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293
Basics of Light-Tissue Interaction
The main purpose of using phototherapy is to
achieve some kind of clinical effect in the target
tissue through the use of light energy, such as
wound healing or pain relief. If the incident
power is too high, heat will be the end product as
with the surgical laser. If a too-low photon inten-
sity is delivered, there will be very little or no
reaction. The trick in LED phototherapy is to
deliver just the right amount of photon intensity
to achieve the desired clinical effect but in an
athermal and atraumatic manner.
Photothermal and Athermal
Reactions
Despite their very different output powers, lasers,
IPLs and LEDs all depend on the ‘L’ which is
found in all their names, standing for ‘light’. It
could be said that they are all different facets of
the same coin, but even in photosurgery, photo-
therapy plays a very important role. If we con-
sider the typical beam pattern of a surgical CO2
laser in tissue, we see the range of temperature-­
dependent bioeffects as illustrated schematically
in Fig.  18.6, ranging from carbonization above
200 °C, vaporization above 100 °C, through coag-
ulation around 60–85  °C, all the way down to
photobiomodulation, which occurs atraumatically
when there is no appreciable rise in the tissue tem-
perature at the very perimeter of the treated area.
These effects occur virtually simultaneously as
the light energy propagates into the target tissue
with photon intensity decreasing with depth, and
can be divided as shown into varying degrees of
photosurgical destruction and reversible photo-
damage, and athermal, atraumatic photobiomodu-
lation. The photothermal and athermal zones are
also shown in a typical CO2 laser specimen stained
with hematoxylin and eosin (Fig. 18.6).
Photophysics tells us that each photon is a
weightless packet of pure energy, with the energy
measurable in electron volts (eV). Photobiology
tells us that the photobiomodulation zone com-
prises cells which have absorbed the incident
photons, directly or indirectly transferred the
photon energy to the cells’ own energy stores in
an athermal and atraumatic manner, and have
become photoactivated. Photoactivated cells are
associated with three reactions, one, two or all
three of which may occur in photoactivated cells:
Box 18.2
• Light-emitting diodes deliver ather-
mal
and
atraumatic
cellular
photoactivation
• “All light is absorbed in the first mil-
limeter of tissue”—FALSE!
• LEDs are a viable and valuable pho-
totherapeutic tool
• LEDs are capable of interesting light-­
tissue interactions, provided certain
criteria are met. The most important
criteria are:
–– Wavelength.
Determines both the target and the
depth at which the target can be
reached
Quasimonochromaticity is essential
Wavelengths should be applied sepa-
rately and not combined at the
same time
–– Irradiance (power density).
Gives suitably high intensity at all
levels of target cells or materials
Ensures sufficient athermal energy
transfer to raise targets’ action
potentials
–– Dosimetry.
Provided the wavelength and power
density are appropriate, correct
dosage obtains the optimum effect
with the shortest irradiation time
–– Temporal beam profile.
Continuous wave would appear to be
more efficient for most cell types
in  vivo, compared with ‘pulsed’
(frequency modulated) light
• Usually, cells should be targeted with
only one LED wavelength at a time
• “Watts a joule”—the parameters
must be appropriate
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

294
• if the cells are damaged or compromised, they
will repair themselves, or be repaired
• if the cells have a function, they will perform
it more efficiently
• if more of the cells are required for either of
the above, the cells will proliferate, or more
will be recruited into the area through
photochemotaxis
Laser
surgery
usually
creates
all
the
photothermally-­mediated zones mentioned, but
the importance of the photoactivation zone
­cannot be stressed enough. It is the existence of
this zone which sets laser surgery apart from any
other thermally-dependent treatment, such as
electrosurgery, or even athermal incision with the
conventional scalpel, and it is the photoactivated
cells in this zone which provided the results that
interested the early adopters of the surgical laser
compared with the cold scalpel or electrosurgery,
namely equally good healing but with less inflam-
mation and much less postoperative pain.
Figure 18.7 demonstrates this in action, courtesy
of Toshio Ohshiro MD PhD, a pioneer of laser
surgery in Japan and worldwide. In the late
1970s, Ohshiro started using lasers in the treat-
ment of vascular and melanin group anomaly
nevi: all that was available then to him was a 1 ms
pulsed ruby laser and a C/W argon laser. In
Fig.  18.7a can be seen a case of hemangioma
simplex (port wine stain) that had been somewhat
unsuccessfully treated previously with needle
electrolysis: the abnormal color was not removed,
and the site of each needle application was
marked with a small raised white scar. The argon
laser was used in Ohshiro’s zebra technique,
whereby linear areas 2  mm wide were treated
leaving a 2 mm area of untreated tissue between
them [8]. As can be seen in Fig. 18.7b, not only
did the argon laser treatment remove the port
wine stain color, it also treated the abnormal con-
figuration in the form of the pinpoint scarring left
by the previous electrolysis treatment. Four to
6 weeks later, when the treated areas had com-
pletely healed, the untreated areas were then irra-
diated to complete the treatment. This was the
power of the “L” component of laser, the light,
aided by the photobioactivation zone, referred to
by Ohshiro as “simultaneous LLLT” [8].
IPL systems, and the so-called nonablative
lasers, produce areas of deliberate but controlled
coagulative damage beneath a cooled and intact
epidermis (Fig. 18.8), however they also produce
the zone of simultaneous LLLT to help achieve
Phototherapy
Photothermal NSR
Laser surgery
TARGET TISSUE
Carbonization & Burn-off
(>200°C)
Vaporization (>100°C)
Coagulation (>60°C)
Protein Degradation (>55°C)
Protein Denaturation (>40°C)
ATHERMAL CELLULAR
PHOTOBIOACTIVATION
Fig. 18.6  Range of photothermal and athermal photobio-
reactions in tissue following a typical surgical laser
impact, e.g., a CO2 laser. A hematoxylin and eosin stained
specimen of actual CO2 laser treated skin is also included
to show the typical histopathological changes for each of
the bioreactions: the epidermis has been totally vaporized
leaving a layer of carbon char above the coagulated der-
mis. The outermost layer, the photobioactivation layer,
shows normal tissue architecture, even though some pho-
tons will have reached this layer and transferred their
energy to the cells in an athermal and atraumatic manner.
Laser surgery involves all levels of bioreactions.
Photothermal nonablative skin rejuvenation (NSR) deliv-
ers controlled coagulative photothermal damage, with all
the subsequent layers, whereas phototherapy only delivers
athermal and atraumatic photobioactivation
R. G. Calderhead

295
the desired effect of neocollagenesis and neoelas-
tinogenesis through the wound healing process in
the dermal extracellular matrix (ECM). LED-­
based phototherapy systems, on the other hand,
athermally and atraumatically induce only cellu-
lar photobioactivation, but are still capable of ini-
tiating the wound healing process almost as
efficiently as IPLs and nonablative lasers, as will
be shown in detail in a later section.
Wavelength and Its Importance
The first law of photobiology, the Grotthuss-­
Draper Law, states that only energy which is
absorbed in a target can produce a photochemical
or photophysical reaction. However, any such
reaction is not an automatic consequence of
energy absorption. It may be converted swiftly
into heat, as in the surgical and non-ablative
lasers or IPL systems, or re-emitted at a different
wavelength (fluorescence). The prime arbitrator
of this ‘no absorption-no reaction’ precept is not
the output power of the incident light, but the
wavelength of the photons making up the beam,
and this comprises two important considerations:
wavelength specificity of the target, or the target
chromophore; and the depth of the target. Based
on these two considerations, the wavelength must
not only be appropriate for the chosen chromo-
phore, but it must also penetrate deeply enough to
reach enough of the target chromophores with a
a
b
Fig. 18.7  Illustration of how the “L” in laser, “light”,
made it different from other surgical systems. (a) This
example of a hemangioma simplex lesion (port-wine
stain) had been treated previously with needle electroly-
sis. The abnormal color of the lesion has not been
removed, and small white hypertrophic scars can be seen
where the needle was inserted. Heat only (electrothermal
damage) was not successful in treating this lesion. (b) The
lesion was treated with Ohshiro’s zebra method (large
open arrow shows the treated linear area). Normal skin
color can be seen. In areas where hypertrophy existed,
these too have been treated successfully with heat plus
light. The area between the black arrows shows an
untreated zone where the hypertrophic spots are clearly
seen. (Courtesy of Prof Toshio Ohshiro MD PhD—Ref.
[8], used with permission)
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296
high enough photon density to induce the desired
reaction. In theory, a single photon can activate a
cell, but in actual practice multiple photon
absorption is required to achieve the desired
degree of reaction.
Phototherapy is athermal and atraumatic,
hence achieving selective photothermolysis is of
no concern as it would be for surgical or other
photothermal applications. The penetration of
light into living tissue is, however, extremely
important in phototherapy, and very frequently
displays characteristics which are often in dis-
cord with results produced by mathematical
models, a point frequently totally ignored by
some researchers. A favorite, but photobiologi-
cally false, axiom beloved of phototherapy oppo-
nents, is that ‘all light is absorbed within the first
millimeter of tissue’. Anyone who has shone a
red laser pointer through their finger, transillumi-
nating the entire fingertip and completely visible
on the other side, has already disproved that
statement. A totally different finding is seen with
green or yellow laser pointers, however, because
of their poor scattering and penetration character-
istics. Figure 18.9 is based on a transmission pho-
tospectrogram of a human hand captured in vivo
over the waveband from 500  nm (visible blue/
green) to 1100 nm in the near infrared [9]. The
photospectrometer generator was positioned
above the hand, delivering a ‘flat spectrum’ of
‘white light’, and the recorder placed beneath it.
The wavelength is shown along the x-axis, and
the calculated optical density (OD) is on the
y-axis, from lower ODs to higher. The higher the
OD, the greater is the absorption of incident light,
and hence the lower the transmission, or penetra-
tion depth into the tissue. It must also be remem-
bered that the OD is not an arithmetic but a
logarithmic progression, so that the difference
between an OD of 3 and one of 8 is not simply 5,
but 5 orders of magnitude, i.e. a factor of 10,000.
From 500 to 595 nm (blue-green to yellow),
the OD was from 8.2 to approximately 7.6,
respectively, resulting in poor penetration. At
Fig. 18.8  Theory behind photothermal nonablative skin
rejuvenation: the laser energy passes through the cooled
epidermis without harming it, and delivers a controlled area
of coagulation in the typically elastotic dermis associated
with photoaged skin. However, the photons do not stop
there, and there are zones of protein denaturation and, most
importantly for the good result, athermal and atraumatic
photoactivation around and beyond the controlled thermal
damage. The photoactivated cells in the last of these three
zones will assist with the wound healing process
Fig. 18.9  Photospectrogram of a human hand in vivo. The
generator, delivering uniform ‘white light’ at the waveband
shown on the x-axis, was placed above the hand and the sen-
sor below the hand. Optical density on the y-axis is shown in
logarithmic units. Penetration is shown on the right-hand
axis. The further down the curve reaches, the better the pen-
etration at that wavelength into living human tissue.
(Adapted from Smith KC: The Science of Photobiology.
1977. Plenum Press, New York, USA—Ref. [9])
R. G. Calderhead

297
633 nm, the approximate wavelength of the HeNe
laser, the photobiological efficacy of which is
well recorded, the OD was approximately 4.5. In
other words, red light at 633 nm penetrated living
human tissue by 3 orders of magnitude better
than yellow at 595 nm, because of the pigment-­
specific absorption characteristics of the 2
­wavelengths. Visible yellow at 595 nm is at the
peak of the oxyhaemoglobin absorption curve,
and is also much more highly absorbed in epider-
mal melanin than 633 nm, which is why the yel-
low light in the spectrogram did not transmit at
all well into the tissue due to the competing chro-
mophores of epidermal melanin and superficial
dermal blood. Accordingly, cellular and other tar-
gets in the mid to deep reticular dermis are inac-
cessible to yellow light with sufficient photon
intensities to achieve multiple photon absorption
in the target cells. On the other hand, epidermal
cellular targets such as the mother keratinocytes
in the stratum basale, or basal layer, are definitely
accessible to 595 nm yellow light.
The deepest penetration in this experiment
was achieved at 820–840 nm in the near infrared.
At this waveband, pigment is not a primary chro-
mophore with the cell membrane, and flavonoids
in it, as the major chromophore, and this 820–
830 nm waveband coincides with the bottom of
the water absorption curve. The most successful
of the laser diode systems used in laser therapy as
distinct to laser surgery, delivered a wavelength
of 830  nm for this very reason [10], and was
shown to penetrate living hands, and even bone,
very successfully [11]. After around 1000  nm,
water absorption once again starts to play a sig-
nificant role, and in the curve in Fig. 18.9 the OD
was seen to increase thereafter. In general, shorter
visible wavelengths penetrate less than longer
visible and near IR wavelengths, up to a given
waveband,
depending
on
the
absorbing
chromophore.
Following these findings, it made a great deal
of sense to source LEDs for LED-based photo-
therapy systems at wavelengths already tried,
tested and proven in the more than three decades
of laser therapy application and research.
Furthermore, Karu has clearly shown that there is
a “tissue window” for phototherapy between
around 610 nm visible orange-red and 860 nm
near-infrared [12]. LED systems delivering
633  nm or thereabout in the visible red and
830 nm in the near infrared, and at high enough
photon densities were therefore developed, and
have been reported as having significant effects
on their target tissues at a good range of depths
well into the mid and deep reticular dermis, and
even into the muscle and bone. The usefulness of
visible red and near IR LED phototherapy has
already been reported in a wide range of medical
specialties, including dermatology. Yellow light
at 590–595 nm has also attracted attention, but
the penetration properties of yellow light must be
carefully considered, as illustrated in vivo in
Fig. 18.9. From the standpoint of photobiological
theory, yellow light has very good potential spec-
ificity in a number of subcellular targets such as
cytochrome-c oxidase, and superficial vascular-­
related targets, however its very poor penetration
into the intermediate and deeper dermis, where
cellular targets such as fibroblasts lie, limits the
practical efficacy of yellow light for these deeper
targets. On the other hand, there are interesting
targets in and around the basal layer of the epi-
dermis which do react well to visible yellow
light, such as the mother keratinocytes, melano-
cytes and the epidermal Merkel cells, all of which
are rich in mitochondria and therefore contain
cytochrome-c oxidase, a major chromophore for
visible yellow light, and the source of intra- and
intercellular adenosine triphosphate (ATP) and
enhanced levels of cell-cell signaling compounds
such as Ca2+ ions.
Blue light at around 415 nm has very interest-
ing properties regarding the eradication of the
bacterium Propionibacterium acnes (P. acnes)
through endogenous photodynamic therapy
(PDT) although the photoreaction is different
from photoactivation and will be discussed later
in the chapter. LED energy at 1072 nm has pro-
vided a convenient and easy-to-use LED irradia-
tor for effective treatment of herpes simplex
labialis in the home [13]. LED systems with
many other wavelengths have been produced,
gaily flashing or not, but basically these other
wavelengths have very little or no published work
to back up the claims of the manufacturers, and a
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

298
careful consideration of the wavelength/penetra-
tion ratio will rule out many of the shorter visible
light wavelengths. “Any old LED will not do” is
an axiom which must be borne in mind by the
dermatologist wishing to incorporate LED photo-
therapy into his or her practice.
Finally, the different wavebands, visible light
and invisible infrared light, have different pri-
mary mechanisms even though the therapeutic
endpoint may be similar. Absorption of visible
light photons at appropriate levels induces a pho-
tochemical reaction, and a primary photochemi-
cal cascade occurs within the cell induced mainly
by cytochrome-c oxidase, the end enzyme of
respiratory chain of the mitochondria which, as
mentioned above, are the adenosine triphosphate
(ATP)-producing power-houses of the cell [14].
ATP is not just required to fuel cells, but the
energy of the entire organism is based on ade-
quate levels of ATP. Infrared photons, unlike vis-
ible light, are primarily involved in photophysical
reactions which occur mostly in the cellular
membrane, changing the rotational and vibra-
tional characteristics of the membrane molecules.
Through subsequent activation of the various
membrane-located transport mechanisms, such
as Na+/K+-ATPase (better known as the Na+/K+
pump) and Ca+-ATPase (Ca+ pump) the cell per-
meability is altered allowing in- and excellulation
of compounds. The chemical and osmotic bal-
ance in the cytosol are swiftly altered in turn
increasing the energy requirements of the cell
and energy in the form of ATP is demanded from
the mitochondria. This finally results in the
induction of a secondary chemical ATP-­
producing cascade which gives more or less the
same endpoint as the visible light photons,
namely cellular activation or proliferation [15].
These photoreactions are illustrated schemati-
cally in Fig. 18.10.
To sum up, the wavelength of a therapeutic
source therefore has a double importance, namely
to ensure absorption of the incident photons by
the target chromophores, and to be able to do so
at the depths at which these chromophores exist.
The waveband in which the wavelength of the
incident photons is located determines not only
which part of the cell is the target, but also the
primary photoaction i.e., photochemical or pho-
tophysical. Wavelength is thus probably the sin-
gle most important consideration in LED
phototherapy, because without absorption, there
can be no reaction.
Irradiance (Photon Intensity)
Light energy travels in the form of photons. It is
obvious that the more photons which are incident
per unit area of tissue, the greater will be the
bioeffect as the energy is transferred to the target
cells and the tissues. This incident photon inten-
sity is called the power density, or irradiance, of a
beam of light. The power density (PD) is an
extremely important factor in laser surgery and
medicine, but taking second place to wavelength,
and is calculated using the following formula:

