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1.6 Perfusion Monitoring and the Advent of the Laser Doppler 23
technology, they had used thermography in a number of publications on skin blood
flow. With laser Dopplers, testing the effects of drugs such as prostaglandin E1
on Raynaud’s syndrome was being introduced. There were warnings that the tech-
nique would be discredited unless better standardized. Already in 1991, automatic
scanning with multipoint laser Doppler flux recordings were being introduced
[88], and Stringini and Ryan [89] used the technique for wound healing studies.
Perhaps the most remarkable feature of the microcirculation is its enormous
temporal and spatial heterogeneity. This has given rise to the introduction of
a multichannel instrument and the laser Doppler perfusion imager (LDPI). The
multichannel array providesfor the spatialassessment of blood flowwithout the loss
of temporal resolution. This facilitates the continuous and real-time measurements
of the effects of vasoactive stimuli on different compartments of the same organ
or interorgan comparisons. It can be particularly useful in disciplines in which
it is necessary to control the blood supply on a regional basis. One example
is the use of pharmaceuticals to restrict the blood supply to the tumoral area
without affecting local normal tissue. By simultaneously monitoring the perfusion
at microregional sites within and in the locus of the tumor during infusion of
such agents, immediate information is given as to the selectivity and severity of the
drug’s effect [90]. Similar, but more graphic information, may be obtained using
the LDPI [91] where the entire area of interest is visible and blood flow variations
are expected to occur over a much longer time course (Figure 1.12).
The laser Doppler technique is cost effective and easy to use. It is possibly
this advantage that has paradoxically become a stumbling block to more universal
use of the instrument, because it is quite possible to use the instrument with
little knowledge of what is being measured and how. The main laser Doppler
6
6
3
3
8
9
2
1
10
11
7
4
5
Figure 1.12 First laser Doppler perfusion imager version.
(1) Laser, (2) laser beam, (3) mirrors, (4) underlay, (5) liv-
ing tissue, (6) stepper motors, (7) PC, (8) scanning pattern,
(9) photodetector, (10) pre-amp and A/D, (11) Perfusion im-
age. (Source: From patent application 1989.)
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24 1 A Historical Perspective of Imaging of the Skin
developers cooperated in an European Commission-sponsored concerted action
(CA) to provide a greater means of comparison of results between active groups,
through the establishment of internationally standardized protocols. This CA
published a report setting out the principles and practice of the laser Doppler
perfusion monitoring and imaging [92]. The continuous, real-time nature of
laser Doppler provides an excellent means of following an occlusion and reactive
hyperemia and vasomotion (from 0.001 to ∼10 Hz) including that mediated by
heartbeat, breathing, myogenic, and endothelial function [93]. Mike Stern declared
that ‘‘We know of no comparable method of demonstrating these microvascular
reflexes’’ [79]. However, since then, a related technique based on an analysis of the
speckles in backscattered laser light (laser speckle perfusion imaging, LSPI) and
another based on diffuse reflectance spectroscopy, tissue viability imaging (TiVi)
[94], have been shown to similarly follow these microvascular reactions.
As the angles in LDP are more or less random and a wide range of velocities
are present in the microcirculation, a continuous Doppler frequency spectrum
is produced. It is interesting to note that a similar result can be achieved by
considering the scattering particle to be a moving reflector of light. The reflected
light willinterfere with the reference beam, and theresultant intensity will vary with
the difference in optical path between the two beams. The number of interference
fringes to pass the detector in time is related to the speed of the moving cells. Each
time the mirror (cell) moves through a distance equal to half the wavelength of the
light, the detector ‘‘sees’’ an interference fringe pass. That is, a fluctuation in light
intensity is recorded. Variations in speckle contrast will then be dependent on the
velocity distribution of the scatterers. Therefore, this velocity can be determined
using a measurement of the statistical behavior of the speckles over time. This
is similar to the reading given by a laser Doppler measurement, and in fact, it
has been demonstrated that Doppler and time-varying speckle are two methods of
arriving at the same result [95].
