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Lasers Med Sci 2002, 17:173–186
Ownership and Copyright
© 2002 Springer-Verlag London Limited
Laser and Non-laser Light Sources for
Photodynamic Therapy
L. Brancaleon
1,2
and H. Moseley
1,2
1
Department of Medical Physics,
2
The Photobiology Unit, Ninewells Hospital and Medical School, Dundee, UK
Abstract. Photodynamic therapy (PDT) is an anticancer combination therapy, which requires a photo-
sensitiser, which tends to accumulate preferentially in the tumour, and light. Historically large, complex
lasers have been used to carry out PDT treatment. Nowadays there is a wide range of coherent and
non-coherent sources that can be used. This paper considers the important characteristics of light sources for
PDT, including dye lasers pumped by argon or metal vapour lasers and frequency-doubled Nd:YAG lasers.
Non-laser sources including tungsten filament, xenon arc, metal halide and fluorescent lamps are also
discussed. New exiciting developments such as LEDs and femtosecond lasers are also reviewed. The relative
merits of laser and non-laser sources are critically examined.
Keywords: Cancer treatment; Light sources; Photodynamic therapy (PDT); Photosensitisers
INTRODUCTION
Photodynamice therapy (PDT) is a treatment
modality available for palliation or eradi-
cation of several cancers. PDT involves the use
of a photoactive drug (photosensitiser) and
light (typically visible or infrared) [1,2]. Upon
absorption of light, the photosensitiser (PS)
initiates chemical reactions that lead to the
direct or indirect production of cytotoxic
species such as radicals and singlet oxygen
[3,4]. The reaction of the cytotoxic species with
subcellular organelles and macromolecules
(proteins, DNA, etc) lead to apoptosis and/or
necrosis of the cells hosting the PS. The
preferential accumulation of PSs in cancer
cells [5,6] (which in many cases can be signifi-
cant) combined with the localised delivery of
light to the tumour, results in the selective
destruction of the cancerous lesion [5]. Com-
pared to other traditional anticancer thera-
pies, PDT does not involve generalised destruc-
tion of healthy cells. In addition to direct cell
killing, PDT can also act on the vasculature,
reducing blood flow to the tumour causing its
necrosis [7,8]. In particular cases it can be used
as a less invasive alternative to surgery [9–12].
Since PDT depends on localised light deliv-
ery, it can be applied only to tumours that can
be reached by light either directly or through
an optical fibre. E$cient PDT is limited, how-
ever, by the penetration of light into the tissue,
which confines the treatment to superficial
cancer [13]. Despite its e$cacy, the application
of PDT in humans is still relatively experimen-
tal and for the treatment of the same type of
tumours protocols can vary considerably.
Quite obviously the light source and light
delivery are two of the fundamental aspects in
PDT. The choice of light source for PDT can be
dictated by the location of the tumour, by the
light dose delivered and by the choice of pho-
tosensitiser. Lasers and lamps have both been
employed to perform PDT and the superiority
of one source over the other has not been
demonstrated, therefore the use of lasers or
lamps depends on the specific application.
Although PDT has been traditionally per-
formed using lasers, the availability of broad-
band sources (lamps) is challenging the use of
lasers where light can be directly delivered to
the tumour (skin, oral cavity, etc.) without the
need to couple the source to an optical fibre.
This paper reviews the characteristics of the
light sources presently employed in PDT and
their preferred application. PDT research is
widespread and includes studies at various
stages of clinical trials, animal studies, in vitro
Correspondence to: Dr H. Moseley, University of Dundee,
The Photobiology Unit, Ninewells Hospital and Medical
School, Dundee, DD1 9SY, UK.
investigation, cellular studies, etc. We will not
review light sources used for scientific
research in PDT where the choice of sources
for PDT is somewhat less constrained, and we
will rather concentrate on sources used for
PDT in human subjects. Although PDT has
been the subject of many reviews, to date there
has not been a comprehensive description of
the light sources available to scientists and
clinicians.
PHOTOSENSITISERS AND MECHANISMS OF
PDT
In PDT, absorption of light by the PS initiates
chemical reactions that produce transient
phototoxic compounds. The mechanism of pro-
duction of these transient species has been
thoroughly described elsewhere [1,4,14,15].
Briefly photodynamic mechanisms proceed
from the first excited single state (S
1
)ofthe
photosensitiser produced by the absorption of
a photon elsewhere [14]. From S
1
the molecule
either loses an electron to originate a radical
cation (PS
.