PD
OP
TA W cm
=
(
)
/
2

where OP is the output power incident on the tar-
get in watts (W) and TA is the irradiated target
area in square centimeters (cm2). PD is usually
expressed in watts per square centimeter (W/cm2)
or milliwatts (mW)/cm2. It is the power density of
a beam that will determine more than anything
else (apart from wavelength) the magnitude of
the bioeffect in the target tissue. Consider
Table 18.2, where a laser with a constant incident
output power of 2 W targets tissue with a range of
spot sizes from 100 μm to 1 cm. Simply changing
the spot size, and thus the power density, can
have dramatically different effects on the target
tissue. Because the power density is worked out
per unit area, calculated by the formula πr2,
where π is the constant pi, 3.142, and r is the
radius (half the diameter) of the irradiated area,
we have to remember that there is an inverse
square ratio between spot size and power density
for a constant output power. Doubling the spot
size will not cut the power density by one-half,
but by one quarter: increasing the spot size by a
factor of 10 will cut the power density by one-­
hundredth, and vice-versa.
In LED phototherapy, it is therefore necessary
to achieve a high enough incident photon intensity
R. G. Calderhead

299
to achieve the desired degree of multiple absorp-
tion in the target cells, but not so high as to cause
any degree of photothermally-mediated changes
in the tissue architecture, in other words ideal
LED phototherapy should achieve athermal and
atraumatic photoactivation of the target cells. The
Arndt-Schultz law, first appearing in the mid-
nineteenth century, states that weak stimuli excite
biologic behavior, stronger ones favor it, powerful
ones arrest it and very powerful ones retard it.
This was adapted by Ohshiro and Calderhead in
1988 into the Arndt-Schultz curve to explain the
efficacy of LLLT (Fig. 18.11) [10, 16] from which
it is clear that photon intensity should not be too
weak (no reaction) or too strong (retardation or
cell death) but must be adjusted to achieve maxi-
mum optimum photobiomodulation of the target
cells or materials.
A final note on intensity: one single LED,
even one of the new generation of LEDs, when
PHOTORECEPTION
SIGNAL TRANSDUCTION
AND AMPLIFICATION
BASIC REACTION
a
b
Same end result
Visible red light
Invisible near infrared light
Cell
membrane
Cytoplasm
Nucleus
Mitochondrion
1
1
2
2
3
3
4
4
5
5
6
7
PHOTORESPONSE
Cell proliferation enhanced
Cell function upregulated
Repair of injured/compromised cell
Fig. 18.10  Schematic depicting photoreception (absorp-
tion) of light in a cell, and the subsequent wavelength-­
specific response. The basic reaction as defined by Karu is
absorption, which is followed by signal transduction and
amplification within the cytosol, and leads to the photore-
sponse involving the nucleus and membrane transport
mechanisms. (a) (1) Visible red light induces a primary
photochemical cascade initiated in the mitochondrion, the
energy factory and cell power house, which results in
increased levels of nicotinamide adenine dinucleotide
(NAD) extremely important in a wide range of redox
(reduction-oxidation) reactions, one of the results of
which is the generation of adenosine triphosphate (ATP)
which is the ‘gasoline’ for the cell. (2) The increased lev-
els of cytoplasmic ATP fuel the membrane transport
pumps, the Na2+K2+ and Ca2+K2+ pumps (3) which induce
extra- and intracellulation of messenger Ca2+ ions and pro-
tons (H+) which are elementary particles carrying a posi-
tive electric charge, the flow of which is used to generate
energy from ATP via ATPase. Cytoplasmic levels of Ca2+
ions and H+ dramatically increase. (4) This in turn upregu-
lates intracellular signaling including mRNA production
from ribosomes on the rough endoplasmic reticulum, and
finally (5) nuclear activity is also up regulated. (b) In the
case of near infrared light, the primary mechanism of
absorption is completely different (1) resulting in a photo-
physical reaction which changes the energy levels of the
cell membrane, in which near IR energy is absorbed. This
kick-starts the Na2+K2+ and Ca2+K2+ pumps so that cyto-
plasmic levels of Ca2+ and H+ dramatically increase (2)
and (4), prompting the mitochondrion to manufacture
more ATP to fuel the increased energy requirement (3),
thereby raising cytoplasmic levels of ATP (4) which again
impacts on the transport mechanisms of the membrane not
affected by the near IR light. Despite the totally different
pathways, the end result is however the same as in the case
of visible light, namely further cyclic increased energy
levels in the cytoplasm (6) and upregulation of nuclear
activity (6)
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

300
used on its own, will not achieve anywhere near
a clinically useful photon intensity in the target
tissue (Fig.  18.12a). When multiple LEDs are
mounted close together in a planar array, how-
ever, as in the examples shown in Fig. 18.3, and
precisely positioned according to the angle of
divergence of the beam, the interaction where
the beams impact with each other gives an
extremely intense photon density due to the phe-
nomenon of photon interference. When this is
combined with the excellent physical forward-,
lateral- and backward scattering characteristics
of red and near IR light, the result is that the
highest photon intensity is beneath the surface of
the skin, exactly where it should be to achieve
the optimum therapeutic effect (Fig. 18.12b). If
the distance between the LEDs is too great, how-
ever, then the intensity will drop off dramatically
because of the lack of interaction between the
individual
LED
beams
(Fig. 
18.12c).
Furthermore, some LED system manufacturers
combine LEDs of different wavelengths, e.g.,
red and yellow, and then claim they are deliver-
ing ‘orange’ light (Fig.  18.12d) … incorrect!
The skin cells will not ‘see’ orange from a mix-
ture of red and yellow light as our eyes do, but
will react separately to the incident red photons
and yellow photons. Karu has pointed out that
there are many pairs of wavelengths which actu-
ally inhibit cellular activity when used together,
yet enhance activity when applied separately
[12]. Light energy represents information for
cells, and then they act on that information.
Imagine a cell receives receiving conflicting
information from two different wavelengths: one
tells the cell to “turn right” and the other to “turn
left”. At best the cell will be confused and do
nothing. At worst, it will shut down partially or
completely. Unless there is a specific reason
based on photobiological knowledge, one wave-
length at a time should be the order of the day in
LED phototherapy.
As noted above, LEDs emit energy in a diver-
gent manner thereby causing an exponential
drop in the available photon intensity the further
the target is from the LED array. It is possible
using optics to maximize the output of an LED
array, and one manufacturer of an FDA-cleared
LED system has overcome this by adding what
they term Optical Lens Array Technology, or
OLAT™. An optically clear sheet embodying
precisely-­placed mini-collimating lenses is fixed
Table 18.2  Illustration of the importance of altering the
power density to achieve a complete range of bioeffects
from incision to photobiomodulation with a constant inci-
dent output power
Incident
power
(W)
Spot size
(∅, units
as given)
Power
density
(W/cm2)
Bioeffect
2
100 μm
25,000
Incision; excision
2
200 μm
6250
Vaporization; deep
coagulation
2
1 mm
250
Mild coagulation;
protein denaturation
2
1 cm
2.5
Athermal, atraumatic
photobiomodulation
Fig. 18.11  Ohshiro and Calderhead’s Arndt-Schultz
curve (1988) [10], based on the Arnd-Schultz law. From
stimulus strength A to B, no reaction occurs: the stimulus
is too weak. From B to C there is a sharp rise in bioeffect,
plateauing at C–D. This curve is based mostly on incident
power density (photon intensity), but the ideal combina-
tion of intensity and dose in phototherapy must therefore
be attained to reach the effect shown by the dark green
shaded area, preferably as much as possible at the C–D
effect plateau. From point D onwards there is a sharp drop
in the effect, although it is still higher than normal until
point E. Strength B–E corresponds to the zone of athermal
photobioactivation in Fig. 18.5 above. At stimulus strength
E–F the bioeffect is gradually retarded, corresponding to
the protein denaturation/degradation zones in Fig. 18.5,
and target death results from strength F–G corresponding
to the coagulation and vaporization zones in Fig. 18.5
R. G. Calderhead

301
in front of the LED arrays, each lens being in
front of an LED in the array. The output from
each LED is therefore partially collimated to
reduce the angle of divergence by some 30%.
This means that there are still intersecting beams
to make use of the photon interference phe-
nomenon, but the photon intensity is now 30%
higher at any given plane in the LED beam pat-
tern. Therefore, for the same irradiance, the pho-
ton intensity at the target has been increased to
allow for a more efficient irradiation of the target
tissue (Fig. 18.13).
a
b
c
d
Fig. 18.12  Arrays of precisely spaced multiple LEDs are
required to achieve clinically useful photon densities in
tissue. This illustration is modeled on the actual LED
array seen in Fig. 18.3 above, and is to scale. The distance
from LEDs to the tissue is approximately 2.5 cm. (a) A
single LED has insufficient photon intensity to achieve
any recordable clinical effect. (b) On the other hand, when
LEDs with similar output characteristics are mounted a
precise distance apart to make use of the 60° divergence,
the beams will interact where they cross each other to pro-
duce an extremely high photon intensity due to the phe-
nomenon of photon interference. When this is coupled
with the very strong forward and backward scattering
characteristics of red light, which is even stronger for near
IR energy, a zone of extremely high photon density,
greater even than the intensity at the LEDs themselves, is
created under the surface of the target tissue. (c) If LEDs
are spaced too far apart, the photon intensity is sacrificed
and is not clinically useful. (d) This is the case in treat-
ment heads with individual LEDs of different wave-
lengths, e.g., red and yellow, claimed as delivering
“orange” light … but not so!
a
b
c
Fig. 18.13  One example of how a manufacturer has
enhanced the beam intensity without increasing the output
power of the LEDs. (a) An optically clear sheet incorpo-
rating precisely placed semi-collimating lenses (optical
lens array technology, OLAT™) is placed under the same
schematic LED array as seen in Fig. 18.12b above. The
divergence of each LED is decreased, thereby increasing
the photon intensity within each beam. (b) A near-IR
array (830 nm, 100 mW/cm2) is captured with an IR cam-
era: note the loss of energy delivered to the target through
lateral scattering. (c) The same LED array at the same
LED irradiance but fitted with the optical lens array which
can be seen on top of the LED array. A much higher pho-
ton intensity is concentrated and delivered to the target
with significantly less energy lost to lateral scatter.
(Photography courtesy of Medicoscientific Affairs,
Lutronic Corporation, Goyang, South Korea: LED array
from HEALITE II 830 nm LED phototherapy system)
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

302
Dosimetry
Up to this point in the section, the time for which
light of a given irradiance or power density is
incident on a target has not been mentioned.
When treatment time comes into the therapeutic
equation it quantifies the dose of light delivered.
When 1 W of power is incident on target tissue
for 1 s, the energy delivered is 1 joule (J). The
joule in itself is a particularly useless therapeutic
parameter since it expresses only power over
time, and does not take into account the unit area
of tissue being treated. The most important
parameter for the therapeutic dose in LED photo-
therapy is the energy density (ED). ED is calcu-
lated as follows:

ED
OP
TA
J cm
=
´ (
)
t
/
2

where OP is the output power incident on the tar-
get in watts, t is the time in seconds and TA is the
irradiated area in cm2. ED is expressed in joules/
cm2 (J/cm2). However, too much is often made of
the dose as the most important parameter in pho-
totherapy, and criticism has been leveled at an
LED system that ‘the dose is too high’. In fact, as
stated in the previous subsection, it is the power
density, rather than the energy density, which
more than anything else determines the bioreac-
tion, and this is illustrated in Table 18.3 where a
constant dose of approximately 25  J/cm2 can
achieve the entire gamut of bioeffects from pure
athermal photobiomodulation to severe photode-
struction. The total uselessness of joules as a
meaningful parameter is also illustrated: the
greatest amount of energy in the table, 2000 J,
produced a phototherapeutic effect, whereas the
smallest, 8 mJ (0.008 J), produced a photosurgi-
cal effect [17]. In an experiment performed
20 years ago by the author of this chapter, the
exposed rat knee joint, both encapsulated and
unencapsulated, was irradiated with a GaAlAs
diode laser giving an incident power density of
1  W/cm2. A range of doses was applied from
20 J/cm2 (20 s exposure) up to 1800 J/cm2 (30 min
exposure). Tissue was examined macroscopically
and microscopically immediately after irradia-
tion for any signs of damage: none was found.
The wounds were closed and followed up at dif-
ferent time points over 2 weeks. No differences
were seen in coded specimens from each group at
all time points regarding morphological changes
compared with the unirradiated control speci-
mens [18]. In pharmaceutical science, the medi-
cine must be correct before adjusting the dosage.
In phototherapy, the power density is analogous
with the medicine, and the energy density is the
dose. If the medicine is incorrect, i.e., a photon
intensity which is too low (no effect) or too high
(photothermal damage), no amount of playing
around with the dose will achieve the optimum
result [17].
Temporal Profile of the Beam
The temporal profile of a beam of light energy sim-
ply means the output mode in which the light is
delivered to the target. There are two modes, con-
tinuous wave (CW) and pulsed, with Q-switching
Table 18.3  This illustrates a variety of bioeffects (Δα) achieved with the same approximate energy density, or dose, of
25 J/cm2
P
S ∅
[a] (cm2)
PD (W/cm2)
t
e
ED (J/cm2)
Δα
100 W
10.0 cm
78.6
1.3
20 s
2000 J
25
−
50 W
3.5 mm
0.1
500
100 ms
5 J
25
+
10 W
1.0 mm
0.0008
1250
20 ms
0.2 J
25
++
1 W
200 μm
0.0003
3180
8 ms
8 mJ
25
+++
75 mW
3.0 mm
0.07
1.1
23 s
1.725 J
25
−
As can be seen from the table, the power density (PD) is the most important determinant of the bioeffect and the energy
density given alone is therefore not a real determinant of effect
Key to table: P: Incident power (units as shown), S∅: spot size diameter (units as shown), [a]: irradiated area, PD: power
densityt: exposure time (units as shown), E: energy (units as shown), ED: energy densityΔα: graded bioeffects (+++,
severe photodestruction; ++, medium photodestruction; +, mild and/or reversible photodestruction; −, bioactivation)
R. G. Calderhead

303
of a pulsed beam technology dramatically shorten-
ing the pulse width and increasing the peak power
of pulsed beams. In CW, as the name suggests,
when the light source is activated the power reaches
its maximum level, from mW up to 100 W or so,
and stays there till the system is switched off
(Fig. 18.14a, left panel). An alternative to CW is
when the beam is ‘gated’ to produce a train of
square waves: this is often incorrectly referred to as
‘pulsed’ light (Fig. 18.14a, right panel). Gating can
be accomplished by a mechanical shutter, or be
achieved by simply switching the light source on
and off. The correct name for this process is ‘fre-
quency modulation’, because an exogenous fre-
quency (the on-off sequence) is being superimposed
on the inherent frequency of the beam which is pre-
determined by the wavelength, each wavelength
having a fixed frequency. For example, near infra-
red at 830 nm, visible red at 633 nm and visible blue
at 415 nm have ‘built in’ frequencies of approxi-
mately 3.6 × 108, 4.7 × 108, and 7.2 × 108 MHz,
respectively. From this it can be seen that as the
wavelength decreases, the frequency increases.
Increased frequency is also positively associated
with an increase in energy of the individual photons,
expressed as electron volts (ev), and for the previous
three wavelengths the respective photon energies
are approximately 1.49, 1.96 and 2.99 ev. Photon
energy determines the type of interaction between
the incident light and skin cells. For 830  nm, as
explained already, photophysical rotational and
vibrational changes occur in the electrons making
up the cell membrane, whereas for visible light
there is a direct induction of an intracellular photo-
chemical cascade. At very high ev values, such as
those associated with ultrashort wavelengths,
namely X- and γ-radiation, the very large photon
energies result in molecular disassociation of cells
with sufficient exposure, in other words the cells are
literally blown apart or “ionized”. These ultrashort
wavelengths are classed as ionizing radiation and
are inherently extremely harmful to living tissue
with a strong carcinogenic potential. LED-LLLT is
very much nonionizing radiation.
Time (s)
Pulse width (in ns)
Time (units as shown)
Average power (in W)
Peak power
15 GW
Interpulse interval (in ms)
off
on
0
0
15
80
C/W beam
Frequency modulated C/W beam
(50% duty cycle)
Output power (mW)
Output power (GW)
a
b
Fig. 18.14  Temporal profile of a beam of light. There are
two basic profiles, continuous wave (CW) (a) or pulsed
(b). In CW (a, left panel), the system is switched on, the
light very rapidly reaches its maximum, and remains there
till the system is switched off. This CW beam can be
‘gated’ mechanically or electrically, i.e. rapidly switched
on and off (a, right panel), which is often incorrectly
referred to a ‘pulsing’. The correct name is frequency
modulation. This gives a series of rectangular waveforms:
a 50% duty cycle is illustrated. When a laser beam is truly
pulsed, a tremendously high peak power, measured as
high as gigawatts (GW) is released in an ultrashort pulse
interval, measured in nanoseconds (ns) (b, left panel). If a
train of these pulses is emitted with a comparatively long
interpulse interval of milliseconds (ms) (b, right panel),
then the target tissue ‘sees’ only the average power of the
beam, measured in watts. This is called quasi-CW, also
known as ‘superpulsing’ the beam
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