An exciting new idea first formulated by Takuo Aoyagi in 1972 in a patent filed
by the Nikon Kohden Corporation, Japan, was to become the basis for continuous
in vivo arterial oxygen saturation. This novel concept, which used the fact that
light transmission in human tissue varies with arterial pulsations, to isolate the
relative absorption of red and infrared light by arterial blood was later published
by Nakajima et al. [96]. They postulated that the cardiac synchronous variations
in the light intensity reaching the detector were entirely attributable to blood
volume changes in the small arteries and arterioles ‘‘seen’’ by the probe. Therefore,
comparing only the pulsating portion of the red and infrared signals should
yield absorption data for arterial blood alone, the absorption of venous blood and
other tissues being constant or slowly varying. This filtering mechanism was of
tremendous benefitin the area of critical care medicinebecause the oxygen status of
the blood supply rather than that of the mixed vascular bed could be measured. This
is a parameter that is subject to reasonably precise regulation in the normal healthy
individual at rest (∼95 –97% saturation) but may suddenly reduce to dangerous
levels in the critically ill. In smokers, the maximal value can be only 84% due to a
COHb of 15% [97].
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1.6 Perfusion Monitoring and the Advent of the Laser Doppler 25
The clinical significance of this instrument, particularly for anesthesiology, was
realized by William New, himself an anesthesiologist at Stanford University. New
developed and marketed a pulse oximeter (Nellcor N100) primarily for monitoring
oxygen saturation in patients under anesthesia. Because of the tremendous impor-
tance of the technique, more than 20 manufacturers now produce pulse oximeters.
Widespread use has, however, led to significant criticism of the technique in certain
clinical situations. The instrument was shown to be unreliable in conditions of low
perfusion (at the site of measurement, normally the finger), subject movement or
shivering, thepresence ofabnormal hemoglobins (hemoglobin bound to molecules
other than oxygen), and even the presence of interfering contaminants such as
nail polish in the light path. However, despite these criticisms, the use of a pulse
oximeter was firmly established as a ‘‘standard of care’’ in every operating room
and intensive care unit in the developed world [98]. The pulse oximeter is a triumph
of noninvasive biophotonic monitoring with an elegant technical solution to a real
clinical need and enormous commercial success. A comprehensive review of the
principles and practice of pulse oximetry was published by Moyle in 1994 [99].
The advent of ultrasound to indicate the relative density of the dermis shed light
on the water content of the upper dermis. It was observed that it was increased by
venous congestion and relieved by elevation [100]. A series of publications from the
laboratory of Serup in Denmark followed.
While the technology allowing frame-by-frame analysis of red cell flow separated
by plasma gaps had improved the accuracyof velocity measurements, interpretation
of flow and capillary shapes was slow to take into account normal variation in the
population. In the 1920s, a single capillary alteration in shape might be correlated
with a wide range of diseases, including disturbances in mental health. From the
1970s Bosley working with Gibson, Maricq working with her collaborators, as well
as Ryan tried to introduce controls and population surveys as comparisons for
problems such as Raynaud’s syndrome in which there is vasospasm on even slight
cooling or from the use of vibrating industrial tools.
Optical techniques such as illuminating a tissue at a wavelength at which
hemoglobin absorbs maximally, thus increasing the contrast of the blood vessels,
and adding fluorescing agents to the plasma helped to further show up the full
content of the flowing blood up to the vessel wall. This work was led by Konrad
Messmer and others, resulting in a technique called orthogonal polarization
spectral imaging (OPS). This used a high absorbing, Isobestic point of hemoglobin
to enhance contrast in the microcirculation and orthogonal polarizers on the light
source and camera. This had the effect of flooding the tissue bed with diffuse
light and, as described by Messmer, creating an apparent light source 1mm below
the surface. Technical development is continued now by Can Ince and coworkers
(Chapter 2), and several clinical applications have been explored by Jean-Louis
Vincent, Daniel de Backer, and others (Chapter 3).
Two- and three-dimensional techniques are the mainstay of this book, so only a
brief introduction is required here. Perfusion imagers have recently been reviewed
by O’Doherty et al. [94]. A brief description is provided in the following paragraphs.
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26 1 A Historical Perspective of Imaging of the Skin
In the1990s, groupsled byGert Nilssonat Link
¨
oping andTim Essexat Newcastle
upon Tyne extended laser Doppler to an imaging technique [91, 101, 102] by raster
scanning the laser and detector 15–20 cm above thesurface. This gave rise to at least
two commercial LDPIs currently marketed by Perimed and Moor Instruments.
Most of the instruments are sold for clinical research purposes, and although it has
been used for almost every conceivable application involving the microcirculation,
it appears that burn depth assessment [103] is the only FDA-approved diagnostic
use of LDPI.