) or quickly relaxes into the first
excited triplet state (T
1
). Both PS
.
and T
1
have a relatively long lifetime and can interact
with molecular oxygen to generate highly
reactive compounds such as peroxides and sin-
glet oxygen. The reaction that proceeds via PS
.
is normally called Type I and the one that
proceeds from T
1
is called Type II [3]. The
species produced are very reactive and can
induce oxidative stress of the cell hosting the
PS with consequent cell death via apoptosis
and/or necrosis [16,17].
The high reactivity of radicals and singlet
oxygen also produces photobleaching of the
PS. This occurs when the PS itself reacts with
the transient species to undergo reversible or
irreversible chemical reactions that lead to
the creation of photoproducts. Such photo-
products have di#erent absorption character-
istics (di#erent extinction coe$cient and/or
di#erent absorption maxima) [18,19]. Photo-
bleaching is normally regarded as a limiting
factor in PDT as it depletes the amount of PS
available during treatment. However, the role
of photobleaching in PDT is not fully under-
stood and it may also produce some benefits
such as increase the penetration of PDT into
the tumour as a result of the change in absorp-
tion at the excitation wavelength. Moreover
the role of photoproducts on PDT in vivo has
not been investigated.
The number of photosensitisers undergoing
various stages of clinical trials is large and
includes mostly various types of tetrapyrrolic
rings such as porphyrin derivatives [20–25],
phthalocyanines [15,26] and chlorins [25,27,28].
These compounds are all characterised by a
large absorption band between 400 and 430 nm
(Soret Band) [15,19] and smaller absorption
bands (Q-bands) above 550 nm [15,19]. Q-bands
above 600 nm are normally targeted for PDT
purposes; they retain high quantum yields for
Type I or II reactions and at the same time light
above 600 nm penetrates deeper into the tissue.
The absolute penetration of light depends on
the optical characteristics of the tissue, and
the geometry of light delivery [29–32]. The op-
tical penetration depth (OPD) is defined as the
depth at which the intensity of the propagating
light is attenuated approximately 37% (1/e) of
its initial value (at the air/tissue interface)
[13]. For instance in brain tissue the OPD at
635 nm is 800 m whereas in the bladder it is
4 mm [32]. Moreover, according to most tissue
modelling, light in the 600–700 nm region of the
spectrum penetrates 50–200% more than light
in the 400–500 nm region [33,34]. When the
optical properties of photosensitisers are also
considered in determining tissue penetration
[13] then penetration at 630 nm (for instance)
is 3–4 times larger than penetration at 400–
420 nm where the absorption coe$cient of pho-
tosensitisers is much larger. As a result PDT is
usually performed at wavelengths longer than
620 nm so that a larger volume of diseased
(cancerous) tissue can be treated.
These requirements have pushed the devel-
opment of light sources for PDT mostly (there
are exceptions as are described below) towards
outputs in the red region of the spectrum and,
with the advent of newer generation of PSs,
towards the near-infrared where penetration of
the incident radiation is even larger.
Despite the many studies performed using
di#erent photosensitisers, only a few have
reached the stage of advanced human clinical
trial or even FDA approval for clinical use.
These drugs include Photofrin
, Levulan
,
Foscan
and Visudyne
. The characteristics
of these photosensitisers are summarised in
Table 1. Photofrin
, Foscan
and Visudyne
are porphyrin or chlorins (two forms of
tetrapyrrolic rings) and are administered
systemically by intravenous injection and
have been used mostly for malignant or
premalignant lesions of internal organs such
as brain [35], head and neck [9], bladder [5],
174 L. Brancaleon and H. Moseley
lung [6], etc., and occasionally for malignan-
cies of the oral cavity [12]. Visudyne has been
used for treatment of age-related macular
degeneration [36] although its application to
other lesions (e.g. actinic keratosis) is under
investigation. Levulan
is the commercial
name for 5-aminolaevulinic acid (ALA), which
is a precursor of protoporphyrin IX (PPIX)
which is a clinically useful photosensitiser
[24]. By supplying ALA to cells it is possible to
overcome the negative feedback mechanisms
in the synthesis of haem [24] and accumulate
PPIX well above the physiological concen-
tration. Unlike the other PSs, ALA can be
administered topically and orally and is the
preferred choice for superficial lesions in skin
[23,37] and oral cavity [38] and it has been used
in oesophageal and stomach malignancies and
dysplasia [39]. Investigations and clinical
trials are ongoing to study the benefits of
ALA-esters [23]. These molecules introduce the
benefit of a long lipophilic chain attached to
ALA which increases penetration into tissues
and through the stratum corneum (particu-
larly important for ALA-PDT in skin) and their
metabolism still leads to the formation of
elevated intracellular levels of PPIX.