304
In a true pulsed beam, from a high-powered or
Q-switched laser, an extremely high peak power is
reached in a spike-like waveform, with a very short
pulsewidth, 1  ms or less or in the ­nanosecond
domain for the Q-switched systems. The peak
power may be in mega- or even gigawatts
(Fig.  18.14b, left panel). If a train of such true
pulses is delivered with a set interpulse interval
often orders of magnitude longer than the pulse
width, then the target tissue ‘sees’ only the average
power of the beam, usually at CW output levels.
This is also referred to as ‘superpulsing’, or more
correctly, quasi-CW (Fig. 18.14b, right panel). No
current therapeutic LED system is capable of deliv-
ering a true pulsed beam, although LED-LLLT
devices are available in which the LEDs are turned
on and off to give flashes of energy in a range of
frequencies which are superimposed on the fre-
quency inherent to the wavelength of the emitted
light. This is frequency modulation, but is often
incorrectly referred to as “pulsing” the LEDs.
LED Phototherapy: Mechanisms
of Action
When light energy is incident on a target, the reac-
tion in the target following absorption is known as
the mechanism of action. In LED phototherapy,
there are two main mechanisms of action: photody-
namic therapy (PDT) and athermal and atraumatic
photobiomodulation, which are totally different
mechanisms of action.
Photodynamic Therapy (PDT)
PDT can be exogenous or endogenous, the better
known form of which is exogenous.
Exogenous PDT
Exogenous PDT is typically defined as: “The
use of a chemical, given orally, intravenously or
topically (directly to the skin), that can be acti-
vated or energized by light to destroy a target
tissue in which the chemical or substance has
preferentially located. This activation causes
the formation of new molecules and free radi-
cals such as reactive oxygen species (ROS)
which may also form other chemicals that, in
turn, may destroy the targeted material to a
varying extent, such as through ROS-mediated
apoptosis of the photosensitized cells or closure
of blood vessels feeding the target tissue.” PDT
is another arm of phototherapy, and whilst
exogenous PDT is thus still an athermal reac-
tion, it is not atraumatic as deliberate induction
of apoptotic cell death is the main goal. The
first main application for photodynamic therapy
was in the treatment of certain cancers, with
such photosensitizers as hematoporphyrin
derivatives activated with low incident levels of
laser light, particularly with visible red light
such as from the HeNe laser due to this wave-
length’s better penetration than the shorter vis-
ible wavelengths in living human tissue [19].
This activated an oxygen-dependent phototoxic
cytocidal action within the cells containing the
agent, and the free radical singlet oxygen (1O2),
a short-lived product from the reaction between
an excited sensitizer molecule and oxygen,
played a very important part in the induction of
cell death (apoptosis) and destruction of the
microvasculature feeding the tumor.
One of the first applications for LED photo-
therapy was in fact PDT for non-melanoma skin
cancers (NMSCs), such as basal cell carcinomas
Box 18.3
• LEDs are ideal for cellular photobio-
modulation (low level light therapy,
LLLT), an atraumatic and athermal
direct exchange of energy raising the
target’s action potential
• LEDs can be successfully used in pho-
todynamic therapy (PDT)
–– Exogenous
PDT
with
5-­aminolevulinic acid (5-ALA) for
treatment of non-melanoma skin
cancers and severe photodamage.
–– - Endogenous PDT in porphyrins
endogenous to Propionibacterium
acnes, for example, in the treatment
of acne.
R. G. Calderhead

305
and superficial squamous cell carcinomas, or
severe sun damage such as actinic keratosis with
the use of another exogenously-applied com-
pound, 5-aminolevulinic acid or 5-ALA in any
of its forms. This application continues to the
present with good success and robust long-last-
ing results [20, 21]. The topically applied 5-ALA
penetrates into the dermis under an occlusive
wrap, and is converted as part of the
mitochondrial-­based heme cycle into copropor-
phyrin III (Cp III), a member of the powerful
porphyrin photosensitizing family. When the
maximum amount of Cp III has been converted,
the remainder of the 5-ALA is converted into
another porphyrin, protoporphyrin IX (Pp IX).
These two porphyrins become the specific tar-
gets of the LED energy at specific wavelengths,
and, following photoactivation, nonselectively
damage all of the superficial dermal tissue in
which they exist, as illustrated schematically in
Fig. 18.15.
When a photoreaction is desired such as in
5-ALA PDT for any purpose, an action spectrum
has to be run to investigate the action potential of
a range of wavelengths in the target compound.
Figure 18.16 shows the absorption spectra of Pp
IX and Cp III.  There is a very large peak at
415 nm in the visible blue Soret band, but as will
be remembered from the previous section on
wavelength, blue light has very poor penetrative
capability into the dermis, and so it would not
cause deep enough damage to treat NMSCs
successfully. Another series of much smaller
peaks is however seen from the yellow to the red
waveband (the Q-band), the latter occurring at
around 633 nm, which was used in the early days
of hematoporphyrin derivative PDT for other
cancer types as a much better-penetrating wave-
length, thus giving a much deeper zone of por-
phyrin activation and hence a deeper zone and
greater volume of controlled photodamage. Red
633 nm LED-activated 5-ALA has been success-
fully used for NMLCs and actinic keratoses,
photorejuvenation and inflammatory acne vul-
garis. These will be discussed in more detail
a
b
c
d
Fig. 18.15  Nonselective en bloc infiltration of skin by Pp
IX and Cp III of 5-ALA origin illustrated schematically.
(a) Target lesion in superficial dermis. (b) 5-ALA oint-
ment applied topically to epidermis. (c) As 5-ALA pene-
trates en bloc into skin cells, it is transformed into Cp III
and Pp IX, photosensitizing porphyrins. (d) Light at an
appropriate wavelength activates the porphyrins to pro-
duce powerful but very short-acting reactive oxygen spe-
cies, such as singlet oxygen, and the affected skin cells die
through oxidative-stress mediated apoptosis (induced cel-
lular destruction)
Fig. 18.16  Action spectra for coproporphyrin III and
protoporphyrin IX. Note the extremely high peak at
415 nm, and the minor peak at 633 nm, visible red, par-
ticularly in Pp IX, which suggests the red wavelength for
deeper activation of 5-ALA-induced porphyrins in PDT
for cutaneous lesions
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

306
in the appropriate subsection on LED photother-
apy in clinical practice.
Endogenous PDT
Exogenous PDT as discussed above depends on
an external photosensitizer, such as 5-ALA. In
endogenous PDT, the photosensitizer, or photo-
sensitizing substances, can be found occurring
naturally within the target cells or tissue. The
exogenous application of 5-ALA induces the
synthesis of the porphyrins Pp IX and CP III
nonselectively in the tissues of the epidermis
and dermis under the area of application as
already explained above. However, in the case
of acne vulgaris the inflammatory acne lesions
are associated with the presence of their caus-
ative bacterium, Propionibacterium acnes (P.
acnes). It has been well demonstrated that both
Pp IX and Cp III are endogenous to active P.
acnes, and the more active is the bacterium, the
higher the porphyrin concentration [22–24].
Referring again to Fig. 18.16, maximum photo-
activation of both Pp IX and Cp III occurs at
around 415 nm. Light at that wavelength, with a
high enough photon intensity, could therefore
achieve activation of the porphyrins within the
P. acnes, thereby selectively destroying or at
least severely damaging the P. acnes through
oxidative stress-induced apoptosis [25], but
without harming the surrounding skin cells.
Endogenous PDT could therefore be applied in
the light-only treatment of inflammatory P.
acnes lesions without the need for any exoge-
nous 5-ALA.  This will be discussed in more
detail in the appropriate part of the following
section.
Photobiomodulation
Basically the majority of the information in sec-
tions “Introduction” and “Basics of Light-Tissue
Interaction” has been based on the concept of
photobiomodulation, also known as photoacti-
vation therapy, and this approach completely
fulfills the definition of phototherapy, namely
direct cellular activation in an athermal and
atraumatic manner which has been the umbrella
mechanism of action long-associated with LLLT
(low level light therapy) over its 30-year-plus
history, whether with laser or non-laser sources.
Atraumatic and athermal LLLT thus differs
from PDT which actively seeks to damage the
target cells and tissues, although still in an
athermal manner. As has already been discussed
in section “Wavelength and Its Importance” on
wavelength, near infrared and visible light have
different absorption targets (cell membrane and
subcellular organelles, respectively) but the end
result is the same, and the energy level of the
cell is raised by both near IR and visible light of
appropriate wavelengths through direct absorp-
tion of the incoming photon energy, which is
then transferred to the receptor cell with no loss
through heat or luminescence. The main mecha-
nism of action is connected with increased ade-
nosine triphosphate (ATP) production and
increased Ca2+ ion intra- and intercellular sig-
naling [26].
Under photoactivation, three things can hap-
pen to the energized cell: if it is compromised
or in some way damaged, the cell will heal
much faster; if the cell is designed to perform
some specific function, such as fibroblast col-
lagenesis and elastinogenesis, then the LLLT-
treated cell will perform these functions better
and faster; finally, if the cell is designed to rep-
licate, then it will replicate faster [14]. These
may happen singly, or in combination, and form
the basis of the three decades of LLLT literature
in which some, but not all, of the mechanisms
under the umbrella of photobiomodulation have
already been at least partly elucidated as sum-
marized in Table 18.4 and at a molecular level
in Table 18.5. In addition, in the past decade in
particular, a good number of solid clinical and
basic science papers have corroborated the pre-
vious basic and clinical findings for LED pho-
totherapy, and some exciting new science on
LED-LLLT has been appearing in the last
R. G. Calderhead

307
5 years. LED-LLLT can be used in combination
with other conventional modalities to improve
results and hasten healing time, and can also
offer a very interesting combination with either
exogenous or endogenous PDT in the treatment
of inflammatory acne vulgaris. Once again, a
detailed discussion will be found in the follow-
ing section.
Table 18.4  Summary of the major mechanisms associated with photobioactivation and LLLT
Mild thermal
(<40 °C)
Biochemical (primary for visible
light)
Bioelectric
Bioenergetic
↑ Nerve
conduction
(Mitochondrial events)
↑ ATP production
↑ Release of nitric oxide (NO)
↑ Very low levels of reactive oxygen
species (ROS)
↑ Electromotive action on
membrane bound ion transport
mechanisms
↑ Rotational and
vibrational changes to
membrane molecule
electrons
(Primary for near-IR)
↑ Capillary
dilatation
↑ Fibroblast
proliferation → Collagen and elastin
synthesis
↑ Intracellular extra-cellular ion
gradient changes
↑ Stimulation of
acupuncture meridian
points
↑ Mast cell degranulation: cytokine,
chemokine and trophic factor release
↑ Depolarization of synaptic
cleft → closure of synaptic
gate—pain control
↑ Increased
biophotonic activity
↑ Macrophage activity (chemotaxis
and internalization) → release of
FGF
↑ Activation of the dorsal horn
gate control mechanism → pain
transmission slowed, pain control
increased
↑ Keratinocyte activity → cytokine
release in epidermis and dermis
↑ Opiate and nonopiate pain control
(endorphins, dynorphins and
enkephalins)
↑ RNA/DNA synthesis
↑ Enzyme production
↑ Superoxide dismutase (SOD)
production (mast cells)
Table 18.5  Molecular level activation by LLLT with appropriate LEDs (based on data from Gao X, Xing D. Molecular
mechanisms of cell proliferation induced by low power laser irradiation. J Biomedical Science. 2009 16:4
ncbi.nlm.nih.gov/pmc/articles/PMC2644974/)
Classification
Molecules
LLLT-associated biological effects
Growth factors
BNF, GDNF, FGF, bFGF, IGF-1, KGF, PDGF,
TGF-β, VEGF
Proliferation
Differentiation
Bone nodule formation
Interleukins
IL-1α IL-2, IL-4,IL-6, IL-8
Proliferation
Migration
Immunological activation
Inflammatory
cytokines
PGE2, COX2, IL1β, TNF-α
Acceleration/inhibition of inflammation
Small molecules
ATP, cGMP, ROS, CA2+, NO, H+
Normalization of cell function
Pain relief
Wound healing
Mediation of cellular activities
Migration
Angiogenesis
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

308
LED Phototherapy in Clinical
Practice
Good basic science is of course extremely impor-
tant to understand how LED-LLLT can be applied
in current dermatological practice, to help bolster
up evidence-based medicine from the practical
clinical arena. However, a thorough understand-
ings of the true capabilities, and indeed limita-
tions, of LED phototherapy in clinical practice is
even more essential to go about amassing the
required evidence-based medicine in the most
efficient manner. A large number of LED-based
systems is commercially available now in the
USA and world-wide, but a very, very small
number has actually made it into the peer-­
reviewed literature with the vast majority of man-
ufacturers content to ride on the coat-tails of the
companies who have done the actual work, both
basic science and controlled clinical trials, even
though the science of these bandwagon-jumping
systems is sketchy at best, and nonexistent or
even erroneous at worst. Of particular concern
are the ‘look-alikes’ of far-east origin, particu-
larly China, based on proven systems but with
inferior quality LEDs which give neither the
rated wavelength, nor sufficient and stable output
power. Some of these systems mimic the free-­
standing planar LED-based units, and others are
small hand-held devices with a mesmerizing
array of pretty flashing multicolored LEDs,
designed for the home-use market. These groups
of ‘toy’ systems are doing more harm than good
to the reputation of LED phototherapy, although
one hopes that they are not visiting actual harm
on patients with ‘no effect’ hopefully being the
worst that they achieve. The negative impact on
‘good’ LED phototherapy has been and remains,
however, very large. Hopefully this entire chapter
will go some way to redressing that. Another
important point for anyone considering purchas-
ing an LED phototherapy system is that some
LED system manufacturers claim that their LEDs
are ‘NASA technology’. This is totally mislead-
ing. Although the new generation of LEDs is
based on the ‘NASA LED’, they are not actual
NASA technology, and some of the LEDs thus
described are still of the previous generation:
caveat emptor! The reader must always bear in
mind that with LED phototherapy, ‘any old LED
will NOT do’.
The treatment categories dealt with in this
very important section are based on published lit-
erature, not so-called ‘white papers’, and so the
reader can obtain the original articles from online
Box 18.4
• LED-LLLT in the adjunctive combi-
nation approach is the key to clinical
efficacy.
• LED-LLLT is not magic … it cannot
target everything as monotherapy.
• Based on the published peer-reviewed
literature, certain wavelengths can
accomplish different things in effec-
tive LED-LLLT.
–– 633 nm has proved effective in 5-ALA
PDT for non-melanoma skin cancers,
and has found applications in hair res-
toration and baldness prevention.
–– Blue 415 nm endogenous PDT com-
bined with red 633 or 830 nm LED-­
LLLT applied sequentially has been
reported as a very effective light-only
therapy for moderate to severe acne
vulgaris.
–– Combined near infrared 833 and
633  nm red LED-LLLT, applied
sequentially, was reported as very
effective in skin rejuvenation and all
aspects of wound healing, but more
recent literature suggests that 830 nm
on its own is the key wavelength in
these indications.
–– Visible yellow light (590  nm,
595  nm) has shown efficacy in the
treatment of superficial conditions,
e.g., in the treatment of rosacea.
–– Adjunctive LED phototherapy will
complement any and all existing con-
ventional modalities which alter in
any way the architecture of the skin
to achieve the desired clinical result.
R. G. Calderhead

309
indexing sources such as PubMed, and see in
detail what has, and what has not, been scientifi-
cally proven and clinically corroborated. The
author would like to point out that any suggested
treatment protocols are inserted only for example
and guidance, and must not be taken as concrete.
Manufacturer’s recommendations are also only
recommendations, and the reader should look to
the published literature or presentations from
leaders in the field at leading national and inter-
national congresses for more detailed and accu-
rate treatment protocols. It is the hope of the
author that the reader will see the true possibili-
ties of LED phototherapy to enhance his or her
clinical practice, and will moreover choose an
LED system based on the criteria which will
appear throughout the section, rather than on
hype, pretty flashing colors and pseudo-science.
If the actual systems referenced seem to be
extremely limited, that is because they are the
only ones which have been published in the lit-
erature, and the author offers no apologies for
this. He can only demonstrate and present to the
reader what has been published on systems which
have met or exceeded the required criteria by the
relevant regulatory bodies.
Non-melanoma Skin Cancers (NMSCs)
and Actinic Keratosis
NMSCs, including Bowen’s disease and basal
cell carcinoma, were the first entity to be treated
with LED PDT using specifically-designed
633  nm LED-based system to activate 5-ALA,
and the pioneering company was Photo
Therapeutics (Fazeley UK and Carlsbad, CA)
with their Omnilux® PDT™ system. The
Omnilux brand is currently owned by Radiency
Ltd., Hod Hasheron, Israel (parent company).
Having established that an effective activation
peak for the relevant porphyrins created from
exogenous PDT existed at around 633 nm, a UK
company in 1996, working in tandem with the
British Cancer Research Council, developed the
Paterson Lamp, a filtered xenon-powered lamp
which delivered most of its light energy at
633 nm, to be used with exogenous 5-ALA PDT
in the treatment of NMSCs [27]. The lamp was
the brainchild of Dr. Colin Whitehurst, and it was
he who saw the potential for using the new gen-
eration of LEDs which became available in 2000
following Whelan’s work with the NASA Space
Medicine program referenced earlier. The new
generation of LEDs emits quasimonochromatic
light and does not require filtering, plus the LEDs
can be mounted in planar arrays to irradiate large
areas at the same time, such as the entire face. Dr
Whitehurst then helped found Photo Therapeutics,
who built the first large-array 633 nm LED ther-
apy source for LED PDT for the treatment on
NMSCs with input from Prof Whelan. Large-­
scale clinical trials in the UK and elsewhere in
Europe gave excellent results [28].
The basic protocol which has evolved for
633  nm LED PDT for NMSCs is as follows:
please note that differences in LED systems and
photosensitizer do not make this an absolute pro-
tocol, and the recommendations of the manufac-
turer of both the LED system being used and the
photosensitizer being applied must always be
studied and carefully followed. Following thor-
ough cleaning of the treatment area, 5-ALA of
the appropriate strength (usually 20%) is applied,
and occluded with sterile cling film for the rec-
ommended incubation period (up to several
hours, depending on the lesion being treated). At
the end of incubation, the occlusive dressing is
removed and any excess 5-ALA wiped off.
Activation of the porphyrins induced in the target
tissue is then achieved with 633 nm light, with a
dose usually around 45–90  J/cm2. This can be
extremely painful, and some kind of forced air
cooling may be applied during this phase for
patient comfort. Following activation, the wound
is dressed, and the patient returns after 24 h for
dressing removal and the situation is then fol-
lowed for 4–6  weeks. In a large percentage of
lesions, recurrence is not a problem. Persistent
lesions are retreated till no recurrence is seen.
Figure  18.17 shows a typical example of the
results of 633 nm LED PDT for an NMSC.
In the case of actinic keratoses (AKs), which
are much more superficial than NMSCs, a much
lower concentration of 5-ALA is applied with a
shorter incubation time. The protocol is otherwise
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

