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1.3 A Tour of Microcirculatory Centers in 1968 13
Figure 1.6 Edward Bloch’s equipment in a laboratory in
Cleveland, USA. Inn1968, this was the most advanced tech-
nology of the time. Anyone wishing to be up to date in
microcirculatory studies would try to visit it. Edward Bloch
provided a program of instruction.
are some teaching sessions lasting only a couple of hours that can change one’s
understanding of a field forever.
In 1831, Hall [55] described the transparency of the hibernating bat’s wing. Paget,
six years later [56], used it to study inflammation, and Jones in 1852 [57] noted the
contractility of the veins in the bat’s wing. After its reintroduction by Nicoll and
Webb in 1946 [58], it was a popular preparation in the United States during the
1950s–1960s [59] until rabies became a recognized risk.
The bat’s wing was second only to Ryan’s first look at the conjunctiva as an
impressive introduction to the visualization of blood vessels and lymphatics. Here
was a hibernating animal that did not need anesthetics, whose transparent wing
when spread out under the microscope revealed adnexa such as sebaceous glands,
complete with blood supply and lymphatic drainage, which kept the wing well
greased when flying. Following any, even slight, manipulation, one learned just
how many cells, red and white, were flowing into and along lymph vessels.
It was the topic of bat wings that provided the most worrying lecture Ryan ever
attended. This was a plenary lecture by Paul Nicholl at the World Congress in
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14 1 A Historical Perspective of Imaging of the Skin
San Diego, (1979). He had at one time found a bat in his attic and while throwing it
out of the window noticed the sun shining through the wing showing up blood vessels.
Sitting with him at breakfast and at the 9 am lecture, he was clearly very ill from
cardiac pain but insisted on giving the prestigious lecture remaining seated and died
shortly afterwards.
Following some pure clinical dermatology visits in the United States on that
tour, Terence Ryan went on to Sydney where Dintenfass and Palmer had some
wonderful low technologies for visualizing red cell flow, such as along scratch
marks on glass slides, and Dintenfass [60] also had a huge knowledge and passion
for the clinical effects of high blood viscosity. The tour continued through Asia,
lecturing on skin blood supply in Singapore, Calcutta, and Delhi, and ended at
a European Microcirculation Congress (1968) in Gothenburg organized by the
surgeon Charlie Gelin. He had worked in Boston, on the topic of rheology.
He was the organizer of the first European meeting in 1959. Here, in 1968,
the main interest was rheology and the effect of dextran in humans on lower-
ing blood viscosity and making microcirculatory flow faster. Hildegard Maricq,
attending this meeting, had become the leading exponent of nail fold capillary
measurement and had greatly improved the imaging of the human nail fold by
selecting transparent nail folds for study, and later, with widefield photography
and cinephotography, used this increasingly for the study of both scleroderma and
schizophrenia [61]. Maricq with her collaborators tried to introduce controls and
population surveys as comparisons for problems such as Raynauds syndrome in
which there is vasospasm on even slight cooling or from vibration from industrial
tools.
Meeting almost annually at microvascular conferences, Hildegard was noted
for focus on the human nail fold, her mixed American and Estonian accent, as
well as for getting lost; for example, going the wrong direction on the Great Wall
of China when returning to the conference bus. For those wishing to image the
skin, the nail fold capillary had been the topic of study throughout the twentieth
century. Nail fold enthusiasts such as Bosley tried to make sense of variability
in the normal population at the First European Congress in Hamburg in 1960.
He published [62] with the Nobel Prize winner Sherrington’s prot
´
eg
´
e, William
Gibson, who was still publishing in 2010, the year he died at the age of 94. Eli
Davis of Jerusalem was another nail fold enthusiast and the author of a splendid
atlas of the human nail fold [63]. He was host to the European Microcirculation
Conference in1964. Terence Ryan arranged an opportunity forviewing skin disease
through the capillary microscope first in Oxford in 1966, and then in London (1969)
at conferences for dermatologists. Over the years, a number of dermatologists
had shown that although, apart from the nail fold healthy human skin was not
transparent, skin pathology such as that of the legs with venous disease often
had surprising transparency but morphologically, very abnormal shapes and sizes
[34, 64].