Naturally, most of the light sources for PDT
application have developed to optimise the
output near the absorption wavelengths
reported in Table 1. Moreover the tendency of
agencies, such as the US Food and Drug
Administration, has been to approve not just
the drug but the drug and the light source to
be used for its optical excitation.
PDT LIGHT SOURCES
Lasers
Historically argon lasers and metal vapour
lasers (see below) were the initial choice for
PDT. These lasers combined several character-
istics such as high power output, the possi-
bility of pumping dye lasers that would in
turn give access to the wavelength region for
excitation of porphyrins and easy coupling to
optical fibres for use with endoscopes.
Argon Lasers and Argon-pumped Dye
Lasers
Argon lasers-pumping dye lasers are among
the most popular devices for PDT treatment.
Laser dyes (such as rhodamine B, rhodamine
101 and sulphorhodamine 640) can be chosen
with absorption at one of the two main
emission lines of the argon (488 nm and
514 nm) and emission in the 600–650 nm region
to match the absorption of porphyrins
(Table 1). These lasers require a high level of
technical support. For instance, because the
argon laser beam has a narrow cross-section,
the alignment with the dye module is critical
and tends to require regular re-adjustments.
Argon lasers provide high irradiance at the
emission lines (up to 1 W/cm
2
) (Table 2). The
output of the dye laser pumped by the main
argon lines is in the range 10–500 mW/cm
2
despite the intrinsic losses of the dye laser. The
spectral output of the dye laser has a band-
width of 5–10 nm. The fluence rates reported in
Table 2 are su$cient to deliver e#ective PDT
by both direct or fibre-mediated irradiation.
Argon-pumped dye lasers coupled to an optical
fibre have been used in primary lung cancer
[40,41], oral precancer [38], oesophagus [42]
and bladder cancers [5]. The core of the fibre is
variable depending on the site treated and may
be 200–600 m. In many applications, a di#user
is fixed at the end of the fibre to allow uniform
irradiation within a lumen or tumour. The
direct expanded and attenuated beam of
argon-pumped dye lasers has also been used
for PDT of superficial skin cancer [10] and
for PDT of vulval neoplasia [43]. The direct
Table 1. Summary of the main characteristics of the most common commercially available photosensitisers
Commercial name Chemical definition
Absorption
maximum
Delivery
Photofrin Mixture of di-hematoporphyrin esters and ethers 630 nm Systemic
Foscan Meta-tetrahydroxyphenylchlorin (m-THPC) 652 nm Systemic
Visudyne Benzoporphyrin derivative 690 nm Systemic
Levulan 5-Aminolaevulinic acid (ALA)
converted into protoporphyrin IX (PPIX)
635 nm Oral/topical
Laser and Non-laser Light Sources for Photodynamic Therapy 175
Table 2. Types of lasers available for clinical PDT
Wavelength(s) Bandwidth Irradiance
Pulse
duration
Light
delivery
Argon laser 488 and 514.5 nm Monochorom 0.5–1 W/cm
2
CW Direct or optical fibre
Dye laser pumped by argon laser 500–750 nm (depending on the dye) 5–10 nm 10–200 mW/cm
2
CW Direct or optical fibre
Metal vapour laser UV or visible (depending on metal) Monochrom Up to 10 W/cm
2
10–50 ns quasi-CW Direct or optical fibre
Dye laser pumped by
metal vapour laser
500–750 nm (depending on the dye) 5–10 nm 10–500 mW/cm
2
10–50 ns quasi-CW Direct or optical fibre
Solid state For a Nd:Yag 1064, 532, 355, 266 nm Monochrom Up to 10 W/cm
2
10 ps–30 ns quasi-cw Direct or optical fibre
Dye laser pumped by
solid state laser
400–750 nm (depending on dye) 5–10 nm 10–500 mW/cm
2
10 ps–30 ns quasi-cw Direct or optical fibre
Solid state optical
parametric oscillator
250–2000 nm Monochrom Up to 1 W/cm
2
10 ps–30 ns Direct or optical fibre
Semiconductor diode lasers 600–950 nm Monochrom Up to 700 mW/cm
2
CW Optical fibre
176 L. Brancaleon and H. Moseley
monochromatic emission of the argon laser has
not been widely employed in PDT because of
the lower penetration into the tissue of the 488
and 514 nm wavelengths. However, prelimi-
nary animal experiments are ongoing using
the line at 514 nm [44]. As a final note we
would like to point out that argon lasers (and
argon-pumped dye lasers) are especially indi-
cated for endoscopic PDT because the output
beam has a very small cross-section (<1 mm)
and can readily be coupled to optical fibres.