The LDPI approach raises challenges, particularly in temporal resolution (due to
the raster scanning) and in coping with the speckle nature of images where the
light source is a laser. Normally, the number of speckles is dependent solely on
the detector configuration. However, the LDPI systems use a large area detector
collecting as much light as practical from the illuminated spot on the tissue surface.
The spot itself then determines the effective area of detection and is dependent on
the tissue properties. It is perhaps because of this and the high variability in surface
reflections that most manufacturers have moved to normalize the laser Doppler
signal by DC light intensity rather than by the square of the DC light intensity
(Chapter 6).
LSPI takes advantage of the speckled nature of laser-illuminated images and
specifically the blurring of speckle caused by moving scatterers (red blood cells)
to extract an alternate measure of perfusion (cf. Chapter 8). Essentially, when the
shutter speed or integration time of the camera is∼10 ms, a greater number and
speed of red blood cells in the tissue under study will provide greater blurring.
Since it is unnecessary to capture the full laser Doppler spectrum (requiring
>25 000 fps), the technical requirements for full-field speckle imagers are much
lower than for LDPI. Thus, with uniform illumination of the tissue with an
appropriate laser and a standard video rate camera, full-field images of flow-related
speckle can be obtained.
Optimal integration time varies from 1 ms for faster flow to 20 ms where the
flow in smallest vessels (with slower flow) is being studied [104, 105]. Issues such
as the need to know the flow range a priori and the fact that the theoretical basis
is not as rigorous have meant that laser speckle has a much slower uptake than
LDPI. However, later work by Thompson, Dunn and Boas, Duncan shows that the
use of multiple integration times may provide a more solid basis for measurement
and more reliable perfusion images.
The early demonstrations of speckle imaging for blood flow were in the eye
(retinal artery) [106]. With more advanced image processing, Briers and others
were able to measure the speckle blurring directly and produce false color maps
of the microcirculation in many tissues. LSPIs are much less sensitive to deeper
(
>
200 µm) perfusion, whereas LDPI is sensitive to flow at depths up to approxi-
mately 1 mm [107] (Chapter 8). Full-field laser Doppler imaging has become
possible with the advent of fast CMOS cameras, and it has been implemented by
the groups led by Steenbergen in Twente and Lasser in Lausanne. Currently, the
number of pixels and the bandwidth of signal acquired are limited by available
cameras as well as high-speed data transfer and signal processing challenges.
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1.7 3D and 4D Tomographic Methods 27
G
Light source
Melanin layer
Epidermis
Ca
p
illaries
Filter 1
Linearly
polarized
Depolarized
R B
Linearly
polarized
Filter 2
Figure 1.13 Schematic showing the operating principle of
subsurface spectroscopic imaging.
Furthermore, there remains the challenge of motion artifact since the Doppler
signal due to movement of the living subject is entangled with the blood perfusion
signal. A diffuse reflectance techniquecalled ‘‘tissue viability imaging’’ was developed
to avoid this motion artifact (Figure 1.13). It produces two-dimensional images
of the concentration of red cells using an RGB camera to pick out the spectral
signature of hemoglobin. Crossed polarizers are used to select only light that has
penetrated more than a few hundred microns within the tissue, reducing the
influence of surface reflections and melanin [108].
1.7
3D and 4D Tomographic Methods
Microcirculation is of course a three-dimensional structure, and as such, a com-
prehensive understanding requires a means to study it in three dimensions. Since
it is also functional, a fourth dimension, that is, time, is also important. Recently,
technological developments have allowed the exploration of the microcirculation in
all its exquisite glory and function over time. These include confocal (fluorescence)
microscopy, multiphoton microscopy, photoacoustic imaging, and functional opti-
cal coherence tomography. Since the first two involve the injection of fluorescent
dyes, they have limited potential for application in humans. We compare OCT
and fluorescence microscopy in Chapter 13. Photoacoustic tomography and mi-
croscopy has enjoyedenormous interest since aseminal paper byLihong Wang et al.