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1.4 TV Video Projection 15
1.4
TV Video Projection
Better microscopywas developedwhen Intaglietta assisted with TV video projection
observers of the skin such as Fagrell and Bollinger [65], especially in case of venous
disorders of the leg that they reviewed, and he had also provided assistance to Xiu
Rui Juan for the clinical application that included remarkable studies conducted in
China on the effects of Chinese Medicine [66].
She hada laboratoryin Beijing,which trained many young Chinese investigators.
Her interests began during the revolution when working at the center of a
meningitis epidemic and observing in neonates the effects of shock on the blood
supply of the skin.
Madame Xui (Figure 1.7) appeared on the World forum in 1984 at the World
Congress of Microcirculation. Educated at a Christian Missionary School, after
qualification as a medical practitioner she found herself expelled to the countryside at
the very difficult time of the Cultural Revolution. There was a meningitis epidemic
and the death toll of infants was very high. She noted that on one hill side the babies
were surviving. She noted that their fingers were pink, whereas those of that died
were blanched. Persuading the authorities that it was necessary for a relaxation of
rules and the import of American microscopes, she demonstrated that treatment of
shock by ephedrine shut down the capillary bed in the infant nail fold, while Chinese
Medicine practiced on the hillside did not. Adapting these technologies using television
microscopy to both finger and toenail fold has continued to be found valuable for the
promotion of Chinese medicine.
Technological developments in the study of the microcirculation during the
decade 1960–1970 were reviewed by Intaglietta and Messmer [67] as a period
of ‘‘rapid advances in electronic instrumentation, led by investigators such as
Wiederheilm, Baez, Wayland, and Johnson and to the development of quantitative
methods for the measurement of pressure, diameter, and flow velocity. Progress
in television and the introduction of video equipment for consumer use in the
1970s allowed Intaglietta and coworkers to introduce the electronic techniques for
obtaining dynamic information directly from the microvascular video image. From
the beginning of the 1980s, the advances in fluorescence microscopy used in con-
junction with low-light-level video cameras have expanded the range of phenomena
accessible to in vivo microscopy to include tissue injury, tissue metabolism, and
biochemistry.’’ The Japanese, led by Tsuchiya [68] at Keio University in Tokyo, fo-
cused on the gastrointestinal tract in animals and humans, with beautiful imaging
of lymph flow through Peyer’s patches. They hosted the 4th World Congress of
Microcirculation (Figure 1.8).
Scattered around the world were studies of the brain. William Feindel and his
Canadian colleagues had previously introduced brain studies at the 4th European
meeting in Cambridge in 1966, and Russian investigators demonstrated studies on
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16 1 A Historical Perspective of Imaging of the Skin
Figure 1.7 Madam Xui Rui-Juan, while
singing a Methodist Hymn learned in her
childhood in China, dancing with Terence
Ryan to a Jazz band at a European Mi-
crocirculation Meeting in Maastricht. She
had a laboratory in Beijing, which trained
many young Chinese investigators. Her
interests began during the revolution
when working at the center of a meningi-
tis epidemic and observing the effects of
shock in neonates on the blood supply
of the skin.
Figure 1.8 At 4th World Congress of Microcirculation in
Tokyo. From left to right Phil Harris (incoming President)
Masharu Tsuchiya (President, 4th World Congress of micro-
circulation), Terence J Ryan (President 3rd World Congress),
and Ben Zweifach (President 2nd World congress) opening a
ceremonial container of Saki.
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1.4 TV Video Projection 17
Table 1.1
Methods used on the study of the microcirculation.
Introductory comments Harold Wayland
Flow, pressure, and dimension measurements in the microcircu-
lation image time and image transformation
Edward H. Bloch
Edge clamped mesenteric preparation Wallace G. Frasher, Jr.