Conversely argon lasers are not the most con-
venient choice in typically large skin or oral
lesions where its use involves the addition of a
beam expander which can become cumbersome
and reduce the fluence rate.
Metal Vapour-pumped Dye Laser
These lasers have also been (and still are) a
popular choice for PDT particularly among
European investigators. Unlike truly CW
argon lasers, metal vapour lasers are normally
pulsed, with pulsewidth ranging from 10 to
50 ns (Table 2) and pulse rates of 1 KHz. Such a
high repetition rate makes the source quasi-
continuous for clinical purposes. The pump
beam (in the UV or visible depending on the
metal mixture) provides high primary output
power that can be used to pump tunable
dye lasers, which in turn give access to the
spectral region where porphyrins absorb.
Metal vapour-pumped dye lasers are able to
deliver light at irradiance up to several
hundred mW/cm
2
(Table 2). These lasers can be
coupled to optical fibres and used for endo-
scopic PDT such as in oral precancer [12], in
head and neck cancer [9], the oesophagus [45],
lung [11], bladder [5]. The bandwidth of the dye
laser is the same as that of argon-pumped dye
lases. Because of their large beam cross-
section (typically 1–3 cm
2
), the metal vapour
laser can be applied for PDT of large lesions
such as those occurring in the skin [46,47]
without the need to use a beam expander. As
with argon laser systems these lasers do
require a good level of technical support.
However, because of the large cross-section of
the pump-laser beam, alignment with the dye
module is not as critical as for argon lasers.
Solid State Lasers
Solid state lasers such as Nd:YAG lasers are a
more recent development in laser technology
and can be applied in PDT similarly to argon
and metal vapour lasers. They o#er more
compact design than the previous lasers with
obvious advantages for laboratory or clinical
use. They are normally pulsed at higher
rates (MHz) and shorter pulsewidths (sub-
nanosecond). These lasers normally emit a
fundamental line in the near infrared (e.g. for
Nd:YAG at 1064 nm). The output from the
fundamental line has energies of up to seven
J/pulse. Pulses from Q-switched NdYAG lasers
are 5–10 ns which translates into large peak
energies and irradiances (Table 2) and can
e$ciently undergo frequency doubling to give
lines in the visible (532 nm for Nd:YAG) or in
the UV (266 nm for Nd:YAG) with energies of
up to 50 mJ/pulse. The frequency-doubled out-
put can then be used to pump a dye laser and
obtain high power output in the region of
porphyrin absorption with the same bandwidth
as for the other laser-pumped dye lasers.
Optical Parametric Oscillators Lasers
Optical parametric oscillator (OPO) lasers can
be used for irradiation of up to several hun-
dred mW/cm
2
. OPO are solid state-based
pulsed lasers that via frequency doubling and
wave-mixing give access to a large number of
monochromatic wavelengths from the UV to
the near-IR region of the spectrum [48]. Wave-
length tunability and fluence rate for PDT are
easily obtainable with these lasers (Table 2).
Solid state lasers have been applied for PDT
of skin lesions, oesophageal cancer [39,49],
oral precancer and cancer [9,39], lung [50] and
bladder [5]. A potential future advantage of
solid state lasers compared to argon and metal
vapour is the possibility of using the near
infrared monochromatic fundamental emission
of these lasers. Indeed one of the possible
developments of PDT is the synthesis of photo-
sensitisers that can be excited in the near
infrared where radiation would penetrate
deeper into tissues and extend PDT treat-
ment to less superficial tumours. Solid state
lasers would then be one of the main sources
available.
Diode Lasers
These lasers represent a potential major
breakthrough in the widespread clinical use of
PDT. Lasers made with semiconductors are
extremely compact (Fig. 1a) yet retain high
output (Table 2). They are extremely versatile
as they can be used in CW mode or be pulsed
Laser and Non-laser Light Sources for Photodynamic Therapy 177
(picosecond to millisecond). Their bandwidth
is typically 6 nm; the power supply is also
compact and they are normally air-cooled.
These lasers are very attractive for clinical use
as they are easy to operate and portable for use
in laboratory and clinical settings. They are
normally coupled to optical fibres and are ideal
for endoscopic PDT. Diode lasers have been
used in the treatment of a variety of lesions
in the skin, oral cavity and in the eye [51],
pituitary adenomas [35], and also to treat age-
related macular degeneration [36]. The fibre
output can also be expanded for use in large
lesions in the skin. At present diode lasers tend
to o#er only a single output wavelength, which
limits their versatility. However, systems are
being developed that will allow interchange-
able laser modules with multiple wavelengths.