(St. Louis) in 2003 [109]. It takes advantage of the diffuse nature of light in tissue to
deliver energy to the deep blood vessels even if there is a larger upper vessel in the
direct path. The light energy is absorbed preferentially by blood if a suitable wave-
length is used (e.g., 560 nm) and, if a suitable short pulse releases an ultrasound
pressure wave, which is not scattered in the return path. Since the speed of sound
is 1 million times smaller than that of light, the locations of absorbers within the
tissue can easily be determined by back projection (Chapter 12). Using this method,
many exquisite 3D images of the microvascular architecture have been produced in
mouse brain and ear. More recently, the first images were obtained from monkey
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28 1 A Historical Perspective of Imaging of the Skin
3
3
1
1
1
4
5
4
6
5 mm
2
2
1
2
4
5
4
6
2
Abdomen
(
a
)(
b
)(
c
)(
d
)
Thorax
Head
Figure 1.14 (a– e) Whole body mouse imaging using multi-
spectral photoacoustic tomography [111].
brain and the human palm. Zharov and Galanzha have developed methods for
tagging, tracking, and destroying tumor cells [110]. Limitations of the technique
include the requirement for physical contact (e.g., water or gel). Although it is
possible to interferometrically measure the perturbations arriving at the surface, it
is quite challenging since these vibrations are of the order of a few nanometers.
Penetration and signal to noise require low frequencies, whereas high resolution
requires higher frequencies of ultrasound. These factors combine to dictate a depth
resolution of 200 pixels. Depths of 30 mm have already been demonstrated and
50–70 mm is theoretically possible (Chapter 12). Ntziachristos and coworkers [111]
have advanced multispectral photoacoustic imaging to facilitate whole body mouse
scanning in <30 min without water immersion (Figure 1.14).
Perhaps the greatest and most exciting current activity is in 3D and 4D imaging
of the microcirculation based on OCT. In contrast to the other techniques, OCT
throws away all scattered photons, using an interferometric scheme to select only
ballistic photons. This allows a three-dimensional image of the structure to be
built up based on the intensity variations due to refractive index variations in
the tissue layers. First attempts to add the microvascular architecture were based
on the Doppler effect, although this was necessarily weak since the heterodyne
mixing efficiency is determined by the coherence between the source and reference
beams. Furthermore, it is dependent on the angle between photon and the velocity
vector. Since the feeding network of vessels under the papillary loops is generally
horizontal, it is almost impossible to detect any flow in that region, and the papillary
loops at 5 µm themselves are below the resolution of most OCT systems. A closely
related alternative is to determine the velocity from the phase shift, and this is
much more sensitive to small Doppler shifts. Most ‘‘Doppler’’ OCT systems now
operate on this basis.
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1.7 3D and 4D Tomographic Methods 29
Ruikang Wang and coworkers introduced a spatial modulation in the interfer-
ogram to separate structure from moving scatterers within the tissue. Originally,
this was achieved using a scanning mirror in the reference arm, but more recently,
the inherent modulation due to blood flow has been used. Several groups have
developed methods to take advantage of speckle variance, which is higher in blood
vessels than in static tissues. Variance measures how much the speckle intensity
varies over say 10 frames, and this can produce good separation of flowing blood
from static tissue. Finally, Martin Leahy’s team in Galway have developed a scheme
based on dense scanning (separation ∼one-fifth of the resolution of the OCT
system) where a simple cross-correlation between two adjacent frames will give
excellent separation of structure and flow. The simplicity of this technique facil-
itates high-speed processing, enabling 4D imaging of microvascular architecture
and function. It has been shown to produce high-quality images in humans [112]
and brings clinical microcirculation imaging within reach (Figure 1.15).
117 µ
m
0 µm
234 µ
m
350 µ
m
468 µ
m
500 µm
585 µ
m
703 µ
m
820 µ
m
(a)
(b)
(c)
(d)
Figure 1.15 (a– d) Correlation mapping
OCT. 2D correlation map of sequential
frames average correlation value for a
square grid of 7 × 7 pixels. The decorre-
lated (bright) volume contains moving blood
cells. The volume shown dark is the re-
gion without blood perfusion. Structure and
function are automatically coregistered since
they are reconstructed from the same origi-
nal dataset. Using a simple algorithm such
as correlation mapping OCT (cmOCT) makes
it possible to do 4D imaging at clinically rel-
evant speeds and depths.
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30 1 A Historical Perspective of Imaging of the Skin
1.8
Nonoptical Microcirculation Imaging
For completeness, this text provides three chapters on nonoptical techniques
for imaging the microcirculation. These include high-frequency ultrasound,
micro-CT, and NMR. Ultrasound is tremendously important for its success in
preclinical studies and has advantages of an established clinical follow-up method
combining depth with reasonable (circa 100 µm) resolution. Substantial progress
in this area has been made by Stuart Foster at the University of Toronto and
others (Chapter 15). However, ultrasound requires physical contact with the
tissue and bone eliminates the signal, except at very low (1 MHz) frequencies.
