-
tion. The water tank removes heat, and optical filters limit
the light to UV-specific wavelengths. A liquid light guide
transmits the UV-B radiation to the conical applicator with a
lens diverging the beam. (Source: After Ref. [26], reproduced
with permission.)
an area of the skin and are subject to a visual assessment scoring scale. The radial
UV-B methodology has been validated by way of evaluating the anti-inflammatory
effects of topically applied substances [27]. The instrumentation for provoking the
UV-B reactions is shown in Figure 9.18.
Visually assessed diameters were also determined to match LDPI determined
reaction diameters within a 95% confidence interval [28] and allowed the plotting
of dose–response curves using the quantitative response data of the LDPI images
against the corresponding dosimetry data. It has also been recently determined that
if naked eye readings are to be used to assess UV-B reaction diameters and then
advantages are shown by the use of a sharp-edged reaction, whereas the use of an
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9.5 Evaluation 185
0123401234
(a) (b)
Figure 9.19 (a) Six hour delay photo-
graph and (b) corresponding LDPI image.
(Source: After Ref. [29], reproduced with
permission.)
assessment technology such as LDPI (or perhaps TiVi) is advocated if the borders
between the reaction and normal tissue is diffuse (as in the radial provocation) [29]
(Figure 9.19).
The improved spatial resolution of TiVi over LDPI allows a more accurate
visualization of the increased concentration of RBCs, as is shown by the delayed
reaction in Figure 9.20. The group determined the reaction diameter by using the
Original image
200
150
50
100
TiVi value
35
25
15
5
30
20
10
0
0 5 10 15 20 25 30 35
Width (mm)
Height (mm)
35
25
15
5
30
20
10
0
0
0
5 101520253035
Width (mm)
Height (mm)
35
25
15
5
30
20
10
0
5 101520253035
Width (mm)
Height (mm)
Processed
2 std. dev.
4 std. dev.
(a)
(c)
(d)
(b)
Figure 9.20 (a) A photograph of a 6 h delay UV-B provo-
cation, (b) standard processed image showing background
regions (dashed), and (c,d) the thresholded image using two
times the standard deviation of the background regions and
also by four times the standard deviation. (Source: After Ref.
[26], reproduced with permission.)
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186 9 Tissue Viability Imaging
450
350
250
150
50
0
0
400
300
200
100
TiVi value (A.U.)
2 4 6 8 10 12 14 16 18 20 22
Distance from centre
(
mm
)
100%
75%
20%
0%
VUS
20–75
VUS
20–75
Figure 9.21 Plot of five responses to provo-
cations by radial analysis. The volume under
different parts of the curve reflects the
‘‘amount’’ of erythema under the surface of
the skin at the test site and can be used as
a method of comparison between responses.
It should be noted that the same provoca-
tion dose does not elicit the same intensity
of reaction in each individual. (Source: After
Ref. [26], reproduced with permission.)
method of thresholding the image by two and four times the standard deviation
of the four regions of background, a method well used with thresholding of LDPI
images [27]. They compared these results to the values provided by a radial analysis
tool, which divided the reaction into concentric isodose rings centered on the
reaction. Each ring is averaged to produce an intensity at a distance from the
reaction center. Figure 9.21 details the dose–response of five test subjects 6 h
postexposure to the volar forearm. The group used a linear fit between 20 and 75%
of the reaction maximum (at the center) to estimate the reaction radius and used
calculations of the area under the curve that estimates the volume under thesurface
of the skin reaction. The group also describe how the mismatch of the clinician
and TiVi technology may be due to the polarization detection of the system, which
is effectively seeing a deeper range of returning photons from the tissue than the
clinician detects. Owing to the known effects of TiVi response variation of 10%
on imaging a curved area such as the forearm [19], efforts should be made to
standardize testing, and other work is geared toward dewarping the images of the
forearm, to effectively ‘‘flatten out’’ the image for a more reproducible analysis [26].