We foresee that in the future these lasers will
be more widely used for PDT.
Lamps
Lasers are not the only option for PDT. In
clinical settings especially, several PDT
sources now use filtered output high power
lamps (Fig. 1b,c). General maintenance of
lamps is normally easier and cheaper. In com-
parison with lasers, lamps emit a much wider
spectral output. Because of the broad emission
spectrum of lamps, a combination of narrow-
band, longpass and shortpass filters are often
required. Narrowband filters select the
irradiation wavelength within 10 nm, longpass
filters help to cut high-power UV radiation
associated with the lamp output and shortpass
filters are usually necessary to cut IR emission
from the filament which could cause heating of
the treated area and may also damage the
optics of the lamp. Although the combination
of PDT and hyperthermia (due to IR radiation)
has been suggested [52], in skin this is avoided
as hyperthermia is associated with higher
levels of pain.
Therefore, instead of a high intensity mono-
chromatic source they produce high intensity
over a larger spectral range. The superiority
of monochromatic over broadband light
delivery has not been demonstrated for PDT.
The e#ectiveness of light sources depends
on several factors, some of which can be
simplified under the concept of ‘total e#ective
fluence rate’ [53] which combines incident
spectral irradiance, tissue transmission and
the absorption properties of the photo-
sensitiser. Dosimetry is important if meaning-
ful comparisons are to be made between di#er-
ent light sources. If a laser is being used, then
the wavelength is clearly identified. This
becomes more complex with a broadband light
source and in this case the spectral irradiance
should always been given. What is required is
the e#ective photodynamic dose. Total e#ec-
tive fluence rate indicates that, for instance,
light in the green region of the spectrum may
be more e#ective within a depth of 2 mm,
beyond which red light appears to be superior
for PDT. Lamps are portable and easy to use.
They deliver light over a large area and can be
(a)
(b)
(c)
Fig. 1. (a) Example of operating diode laser (Diomed 630);
(b) example of operating tungsten filament lamp (Photocure);
(c) example of metal halide lamp (Waldmann PDT 1200).
178 L. Brancaleon and H. Moseley
coupled to large cross-section light guides and
are therefore suitable for the treatment of
large superficial lesions. Conversely the out-
put of a lamp cannot be easily coupled into
small optical fibres without greatly limiting
their power output. For these reasons the
use of lamps has been limited to skin lesion
and they have not been used for endoscopic
PDT.
Tungsten Filament Quartz Halogen Lamps
These are essentially incandescent sources
where the temperature of the tungsten fila-
ment is raised to approximately 3000K. At this
temperature there is a considerable amount of
optical radiation emitted from UV to near-IR.
The use of these lamps for PDT was introduced
by Pottier and Kennedy [54] who conducted
animal experiments using the filtered output of
a slide projector. Since then, commercial appli-
cations of the concept have been developed.
These lamps can deliver up to 250 mW/cm
2
over a wide spectrum (350–850 nm) (Table 3). A
single wavelength can be selected using com-
binations of long-pass, and narrowband filters.
The output of these sources can be coupled
into a liquid light guide (up to 1 cm in
diameter) or expanded to several cm
2
. These
lamps have been mainly employed for topical
ALA-PDT (i.e. PDT performed after topical
application of 5-aminolaevulinic acid) in
which the targeted photosensitiser is proto-
porphyrin IX whose absorption maximum is at
635 nm (see above). A representative spectral
output, recorded using a calibrated double-
grating spectroradiometer, is shown in Fig. 2.
Xenon Arc Lamps
In these lamps, radiation is provided by an
electrical arc that forms between the elec-
trodes in the presence of Xenon vapour. They
are another possible light source for PDT.
They are characterised by a broad spectral
emission (300–1200 nm) and by high output (up
to 8 W for direct exposure and up to 1 W using
a liquid light guide) leading to potential
fluence rates of several hundred mW/cm
2
.
Combination of band-pass and narrow-band
filters can be used to eliminate IR radiation
(consequently heat) and to select irradiation
wavelengths within 60 nm (Table 3).
Although many of these light sources were
assembled and used by research laboratories
[23], a number of them are also available com-
mercially. These sources have mostly been
used for PDT of non-melanoma skin cancer
and other skin disorders [23,55–58].