310
the same and the activation dose is still recom-
mended to be around 96  J/cm2. Figure  18.18
shows AK on the upper sternum of a female
patient before and after 633 nm LED PDT. One
treatment usually suffices for AKs.
Acne Vulgaris
Acne vulgaris still represents a major problem for
the practicing dermatologist, despite advances in
clinical and medical therapy. Many approaches
have been tried with varying degrees of success,
but results are inconsistent, even in the same
regimen with the same patient. If untreated, or
treated improperly, active ace almost always
leads to unsightly acne scarring, as disfiguring
and psychosomatically troublesome as the active
lesions, but more difficult to treat. It therefore
made sense to attack and eradicate acne while at
the active stage, before scarring was an issue. In
addition to the conventional approaches, LED
exogenous 5-ALA PDT with 633  nm and nar-
rowband blue light LED and non-LED sources at
around 410–425 nm attracted attention with good
results, but with some downtime and pain associ-
ated with the activation stage of the photosensi-
tizer [29–31]. The recurrence rate was, however,
still rather high. The development of quasimono-
chromatic LEDs at the peak wavelength of
415  nm offered a new approach, given the
extremely high peak in the activation spectra of
Pp IX and Cp III, both of which porphyrins are
endogenous to active P. acnes as already
a
b
Fig. 18.17  A basal cell carcinoma before (a) and 4 weeks
after 633 nm 5-ALA PDT (b) (20% 5-ALA, 5 h incuba-
tion, 20 min activation at approximately 96 J/cm2. System
used, Omnilux® PDT™, photographs courtesy of Colin
Morton MD, Falkirk, Scotland)
a
b
Fig. 18.18  Actinic keratosis on the décolleté of a
45 year-old female before (a) and just over 6 weeks after
633 nm 5-ALA PDT (b) (10% 5-ALA, 30 min incubation,
20 min activation at approximately 96 J/cm2. Same system
as in Fig. 18.14, photographs courtesy of Colin Morton
MD, Falkirk, Scotland)
R. G. Calderhead

311
discussed above. With a high enough photon
intensity at 415 nm it would therefore theoreti-
cally be possible to activate the endogenous por-
phyrins in P. acnes selectively, thereby disabling
or eradicating the P. acnes [32, 33]. On the other
hand, trying to activate porphyrins from exoge-
nously-applied 5-ALA PDT with narrow band
415  nm LED energy should be attempted with
extreme caution, as the activation process will be
both extremely painful and rather shallow owing
to the physical characteristics of 415  nm light,
with a prolonged downtime owing to the serious
damage to the irradiated tissues.
In order to understand why the blue light ther-
apy on its own was achieving good results but
with a still unacceptably high recurrence rate, the
etiology of acne must be considered. Acne is
often considered as an inflammatory disorder,
full stop, with colonization of blocked follicles
by P. acnes as the main culprit. In fact, acne is
multifactorial with major influences other than
merely inflammation, such as hormonal and
­autoimmunological imbalances [34]. Acne is the
result of the establishment of a vicious circle set
up between P. acnes and some t-cells originally
homing into the site to help the defence system,
but ultimately converted by P. acnes to the black
side as ‘rogue t-cells’. Whereas 415 nm will pre-
cisely target the P. acnes via the endogenous por-
phyrins and thereby remove one of the major
causes of the inflammation, the rogue t-cells and
any hormonal imbalance remain untreated by the
415  nm light, thus leaving the vicious circle
unbroken and paving the way for recurrence at
some stage in the near future. If light-only ther-
apy for acne were to work well and with robust
results, it would therefore be necessary to find
another approach whereby the targets not dealt
with by the blue light could be attacked with
another wavelength. A very interesting paper
appeared from Papageorgiou and colleagues in
which they achieved excellent and long-lasting
results in acne treatment with a combination of
filtered blue (415 nm) and red (660 nm) non-LED
light applied simultaneously [35]. It was then
suggested that sequential rather than simultane-
ous application of blue and red light might have
an even better effect through selective targeting
of
the
different
cellular
and
subcellular
wavelength-­specific targets, and the quasimono-
chromatic nature of LED therapy would assist in
precise targeting. In addition, applying the blue
and red components together might actually go
some way to defeating the object of the exercise,
as one of the effects of the red light is to try and
repair damaged cells, including the P. acnes tar-
geted by the blue light.
Two clinical papers were published in 2007
using this sequential approach of 415 nm LED
light-only therapy followed by 633 nm red LED
treatment, repeated over a 4-week period. One
patient group was Caucasian [36] and the other
Asian [37], and both groups had a meaningful
number of patients (>25) with a good selection of
Burton grades 3–5, representing moderate to
severe inflammatory acne. The system used in
both studies was the Omnilux (Radiancy, Israel)
with the blue™ (415 nm) and revive™ (633 nm)
heads, and the same protocol was followed in
both the USA and Korea study centers. A two-­
week washout was imposed for anyone on oral
medication, and no other form of topical or ther-
apy was allowed during the study and followup
period. A comedonal scrub was recommended
before each treatment session. The blue head was
applied first for 20 min, followed at least 48 h
later by the red head. This was repeated for
4  weeks. Assessments were performed at pre-
treatment baseline, at each of the 4 weeks during
treatment, and then at 4, 8 and 12 weeks after the
final treatment session.
The most interesting point in both studies was
that the improvement obtained after the final
treatment session, which ranged from 50% to
60% clearance of inflammatory lesions, contin-
ued to improve up to 12  weeks after the final
treatment with no other therapeutic intervention,
reaching from 83% to 90% clearance, and if
extrapolated beyond the trial period would have
in many patients reached 100%, which from per-
sonal communication with the authors of both
papers, it in fact did. Figure 18.19 is a graphic
representation of the inflamed lesion reduction
curves of the two referenced papers.
No secondary hyperpigmentation was seen in
any patients in both studies, which is of particular
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

312
interest in the Asian skin type. In addition, over-
all skin condition was subjectively assessed to
have improved, and in the case of the Asian popu-
lation, skin lightening was objectively shown
across the population with an instrumental assay.
Figure  18.20 shows examples of the treatment
efficacy courtesy of the authors of the papers. At
6 months after the final session, recurrences in
both trial centers were extremely few and mild,
easily treated with another regimen of the blue/
red LED therapy (David Goldberg and Celine SY
Lee, personal communication).
As with all approaches not involving exci-
sional surgery, there will always be a small per-
centage of patients in whom light-only LED
phototherapy for acne vulgaris will have disap-
pointing results, but from the above studies the
overall efficacy is high enough to warrant apply-
ing this approach as the primary treatment of
choice. Sequential combination LED photother-
apy for acne can be combined with other topical
approaches with even better results and improved
maintenance, provided none of these involves
any kind of photosensitizing agents, any of which
have the potential to create painful and possibly
severe side effects. The validity of the substitu-
tion of another LED wavelength to the current
protocol, namely near infrared at 830 nm with its
own unique cellular and tissue targets, in place of
the 633  nm visible red approach, is currently
being assessed in ongoing clinical studies world-
wide, and the results are extremely promising
probably owing to the specific cellular entities
targeted by 830 nm compared with those affected
by 633 nm.
Skin Rejuvenation
Skin rejuvenation and antiageing have become
very ‘hot’ topics. Excessive skin exposure to
solar UVA and UVB brings about damaging mor-
phological and metabolic changes in the epider-
mis and dermal extracellular matrix (ECM),
combining with and accelerating the effects of
chronological ageing and resulting in the lax, dull
and wrinkled appearance of ‘old’ skin. Oxidative
stressors such as singlet oxygen are photochemi-
cally generated following absorption of UV radi-
ation in the ECM and damage the matrix integrity
Goldberg & Russell (29)
Lee et al (30)
0
20
40
60
Clearance rates (% of lesions)
80
100
0
1
2
Treatment weeks
Follow-up weeks
3
4
4
8
12
Extrapolated clearance
Fig. 18.19  Inflammatory lesion clearance rates follow-
ing the blue/red combination LED phototherapy for acne
adapted from the studies by Goldberg and Russell [29]
and Lee et al. [30]. The Goldberg study had a 12-week
follow-up after the final treatment, i.e. 16  weeks from
baseline, whereas the Lee study had an 8-week follow-up
(12 weeks from baseline). However, by extrapolating the
clearance rates in both studies, which were clearly linear
in nature, the continued improvement is evident. No other
therapy was used in either study. System used: Omnilux®,
Radiancy, Israel
R. G. Calderhead

313
with elevated levels of the matrix metalloprotein-
ases (MMPs) 1 and 2, formerly known as colla-
genase and gelatinase; elastotic damage to the
underlying connective tissue occurs, with inter-
stitial spaces appearing in a poorly-organized
matrix; the viscosity and quality of the ECM
ground
substance
glycosaminoglycans
is
reduced; and a chronic inflammatory infiltrate
can be identified. As this damage is caused by
light, an elegant concept to use the power of light
a
b
c
d
Fig. 18.20  Representative examples from the Goldberg
and Lee studies on light-only combination blue/red LED
phototherapy for inflammatory acne. (a) Cystic acne at
baseline in a 21-year-old female, skin phototype II, from
the Goldberg and Russell series. (b) Six weeks after the
final treatment session (10  weeks from baseline).
Excellent clearance and very good cosmesis. Photographs
courtesy of Bruce Russell MD. (c) Inflammatory acne on
the cheek and jaw line of a 19-year-old Korean male
patient from the Lee series, skin type IV. (d) Eight weeks
after the final treatment session (12 weeks from baseline).
Good clearance with no secondary hyperpigmentation, a
major problem in the Asian skin. The remaining small
areas of redness will fade with time. Photographs courtesy
of SY Celine Lee MD
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

314
to reverse the damage led to the application of
lasers, usually the CO2 or/and the Er:YAG, in
what became known as ablative laser resurfacing.
Although still regarded as the ‘gold standard’ in
the rejuvenation of severely photoaged skin in
general and deep wrinkles in particular, the usu-
ally severe side effects and a prolonged patient
downtime of up to several months associated
with this approach drastically reduced its
popularity.
To attempt to overcome these problems, so-­
called nonablative resurfacing was developed
using specially adapted laser or intense pulse
light sources. The theory was to deliver a con-
trolled zone of deliberate photothermal damage
beneath an intact epidermis, so that the wound-­
healing processes, including collagenesis and
remodeling, could occur under the undamaged
epidermis, thereby obtaining rejuvenation of the
skin without any patient downtime and was pop-
ularized as the ‘lunch-break rejuvenation’. The
theory was good, but in clinical practice patient
satisfaction was very low, [38, 39] because the
good dermal neocollagenesis seen in post-­
treatment histological analysis was not reflected
in a ‘younger’ epidermis [40]. In an attempt to
bridge this gap between ablative and pure nonab-
lative rejuvenation, so-called fractionated or
fractional technology was developed whereby
many spots of almost grossly invisible epidermal
and dermal ‘microdamage’ were delivered via a
scanner or ‘stamp-type’ head, all surrounded by
normal epidermis and dermis to obtain swift
reepithelialization and dermal wound healing
[41]. Unfortunately, once again the clinical
results of the first generation of nonablative frac-
tional lasers were not satisfactory to the majority
of patients, with good dermal neocollagenesis
not being echoed in the epidermis. In both the
nonablative laser/IPL and the first generation of
fractional nonablative technologies, the big
problem was that what the patient first sees when
looking in a mirror is the epidermis, not the der-
mis. It does not matter to the patient (or her
friends) that her dermis is wonderfully better
organized if her epidermis remains unchanged,
what the author refers to as the SOE syndrome—
‘same old epidermis’. Recognizing this, manu-
facturers of the more recent second generation of
fractional systems have returned to the original
ablative wavelengths, the CO2 and the Er:YAG,
in addition to increasing the parameters of the
nonablative fractional Er:glass systems, to
deliver fractionated microbeams that visibly
damage the both the epidermis and the dermis
with a recognizable amount of erythema and
some edema post-treatment.
This in some way takes us back towards our
gold standard of ablative resurfacing, as once
again heat deposition, combined with controlled
epidermal damage, becomes a pivotal consider-
ation to achieve the ideal rejuvenation results on
a patient-by-patient basis [42]. This approach has
been much more successful from the patient sat-
isfaction criterion, although at the cost of a little
downtime, because it is involving the epidermis
more than the previous nonablative and fractional
approaches.
In the meantime, other clinical researchers
were wondering if there was a role for LED pho-
totherapy in skin rejuvenation, and the first
approach was to use a lower strength of topically-­
applied low-strength 5-ALA activated with
633 nm LED in LED-PDT [43]. The results were
good, but begged the question as to why more
damage, and indeed some pain, should be
inflicted to treat what was essentially compara-
tively mild skin damage. Another approach has
been to deliver the 5-ALA at very low concentra-
tions (<2%) via liposomes and activate the target
tissue using intense pulsed light, achieving com-
plete quenching of the porphyrins and thus avoid-
ing the side effect of residual photosensitivity
[44, 45]. Because of its totally noninvasive, ather-
mal and atraumatic nature, light-only LED pho-
totherapy for skin rejuvenation has also attracted
attention first with a single wavelength system in
the visible yellow [46], but once again a sequen-
tial combination technique, initially at least,
proved more effective than the single wavelength
just as was the case with LED phototherapy for
acne [47, 48]. The wavelengths used for LED
skin rejuvenation in the published literature were
originally near IR at 830  nm applied first, fol-
lowed by 633  nm 72  h later, repeated over
4  weeks. The rationale for using these wave-
R. G. Calderhead

315
lengths and the order in which they are applied
are photobiologically based on the precepts of
the wound healing cycle, and will be covered in
some detail in the next subsection dedicated to
wound healing. Both of these wavelengths
involve the mother keratinocytes in the basal
layer of the epidermis, however, in addition to the
target dermal cells, with beneficial effects to both
the cellularity and organization of the epidermis,
but with no heat and no damage.
Lee and colleagues, in the first and really
detailed controlled study in the peer-reviewed
literature, which was published in the very
prestigious Journal of Photochemistry and
Photobiology (B), [49] compared LED skin
rejuvenation in a total of 76 patients randomly
assigned to four groups: 830 nm LED therapy
on its own, 633 nm LED therapy on its own, the
combination therapy with 830 and 633 nm and
a sham irradiated group. All patients were
treated hemifacially, so there was intrapatient
as well as intergroup controls. In addition to
clinical photography and subjective patient
assessment, Dr Lee tested the results with pro-
filometry and instrumental measurement of
skin melanin and elasticity. She also carried out
histological, immunohistochemical and bio-
chemical assays. Dr Lee found that wrinkles
and skin elasticity were best improved in the
830  nm-treated groups and a statistically sig-
nificant improvement existed between the
treated and occluded sides in all of the experi-
mental groups, but not in the sham irradiated
group. Subjective patient satisfaction showed
statistical significance between all the treated
groups and the sham-irradiated group, but it
was clear that a strong tend was shown in favor
of the 830  nm group compared with the
830/633 nm and 633 nm groups. Figure 18.21
compares the subjective patient “excellent” rat-
ings among the 633 nm, 830 nm + 633 nm and
830  nm groups from the final treatment ses-
sions through the 12-week assessment period.
For all groups, and interesting and clear
Fig. 18.21  Graphical comparison of only the “excellent’
result ratings by the LED rejuvenation trial subjects in the
630 nm, 830 nm plus 633 nm and 830 nm groups based on
data from the cited paper by Lee et al. [49]. Ratings start
from immediately after the final treatment session, then at
4, 8 and 12 weeks thereafter with no further treatment. An
interesting increase in satisfaction levels is seen during
this 12-week period for all groups corresponding to the
ongoing remodeling stage of the wound healing process.
The patients who noted the greatest satisfaction, soonest,
were in the 830 nm group
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

316
improvement was echoed in the patient satis-
faction during that 12-week period: that
phenomenon can be explained by the remodel-
ling process, continuing long after the final of
the eight treatment sessions. However, based on
a closer examination of the study data, the best
results were achieved not in the combination
group but in the 830  nm group, and were
achieved fastest among the three groups.
The clinical photography was backed up by
the histological findings for both collagenesis
and elastinogenesis, both of which were shown
to take place in all dermal layers down to the
deep reticular dermis. No MMP activity was
noted, and on the contrary the levels of tissue
inhibitors of MMPs (TIMPs) 1 and 2 were sig-
nificantly elevated in all treatment groups, but
with a strong but nonsignificant trend noted for
the 830 nm group over the others, suggesting a
photoprotective effect against degradation of the
newly-­formed extracellular matrix.
This was an excellent and thorough study, and
the author recommends the reader to get hold of
it and read it, all 17 pages of it. It will go a long
way to convincing even the most skeptical of the
real efficacy of LED-LLLT for light-only skin
rejuvenation, backed up with real science.
Figure 18.22 shows examples of the efficacy of
light-only combination LED skin rejuvenation,
including histological findings from the Lee
study demonstrating photorejuvenation of both
the dermis and epidermis at only 2 weeks after
the final treatment session: as remodeling pro-
gressed, these histological results would have
become even better in conjunction with the
steady improvement in patient satisfaction in the
12-week follow-up after the final treatment ses-
sion, as noted above.
a
b
c
d
e
f
g
h
Fig. 18.22  Representative examples of combination near
IR/red light-only LED skin rejuvenation. (a) A 29-year-­
old female, skin type II, at baseline: note the mild rosacea
on her cheek. (b) The result at 6 weeks after the final treat-
ment session (10 weeks from baseline). Smoothing of the
periocular wrinkles can be seen, with overall better skin
tone. The rosacea has almost gone. Photographs courtesy
of Bruce Russell MD [40]. (c) Baseline findings in a
26-year-old Korean female, skin type IV. (d) Result
12  weeks after the final treatment session. Excellent
removal of the fine ‘crow’s feet’ wrinkles and overall
improvement and lightening of the skin tone. (e)
Histological findings at baseline, showing a typical elas-
totic dermis under a thinned epidermis with a highly dis-
organized stratum corneum. (f) Histology at only 2 weeks
after the final treatment session. Note the much better-­
organized dermal collagen, extending down into the
deeper reticular dermis, and the highly visible Grenz layer
running under and attached to the basement membrane at
the dermoepidermal junction. The epidermis is much
thicker with good cellularity and a very well-delineated
stratum corneum. (Hematoxylin and eosin, original mag-
nification ×100). The same improvement could be seen in
the elastin content comparing baseline (g) with the find-
ings 2 weeks after the final treatment (h) (Verhoeff van
Giesen, original magnification ×200). Photographs and
photomicrographs courtesy of SY Celine Lee MD [42].
System used: Omnilux®, Radiancy, Israel
R. G. Calderhead