Methods of investigating plasma skimming A. A. Palmer
Dynamic pressure grams of the pulmonary microcirculation John W. Irwin
Subcutaneous tissue pressure J. F. Merlen
Estimation of relative blood flow by impedance plethysmography J. F. Merlen and J. Coget
Optical methodsof measuring erythrocyte velocityin living animals P.A.G. Monro
Methods for in vivo measurements of tubular urine flow, flow re-
sistance, compliance, and fluid reabsorption in mammalian kidney
Michael Steinhausen
Measurement of capillary filtration and permeability; optical mea-
surements of transcapillary and interstitial transport
Curt Wiederhielm
Autoradiographic investigations of capillary permeability G. Freytag
In vivo studies of fluid movement across single capillaries B. W. Zweifach
The use of fluorescence microscopy in the study of capillary
permeability
S. Witte
Studies of vascular geometry
The microvascular architecture S. S. Sobin
Selective pulmonary angiography in microcirculatory studies in
man
Wilhelm Bolt
Data processing techniques forthe microcirculationdigital video
data handling
Robert Nathan
Online analog computers in microcirculatory studies Paul C. Johnson
Source: Courtesy of Harold Wayland Cambridge 1987.
the brain at all meetings up to 1968. Feindel made sure that we were well informed
at the First World Microcirculation Congress in Toronto [69]. All these depended
on the microscope. Wayland, an engineer adviser to all the microcirculation studies
and a great traveler (always accompanied by his wife as a passionate collector of and
lecturer onplaying cards), repeatedly expressed the view that new technologieswere
needed. At earlier meetings, he focused, as did Alexander Munro, on measuring
red cell velocity in vivo. At the 4th European Conference on Microcirculation,
Harold Wayland [70] organized a symposium on Methods Used in the Study of
Microcirculation. Table 1.1 lists the content.
All studies of the skin require sampling at rest compared to that under some
stimulus such as posture change, pin prick, heating, the application of vasodilators
[71], such as methylnicotinate, and vasoconstrictors such as steroid creams, or
cooling.
At the 1968 Microcirculation Congress in Gothenberg, fibrinolysis autography
was also demonstrated and was adapted for a number of studies of blood vessel
behavior in the skin for a few years. It was an indicator of functional changes in the
endothelium in response to a number of stimuli. The fact that endothelium in the
skin was under the influence of the epidermis was demonstrated by the discovery
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18 1 A Historical Perspective of Imaging of the Skin
in the epidermis of a plasminogen activator inhibitor as a controller of endothelial
fibrinolysis. It was demonstrated by incubating frozen sections of skin on a bed of
fibrin [72, 73].
Once diabetes mellitus became a hot topic for the study of its microvascular pathology
and skin fibrinolysis it was studies of the eye that provided most insight into
microvascular change. Animals made diabetic by streptotocin included the pig. These
pigs became giants and examining their eyes while keeping them anaesthetised
provided Oxford’s Professor of Opthalmology with a temporary overdose of halothane!
The technologies before 1969 were described and published by the BMS [74]
and Ryan et al. [75]. This second manual on microcirculatory techniques included
descriptions of photoplethsysmograhy and thermoclearance techniques favored,
respectively, by Ramsay and Challenor as well as the technique of fibrinolysis
autography. A passion for studying vascular systems can be inhibited by the size
and immobility of the humans when trying to position them under an imaging
device.
Animal preparations require correct supervision to satisfy animal rights. Barnhill
and Ryan [76] found the chorioallantoic membrane to be an exciting model not
only because of easy viewing but also because it did not require consent of animal
rights activists. Indeed, the only disadvantage of having this preparation in a
dermatological ward was the rare appearance of a chick tweeting under a patient’s
bed after a nocturnal hatching.
1.5
The Third World Congress of Microcirculation
At a European conference in Denmark 1970 Terence Ryan became a treasurer,
for the first time, of the European Society (a hand over of £370) Finances were
linked to Karger, the Swiss publisher by whom microcirculation Proceedings Biblio
Anatomica were long published by Karger, and readers will find most of the history of
1970s’ imaging therein. The Swiss franc did very well and Ryan received undeserved
thanks for an accumulation of wealth when he gave the post up. When Harold
Wayland chaired an International Liaison Committee to decide the location of the
third World Congress, the BMS put Terence Ryan’s name forward. Being a clinician,
the American Scientists would have preferred the distinguished scientist Charles
Michel to be President, but he was × European Society for Microcirculation. Terence
Ryan was thrown thus in the deep end hosting the conference in the city of Oxford
with no large conference facilities but a new Hospital with an Academic block that
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1.5 The Third World Congress of Microcirculation 19
had previously been unused and unprepared lecture theatres, for audiences of 600,
450, and 200. Getting in quick, space was made use of that was never again used
for conferences. The Americans were not impressed when the conference organiser
employed went bankrupt. Eventually, the dermatology team organised the conference
very successfully, 900 people attended a barbecue at Terence and Anne’s home, Anne
sewed all the curtains for the conference center, participants dined simultaneously in
three College halls and took over Blenheim Palace for a reception and ate afterwards
at Green College in a tent with crystal chandeliers.