Metal Halide Lamps
These lamps comprise a mixture of mercury
and metal halide vapour that is ignited by an
electrical discharge. This produces a broad
emission spectrum superimposed on a series of
emission lines that depend on the gas used to
fill the bulb. These light sources are another
example of broadband lamps that can be used
to perform PDT. The emission spectrum from
one of the commercially available sources,
recorded using a calibrated double-grating
spectroradiometer, is shown in Fig. 3. Selec-
tion of the waveband can be achieved with
filters to obtain spectral output in the 590–
720 nm range (Fig. 3). The irradiance range is
between 10 and 250 mW/cm
2
and the treat-
ment area is potentially large (up to 20 cm in
diameter) (Table 3). Unlike xenon arc and
tungsten filament lamps, these sources are
always used for direct exposure rather than
coupled into a large core liquid light guide.
Like the other broadband sources, metal
halide lamps have been mostly employed in
PDT of superficial lesions such as non-
melanoma skin cancer [47,59], vulval intraepi-
thelial neoplasia [60,61]. Although most of
these lamps have been home built [47], exam-
ples of commercial metal halide lamps can also
be found.
Phosphor-coated Sodium Lamp
The working principle of this lamp is similar
to the metal halide lamps where an electric
Fig. 2. Emission spectrum of the Photocure PDT Lamp
(Tungsten filament lamp). The spectrum was recorded in our
laboratory using a calibrated double-monochromator spectro-
radiometer.
Laser and Non-laser Light Sources for Photodynamic Therapy 179
Table 3. Types of lamps available for clinical PDT
Wavelength(s) Bandwidth Irradiance Light delivery
Tungsten filament 400–1100 nm 10–100 nm (depending on filters used) Up to 250 mW/cm
2
or
typically up to 1.8 mW/cm
2
/nm
Direct or via
liquid light guide
Xenon arc 300–1200 nm 10–100 nm (depending on filters used) Up to 300 mW/cm
2
or
typically up to 3 mW/cm
2
/nm
Normally liquid light guide
Metal halide Depending on the metal,
lines between 250–730 nm
(can be phosphor coated)
10–100 nm (depending on filters used) Up to 250 mW/cm
2
or
typically 1.2 mW/cm
2
/nm
Direct or liquid light guide
Sodium (phosphor coated) 590–670 nm 10–80 nm (depending on filters) Up to 100 mW/cm
2
Direct illumination
Fluorescent 400–450 nm Approximately 30 nm Up to 10 mW/cm
2
Direct illumination
180 L. Brancaleon and H. Moseley
discharge is produced in the presence of
sodium vapour. The surface of the bulb is
coated with phosphors that absorb the sodium
lines and emit in a di#erent region acting
similarly
to the dye lasers described previously. The
spectral output includes wavelengths in the
590–670 nm region and the intensity is in
the 25–100 mW/cm
2
range (Table 3). Similarly
to the metal halide lamp, the area illuminated
is large (up to 100 cm
2
) and it can be used to
perform PDT of skin lesions [62].
Fluorescent Lamps
These sources represent a di#erent approach
to PDT. As discussed above, light sources for
PDT were developed to emit in the 600–700 nm
region as in this region the photosensitisers
currently used in therapy or clinical trials
have one of their absorption maxima and light
penetrates deeper into the tissue allowing
treatment of thicker lesions. As described
earlier photosensitisers have a more intense
absorption band in the region between 400 and
450 nm (Soret Band). Fluorescent lamps have
been developed to match this region of the
spectrum. Higher absorption coe$cients of
the PS produce equal or higher e$ciency of the
photodynamic e#ect with a lower concen-
tration of the drug in the tissue (smaller
amount of drug administered either topically
or systematically). Treatment, however, is
limited to very superficial skin lesions since
the penetration of light between 400 and
450 nm is approximately 300–400 m. Fluor-
escent lamps for PDT have a maximum near
4175 nm and bandwidth of 30 nm. The power
output is only 10 mW/cm
2
but their ease of use
can be attractive for clinical settings. Their
spectral characteristics match the absorption
of protoporphyrin IX and their use has been
limited to topical ALA-PDT of superficial skin
lesions [63].
Laser vs. Lamp
As briefly discussed earlier, to date there has
not been a thorough comparison between
lasers and lamps in treating the same type of
tumours in vivo and only sporadic studies have
been reported [47,64,65]. We believe that such
a comparison is fundamental for the develop-
ment of PDT, and in our group, studies are
ongoing on this particular topic. Lasers
provide a monochromatic, very powerful
source of light that can reduce the time neces-
sary to deliver the final PDT dose. Because
they are monochromatic the choice of laser
wavelength becomes crucial as it must be
matched with the often narrow absorption
band of the photosensitiser (see Table 1) with
the result that one laser can only be used in
combination with one (or a limited number)
PS. On the other hand, lamps provide a broad
range of wavelengths at reduced fluence rates.