317
The important point to be taken from these
findings is the that epidermis also showed
improved morphology and not just the dermis,
thus avoiding the SOE (same old epidermis) syn-
drome which was the major problem with photo-
thermal nonablative skin rejuvenation. As with
LED phototherapy for acne, adjunctive comple-
mentary treatment and maintenance techniques
with high quality creams and sera will certainly
improve the good results consistently shown for
light-only LED skin rejuvenation in these stud-
ies. The role of protective daily maintenance with
a UVA/B sunblock of at least SPF 50 should also
be considered.
More discussion on the 830 nm/633 nm LED
combination has appeared in Viewpoint 3
(Trelles, Mordon and Calderhead) and Comment
3 (Goldberg) in an article on redressing
UV-mediated skin damage in Volume 17 of
Experimental Dermatology [50]. However,
although Lee concluded that the combination of
the 830 and 633 nm was optimum, if we read
between the lines of the study it is clear that
830  nm on its own was extremely interesting
(Fig.  18.21), which was backed up by a 2011
article by Kim and Calderhead on the efficacy of
LED-LLLT [51], and by a 2013 wound-healing
study by Min and Goo [52]. Although LED pho-
totherapy has a well-proven role in stand-alone
indications, especially for wound healing
whether traumatic, delayed or iatrogenic, the
adjunctive role of LED phototherapy is perhaps
even more exciting and is the way of the future.
Adjunctive LED low level light therapy (LED-
LLLT) for the aesthetic dermatologist and plas-
tic surgeon, especially at 830 nm, has been well
argued recently in articles appearing in 2015
and 2016, respectively, in Laser Therapy [53]
and Clinics in Plastic Surgery [54].
The wavelengths and systems that have been
reported in the six studies cited above are 595 nm
(Gentlewaves®, Light Bioscience, VA, USA) [39],
the 830  nm/633  nm combination (Omnilux®
plus™ and revive™, respectively: formerly Photo
Therapeutics, Fazeley, UK & Carlsbad, CA, USA,
currently Radiancy, Ltd, Israel) [40–43] and the
new generation 830  nm HEALITE II (Lutronic
Corporation, Goyang South Korea) [51–54].
Wound Healing
Wound healing underpins all applications of LED
phototherapy involving photoactivation therapy
(PaT), and plays a major role in obtaining good
cosmetic results in combination LED PDT/PaT
for the treatment of acne, and in LED skin rejuve-
nation, in addition to the treatment of traumatic
or post-surgical wounds themselves. A brief
overview of the wound healing process is there-
fore warranted. Three distinct phases make up the
wound healing process, namely inflammation,
proliferation and remodeling, and although they
are distinguished by their timing and cellular
components, there is always some degree of
overlap between them.
The Three Stages of Wound Healing
Inflammation is often regarded as a major prob-
lem, but in the wound healing process it is abso-
lutely essential that inflammation occurs before
proceeding
into
the
proliferative
phase.
Inflammation only becomes a problem when it is
out of control, such as the end product of the
vicious circle instigated by P. acnes and rogue
t-cells in acne vulgaris.
In the inflammatory phase, from wounding
until about day 3–5, mast cells (already present
or recruited through chemotaxis), macrophages
(already present, recruited or differentiated from
monocytes
or
pericytes)
and
neutrophils
(recruited or differentiated from hematopoietic
stem cells) peak in the wound and surrounding
tissue. The macrophages ensure that all debris
and detritus from the wound are removed through
engulfment and internalization, and the leuko-
cytes are the first line of defence of the autoim-
mune system against invading pathogens. When
they are at work, the macrophages release an
important trophic factor, fibroblast growth factor
(FGF), and leukocytes are associated with TGFα
and
β
(transformational
growth
factor).
Connective tissue mast cells are granule-filled
cells differentiated from CD34-expressing bone
marrow precursors which circulate in the ECM
till they mature in situ, found normally around
capillaries and arterioles. In fact, the mast cell
was first described and named by the German
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

318
physiologist Paul Ehrilch in the latter part of the
1800s. Mistakenly believing that the purpose of
the granules was to nourish the ECM, he called
the cells ‘mastzellen’, (German for ‘feeding
cells’), giving us our Anglicized version. Their
part in the wound healing process is to release
their granules into the ECM. Although the gran-
ules released first are proinflammatory, the later
granules contain antiinflammatory chemokines
and cytokines, chemotactic factors to recruit
more wound-healing cells to the area, and a mix
of trophic factors. In the final degranulation, the
most powerful antioxidant endogenous to our
bodies, superoxide dismutase (SOD), is depos-
ited into the ECM to help protect against future
UV exposure-related oxidative stress. The com-
bined efforts of all the inflammatory stage cells
with their different but interlocking functions
thus leave the ECM in an ideal and favorable con-
dition for the proliferative stage cells.
In the proliferative stage, from around day 4 to
day 21, the inflammatory stage cells decrease in
number and fibroblasts and endotheliocytes peak.
Fibroblasts, (already in the area or differentiated
from pericytes), are an extremely important mul-
tifunctional cell. They are not only responsible for
synthesizing collagen to replace damaged ECM
collagen fibers, but they also produce new elastin
to form elastic fibers and additionally manufac-
ture the ground substance, the glycoproteinous
viscous gel-like liquid which lubricates and
hydrates the ECM, and which also facilitates
intercellular signaling and oxygen transport to
ECM components from arteries. It is also the
fibroblasts’ task to maintain ECM morphological
integrity through constantly monitoring the state
of the collagen and elastic fibers, lying along
which they can often be seen. In this respect, the
quality of both proliferative wound repair and the
final wound appearance rests firmly on the back
of the fibroblast. Endotheliocytes (already present
in the wound or differentiated from endothelial
progenitor cells), clump together to start the neo-
vasculogenesis process, culminating in the repair
of damaged blood vessels and production of new
blood vessels to oxygenate the newly-­forming
ECM and provide essential nutrients. From a peak
at around day 12–18, the increased number of
fibroblasts and endotheliocytes gradually returns
by day 20–22 to the pre-wound baseline, leaving
the ECM in a regenerated state with newly formed
but somewhat haphazardly arranged clumps of
collagen and elastin fibers, a fresh supply of gly-
cosaminoglycans and well-vascularized.
In the final and much longer stage of the
wound healing process, remodeling, which starts
around day 19–23, these new fibers and struc-
tures gradually mature and are slowly reorga-
nized into better alignment to give a strong,
flexible and plump ECM under an epidermis
firmed and tightened by the Grenz layer of colla-
gen fibers running under and attached to the der-
moepidermal junction basement membrane.
After the proliferative phase there are too many
fibroblasts in the ECM. One method by which the
body reduces the number is through transforma-
tion of some of the fibroblasts to a cell of great
importance, namely the myofibroblast, which is
simply a fibroblast that has grown smooth mus-
cles (myo, Greek for muscle) at each end of its
longitudinal axes. These tufts of muscles are fit-
ted with small barbs which hook onto the newly-­
formed collagen fibres and exert force on them to
bring the fibers into good linear alignment. Once
their task is completed, myofibroblasts go into
apoptosis, programmed cell death. If there are
still too many fibroblasts, some more will be
induced to dedifferentiate into quiescent fibro-
cytes, a kind of unipotent stem cell, which join
the stem cell pool in the dermis to replace fibro-
blasts as they age. The remodeling process can
take up to 6 months, or even longer, to complete,
and this is important when thinking of patient
education regarding when they can anticipate the
final optimal appearance of their treated tissue,
taking the findings of Fig. 18.22 above into con-
sideration. Figure 18.23 illustrates in schematic
form the time course of the wound healing pro-
cess, showing the peaks and lows of the cells
associated with each of the three phases.
The Influence of Different Wavelengths
of Light on the Wound Healing Cells
When we consider LED phototherapy, it is very
tempting to go ahead and invent ‘new’ wave-
lengths for ‘new’ photoprocesses. It must never
R. G. Calderhead

319
be forgotten that the original LLLT, low level
laser therapy, has a rich and well-documented
history which extends back over almost the last
four decades, so by examining this wealth of pub-
lished literature it should be possible not to have
to reinvent the wheel all over again. Sadly,
because the US Food and Drug Administration
did not grant 510(k) approval to a laser therapy
system in the process erroneously called ‘bios-
timulation’ until 2002, there is not a lot to be
found in the US literature until more recently.
However, those early US papers which are there,
have been quietly forgotten, probably on the prin-
ciple that if one doesn’t understand it, one simply
ignores it.
A great deal of literature exists on red light-­cell
reactions, because the mainstay light source of the
early pre-LED investigators was the HeNe laser,
delivering 632.8  nm, basically the same as the
633 nm of current array-based LED systems, also
in continuous wave (C/W) rather than frequency
modulated as discussed already. As mentioned in
the Introduction, the effect of red light specifically
on subcellular organelles was first published by
Fubini and colleagues in the late eighteenth cen-
tury! [3]. The last three decades, however, have
added tremendously to the knowledge regarding
red light and skin cells. It was reported that
632.8 nm red light from the HeNe laser induced
fibroblast monosheet formation in vitro faster and
with much better alignment, almost double the
speed
of
the
unirradiated
controls
[55].
Furthermore, in the same study, a ‘wound’ created
in the monosheet was repaired much faster in the
HeNe-irradiated groups. More recent in vivo work
with 633 nm LED energy in human subjects dem-
onstrated dramatic fibroplasic changes in speci-
mens from irradiated subjects compared with
unirradiated controls [56]. Tiina Karu, probably
the most well-known living photobiologist, has
produced an enormous amount of work in her
lifetime on the effects of low incident levels of
light on cells and their organelles. She confirmed
the much earlier work by Fubini and further iden-
Inflammation
Proliferation
Remodelling
Mast
cell
Relative total number of cells
0
3
Approximate time (days)
20
100
Macrophage
Fibroblast
Myofibroblast
Endotheliocyte
Leukocyte
Monocyte
Fibrocyte
Fig. 18.23  Schematic illustration of the cell cycles and
numbers during the three phases of wound healing.
During inflammation, which occurs from day zero to day
3–5, the inflammatory cells (leukocytes, mast cells and
macrophages) increase in number, peak and then return to
baseline levels. During proliferation, the collagen-­
producing cells, fibroblasts, and neovascularization cells,
endotheliocytes, increase in number, and then as remodel-
ing starts, gradually decrease. In the case of fibroblasts,
some remain as active fibroblasts, but some transform into
myofibroblasts, literally fibroblasts with muscles, whose
task is to ensure good linear alignment of the new colla-
gen fibres. It should be noted that the phases overlap, with
no clear border between each
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

320
tified the specific target for 633 nm light as the
cytochrome-c oxidase resident at the end of the
mitochondrial respiratory chain [57]. She also
showed that coherent light was not essential to
achieve effects in vivo, provided the photon inten-
sity at the target was high enough.
Mast cells have been stimulated in vitro and in
vivo to degranulate when irradiated with 633 nm
light, and much faster than when unirradiated:
stimulation with 830 nm speeds up degranulation
even more [58, 59]. The author and colleagues
have shown that, 48 h after a single irradiation
with 830 nm LED energy, mast cells in the fore-
arms of healthy human subjects had 40–60%
degranulated compared with specimens from
unirradiated controls, where no degranulation
was seen at all [60]. In the same study, indepen-
dently performed cell counts per field averaged
over many samples showed a significant increase
in the mast cells, macrophages and even neutro-
phils recruited into the irradiated area, compared
with baseline and the unirradiated control arm
(Table 18.6). Near IR energy at 830 nm has been
demonstrated to induce macrophages to perform
their chemotactic, phagocytic and internalizing
functions better and faster, while releasing almost
30-fold the amount of fibroblast growth factor
(FGF) compared with unirradiated controls [61],
and the same is true for the attack and phagocytic
functions of neutrophils [62, 63].
The epidermal basal layer keratinocyte is too
often forgotten in LED phototherapy, but research
has shown that 590, 633 and 830 nm noncoherent
light both in vitro and in vivo can activate the
keratinocytes to release a large amount of cyto-
kines which drop down into the dermis to assist
with the dermal wound healing processes, so
much so that keratinocytes have been nicknamed
‘cytocytes’ [64]. Additionally, the photoactivated
keratinocytes can improve the cellularity and
organization of the epidermal strata through rais-
ing the levels of extracellular ATP and the signal-
ing elements Ca2+ and H+, and obtaining a better
organized stratum corneum [64].
If the wound healing cells, including epidermal
keratinocytes, are examined for increased wave-
length-specific action potential based on the last
30 years of both LLLT and non-laser light source
literature, the wavelengths which have the most
verified and published results at a ­cellular and sub-
cellular level are 633 and 830  nm in the near
IR. Near IR at 830 has excellent results in activat-
ing the activity levels of the inflammatory stage
cells, mast cells, macrophages and neutrophils,
fibroblasts and in addition to epidermal keratino-
cytes. On the other hand, red light at 633 nm com-
pared with 595  nm yellow is excellent for
photoactivating fibroblasts in vivo, due to its supe-
rior penetrating powers, in addition to epidermal
keratinocytes. With athermal and atraumatic LED-
LLLT at these wavelengths, especially 830  nm,
there is no physical wound, but exactly the same
clinical response is achieved as seen after any
examples of the nonablative or even ablative
approach involving frank photothermal damage.
Why is the 830 nm effective for skin rejuve-
nation as monotherapy, as seen in the Lee et al.
study [49]? Though this indication is not wound
Table 18.6  Numbers of mast cells, macrophages and neutrophils averaged per field (TEM, ×50,000) showing the aver-
aged value of at least eight fields per subject. (Based on data from Ref. [58])
Patient No.
Mast cells
Macrophages
Leukocytes
Pre
Post
Control
Pre
Post
Control
Pre
Post
Control
1
1.5
5.5
1.25
0
6.0
0
0
3.35
0
2
1.5
6.75
1.5
0
8.25
0.25
0
4.0
0
3
1.0
7.0
1.25
0.5
6.75
0.25
0
4.5
0
4
0.5
4.75
0.5
0.25
5.0
0.25
0
4.0
0
5
1.0
8.0
1.0
0.75
7.75
0.5
0
4.25
0
6
1.5
7.25
1.5
1.0
7.0
0.75
0
4.5
0
7
1.25
7.0
1.5
0.5
7.5
0.75
0
3.75
0
8
0.5
6.25
0.5
0.75
6.5
0.5
0
4.0
0
The bold text indicates the significant cell count increase in the specimens from the treated arm compared with baseline
and the control arm
R. G. Calderhead

321
healing per se, it depends on inducing the
wound healing process to clear wrinkles and
tighten up skin. The 830 nm energy degranu-
lates the mast cells, dumping a load of proin-
flammatory substances into normal tissue, such
as heparin, trypsin, histamine and bradykinin.
This gives the tissue the impression that it has
been ‘wounded’, even though there is actually
no wound because of the athermal and atrau-
matic action of LED phototherapy. Macrophages
are also photoactivated, helping to give a clean
ECM ‘seeded’ with FGF, with some TGF
released from neutrophils recruited into the
area by the degranulating mast cells. Because
the inflammatory stage has been established
especially by this mast cell-mediated ‘quasi-
wounding’, the tissue has no option but to pro-
ceed into the next stages of the wound repair
process, starting with proliferation. When this
830 nm irradiation is repeated over eight times
over 4 weeks, separated each week by 2–3 days,
the dermal cells (and epidermal keratinocytes)
are upregulated in a step-wise manner and
maintained in the inflammatory/proliferative
stages. After the final treatment session the
remodeling is allowed to start, and this explains
why the best results are not seen at this immedi-
ately post-­treatment stage, but later on at 4, 8
and 12 weeks or more after the final treatment
(see Fig. 18.21) [49], as was also the case in the
acne studies already mentioned [36, 37].
The same principle for LED-LLLT with
830 nm applies to frank wound healing, whether
it is accidental or iatrogenic trauma. Burns, for
example, are an ideal injury for LED photother-
apy, because of the noncontact and hands-free
application, and the large area of the treatment
heads. In a recent study, the 830  nm/633  nm
combination produced excellent results in large
area burns, as illustrated in Fig. 18.24 [65]. As
mentioned already above, ablative laser resur-
facing lost popularity due to the potential of seri-
ous side effects, especially edema and prolonged
erythema, leading to prolonged patient down-
time. The wound left following laser ablative
resurfacing is simply a full facial burn. In a
recent publication Trelles and co-workers used
830 nm LED therapy following laser ablation of
the face with a combined Er:YAG/CO2 laser sys-
tem [66]. There were two groups of patients,
30  in each group. The experimental group
received the LED therapy following laser abla-
tive treatment, and the control group received
sham treatment from the standby setting of the
system. The average healing times (full reepithe-
lization and resolution of erythema) for the con-
trol and experimental groups were 13 weeks and
6 weeks respectively. The extent of post-procedure
a
b
Fig. 18.24  A 39-year-old male patient with severe full
facial electric spark burn injury before (a) and (b) three
months after the final treatment with combination
830 nm/633 nm LED phototherapy. One full 4 week ses-
sion was performed with the wavelengths being sequen-
tially applied as usual, a resting period of 4 weeks, and
then another 4-week regimen. Photographs courtesy of
Prof Jin-wang Kim MD PhD, Burns Center, Haelym
University School of Medicine, Seoul, Korea. System
used: Omnilux®, Radiancy, Israel
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