Perhaps, the gold standard for accurate determination of the 3D architecture of the
microcirculation is micro-CT since it has the lowest potential for distortion of any of
the methods presented. Unfortunately, it requires the use of ionizing radiation and
usually lethal doses of contrast agents. Nonetheless, it could provide a useful tool
for comparison and validation of other methods to aid clinical deployment. NMR
advancement, especially the exploration of cognitive function using fMRI, has
yielded great insights, linking perfusion or oxygen saturation blood oxygenation
level-dependent (BOLD) contrast variations in specific locations to specific actions
or functions. It does not have the resolution to see individual microvessels, but
is sensitive to bulk microcirculatory perfusion. It has great advantages of depth
penetration, especially through bone, but is limited in resolution and cost.
There are several other techniques used to probe the microcirculation, which
do not yet deserve a Chapter in this book, but we will mention some of them
here. Positron emission tomography (PET) simultaneously detects the two gamma
photons produced in opposite directions when positrons from the injected ra-
diopharmaceutical annihilate with an electron. 3D reconstructions with ∼2mm
resolution can showbloodperfusion, oxygenation, and glucosemetabolism by using
different chemical agents. The radioisotopes must be used within a couple of hours
of their production in a cyclotron, severely limiting the location of PET facilities.
Single photon emission computed tomography (SPECT) uses a gamma camera
to make multiple projections of photons from an injected radionuclide to produce
a 3D dataset. Unfortunately, the resolution of SPECT is limited to ∼1 cm, so like
MRI and PET, its use is limited to bulk microcirculatory perfusion.
1.9
Panel Discussions and International Convergence
In recent years, international efforts have been made to better understand the
techniques available for studying the microcirculation. One such initiative takes
place at the Photonics West BiOS meeting in San Francisco each year, where a
panel of experts report the progress of their technique and debate the merits of
the various approaches with questions and input from the audience. Similarly, the
Microcirculation Societies meet to discuss the new insights they have gained as
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References 31
2.5
1.5
0.5
0
1
2
1960 1970 1980 1990 2000 2010
Year
Microcirculation publications per year
35
0
25
0
15
0
50
30
0
20
0
10
0
0
'000s
All fields
Physical sciences
Figure 1.16 The evolution of microcircu-
lation papers published since the 1960s.
Television and recording technology enabled
videomicroscopy. In the 1980s completion
from several companies brought robust laser
Doppler instruments to the clinicians. The
fraction of the total publications reporting
advancements in the instrumentation has
risen from circa 5 to 15%. This may be
largely due to the arrival of 3D and 4D mi-
crocirculation imaging using mainly OCT and
photoacoustics.
a result of these new techniques. In recent years, there has been an enormous
increase in the publication activity around new techniques for microcirculation
imaging (Figure 1.16), and it is inevitable that these new techniques will accelerate
the understanding of the microcirculation once again. The evolution of papers on
microcirculation published since the 1960s shows the impact of several inventions.
The advent ofTV in thelate 1960s facilitatedvideomicroscopy and themeasurement
of speed from the frame rate. Laser Doppler, although invented in 1974, really
began to impact publications only in the late 1980s as many robust laser Doppler
instruments came on the market. If we only look at the physical sciences journals,
we find a striking increase in publications from 2007. Indeed, the percentage of
the total publications relating, one assumes, to instrumental improvements has
risen from circa 5 –15%. This may be largely due to the arrival of 3D and 4D
microcirculation imaging using mainly OCT and photoacoustics.
In the following chapters, the many approaches to microcirculation imaging are
discussed. Ultimately, the choice of technique will depend on the application site,
the research question, cost, and convenience.
References
1. Zweifach, B.W. (1995) in Clinically
Applied Microcirculation Research,
Chapter 9 (eds J.J. Barker, G.L.
Anderson, and M.D. Menger), CRC
Press, Boca Raton, pp. 129 –138.
2. Ryan, T.J. (1965) A new technique for
studying the microcirculation of the
skin. J. Roy. Microsc. Soc., 84, 230.
3. Ryan, T.J. (1967) in In Vivo Tech-
niques in Histology (ed. G.H. Bourne),
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32 1 A Historical Perspective of Imaging of the Skin
Williams & Wilkins, London,
pp. 192 –202.
4. Newton, I. (1671) A Letter of Mr. Isaac
Newton, Professor of the Mathematics
in the University of Cambridge; Con-
taining His New Theory about Light
and Colors: Sent by the Author to the
Publisher from Cambridge, Febr. 6.