9.5.4
Temporal Studies
Research studies have developed the wide field imaging system further to include a
video mode, applicable to the same instrumentational setup as the high-resolution
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9.5 Evaluation 187
imager with some modifications [30]. Two systems were developed, one with a
light emitting diode (LED) ringlight using a three CCD video camera with direct
streaming of data to a PC for processing [31] and another portable system which
replaced the flash light source with a continuous light source of a similar shaped
spectrum [32]. This system has been tested using the PORH test, a test that has
previously been employed to study microvascular reactivity functionality [33]. Their
results show that greater significance may be placed on the pattern or trend of
behavior in these responses over a defined time period rather than an absolute
measurement of peak reaction or the time to peak reaction. The group also
examined the capillary refilling manoeuvre, a quick physical exam used clinically
that providesimportant information regarding skin perfusion. Abnormal perfusion
of the skin can indicate a number of medical conditions; for example, dehydration,
hypothermia, and many types of shock cause a prolonged capillary refill time that
is >2 s. The pressure on the arteriolar capillaries blanches or whitens the skin
by a clinician pressing on the tissue, so that when the skin is uncompressed this
allows blood to flow back into the vessels and the skin returns to a normal color.
The amount of time it takes for the skin to return to normal is the capillary refill
time. An example of the increase in RBC concentration in the nail fold during an
occlusion maneuver known as the postocclusive reactive hyperemia can be observed
in Figure 9.22. This test was performed with sphygmomanometer occlusion of
the brachial artery with a pressure of 80 mmHg (which inhibits venous return
flow but allows arterial inflow) for 30 s. The increase in concentration during
occlusion can clearly be observed. The vasculature has not returned to normal 90
s postocclusion.
Despite the simplicity of occlusion tests, especially the capillary refilling test,
they are often performed incorrectly thus yielding useless results. The group
attempted standardization of the test maneuver and also quantified its effects using
high-speed TiVi, rather than relying on visual observation. An example time trace
Preocclusion 80 mm Hg 90 s postocclusion
50 100 200150
Figure 9.22 TiVi video frame images at various stages
during the PORH cycle. The resulting RBC concentration in
the nail fold is observed to be higher than the preocclusion
level. (Source: After Ref. [31], reproduced with permission.)
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188 9 Tissue Viability Imaging
0.45
0.4
0.35
0.3
0.25
0.2
Normalized TiVi
index
(A.U.)
0 20 40 60 80 100 120
Time (s)
Preocclusion time
Postocclusion time
Occlusion
time, t
oc
Occlusion region
Nonoccluded region
TiVi
pk
t
pk
Figure 9.23 Time traces from a reactive hyperemia test
using a blunt tool, showing the increase in local RBC con-
centration in the volar forearm. Statistics such as the time
to peak, t
pk
, and peak TiVi value, TiVi
pk
, are used to charac-
terize the response. (Source: After Ref. [32], reproduced with
permission.)
of the reaction is shown in Figure 9.23, using an ROI over the reaction area and a
similar sized area located a distance away from the primary reaction. The influence
of the capillary refilling can be seen in the nonoccluded region, indicating the
far-reaching effects of a local decrease in skin perfusion. The group proved by
correlation functions that longer occlusion times lead to larger differences between
the occluded and nonoccluded time series, although failed to prove any distinction
between men and women and between smokers and nonsmokers. This may be
a result of the small sample size of subjects and the large inter- and intrasubject
variation in TiVi responses [32].
Limitations of the video imaging method with the high-speed imager are the
same as those shared with many noninvasive imaging technologies (i.e., capillary
microscopy, LDPI), with the largest effect being patient motion causing the subject
area to move outside of the imaging frame. Slight patient motion in this method
can be compensated for by the aligning function included in the TiVi600 main
code, and larger motion can be compensated for by zooming out of the area and
refocusing the camera on the new area. This will, of course, cause the loss of data
but provided the new area is refocused, the frames can be aligned. For experiments
using maximum temporal resolution, this may lead to hundreds of iterations of
marking and alignment, even over a time of <20 s.