322
pain, bruising and erythema was significantly
less for the LED-­treated group (Fig.  18.25),
whereas improvement in the skin condition was
much more clearly seen in the LED-treated
group, with a satisfaction index (SI) of 89%
compared with 51% for the control group. The
SI was calculated by adding only the number of
‘excellent’ and ‘very good’ scores from a stan-
dardized 5-element scoring system, and express-
ing the result as a percentage of the total
population. Healing following upper blepharo-
plasty and periocular laser resurfacing in a hemi-
facial study was reported to be cut by one-­half to
one-third following LED therapy at 633 nm, and
the improvement was subjectively rated as two-
to fourfold better compared with the unirradiated
side [67]. LED-LLLT following Er:YAG laser
ablation of deep and extensive plantar warts
roughly halved the healing time, cut the postop-
erative pain by at least one-tenth and gave less
than 6% recurrence rate in 121 cases [68]. The
study by Min and Goo already mentioned above
using 830  nm LED-LLLT showed excellent
healing of a variety of difficult wounds, some
of which were compromised with bacterial or
viral infection (Fig.  18.26) [52]. As for more
difficult targets, LED-LLLT has shown excel-
lent and lasting results in treating psoriasis [69],
and acute herpes zoster ophthalmicus [70].
Additionally, 830 nm LED treatment has cleared
irritant contact dermatitis and dissecting follicu-
litis of the scalp [51].
Long-term nonhealing ulcers which healed
following low incident levels of red light (HeNe
laser, 633 nm) comprised the first topic to appear
in the literature from the Godfather of photother-
apy, the late Prof. Endre Mester of Semmelweis
University, Budapest, Hungary, with a patient
population of over 1000, and started all the con-
troversy surrounding LLLT in the early 1970s
[71]. Very interestingly, Mester reported that
ulcers on the limb contralateral to the one treated
also eventually healed, although more slowly
than the irradiated wounds. This was the first
report on the systemic theory in phototherapy,
whereby photoproducts created in the irradiated
tissue were carried systemically through the body
to have an effect wherever they were required. A
2012 study has shown the systemic effect in
mouse and rat models, whereby standardized
dorsal wounds were created with a fractional CO2
laser. Only the abdomens of the animals were
irradiated with 830  nm LED-LLLT, and at the
6-day assessment point the indirectly LED-­LLLT
treated wounds were significantly better healed
than the unirradiated controls [72]. A study with
Fig. 18.25  Results of a controlled study on LED photo-
therapy after full face ablative Er:YAG/CO2 resurfacing,
30 patients per group. Healing was better than one half of
the time compared with the controls, and sequelae were
all significantly reduced in the group which received
830 nm LED phototherapy (based on data from Ref. [64])
System used: Omnilux®, Radiancy, Israel
R. G. Calderhead

323
830  nm on recalcitrant crural ulcers showed
accelerated healing [73]. Near IR 830 nm does
not only work in soft tissue wounds, but also in
bone where it accelerates the union of fractures,
even in the case of delayed union healing, replac-
ing the usual poorly-organized callus with better-
quality bone so that the remodeling stage is much
shorter [74, 75].
Some of the mechanisms behind the efficacy
of LED phototherapy-accelerated wound healing
have already been at least partly elucidated, such
as the wavelength-specific activation of the der-
mal and epidermal cells associated with the three
phases of wound healing. in a chapter of her lat-
est book (Ten Lectures on Basic Science of Laser
Phototherapy.
2007,
Prima
Books
AB,
Grängesberg, Sweden), Karu has suggested that
the latency effect of phototherapy in cells actu-
ally continues in subsequent generations of the
irradiated cells which is an important consider-
ation in skin rejuvenation [76]. Another impor-
tant mechanism involves improvement of blood
flow following irradiation with 830 nm, and this
has been shown to positively impact on flap sur-
vival in the rat model [77]. Improved blood flow
not only brings in oxygen and nutrients, but
establishes a higher oxygen tension in the treated
area which can establish gradients between the
wound at the surrounding tissue, used as ‘super-­
highways’ by the reparative cells [78]. In the case
of bony tissues, 830  nm has been shown to
increase the metabolism of osteoblasts [79], and
to upregulate some of the genetic pathways lead-
ing to better differentiation of new, active osteo-
blasts from mesenchymal cells [80].
In conclusion, the application of LED-LLLT,
either 830 nm followed by 633 nm, or particu-
larly more recently, 830 nm on its own, has been
shown to enhance all aspects of wound healing,
always provided the incident irradiance (power
density, photon intensity) is sufficiently high and
an appropriate dose is given. In addition to the
excellent and growing reputation of LED photo-
therapy as a stand-alone light-only therapy, this
means that LED-LLLT has proved to be an ideal
adjunctive therapy to any of the conventional
approaches seen in dermatological practice and
this is perhaps the most exciting aspect of LED
phototherapy in the future [53, 54]. No matter
how the aesthetic and cosmetic dermatologist
a
b
e
f
c
d
g
h
Fig. 18.26  830 nm LED-LLLT in the control of inflam-
mation and infection. (a) Fifty-two y.o. male with post-­
filler ischemic ulcerative tissue necrosis, inflammation
and severe pain. (b) Two weeks post escharotomy without
flap and LED-LLLT sessions every other day. Pain was
controlled post 3 Tx. (c) Findings at 3 weeks post base-
line. Wound closure continues with good granulation tis-
sue formation. (d) Final condition 6 weeks post-baseline
and 1 week after the final Tx. Further improvement can be
expected. (e) Fifty-four-year-old female with swollen lips,
fever, severe pain, herpes simplex (HS) and bacterial
infection following an illegal lip tattoo, unsuccessfully
treated elsewhere. Numbness and slight palsy also
reported. (f) Improved condition after 1 week of five daily
830  nm LED-LLLT sessions. HS lesions are resolving
with significant reduction in swelling and removal of
palsy with return of sensation. Pain has been totally con-
trolled. (g) Almost complete improvement, including HS
infection, at 2 weeks post-baseline, treating every other
day. (h) Final excellent result 3 weeks post-baseline with
no HS recurrence in a 3-month follow-up. Clinical pho-
tography courtesy PK Min MD. System used: HEALITE
II 830 nm, Lutronic, South Korea
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

324
alters the epidermal or dermal morphology of his
or her patient, be it through microdermabrasion,
ablative and nonablative skin rejuvenation, frac-
tional technology or conventional surgery, the
addition of an appropriate LED phototherapy
regimen will help to improve already good results
but at a very reasonable cost, thus improving the
satisfaction rates of both the clinician and the
patient. Many clinics in Australia now buy an
830 nm LED system and add 830 nm LED-LLLT
as an adjunct to anything done to their patients,
but at no cost to the patient. This value-added
treatment has resulted in excellent results, happy
patients and an ever-increasing number of patient
referrals, hence happy clinicians as well.
Other Clinical Indications
The indications already discussed have been
well-researched, and are being reported in the
literature. Some other applications exist which
are very much at the experimental stage, but
which should be mentioned to prepare the reader
for what’s coming in the not-too-distant future
and for which LED phototherapy is proving very
interesting. At this stage the author cannot go
into details, because of the early stage of the
clinical and related basic science experiments,
but the reader should watch for articles on the
potential use of LED phototherapy in combina-
tion with platelet-rich plasma (PRP) for wound
healing and for skin rejuvenation. PRP is well-­
established as a valid method in wound healing
to speed up the process and give good cosmesis
or in recalcitrant healing situations. Knowing
how cell-­specific certain LED wavelengths are,
the obvious step is to combine the two approaches
to achieve even better results, even faster. Some
studies are currently well underway in Tokyo,
and the results in a split-face study with 830 nm
vs. unirradiated indicate that this will be a field
to watch closely (Junichiro Kubota MD PhD,
personal communication and as yet unpublished
data). Another emerging field is the transcranial
indication of LED-LLLT, usually at 830 nm or a
similar near-­IR wavelength, for post-stroke
patients, and those who have suffered severe
cerebral trauma [81–83]. With these reports,
taken together with the already well-proven
effect of 830 nm on improving blood flow and its
ability to pass through the skull and measure
blood flow and cerebral ­activity in vivo in a non-
invasive manner [84, 85], the indication of LED-
LLLT transcranially for the treatment of simple
senile dementia, but not Alzheimer’s, merits
some deep thought. The more we can find for
LED-LLLT to do, the more ideas will appear.
Safety with LEDs
Surgical lasers and even intense pulsed light sys-
tems are by their very nature designed to create
thermal damage and are thus subject to stringent
safety codes to prevent accidental irradiation of
tissue, other than the planned target tissues.
Because LEDs are incapable of creating photo-
thermal damage in tissues, the same stringent
codes regarding accidental irradiation of tissue
do not apply. However, as all of the LED systems
discussed above operate in the visible and near
infrared waveband, there is a potential for opti-
cal damage, as the eye is capable of gathering
this waveband and focusing the light onto the
retina at the back of the eye, particularly the
macula and fovea, the area responsible for visual
acuity. This will be looked at in a little more
detail below.
Box 18.5
• LED-LLLT is intrinsically safe
• Eye protection sometimes required
against potential optical hazards
• LED-LLLT is essentially side effect
free
• Few contraindications exist, but sen-
sible precautions should be taken
–– Patient history must be checked for
any photosensitivity-related diseases
or conditions.
–– Drugs, ointments and even cosmetics
being used by the patient must be
checked for photosensitizing elements.
R. G. Calderhead

325
Most LED phototherapy systems are run from
conventional mains electricity, and so present
potential hazards in common with any other such
mains-driven equipment as, for example, DVD
players and television sets. Common sense dic-
tates the safe handling of this group of equip-
ment, leading to the following guidelines:
DO NOT connect or disconnect the mains plug
with wet or damp hands
DO NOT pull the plug from the mains socket
using the power cable
DO NOT place any containers with liquid in
them on top of the unit (e.g., coffee mugs) to
prevent damage from accidental spillage. If
such spillage should occur immediately turn
off the system and have it serviced before
using it again.
DO NOT attempt to perform and unauthorized
servicing of the system which involves open-
ing up the case and/or defeating any
interlocks.
DO connect the mains cable to the system before
plugging the mains plug into the socket
DO check that the power to the wall socket is off
before inserting the mains cable plug
DO switch off the wall socket before removing
the mains plug
Apart from these rather obvious points, common
sense should prevent any electrical-related dam-
age to therapist or patient.
Optical Hazards with LED
Phototherapy
As already mentioned above, any LED system
operating in the visible to near-infrared wave-
band emits light which the human eye can gather,
and focus onto the back of the retina as illustrated
in Fig.  18.27. If the incident power density is
great enough, permanent damage to the fovea
could occur leading to uncorrectable loss of
visual acuity. For example, an incident power
density from a laser source of as low as 75 mW
focused to a 50 μm spot produces a power density
of over 3800 W/cm2, perfectly capable of severely
damaging target biological tissue. However, a set
of values has been established for the maximum
permissible exposure, or MPE, to light at a range
of wavelengths, and these values are significantly
lower for LEDs compared with laser sources,
because lasers emit coherent light, and LEDs
emit a divergent beam of noncoherent light. If an
LED phototherapy system has been indepen-
dently tested to deliver light below the MPE for
its nominal wavelength, then even prolonged
direct viewing of the beam is theoretically safe.
In clinical practice, however, visible light LED
arrays are extremely bright, even when below the
MPE for their wavelength, so some form of eye
protection is usually a good idea if only for patient
comfort. Small, opaque eye cups held in place
with an elasticated cord are popular, which will
still allow the light to reach the periocular region
75 mW, pupillary opening 1 cm
Power Density at cornea:
approx. 590 mW/cm2
λ = 670 nm ∼ 904 nm
Focused spot at fovea = 50 mm dia.
Power density at fovea ≈ 3,820 W/cm2
Fig. 18.27  Schematic illustration of how a low incident
power of 75 mW from a laser beam is capable of being
focused by the unaccommodated eye into a very small
spot, with damaging power densities, right in the center of
the fovea. Although noncoherent and uncollimated LEDs
are significantly more intrinsically safe, the importance of
appropriate protective eyewear should always be consid-
ered. Common sense should be applied
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

326
in the case of LED phototherapy for skin rejuve-
nation. However, if the system delivers light
which is over the MPE, then protective eyewear
becomes mandatory for the patient, and also for
any ancillary staff spending any length of time in
the treatment room to help protect their eyes
against diffuse reflection from the target tissue.
For shorter visible wavelengths such as the blue
waveband, the inherent photon energy of the light
is approximately one-third as high again as visible
red light even though the incident power density
is the same, as discussed above, and so has greater
potential for optical damage. Appropriate eye-
wear is necessary in this case.
The ‘blink reflex’ is nature’s way of helping us
protect our own eyes against an over-bright visi-
ble light source, but near-IR light cannot be
‘seen’ by the human eye and so the blink reflex is
not triggered by energy in this invisible wave-
band. Near-IR is still gathered and focused by the
unaccommodated eye just as visible light is, how-
ever, so suitable protective eyewear is thus man-
datory for LED systems delivering energy in the
near-IR waveband above the rated MPE for the
wavelength being used.
Clinician goggles or glasses are obviously not
opaque, so they have to be specifically sourced
with an appropriate optical density for the wave-
length of the system. Eyewear designed for red
light will not protect adequately against IR or vis-
ible blue light, for example. The eyes of the
patient, and indeed anyone with the patient in the
treatment room during LED therapy, must be
assiduously protected even though LEDs are
often discounted as inherently ‘safe’, compared
with a surgical laser or IPL. It is better to err on
the side of caution!
Finally, national and federal regulatory agen-
cies, such as the US Food and Drug Administration
(FDA), issue approvals of systems for specific
applications for which they have been proved
‘safe and effective’. Although some manufactur-
ers have received such approvals, they are few
and far between. Some less than truthful manu-
factures will claim FDA approval, when in fact
all they hold is a letter from FDA recognizing
that their LED system is a nonsignificant risk
device, or NSRD. This is NOT the same as a sys-
tem’s having gone through the due regulatory
process to obtain what is known as a 510(k)
approval showing significant equivalence to
another system with prior approval based on
which, and only on which, can that device be
legally sold in the USA for clinical use. 510(k)
approvals for existing LED systems can be
searched for on the FDA website (
cdrh/510khome.html), and the systems already
mentioned by name earlier in this chapter all hold
such clearance.
Side Effects
Once again, the inherently ‘safe’ output of LED
systems helps to keep unwanted side effects to a
minimum, but with any kind of phototherapy
there is always the outside chance of triggering
such a side effect. These are almost 100%
photosensitivity-­related, so a careful history of
the patient must always be taken to identify the
existence of pre-existing photosensitivity issues.
For example, if a patient reports that he or she
regularly comes out in an itchy rash when
exposed to terrestrial sunlight, LED photother-
apy, especially in the visible light waveband,
should not be given. Some skin types, such as the
Asian skin, are incredibly sensitive to epidermal
inflammation caused by other wavelengths
despite being very resilient to UV skin damage.
Particularly in the Asian skin, secondary hyper-
pigmentation (PIH) can occur without any appar-
ent physical insult, and a carefully-taken history
will show if the patient is predisposed to this very
upsetting side effect. A very small proportion of
patients treated with LED therapy have reported
post-treatment headaches of varying magnitudes,
all of which have resolved spontaneously. No
reason has been elucidated for this, and treatment
with mild analgesics has been found to speed up
the resolution of the headache. Almost all of
those so afflicted have been undergoing LED
phototherapy for facial skin rejuvenation, but
interestingly only a very few have actually
stopped turning up for their treatments. The main
point is to take a very careful and thorough
patient history to identify the potential of any
R. G. Calderhead

327
LED therapy-related problems, but they are very
much extremely few and far between. For longer
sessions of LED phototherapy, for example in
facial skin rejuvenation, the main “side effect” is
that the patients tend to fall asleep during the
treatment and ‘wake up’ feeling great!
Contraindications
Leading on from the previous subsection, any
kind of endogenous or exogenous photosensitiv-
ity is a contraindication to LED phototherapy.
Patients with any form of porphyria, for example,
should never be treated with LEDs. Those whose
history includes solar-mediated eruptions are
likewise not good subjects. The careful derma-
tologist should also ascertain what the patients
are putting on their skins prior to an LED therapy
session. Ointments or creams containing known
photosensitizers such as coumarins or porphyrins
must be discontinued at least 2 weeks before any
LED treatment. Some oral drugs, e.g., amioda-
rone for cardiac arrhythmia sufferers, strongly
photosensitize patients to UV and visible light:
LED phototherapy in such patients is contraindi-
cated. Even some perfumes contain recognized
photosensitizers. The application or ingestion of
photosensitizing drugs including systemic reti-
noids and the recent use of topical retinoic acid
should also be carefully considered, and some
acne treatments such as Roaccutane® (isotreti-
noin) are all contraindications.
Other potential, possibly more ‘emotional’
contraindications include patients who are preg-
nant or lactating, although these are not as abso-
lute as the in the previous paragraph and if the
LED therapy is not being delivered over the
womb as in the case of facial skin rejuvenation
for example, then it can be given at the discretion
of the treating clinician, and with the informed
consent of the patient. In fact, possible benefits
may well accrue to both the mother and fetus
from the systemic nature of blood-borne benefi-
cial photoproducts.
The most emotional contraindication is for
patients with some form of cancer. It is true that
cancer cells irradiated with visible/near-IR
energy in a favorable in vitro environment will
replicate at a much faster rate than control cells.
However the in vitro environment is totally dif-
ferent to the living body, where the cancer cell
is seen as an out-and-out enemy by the autoim-
mune system, and is in a very unfavorable envi-
ronment surrounded by potential killer cells. As
mentioned above, the very first application of
red LED PDT phototherapy was in the treat-
ment of skin cancers, and application of low
incident levels of light have been shown to
cause regression or even complete removal of
aggressive tumors in animal models [86], and
induce significantly prolonged survival times in
terminally-ill cancer patients [87]. Furthermore,
low incident levels of light energy have been
shown to boost the autoimmune system. Once
again, however, discretion should be used in the
case of a patient with a cancerous condition
who is seeking LED phototherapy for some-
thing else at a site distant from the cancer, such
as skin rejuvenation. As a final note, in the more
than four decades since the laser and other light
sources have been used in medicine and sur-
gery, not one case of iatrogenic, phototherapy-­
linked cancer has been reported in the
literature.
In short, LED phototherapy systems from
reputable manufacturers are inherently safe,
provided they are used according to the manu-
facturer’s recommendations regarding eye pro-
tection, and approved treatment protocols.
LED-LLLT systems are basically side-effect
free, apart from the beneficial side effects, and
will give continue to deliver side-effect free
therapy provided the list of contraindications
discussed above, and always provided by
responsible manufacturers, is carefully applied,
in addition to the taking of a careful patient his-
tory. However, as already said, not any old LED
system will do, and the careful dermatologist
must ensure that the system has appropriate
quasimonochromatic wavelengths, appropriate
photon intensities over a sufficiently large area,
has a proven track record in the published litera-
ture and has marketing approval from regulatory
bodies such as CE marking and US FDA
clearance.
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

328
LED Phototherapy: Quo Vadis?
There is no doubt that LED phototherapy has
come a very long way in less than two decades,
with the ‘NASA LED’ being introduced in 1998.
The big question now is, where can it go? I
believe the answer depends on three main areas:
wavelength; other technical developments; and
applications.
New Wavelengths
It is possible that a ‘new’ (and useful) wavelength
will be ‘discovered’, but unlikely. Having said
that, at the time of writing 1072 nm LED photo-
therapy has attracted a great deal of attention in
the treatment of herpes simplex labialis, or cold
sores as mentioned above. Apart from that, The
current main wavelengths are:
• Soret band short wavelength visible blue light,
with the optimum peak at 415 nm, the peak of
the action spectrum of the porphyrins endog-
enous to P. acnes and created in skin treated
with 5-ALA.
• Visible yellow at 590–595 nm, at a peak of the
action spectrum of cytochrome c oxidase in
the mitochondrial redox chain to instigate
ATP production, although in practical clinical
application this waveband is extremely lim-
ited by its poor penetration into the dermis due
to absorption in the biological pigments mela-
nin and hemoglobin, which are its preferential
chromophores. However, this waveband also
has potential in the treatment of inflammatory
rosacea and other very superficial entities. In
addition, the epidermal keratinocytes and
Merkel cells also present an interesting target
as a form of dermal preconditioning when vis-
ible yellow treatment is followed by 830 nm.