1671/72; in Order to be Communi-
cated to the R. Society. Phil. Trans. Roy.
Soc. Lond., 6 (69-80): 3075–3087. doi:
10.1098/rstl.1671.0072.
5. Doppler, J.C. (1842) Ueber das farbige
Licht der Doppelsterne und einiger
anderer Gestirne des Himmels (On the
coloured light from double stars and
some Heavenly Bodies). Treatises R.
Bohemian Soc. Sci. Ser. V (Abh. Konigl.
Bohm. Ges. Wiss.), 3, 465.
6. Fulton, G.P. (1979) 25th Anniversary
Essay 1974 –1979, The founding of
the Microcirculatory Society, Pam-
phlet of Microcirculatory Society inc.,
New York. Reprinted Anat. Rec., 120,
241– 356 and Angiology, 6, 281–358.
7. Bessis, M. and Delpechi, G. (1981) Dis-
covery of the red blood cell with notes
on priorities and credits of discoveries,
past, present and future. Blood Cells, 7,
447– 480.
8. Van Leeuwenhoek, A. (1673) A Speci-
men of some observations made by a
Microscope, contrived by Mr Leewen-
hoeck in Holland lately communicated
by Dr Regnerus de Graaf. Philos.
Trans. R. Soc. Lond., Ser. A, 8 (94),
6037– 6038.
9. Singer, C. (1922) The Discovery of the
Circulation of the Blood,G.Belland
Sons Ltd., London.
10. Malpighi, M. (1683) De pulmonibus
(Two letters (1930) translated by Young
J). Proc. R. Soc. Med., 23, 1– 11.
11. Spalteholz, W. (1893) Die Veiteilung
der blutgef
¨
asse inder haut. His. Arch.
Anat. Entwicklungsgesch. Physiol., 1 –54.
12. Sandison, J.C. (1924) A new method
for the microscope study of living
growing tissues by the introduction of
a transparent chamber in the rabbits
ear. Anat. Rec., 28, 281.
13. Sandison, J.C. (1928) Observations on
the growth of blood vessels as seen in
the transparent chamber introduced
in the rabbit’s ear. Am. J. Anat., 41,
475– 496.
14. Clark, E.R. and Clark, E.L. (1939)
Microscopic observations on the growth
of blood capillaries in the living ani-
mal. Am. J. Anat., 64, 251–301.
15. Clark, E.R. and Clark, E.L. (1935) Ob-
servations on changes in blood vascular
endothelium in the living animal.
Am. J. Anat., 57, 385 –438.
16. Sanders, A.G. and Shubik, P.A. (1964)
A transparent window for use in the
Syrian hamster. Isr. J. Exp. Med., 11,
118a.
17. Nishioka, K. and Ryan, T.J. (1972)
The influence of the epidermis and
other tissues on blood vessel growth
in the hamster cheek pouch. J. Invest.
Dermatol., 58, 33–45.
18. Starling, E.H. (1896) On the absorp-
tion of fluids from the connective
tissue spaces. J. Physiol. (Lond.), 19,
312– 326.
19. Krogh, A. (1922) The Anatomy and
Physiology of Capillaries, Silliman
Memorial Lectures, Yale University
Press New Haven, CT, pp. 1–276.
20. Knisely, M.H. (1936) A method of
illuminating living structures for
microscopic study. Anat. Rec., 64, 499.
21. Knisely, M.H., Bloch, E.H., Eliot, T.S.,
and Warner, W. (1947) Sludged blood.
Science, 106 , 431.
22. Bloch, E.H. (abstracts), (1954) Confer-
ence on microcirculatory physiology
and pathology: techniques for the
microscopic study of small blood ves-
sels and blood flow. Anat. Rec., 120,
241– 358.
23. Monro, P.A.G. (1967) 4th European
conference on microcirculation at
Cambridge. Bibl. Anat., 9, 1–458.
24. Monro, P.A.G. (1984) The Early History
of the British Microcirculation Society
1963– 1984, Anglo-German Foundation
for the Study of Industrial Society.
25. Florey, H. (1962) General Pathology, 3rd
edn, Lloyd-Luke Medical Books, Ltd,
London.
26. Casley-Smith, J.R. (1995) in Clinically
Applied Microcirculation Research,
Chapter 31 (eds J.J. Barker, G.L.
Anderson, and M.D. Menger), CRC
Press, Boca Raton, pp. 419–434.
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