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9.6 Comparison with Other Instrumentation 189
9.6
Comparison with Other Instrumentation
LDPI and laser speckle perfusion imaging (LSPI) represent well-established
modern approaches to the investigation of microcirculatory function. The princi-
ples of laser Doppler and laser speckle technology are available from other sources
[34–38], and here, it suffices to say that both LDPI and LSPI are sensitive to both
the concentration and velocity of the RBCs in the skin’s blood vessels, whereas TiVi
technology is sensitive only to the concentration of RBCs in the tissue. Table 9.2
outlines the differences between the TiVi, a commercial LDPI system (known as
laser Doppler line scanner – LDLS) and a commercial LSPI system (known as full
field laser perfusion imager).
In order to evaluate the effect of vasoconstrictive agents on the skin microvas-
culature involves the measurement of signals below the normal biological zero for
a subject. The use of LDPI for this test requires an increase in background flow
to enhance contrast, usually achieved by local warming of the area [39]. The use of
TiVi systems to allow vasoconstriction studies without the need for predilation as
required by LDPI studies has been shown to represent an advantage in the reduc-
tion of confounding factors [21]. Other experiments recently performed corroborate
the inability of LDPI and LSPI to measure below the biological background in the
Table 9.2 A comparison table outlining the mechanical and
operational specifications of the LDPI (LDLS), LSPI (FLPI)
speckle, and TiVi imaging devices.
Property LDLS FLPI TiVi
Principle Doppler effect Reduced speckle
contrast
Polarization
spectroscopy
Variable recorded Perfusion (speed ×
concentration)
Perfusion (speed ×
concentration)
Relative
concentration
Measurement sites 16 384 431 680 Up to 18 million
Best resolution (µm) ∼500 ∼100 ∼50
Measurement depth ∼1mm ∼ 300µm ∼ 500 µm
Repetition rate (s) 6 (50 × 64) 4 (568 × 760) 5 (5184 × 3456)
Best capture time (s) 6 4 1/60
Zoom function No Yes Yes
Video rate None 25 fps 30 fps
Video size – 113 × 152 up to 760 × 1080
Pixel resolution
(cm
−2
)
100 40 000 900 000
View angle Top only Top only User selectable
Weight (kg) Scanner 3.2 2 3
Calibration Motility standard Motility standard None
Ambient light
sensitivity
Intermediate Substantial Negligible
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190 9 Tissue Viability Imaging
12
4
4
10
10 12
8
8
6
6
65
4
4
2
2
0
0
50
0
0
Position (cm)
Position (cm)
Position (cm)
Position (cm)
14
12
10
10 12
8
8
6
6
4
4
2
2
0
0
Position (cm)
Position (cm)
14
12
10
10 12
8
8
6
6
4
4
2
2
0
0
Position (cm)
Position
(
cm
)
14
100
150
200
250
300
700
600
350
90
80
70
3
3
2
2
1
1
60
50
40
30
20
10
0
500
400
300
200
100
0
LDLS Perfusion (P.U.)
FLPI Perfusion (P.U.)
TiVi
index
(A.U.)
Figure 9.24 Skin blanching due to a vaso-
constricting corticosteroid by the three sys-
tems. The black dots in the FLPI and LDLS
images bound the area affected by the drug.
The FLPI image is shown over a smaller
scale due to background level; hence, the
border between affected and unaffected
tissue is shown. (Source: After Ref. [40],
reproduced with permission.)
volar forearm, as shown for all three devices in Figure 9.24 [40]. An example of a
vasoconstriction as detected by the three systems is shown in Figure 9.25, showing
that the measurement depth of the LDPI system does not determine the superficial
pattern produced in skin. This is due to the longer wavelength used in the LDPI
as opposed to the FLPI and TiVi systems. These experiments also highlighted the
variation in response with increasing pressure applied to a tourniquet on the upper
arm. The increased spatial resolution of TiVi imaging is also apparent in this work.
Other work in the literature compares and contrasts further the advantages and dis-
advantages between the use of the main microcirculation imaging modalities [41].