One FDA-cleared LED system (HEALITE
II™, Lutronic, Goyang, South Korea and
Freemont, CA, USA) uses the combination of
a period of irradiation with 595 nm-only ultra-­
low-­level light therapy followed by the appro-
priate dose of 830 nm near-IR energy as the
main treatment beam. The advantage of this
lies in the fact that the yellow component con-
tinues to operate while the 830 nm beam is
active. Although there is no longer a clinical
utility, the visible yellow light shows that the
system is operating, a real benefit for the
patient as they can see that something is hap-
pening, not the case where the invisible near-
­IR at 830 nm is used on its own.
• Visible red light from 620 to 680 nm, with a
‘best case’ at 633  nm because of the minor
absorption peak in the action spectrum of the
porphyrins associated with exogenous 5-ALA
PDT, the major peak in the absorption spec-
trum of cytochrome c oxidase, and its deep
penetration into living skin. 633  nm is an
excellent wavelength to activate fibroblasts in
vivo even in the deeper dermis. It is also
attracting attention in hair loss and hair resto-
ration. This wavelength also has a tremendous
published database, because it is the same as
the HeNe laser (632.8 nm).
• Near infrared at 830  nm, because it has the
deepest penetration of any wavelength due to
its being at the bottom of the water absorption
curve, and has a well-proven track record as
the most useful laser therapy wavelength in
near infrared diode laser therapy for musculo-
skeletal and neurogenic pain, enhancement of
local blood and lymphatic flow, and wound
Box 18.6
• ‘New’ LED wavelengths not likely,
but possible
• Further technical advances may
increase the scope of LED-LLLT
• Potential for LED-LLLT in the home
and OTC market
• LED-LLLT is safe, effective, easily
applied, side effect-free and well-­
tolerated by all patients.
• Effective as a stand-alone light ther-
apy, LED-LLLT will also prove even
more invaluable in adjunctive ther-
apy to complement all existing modal-
ities in dermatological practice.
R. G. Calderhead

329
healing. This wavelength as delivered by
LEDs now has a good body of literature show-
ing preferential effects in degranulation of
mast cells, photoactivation of neutrophils and
macrophage cells with associated release of
trophic factors, and enhanced remodeling in
the wound healing process.
There are now many LED devices currently
available that have wavelengths the same or very
near to those given above, but we have to remem-
ber that in many cases an action spectrum peak
has very narrow shoulders, so a difference of
even 5 nm from the peak can in some cases dra-
matically lower the action potential. There are
other wavelengths which have been proved use-
ful in the laser therapy literature, in particular
780 nm for neurological applications and 904 nm
for dental and other hard tissues, including bone.
In the case of neurological indications, such as
repairing transected or crushed nerves, the punc-
tal nature of laser energy with its extremely high
photon intensity delivered within the very small
treatment area is essential to the treatment tech-
nique: it is impossible to concentrate LED energy
from an array onto such a small spot, so LED sys-
tems at this wavelength would simply not have
the same effect as a laser diode-based handpiece
(coherent LD-LLLT vs. noncoherent LED-­
LLLT). In the case of 904 nm in hard tissue, the
laser systems used were based on a GaAs (gal-
lium arsenide) laser diode. GaAs laser diodes are
capable of generating peak power outputs in the
range of 15–45 W, but cannot be operated in con-
tinuous wave because of the tremendous heat
they generate and the need to provide a dedicated
cooling system. The GaAs laser diode is there-
fore operated in a true pulsed mode, with pulse
widths in nanoseconds and interpulse intervals of
milliseconds, so the average power seen by the
tissue is in milliwatts, usually 3 orders of magni-
tude less than the peak power: a 15 W peak power
would this give an average power at the tissue of
15 mW. However, these ultrashort pulses create
effects in tissue other than photoabsorption, such
as photoosmotic and photoacoustic effects. In
hard tissues such as bone, it was therefore pro-
posed that a physical resonance was set up which
acted in coordination with the photoabsorption
effects to give excellent bone healing, even in the
case of slow union fractures [74]. No LED photo-
therapy system is capable of delivering a true
pulsed beam, and simply modulating a continu-
ous wave beam of tens or even hundreds of mil-
liwatts per square centimeter will not produce the
same effect as the very tightly delivered, narrow
pulse-width true pulsed diode laser beam, so this
wavelength is also not an appropriate one for an
LED system, given that one of the main advan-
tages of LED arrays is the ability to irradiate a
large area of tissue rather than a very small treat-
ment target. In all of the wavelengths bulleted
above, and in their clinical application, the tar-
gets are not precise points, and the ability to irra-
diate a large tissue mass is an advantage. Despite
the present and future claims, I do not believe
that we will see a ‘new’ and clinically proven
wavelength for light-only LED phototherapy in
the near future.
New Technical Developments
LED technology is constantly evolving, as seen in
the current transition from the individually board-
mounted dome-type LED to the latest generation
of ‘on-board’ chips which are actually part of the
circuit board. There has been speculation about
developing whole-body LED arrays, particularly
in the sports medicine and sports clinic environ-
ment, so that athletes could have a complete LED
‘photobath’ after a strenuous workout to help relax
overused muscles and dissipate lactic acidosis,
thereby enabling total retention of tonus in a delib-
erate overtraining program to reach absolute peak
power and stamina. The application of such whole-
body arrays in the spa and beauty market would
also be very interesting. Some systems already
exist. The problem with such large arrays of good
quality LEDs is heat. LEDs do not in themselves
generate a lot of heat because they are solid state,
but when mounted in arrays they require on-board
driver circuitry, and this does generate a fair
amount of heat which must be dissipated other-
wise overheating of the LEDs will result in move-
ment away from their rated wavelength, in addition
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

330
to shortening of their useful life. Efficient cooling
of the circuit boards is thus essential and this is not
an easy matter even with the current size of arrays,
to the extent that the method of cooling has actu-
ally been patented in some systems. In order to
cool the number of large arrays which would be
necessary for a whole-body LED generator would
require a dedicated and powerful cooling system,
and this raises the dual problem of developing an
appropriate method of extracting heat, whether it
was based on air- or water-based cooling, and
where the heat extracted from the LED arrays
would go. In a small treatment room, the heat
build-up could be very noticeable, as was the case
in the first generation of large surgical laser sys-
tems. The development of on-board chips has
gone some way to solving this problem, and the
emergence of electrostatic cooling systems which
could be built directly into or onto the LED boards
is very interesting. This is a field which will be
very interesting to watch.
Another area for development may well be in
the optics of the LEDs themselves. Currently
LEDs deliver a divergent beam, typically in the
region of 60°–120° steradian. It is the deliberate
overlapping of these divergent beams that causes
the phenomenon of photon interference, which,
coupled with scattering of light in target tissue,
allows LED arrays to deliver very useful photon
intensities over large areas of tissue. As men-
tioned already, corrective collimating optics have
already been used in one system to reduce the
angle of divergence of LEDS in an array, thereby
giving a higher photon intensity for the same irra-
diance at the LED. However, LEDs are nonco-
herent, so it is extremely challenging to collimate
the beam of light from an LED completely, unlike
the case of the laser diode in the ubiquitous laser
pointer. Likewise, focusing an LED to a very
small point, as can be achieved with a laser
source, is impossible, and the most efficient
focusing lens would produce simply a very small
inverted image of the LED.  Semi-collimation
would appear to be the limit for altering the beam
of energy from an LED, unless there are advances
in chip technology.
The final area is the home market, which is tied
into the previous subsections as far as appropri-
ately selected LEDs are concerned. There are
already a large number of very pretty colored,
happily twinkling LED-based systems being
touted as suitable for home use, however the vast
majority of them are mere toys, especially the
ones with multicolored LEDs, and the poor user
might as well stand in front of their christmas
tree lights as use these systems. This does not
mean that responsible manufacturers have not
been researching correct combinations of appro-
priate
wavelengths
and
intensities
in
ergonomically-­designed
hand-held
self-con-
tained units which will be safe and effective for
home use: some indeed have. These units have
become available in a number of ways: for pre-
scription by a dermatologist or other specialist as
a maintenance program for their in-office LED
treatment regimen; as an over-the-counter prod-
uct from chemists or pharmacists with product-
related training; or from reputable self-health
mail-order companies. The author is aware of
one company who has two such self-contained
hand-held products, one blue/red for treatment
of acne, and one infrared/red for skin rejuvena-
tion, which have achieved FDA 510(k) clear-
ance. Despite their size, they have the same high
quality LEDs delivering the same intensity in
mW/cm2 as the medical versions of the systems
based on LED arrays. When used for the recom-
mended time they will thus deliver exactly the
same dose as their much larger cousins. Naturally
they cover a very much smaller area than the
full-sized planar arrays, but because of their
lightweight nature, it is anticipated that the user
will be able to watch TV or listen to music while
irradiating the target area one bit at a time, and
they will be absolutely ideal for a maintenance
program following office or clinic treatment
with the full-sized systems. Home use LED-
LLLT is therefore yet another area to be watched
with great interest.
Applications: Combination Is Key
The applications for light-only LED photother-
apy continue to grow in a pan-speciality manner,
so that a large range of clinicians is finding useful
R. G. Calderhead

331
applications for LED phototherapy of appropri-
ate wavelength and incident photon intensity.
However, as with lasers, a saturation point will
be reached. This can be combatted by using
LED phototherapy in combination with exist-
ing conventional surgical and nonsurgical
approaches to achieve even better results. A per-
fect example where this is happening is full face
laser ablative resurfacing. Initially hailed as a
superb approach to rejuvenating severely photo-
aged skin, in recent years it has declined dra-
matically in popularity because of potential side
effects such as scarring, unpleasant-looking
sequelae and a very long downtime before the
patient can once again return to work or to soci-
ety. However, everyone agrees it is still the ‘gold
standard’, particularly for deep wrinkles and
severe photodamage. Some reports have now
appeared on the use of LED phototherapy
together with ablative laser resurfacing. The
controlled study already discussed above by
Trelles et  al. is an excellent example which
compared two groups of full-face ablative resur-
facing patients [56]: one group was also treated
with LED phototherapy, and the control group
was not, but otherwise the resurfacing and
wound care regimens were exactly the same.
The healing time in the LED-treated group was
cut by more than one-half, postoperative pain
was cut by more than 70% and the erythema
cleared in less than 7 weeks compared with up
to 4–6 months.
LED phototherapy can and does offer even
better results in any case where the dermatologist
has in some way altered the epidermal and der-
mal architecture of his or her patient, whether it is
as mild as an epidermal powder peel, through
chemical peels to nonablative resurfacing with
lasers or IPL systems, fractional laser and non-­
laser approaches, like microneedling radiofre-
quency, and full-face ablative resurfacing. The
adjunctive application of LED phototherapy will,
I believe, drive its acceptance even more strongly
than its use as a stand-alone modality, and the
major advantage of LED-based systems is their
very competitive pricing in addition to their por-
tability and versatility. Combination therapy is
the key [53, 54].
Conclusions (And Questions
You Should Ask)
LED phototherapy is certainly here to stay, but
unfortunately the medicoscientific waters are
being muddied by a number of manufacturers
who have jumped on the LED bandwagon, mak-
ing extravagant claims and barefacedly using the
data amassed by those companies who have been
responsible enough to go through regulatory
approvals, such as FDA 510(k) clearances, as if
the data were their own. Statements such as ‘….
uses NASA technology ….’ are common, but
totally misleading. The current generation of
LEDs actually exceeds the 1990s NASA technol-
ogy as far as output power and quasimonochro-
maticity are concerned, and in fact have
absolutely nothing to do with NASA! Even worse
than these manufacturers are the companies
which import ‘lookalikes’ from the Eastern
block. They may be cheap, but they are certainly
not cheerful, and the heart of an LED system is
the quality and pedigree of the LEDs used in its
arrays: you get what you pay for. To make sure
you get what you actually want, i.e., an LED pho-
totherapy system that will actually do something
that you want it to do, and make you and your
patients happy, please see the following, which
will not only summarize the main points of the
chapter but will also reinforce my favorite maxim
which is; ‘Any old LED will NOT do’.
Caveat Emptor (Let the Buyer
Beware!)
When considering purchasing an LED-based
phototherapy system for his or her practice, the
wise dermatologist should always ask the manu-
Box 18.7
• LED phototherapy is here to stay!
• ‘Any old LED’ will NOT fit the bill!
• When considering buying an LED
system, ask the right questions!
• Combination treatment is the key!
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

332
facturer or salesperson the following questions
(and take a written note of verified or verifiable
answers!).
What Regulatory Approvals Does
the System Have?
This means appropriate FDA 510(k) approvals in
the USA (no LED system has yet got full premar-
keting approval, PMA), Health Canada in
Canada, TGA in Australia, Ministry of Health,
Labour and Welfare (Kohseishou) in Japan,
appropriate CE marking for medical devices in
Europe, and so on. It does not mean having
‘NASA technology LED’s’ or ‘Approved by the
FDA’, the latter of which usually simply means a
letter from FDA recognizing that the system is a
nonsignificant risk device (NSR) or minimal risk
device (MSR). This is not an approval to market,
but is simply a guide based on which the institu-
tional review board (IRB) of a research center
can classify the system when it does take part in
a properly structured study.
What Is (Are) the Wavelength(s)?
As has been said many times, wavelength is the
most important single factor when attempting to
achieve a photoreaction: no absorption, no reac-
tion. Some targets can respond to a fairly broad
waveband of 30–100 nm or so, but most of the
targets in LED phototherapy are much more
specific. Ask what the nominal wavelength of
the system is, and what is the deviation either
side. For example, the Omnilux revive™ and
HEALITE II mentioned elsewhere in this chap-
ter have LED arrays with a nominal wavelength,
with the range of ±5–7  nm. That means that
93–95% of the photons are at the rated wave-
length and will therefore optimally target
wavelength-­specific chromophores at that wave-
length such as 633  nm for cytochrome c oxi-
dase, and 415 nm for the porphyrins Cp III and
Pp IX endogenous to P. acnes. Visible red at
670 nm, for example, will still have some effect
on cytochrome c oxidase, but that wavelength
just misses the boat as far as peak efficiency of
exogenous porphyrin activation is concerned for
ALA PDT, where 633 nm is the wavelength of
choice.
While on the subject of wavelength, some
manufacturers offer all the colors of the rainbow
in the one system, in one particular system
mounted in a semicircular bar which scans over
the face with the claim that ‘blue is for serenity,
green is for inner peace, yellow is for well-being,
and red is for relaxation’. In fact, this manufac-
turer is not offering phototherapy, but ‘chromo-
therapy’ also known as ‘colorology’ which is an
alternative medical approach based on ‘chakras’
and their associated colors to achieve balance in
an unbalanced system [88]. As with reflexology,
the origin of the approach is Russian, as is a great
deal of the literature, but chromotherapy has a
large following. The methods and English lan-
guage studies used to prove that it works, how-
ever, have been severely criticized [89]. In
addition, as Karu and colleagues have well-­
demonstrated, the intermingling of wavelengths
way well include some which cancel each other
out thus having no effect, or indeed downregulate
cellular activity compared to the wavelengths
applied individually [12]. The fact that the light is
scanned over the face should sound another
warning bell, since this dramatically lowers the
dose, even if the photon intensity were high
enough (which it is not). The answer? Keep to
well-proven wavelengths, applied singly and
with a suitable period (48–72 h) allowed between
applications to allow the targeted cells to respond
to the information they have received.
What Is the Intensity?
You are looking for an answer here in mW/cm2
(milliwatts per square centimeter) of the entire
array, not the ‘lumens’ of an individual LED or
indeed the whole array, nor should you be told
that the system is “very bright”. If in doubt about
this parameter and its paramount importance,
next to wavelength, please re-review section
“Irradiance (Photon Intensity)” above on photon
density, another way of saying ‘intensity’. A
good range, depending on wavelength, would be
anywhere from 40 mW/cm2 up to 150 mW/cm2,
although the higher the intensity, the more prob-
lems will exist in keeping the LED array cool
enough to avoid discomfort to the patient and a
drift away from the LED nominal wavelength. If
R. G. Calderhead