Since most investigators limit fluence rates to
relatively low values of 100–300 mW/cm
2
,to
avoid thermal e#ects, the use of lamps does not
necessarily produce a dramatic increase in the
time required for the treatment. Because of
their broad emission, lamps can be used in
combination with several PSs with di#erent
absorption maxima within the emission
spectrum of the lamp. So, the same lamp could
be used for PDT with Foscan, Photofrin or
ALA (Tables 1 and 2). Moreover, lamps
normally also excite the region where photo-
products absorb. Although the role of photo-
products in PDT is unclear, it is possible that
some additional PDT e#ect can be obtained by
photoproducts themselves. Lasers at present
are the only possible light source to treat
malignancies located in sites that can be
reached only with optical fibres. Beam quality,
dedicated optical accessories and power out-
put are among the characteristics that make
lasers the only real choice if light has to be
coupled to an optical fibre with cores smaller
than 500 m in diameter. Because of the possi-
bility of using light di#users of di#erent shapes
and microlenses to produce uniform collimated
Fig. 3. Emission spectrum of the Waldmann PDT 1200
Lamp (metal halide lamp). The spectrum was recorded in our
laboratory using a calibrated double-monochromator spectro-
radiometer.
Laser and Non-laser Light Sources for Photodynamic Therapy 181
beams, lasers are also suitable for use in direct
illumination of lesions located in accessible
sites (such as skin or oral cavity). Lamps on
the other hand cannot be used in combination
with small optical fibres because of the poor
beam quality, large beam size and small power
density. They can, however, be used direct or
coupled to a liquid light guides of between 5
and 10 mm in diameter. Moreover, compared to
lasers, lamps are normally less expensive and
more user friendly. Because of their character-
istics lamps are well suited for treatment of
accessible lesions especially for larger skin
lesions (with or without the use of liquid light
guides).
Other Sources
With constant advancement in photonics tech-
nology, new sources are constantly developed
and will be available in the near future for
large-scale use in PDT.
Light Emitting Diodes (LED)
In the past few years the development of LED
has advanced them to a stage where their use
in phototherapy (and PDT in particular) is
possible. LED would o#er several advantages
for clinical and laboratory use. The choice of
emission wavelength ranges from UVA
(350 nm) to near infrared (1100 nm). The band-
width is 5–10 nm and the power output can
provide up to 150 mW/cm
2
over an area of
approximately 20 cm
2
(Table 3). The power out-
put can still be a limiting factor in their
widespread use for PDT, however further
improvement in their technology could
improve this aspect. Two major characteristics
in favour of the use of LED are price and
versatility. LED are inexpensive (in compari-
son with all the other sources described so far),
therefore they can be arranged in arrays to
irradiate large areas. They can be powered by
batteries, making them totally and easily port-
able. Moreover, they can be arranged in di#er-
ent geometric combination to compensate for
di$cult anatomic areas (non-melanoma skin
cancer for instance tends to occur in the face
and the head where large curvatures may
reduce the e$cacy of other light delivery
systems). Prototypes for the use of LED in
phototherapy and PDT are currently under
development.
Femtosecond Solid State Lasers
The use of femtosecond lasers has been
proposed for possible two-photon PDT.
Femtosecond lasers are presently used for
two-photon excitation in several advanced
research areas (microscopy and spectroscopy
[66]). Two-photon excitation is based on the
observation that when the incident light is
characterised by a high photon density two
photons of equal energy can be simultaneously
absorbed by a chromophore [67] to excite an
electron to an energy level that is equal to the
sum of the energy of the two absorbed photons.
Therefore, for instance, the excitation of
porphyrins in the 400–450 nm region can be
obtained using light of high photon density in
the 800–900 nm region. To obtain such high
photon density, however, the laser has to emit
a large number of photons during a very short
pulse and the emitted photons have to be
focused into a very small volume. These char-
acteristics match the current femtosecond
solid state lasers (Table 4), that have high
energy, very short pulses and can be focused
into very small (1–5 m
3
) volumes creating
the necessary photon density to produce two
photon absorption. It has been shown that
two-photon excitation can be achieved in
tissues and in vivo [66]. The advantage intro-
duced by these lasers is related to the exci-
tation wavelength. The incident radiation
would be in the near infrared and as a result
its penetration into the tissue would be much
Table 4. Examples of new sources potentially useful for clinical PDT in the near future
Wavelength(s) Bandwidth Irradiance
Pulse
duration
Light
delivery
Solid state lasers
for two photon
PDT
Near infrared Monochorom 1 W in a volume
of approximately
5–10 m
3
0.1–10 ps Direct, scanned
over the lesion
LED Visible and infrared 5–10 nm Up to 150 mW/cm
2
CW Direct
182 L. Brancaleon and H. Moseley
larger [33,34,66] and would increase the depth
of PDT. Despite this attractive advantage
especially for the treatment of less superficial
lesions, their current limitations outweigh the
advantages. Femtosecond lasers are di$cult to
maintain and to operate and would require
additional specialised personnel. More import-
ant, however, is the necessity of scanning the
beam over the lesions. Because two-photon
absorption occurs within a very small volume
the treatment of a lesion would require raster
scanning the incident radiation over the lesion
with additional technical problems and longer
treatment time.