It was HowardFlorey’s second wifeMargaret who opened the the World Congress
of Microcirculation in 1984 to speak of his interest in the lymphatic system. His
pupil John Casely-Smith chaired the lymphatic session. Phillip Shubik who had
pioneered imaging of cancers in the hamster cheek pouch gave a memorial lecture
on Gordon Sanders, which included Sanders’ film using the versions of Malpighi’s
compound microscope that became popular in early Hanoverian London. Possibly,
this was the event that indicated that microcirculation and microscopy had come
of age.
It became necessary to make more formal liaison between many groups. This
had been well done by the American Clinical Physiologist and resident surgeon in
Link
¨
oping, Sweden, David Lewis, whose wit aggregated the societies and ensured
smooth flow (Figure 1.9). Terence Ryan took over such liaison after the 1984
congress.
At the 1984 World Congress, Alfred Bollinger revealed much improved cine
fluorescence in human peripheral circulatory disorders.
Figure 1.9 David Lewis speaking in
the Great Library and Organ Room of
Blenheim Palace before handing over his
successful role as Chairman of the Liaison
Committee for Microcirculation Societies.
‘‘If I had known I was going to be here I
would have brought my library Ticket!’’ As
an American surgeon living in Link
¨
oping,
the home of Perimed, and a distinguished
researcher into shock and many other
circulation phenomena, he was also a fa-
vorite after-dinner speaker over several
decades of microcirculatory events.
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20 1 A Historical Perspective of Imaging of the Skin
1.6
Perfusion Monitoring and the Advent of the Laser Doppler
It was at this meeting in 1984 that continuous, noninvasive, real-time, blood
perfusion monitoring, laser Doppler flowmetry was first demonstrated to a global
microcirculation audience by Allen Holloway and
˘
Ake Oberg (Figure 1.10). The
paper by Holloway and Watkins [77] was by that time well known, and Oberg et al.
had published their seminal paper the year of the congress [78]. The technique
had previously used Leeuwenhoek’s glass, tubes but in 1975, it was Stern who
developed it as a tool for tissue microcirculation [79]. Stern proposed that when
coherent light impinges on the skin, some of it will be scattered by moving red
blood cells and some by static tissue. If this light (which is spectrally broadened
due to the Doppler effect) is brought to the surface of a sensitive photodetector,
optical beating will produce an audio frequency photocurrent output. Spectral
analysis of the photocurrent produced by backscattered He–Ne red laser light from
the fingertip showed a clear difference between normal flow and occlusion of the
brachial artery. The feasibility of real-time monitoring was demonstrated using the
root-mean-square (RMS) of the photocurrentsignal as aflow indicator. Thismethod
was shown to be sensitive to the microcirculatory response to temperature, posture,
respiratory pattern, and emotional stimulation. Furthermore, it was proposed that
‘‘Because it provides information about the flow velocity distribution, it has the
potential ability to analyse the distribution of flow in the different microvascular
compartments’’ [79].
Figure 1.10 Admiring the first commer-
cial laser Doppler flowmeter from Med-
Pacific (around 1978). Left to right: Gert
Nilsson Hans Pettersson (research engineer
at IMT, Link
¨
oping),
˚
Ake
¨
Oberg (Professor
in biomedical engineering IMT), and Allan
Holloway (inventor of the LDF equipment,
University of Washington, Seattle, USA).
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1.6 Perfusion Monitoring and the Advent of the Laser Doppler 21
Figure 1.11 The first commercial version of the Periflux
laser Doppler flowmeter invented by Gert Nilsson et al. [82].
This instrument used two detectors and a differential detec-
tion method to suppress laser and fiber mode noise com-
mon to both detectors. (Source: Gert Nilsson, Wheelsbridge
AB.)
The system demonstrated by Holloway and Watkins included fiber-optics for light
delivery and collection, as well as a photodiode in place of the more cumbersome
photomultiplier tube used by Stern. They evaluated their new instrument against
the 133Xe clearance technique and were able to measure the effect of injection
trauma, which manifests itself as a transient elevation in local blood perfusion due
to either the fear or pain of an injection. This effect was suspected for some time,
but no other method was capable of directly measuring it and following its time
course faithfully.