9.7
Other Technology for Polarization Imaging
Other forms of polarization imaging have also been used with various degrees
of success. The technique of optical polarization spectroscopy (OPS) uses
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9.7 Other Technology for Polarization Imaging 191
4
3
2
1
0
0123456
Position (cm)
450
350
200
100
250
150
50
0
400
300
Position (cm)
4
3
2
1
0
0123456
Position (cm)
0
20
40
60
80
10
0
12
0
14
0
16
0
Position (cm)
LDLS Perfusion (P.U.)
FLPI Perfusion (P.U.)
700
600
500
400
300
200
100
0
4
3
2
1
0
0123456
Position (cm)
Position (cm)
4
3
2
1
0
0123456
Position (cm)
Position (cm)
TiVi
index
(A.U.)
Figure 9.25 Comparison of a topical application of a
common analgesic ‘‘Deep Heat’’ as assessed by the LDLS,
FLPI, and TiVi imaging technologies. The cross-polarized im-
age from the TiVi system can also be used as a visual aid.
Neither LDPI of FLPI offers a standard color image. (Source:
After Ref. [40], reproduced with permission.)
cross-polarized filters at a single wavelength (at 548 nm – the isobestic point of
hemoglobin) employed in a video microscope designed to image in gray scale a
1 × 1 mm area of the microvasculature of many various types of tissue [42, 43]. It
has been shown to provide better image quality than standard capillary microscopy
in the nail fold [44] and has been applied to study superficial and deep burns to
the skin [45, 46], adult brain microcirculation [42], and also preterm infant skin
microcirculation [47]. Other uses include colon microcirculation [48] and studies
in patients with sepsis [49]. Image resolution is stated as 1 CCD pixel ≈ 1 µm,
using a 1 MP CCD. Flow velocity measurements are 20 mm s
−1
− 1 maximum,
and there is no direct contact between the probe head and the tissue surface. Major
advantages are the devices small size and portability for bedside use, while also
avoiding the need for transillumination and dyes for contrast enhancement [47].
Limitations of the device include the small imaging area, with motion artifacts
making a stable set of images from the area difficult to acquire, thus making RBC
velocity difficult to measure and limiting the reproducibility of results [50].
Using combinations of copolarized and cross-polarized images, other research
instrumentation previously discussed in Section 9.2 has shown that differentiation
between freckles, melanocytic nevi, and malignant tumors is possible [11], contrast
of burn scars is improved [8], and visibility of squamous cell carcinomas is greatly
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192 9 Tissue Viability Imaging
enhanced. The determinationoffundamental scattering parametersofturbid media
via the use of backscattered polarization images is also possible [51]. In anisotropic
media such as tissue, the achievable resolution and contrast of polarization-gated
transillumination imaging are significantly influenced by the refractive index of
scatterers in the medium [52].
9.8
Discussion
This chapter deals with an emerging technology – TiVi – intended for quanti-
tative analysis of skin erythema (vasodilatation) and blanching (vasoconstric-
tion). TiVi was designed with ease of use in mind and productive in gaining
investigator-independent data in terms of images visualizing the spatial distribu-
tion of RBC concentration in tissue. TiVi can be said to quantify what can be
observed by the naked eye and take the subjectivity out of skin testing. Preliminary
results also point to the fact that alterations in skin RBC concentration can be
detected at an earlier stage by TiVi than what is possible by naked eye observation,
mainly due to the use of a cross-polarized detection technique. By reducing data
from a sequence of images to curves and indexes, TiVi is a versatile tool in skin
testing including evaluation of new skin care products, assessment of pharmaceu-
ticals, and grading the performance of sensitive skin to various kinds of challenges.
In contrast to what is the situation with Laser Doppler technology, TiVi measures
only the concentration of RBCs and not their velocity, thereby making the images
closer related to what can be observed by the naked eye. TiVi is not sensitive to
movement artifacts and distance to the object but the amount of melanin in the
epidermal layer modulates the output signal. This disadvantage can be effectively
eliminated by recording only alterations in skin RBC concentration, since these
generally appear on a timescale much shorter than that at which the melanin
content of the skin is altered.
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