CONCLUSIONS
The choice of photosensitisers for PDT is still
limited compared to the choice of laser sources
available for treatment and the process for
approval of new photosensitisers has proven
extremely lengthy. Nonetheless, the wide-
spread availability of potentially useful light
sources means that PDT is no longer limited to
centres with high technical expertise; rather it
is now a treatment option, which may be ex-
ploited more widely. Historically, large com-
plex lasers were required for PDT, limiting its
use to centres that could provide the necessary
technical support. In clinical settings these
lasers have been replaced by reliable, easy-to-
use light sources which no longer require com-
plex technologies and expensive maintenance.
This means that PDT can become widely avail-
able as a realistic treatment option and it is
likely that the interest in this therapeutic
modality will increase. The targeted organ,
photosensitiser, reliability, ease of use, cost
and space are the most important variables
that need to be considered in a clinical setting.
In the past decade there has been renewed
interest in the development of both laser and
non-laser light sources for PDT and more
patients will be able to benefit from this
treatment.
ACKNOWLEDGEMENTS
The authors would like to thank the Barbara Stewart
Scottish Laser Centre Trust for Cancer.
APPENDIX
In this appendix we will summarise some of the makers of
light sources for PDT. We acknowledge the fact that light
sources with the proper characteristics for PDT can be
assembled by the investigators in laboratory or clinical
settings, nonetheless we list commercially available
sources specifically designed for clinical PDT. This review
does not intend to advertise one product rather than
another and does not state the superiority of one particu-
lar product. The list is as complete as possible (to our
knowledge) and is limited to companies that advertise
their product for specific PDT application. We apologise if
some manufacturers are not listed.
Lasers
Argon and argon-pumped dye lasers
Coherent Inc., Santa Clara, CA, USA
(www.coherentinc.com)
Spectra-Physics, Mountain View, CA, USA
(www.spectraphysics.com)
Metal vapour and metal vapour-pumped dye lasers
Oxford Lasers, Oxford, UK
(www.oxfordlasers.com)
Solid state
Laserscope, San Jose, CA, USA
(www.laserscope.com)
Coherent Inc., Santa Clara, CA, USA
(www.coherentinc.com)
Diode Lasers
Diomed, Cambridge, UK and Andover, MA,
USA (www.diomed-lasers.com)
Applied Optronics Corp., South Plainfield,
NJ, USA (www.appliedoptronicscorp.com)
Coherent Inc., Santa Clara, CA, USA
(www.coherentinc.com)
Oxford Optronix, Oxford, UK
(www.oxfordshire.co.uk)
Ceramoptec, Bonn, Germany
(www.ceramoptec.com)
Carl Zeiss, Oberkochen, Germany
(www.zeiss.de)
Two-photon technology
Coherent Inc., Santa Clara, CA, USA
(www.coherentinc.com)
Lamps
Tungsten filament
MBG Technologies (Lumacare),
Newport Beach, CA, USA
(www.mbgtech.com or www.lumacare.com)
Photocure, Oslo, Norway
(www.photocure.com)
Xenon arc
Photo Therapeutics, Altrincham, UK
(www.phototherapeutics.co.uk)
ESC Medical Systems, Yokneam, Israel
(www.escmed.com)
Metal halide
Waldmann, Villingen-Schwenningen,
Germany (www.waldmann.com)
Phosphor-coated sodium
Medeikonos, Goteborg, Sweden
(www.medeikonos.com)
Fluorescent
Dusa Pharmaceuticals, Wilmington, MA,
USA (www.dusapharma.com)
Laser and Non-laser Light Sources for Photodynamic Therapy 183
LED
PRP Optoelectronics, Towcester, UK
(www.prpopto.co.uk)
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Paper received 18 June 2001;
accepted 6 December 2001.
186 L. Brancaleon and H. Moseley