Watkins and Holloway, later described their instrument in more technical
detail [80], identified the modal noise caused by the He–Ne laser as a major
developmental problem and found that measurement was limited to 50% of the
observation time. The presence of more than one spectral line in the laser output
may cause beat frequencies to occur on the photodiode, similar to those produced
by Doppler-shifted light. This problem was overcome by Nilsson et al. [81] who
proposed a dualphotodetectionsystem in which thenoise common to bothdetectors
could be rejected. The Doppler signal is not affected as the photons arriving at each
detector are completely independent and random. Later that year, Nilsson et al. [82]
presented a further development, incorporating the algorithm developed by Bonner
and Nossal [83]. This remains the only signal processing algorithm with a sound
theoretical base and has found favor amongt most researchers and manufacturers.
The instruments developed by Holloway and Watkins [77] and Nilsson et al. [81]
were soon commercially available (Figures 1.10 and 1.11). An early comparison by
Fischer et al. [84] demonstrated a good correlation between the instruments as well
as with microvascular blood flow. Clinical trials were undertaken in many areas
and, while good results were often produced, widespread application has eluded
the technique. One reason given by clinicians is that the lack of absolute units
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22 1 A Historical Perspective of Imaging of the Skin
makes interpretation of the data from different patients difficult. However, the
measurand (i.e., microvascular blood flow) is poorly predictable at any given tissue
site and time. The assessment of sufficiency of perfusion must, therefore, be based
on its variation in response to an appropriate physiological stimulus. Diagnostic
differences in microcirculatory response have been consistently reported where
a ratiometric (percentage change) analysis has been employed. This invariably
involves the comparison of a stimulated value to a resting level.
Clinical trials of these improved instruments exposed the problem of motion
artifact noise, which occurs when the modes in which light passes through the fiber
are disturbed by movement of the cable, resulting in small losses of light from the
core into the cladding. This phenomenon manifests itself in intensity fluctuations
at the photodetector similar to the laser Doppler beat frequency. One analytical
study demonstrated that the range of frequencies produced is 0–3.5 kHz [85] and
that the magnitude can be much larger than the perfusion-related Doppler signal.
This problem was accentuated by the fact that the larger-core fibers translated the
movement to the tissue, giving rise to tissue-related Doppler shifting.
Further technological improvements facilitated the use smaller fiber-optic cables,
a wider range of probes encompassing new application areas, and less noisy
semiconductor laser diodes. This led to an increased number of instruments being
made available throughout the 1980s. Smaller diameter fibers reduce sensitivity
to motion artifact in three ways. First, the smaller core produces fewer modes.
Second, the optical beating will be more efficient if there is a reduced spread of
paths traveled by the light collected. Last, less of the movement will be transmitted
to the probe head.
The use of laser diodes in LDPMs was reported by de Mul et al. [86] with the
diode laser source and detection integrated in the probe head. This eliminated
the need for fiber-optic cables and is insensitive to noise contributions from
voluntary motion. The wavelength of the diodes commonly used (780 nm) has
further advantages of deeper penetration and reduced dependence on skin color.
Also, because the absorption of oxidized and deoxygenated hemoglobin is almost
equal at this wavelength, any dependence on oxygen saturation is eliminated.
The choice of laser wavelengths is confined (largely by commercial availability)
to He–Ne red (632.8 nm) and near-infrared laser diodes (780 nm). The He–Ne
system is important for historical reasons as the first instruments were built using
these lasers; however, laser diodes are now used in virtually all instruments sold.
A greater understanding of both the laser Doppler signal and the associated noise
allowed us to develop instruments that can process the entire bandwidth of interest
with excellent signal-to-noise performance.
The first European Laser Doppler Users meeting was held in Oxford in 1991. By
that time, Becker and Vestweber were able to review 356 publications chosen from
almost 1000 studies, and many of Europe’s microcirculation experts were now
studying its potential in skin, nasal mucosa, liver, kidney, inner ear, and bones
and teeth and in disease states such as hypertension and diabetes. Several groups,
including the dermatology department in Oxford were examining phenomena
such as postural vasoconstriction or the effects of smoking [79, 87]. Before this
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