333
this range seems low compared with a diode laser
therapy system, for example, always bear in mind
that the better LED systems cover a large area of
tissue, for example some offer an active array
area of 220 cm2, unlike the laser therapy system
which usually irradiates a spot of only a few mm
in diameter per ‘shot’.
If you get an answer in joules, ignore it … bet-
ter still, laugh loudly. If you get an answer in
joules per square centimeter (J/cm2), that’s better,
but it is actually the answer to the next question!
The incident intensity or power density is
extremely important, because a higher power
density enables a shorter irradiation time, and it
has been reported for a continuous wave system
that shorter irradiation times with a higher inten-
sity got significantly better results in first passage
human gingival fibroblast proliferation in vitro
compared with longer irradiation times at a lower
intensity, even though the dose (in J/cm2) was the
same [90]. Of course, the Arndt-Schultz curve
must always be remembered (section “Irradiance
(Photon Intensity)” above), and the upper limit of
photoactivation must never be exceeded or a pho-
tothermal reaction will occur.
What Is the Recommended Dose?
This is where the J/cm2 unit should be the correct
answer, but NOT the dreaded joule. If you see a
joule running around an LED system, kill it. As
discussed above, the joule is simply a unit of
energy and has no significance whatever on the
clinical effect in a prescribed area of target tissue.
Correlate the dose with the recommended irradi-
ation time. As a matter of interest, if you cannot
find out the intensity from the manufacturer, by
dividing the dose (J/cm2) by the irradiation time
(in seconds), you will end up with the intensity in
W/cm2 (or mW/cm2).
For this category, there is no ‘correct’ dose for
an LED-LLLT system, although it should cer-
tainly be no lower than 20 J/cm2 depending on
the wavelength. If the intensity or power density
is correct, then it is almost impossible to over-
dose. Overdosing is not recommended, however,
simply because it wastes time and will not often
produce dramatically better results than the
recommended dose, which the responsible
manufacturer will have arrived at by conducting
dose-ranging response-related studies. If the rec-
ommended dose is, for example, 120 J/cm2 over
20  min, increasing the irradiation time by
10–30 min will not get a 50% better effect, but on
the other hand, cutting the time down by half to
10 min may well give a result well below 50% of
that achieved at the recommended time. If an
LED-LLLT system supports arrays with different
wavelengths, the manufacturer may well have
standardized the treatment time to the same for
each of the heads, but the dose will almost always
be different for each wavelength, simply because
of a combination of LED characteristics, wave-
length/tissue interactions and the individual pho-
ton energy associated with each wavelength.
How Should the LED Energy
Be Delivered?
The answer here will be ‘in continuous wave (or
CW)’, which is good; or ‘frequency modulated
(also known as photomodulated)’ which is not so
good; or ‘pulsed’, which is actually the incorrect
way of saying the second answer and is totally
wrong! Light at a given wavelength already con-
tains its own frequency, as discussed in section
“Temporal Profile of the Beam” above, and light
represents ‘information’ to cellular targets.
Imposing a secondary frequency on that primary
frequency can not only disrupt the flow of infor-
mation, it also cuts down on the dose since there
is no light incident on the target cells when the
source is switched off. It is true that cells have a
‘dark reaction’ time as shown by Karu [91], but
it occurs well after irradiation, and not in the
short off-duty interval in a frequency modulated
beam cycle. Figure 18.28 is by an independent
research group, Almeida-Lopes and colleagues
at the University of Sao Paulo, Brazil, who
reported the data on power density in Ref. [90]
above, and shows the growth pattern of first pas-
sage human gingival fibroblasts exposed in vitro
to 640 nm at several frequencies and continuous
wave (CW), with constant incident power den-
sity and dose as ascertained in earlier studies.
There was a significant difference seen between
the group of frequencies and the unirradiated
controls (p  >  0.01 for all), with the higher
18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

334
frequencies inducing better cell proliferation,
but the continuous wave beam induced greatest
and most significant proliferation compared with
both the unirradiated controls (p < 0.001) and the
frequency modulated beams (p  <  0.01). The
experiment was repeated ten times and the
results averaged. (Data and graph reproduced
with the permission of Pra. Luciana Almeida-
Lopes, as yet unpublished data). Cells, espe-
cially first passage human gingival fibroblasts,
seem to prefer CW to frequency modulated
energy.
What Has Been Published
on the System/Technology?
What you are looking for here are papers by rep-
utable authors published in the indexed and peer-­
reviewed literature, or at least in well-established
and peer-reviewed journals (15 or more volumes)
which have not yet been indexed by MedLine
and/or PubMed but which do none-the-less have
scientific credence. An alternative source is
appropriate chapters in books from reputable
publishers. What you are NOT looking for are so-­
called ‘white papers’ which any manufacturer
can produce to look like a genuine publication,
although they may actually contain good data, or
articles from the commercially-oriented medical
press unless they are also in turn backed up by
‘real’ papers. All of the referenced works in this
chapter are either from peer-reviewed PubMed
listed journals, or books from reputable publish-
ers. Also, make very sure that the articles offered
by the manufacturer/salesperson are on their
­specific system and wavelength(s). Very often
articles on approved systems by another manu-
facturer will be cited as ‘proof’ that their (unap-
proved) system works, even though sometimes
the intensity, dose or even wavelength is not the
same as in the published articles.
Finally ….
Despite the moaning of the sceptics, LED photo-
therapy has definitely arrived, has been proven to
work in many areas, and is finding a rapidly
increasing number of applications both within
and outside dermatology. LED-LLLT systems
are comparatively inexpensive and robust, LED-­
LLLT itself is easy to administer, safe, effective,
pain free (in fact it can be used to treat pain),
side-effect free, well-tolerated by patients of all
ages from infants to centenarians, and minimally
contraindicated. It offers the possibility of a
stand-alone noninvasive phototherapy method,
but when used together with any of the methods
currently used by the dermatologist to alter his or
her patient’s skin, already good results can be
expected to become even better. LED photother-
apy will not turn a poor dermatologist into a good
one, but it will help the good dermatologist to
become even better, with happier patients. And
finally, please remember, above all, not any old
LED will do the job!
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0
10
Control
10 Hz
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120 Hz
180 Hz
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Incident radiant flux (dose): 2.25 J/cm2
Incident power: 56 mW
λ = 640 nm
20
Cell count x 1000
30
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2
Time (Days)
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‡
Fig. 18.28  An in vitro experiment to assess the effects of
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18  Current Status of Light-Emitting Diode Phototherapy in Dermatological Practice

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© Springer International Publishing AG, part of Springer Nature 2018
K. Nouri (ed.), Lasers in Dermatology and Medicine,
Laser and Light for Wound Healing
Stimulation
Ehsan Azimi, Navid Bouzari, and Keyvan Nouri
Abstract
Understanding wound healing is critical for
health care professionals mainly because of
the enormous burden of chronic wounds on
society. In addition, in many medical special-
ties, creating wounds for diagnostic and thera-
peutic purposes is part of a physician’s daily
practice.
Acute wounds are usually closed using
sutures, staples, or other methods of wound
closure. Conventional modalities include
maintenance of a moist wound bed, and pre-
vention of infection. Although acute wounds
are not challenging in most settings, they
may influence the hospital stay or expenses
related to medical procedures. Chronic
wounds however, are more challenging. The
incidence of chronic wounds in the United
States is approximately five to seven million
per year (Sen et  al., Wound Repair Regen
17(6):763–771, 2009) and the annual costs
for management of these wounds is greater
than $20 billion.
Keywords
Wound healing · Chronic wounds · Tissue
welding · Tissue soldering · Helium-neon
lasers · Gallium-arsenide (GaAs) lasers ·
Gallium-aluminum-arsenide (GaAlAs) lasers
· Nd:YAG lasers · Carbon dioxide lasers ·
Ruby lasers · Krypton lasers · Argon dye lasers
E. Azimi
Department of Dermatology, Cutaneous Biology
Research Center, Massachusetts General Hospital,
Charlestown, MA, USA
N. Bouzari
South Shore Skin Center, Plymouth, MA, USA
e-mail: nbouzari2@med.miami.edu
K. Nouri (*)
Department of Dermatology and Cutaneous Surgery,
University of Miami Miller School of Medicine,
Miami, FL, USA
e-mail: knouri@med.miami.edu
19

340
Summary Box
• Cutaneous wound healing is divided
into three phases: the inflammatory
phase, the proliferative phase, and the
remodeling phase
• The wound healing process can be
applied to both acute and chronic
wounds. Acute wounds are generally
less than 8 weeks, and usually result in a
sustained restoration of anatomic and
functional integrity. Chronic wounds are
defined as wounds that have failed to
proceed through the usual stepwise
fashion. Lasers are used for healing of
both acute and chronic wounds.
• The main techniques of laser-assisted
wound closure of acute wounds are:
simple tissue welding, tissue soldering,
dye-enhanced tissue welding, and addi-
tion of growth factors.
• The potential advantages of laser-
assisted tissue bonding over conven-
tional
methods
include
increased
immediate wound strength, fluid-tight
closure, decreased operative repair time,
reduced probability of infection and
bleeding,
and
improved
cosmetic
results. However, lasers have disadvan-
tages such as their high cost, risk of
dehiscence, risk of thermal damage, and
inconsistency of the results.
• The exact mechanism involved in laser-
assisted wound closure is not com-
pletely understood. The heat produced
by laser energy in the tissue causes col-
lagen fibers to loose their triple helix
structure and become fused, intertwined,
swollen, and dissolved.
• Different lasers for treating chronic
wounds include helium-neon, gallium-
arsenide (GaAs), gallium-aluminum-
arsenide (GaAlAs), Nd:YAG, carbon
dioxide, ruby, krypton, and argon dye
lasers
• The exact mechanism of action of low
intensity laser therapy is not known.
Current hypotheses are: stimulation of
Ca influx and mitosis rate, increased
expression of Heat-Shock-Proteins (e.g.
HSP70 and HSP47), increased expres-
sion of growth factors such as TGF-β,
alteration of mitochondrial activity and
increased ATP synthesis, augmented
formation of mRNA and protein secre-
tion, enhancement of fibroblast and
keratinocyte proliferation and migra-
tion, angiogenesis, improvement of
phagocytosis, and increased rate of
transformation
of
fibroblasts
into
myofibroblasts.
Introduction
Understanding the wound healing is critical for
health care professionals mainly because of the
enormous burden of chronic wounds on society.
In addition, in many medical specialties, creating
wounds for diagnostic and therapeutic purposes
is part of physician daily practice.
Acute wounds are usually closed using sutures,
staples, or other methods of wound closure.
Conventional modalities include maintenance of a
moist wound bed, and prevention of infection.
Although acute wounds are not challenging in
most settings, they may influence the hospital stay
or expenses related to medical procedures. Chronic
wounds however, are more challenging. The inci-
dence of chronic wounds in the United States is
approximately five to seven million per year [1]
and the annual costs for management of these
wounds is greater than $20 billion [2, 3]. Accurate
diagnosis is the key, and can be clinically made in
less than 75% of cases [4]. Treatment usually con-
sists of debridement of necrotic tissue, mainte-
nance of a moist wound bed, and control of
infection. Unfortunately, despite many progresses,
treating chronic wounds is still challenging.
Laser and light based technologies have
recently emerged as alternative therapies for
wound healing. A variety of lasers and light
sources have been introduced as a non-invasive
E. Azimi et al.

341
tool for chronic wound healing as well as an
alternative method of closure of surgical wounds.
This chapter will discuss the role of this new
technology in wound healing.
Wound Healing
Understanding the process of wound repair is a
prerequisite to maximizing our knowledge
regarding the use of lasers for wound healing.
Cutaneous wound healing involves the complex
interaction of several types of cells, their cyto-
kines or mediators, and the extracellular matrix.
After cutaneous injury a cascade of events is
observed, which mediates tissue repair and even-
tually the reestablishment of the barrier function
of the skin. Tissue repair is divided into three
phases: the inflammatory phase, the proliferative
phase, and the remodeling phase [5] (Fig. 19.1).
Inflammatory Phase
The initial event in tissue injury is the damage to
endothelial cells and blood vessels. This causes
extravasation of blood into the wound and colla-
gen exposure which leads to blood clotting,
platelet aggregation and activation, as well as
migration of neutrophils and monocytes (and
Tissue injury
Blood extravasation
Inflammatory phase
Platelet
Neutrophil
Macrophage
Epithelial cell
Fibroblast
Proliferative phase
Remodeling phase
Day 14
Day 7
Day 1
Minutes to hours
0
Months
Phagocytose bacteria
and matrix proteins
Angiogenesis
PDGF
EGF
TGF-β
IGF-1
Serotonin
Fibrinogen
ADP
TXA2
PDGF
FGF
TGF-β
TGF-α
VEGF
Migration and proliferation
IL-1
IL-6
PDGF
GM-CSF
Collagenase,
hyaluronidase
Collagen III degradation
Collagen remodeling
Collagen I synthesis
KGF
HB-EGF
Activin
TGF-β
Migration and proliferation
TGF-α
Fig. 19.1  Phases of wound healing: The inflammatory
phase starts within minutes after tissue injury with extrav-
asation of blood followed by activation of platelets, mono-
cytes and macrophages, release of mediators and
cytokines. These cytokines induce the proliferative phase
by activating keratinocyte and fibroblast proliferation and
migration, as well as release of a variety of growth factors
involve in angiogenesis and granulation tissue formation.
The last phase of wound healing is remodeling via replac-
ing collagen III by collagen I. IL interleukin, KGF kerati-
nocyte growth factor, FGF fibroblast growth factor, VEGF
vascular endothelial growth factor, PDGF platelet-derived
growth factor, EGF epidermal growth factor, HB-EGF
heparin binding EGF, TGF-α transforming growth factor-
alfa, TGF-β transforming growth factor-beta, IGF-1 insu-
lin-like growth factor-1, GM-CSF granulocyte-macrophage
colony stimulating factor, ADP adenosine diphosphate,
TXA2 thromboxane A2
19  Laser and Light for Wound Healing Stimulation

342
subsequently macrophages) to the site of injury.
Activated platelets release a variety of mediators
(Fig. 19.1) which initiate the wound healing cas-
cade by attracting and activating fibroblasts,
endothelial cells and macrophages. Neutrophils,
once in the wound environment, phagocytose
bacteria and matrix proteins. Later in the inflam-
matory phase, monocytes and macrophages
become the dominant figures, and release a vari-
ety of cytokines, inducing epithelial cell migra-
tion and proliferation as well as matrix production
[5, 6].
Proliferative Phase
This phase involves the creation of a permeability
barrier as well as the establishment of an appro-
priate blood supply and reinforcement of the
injured tissue. Keratinocytes and fibroblasts pro-
liferate and migrate to the wound bed. Fibroblast
proliferation and migration are modulated by
PDGF,
EGF,
TGF-α,
TGF-β
and
FGF. Macrophages play a key role in initiating
fibroblast proliferation and migration. When the
number of macrophages begins to diminish,
fibroblasts and keratinocytes are the main source
of the growth factors. The interplay of keratino-
cytes with fibroblasts gradually shifts the micro-
environment away from an inflammatory to a
synthesis-driven granulation tissue.
In the granulation tissue, mesenchymal cells
are maximally activated, cells proliferate, and
synthesize huge amounts of extracellular matrix
which supports the developing capillary loops.
Keratinocytes proliferate and migrate over the
provisional matrix of the underlying granulation
tissue, eventually closing the defect [5, 7, 8].
Remodeling Phase
In this phase, remodeling of the collagen into a
more organized structure occurs in order to
increase the wound’s tensile strength. The type
III collagen of the granulation tissue is replaced
by type I collagen through a tightly controlled
synthesis of new collagen and lysis of old until
the normal skin ratio of 4:1 for type I collagen to
type III collagen is present. In addition, the com-
position of other matrix material such as water,
fibronectin, hyaluronic acid, and proteoglycans
changes over the period of a year or more [5, 9].
Acute vs. Chronic Ulcers
The wound healing process can be applied to
both acute and chronic wounds. Acute wounds
are generally less than 8 weeks, and usually result
in a sustained restoration of anatomic and func-
tional integrity. Chronic wounds are defined as
wounds that have failed to proceed through the
usual stepwise fashion. As a result, the healing
process is prolonged and incomplete, with lack of
restoration of integrity [10]. A large number of
factors can impede wound healing and may pre-
dispose a patient to the development of chronic
wound. These include both local factors (wound
infection, tissue hypoxia, repeated trauma, the
presence of debris and necrotic tissue), and sys-
temic causes (diabetes mellitus, malnutrition,
immunodeficiency, and the use of certain medi-
cations) [11–13].
Lasers for Wound Healing
The use of laser energy for wound healing was
proposed more than 35 years ago [14]. It was first
suggested for bonding skin incisions, and termed
“laser welding”. Interest in the efficacy of lasers
as a noninvasive tool for treatment of all types of
wounds soon grew among researchers in both ani-
mal models [15, 16] and clinical studies [17, 18].
The concept that surgeons can replace their scal-
pels and tedious suturing techniques with a sim-
ple, non-operator-dependent, safe, and rapid
technique, has inspired many investigators to
experiment on different laser systems [19]. The
areas of research can be divided in two major
groups: lasers to augment the healing of acute
wounds (tissue welding, tissue soldering, etc. see
below), and lasers for chronic wound (e.g. low
intensity laser devices, see below). Although these
two groups of lasers share many similarities, there
E. Azimi et al.