Light-emitting diodes belong to the solid state device family known as semiconductors. These are devices which fall somewhere between an electrical conductor and an insulator, although when no electrical current is applied to a semiconductor, it has almost the same properties as an insulator. Simply explained, light-emitting semiconductors or diodes consist of negative (N-type) and positive (P-type) materials, which are ‘doped’ with specific impurities to produce the desired wavelength. The n-area contains electrons in their ground or resting state, and the p-area contains positively charged ‘holes’, both of which remain more or less stationary (Fig. 1a–c). When a direct current electric potential with the correct polarity is applied to an LED, the electrons in the N-area are boosted to a higher energy state, and they and the holes in the P-area start to move towards each other (Fig. 1d), meeting at the N/P junction where the negatively-charged electrons are attracted into the positively-charged holes. The electrons then return to their resting energy state and, in doing so, emit their stored energy in the form of a photon, a particle of light energy (Fig. 1e). The wavelength emitted is noncoherent, ideally very narrow-band, and depends on both the materials from which the LED is constructed, the substrates, and the p-n junction gap. Table 1 shows a list of the main substrates and associated colors. Figure 2 shows the anatomy of a typical dome-type LED. These can be mounted on circuit boards at regular and precise distances from each other to provide an LED array, part of which is shown in Fig. 3. However, the latest generation of LEDs actually form part of the board (so-called ‘on-board’ chips) which are much more compact than the dome-type LED and more efficient.

The laser is a unique form of light energy, possessing the three qualities of monochromaticity, collimation and phase which make up the overall property of ‘coherence’. Monochromaticity means all the photons are of exactly the same wavelength or color; collimation means the built-in parallel quality of the beam superimposed by the conditions of the laser resonator; and phase means that all of the photons march along together exactly equidistant from each other in time and in space. Laser diodes do not have inherent collimation, but because they are still true lasers, and therefore a so-called point source, the light can be gathered and optically collimated: the humble but ubiquitous laser pointer works on this principle. Intense pulsed light is, on the other hand, totally noncoherent, with a very large range of polychromatic (multicolored) light from near infrared all the way down to blue; has no possibility of collimation with extreme divergence; and has its vast variety of photons totally out of phase. The new generation of LEDs, on the other hand, has an output plus or minus a few nanometers of the rated wavelength, and so are classed as quasimonochromatic; some form of optical collimation can be imposed on the photons which are divergent but do have some directionality; but they are not in phase. Laser energy can easily produce high photon intensity per unit area, IPLs much less so, but provided LEDs are correctly arrayed, they are capable of almost laser-like incident intensities. Figure 4 schematically illustrates the differences between lasers, IPLs and LEDs. In short, LEDs for therapeutic applications must be quasimonochromatic, be capable of targeting wavelength-specific cells or materials, have stable output, and be able to deliver clinically useful photon intensities.

There are many excellent laser and intense pulsed light (IPL) systems available to the dermatologist. Why should LEDs be considered as a viable alternative phototherapy source? The main reasons are efficiency and price. The electricity-light conversion ratio of a typical laser is very low, requiring 100 or even 1,000 of watts in to give an output of a few watts. The same applies to IPL systems, where the flashlamp has to be pumped with enormous amounts of energy to provide polychromatic light, which may however be filtered (cut-on or cut-off). Even when filtered, IPL energy is delivered over a waveband rather than at a specific wavelength. In the case of LEDs, which are quasimonochromatic and require no filtering, the conversion efficiency is very high so that very few watts at a low voltage are required to produce a clinically useful output. LEDs are much less expensive than even laser diodes. Depending on quality and wavelength, anywhere from 300 new-generation LEDs can be purchased for the cost of a single laser diode. The cost of laser and IPL systems is very high, so a much cheaper LED-based system offers the possibility to halt the ever-upward spiralling costs of health care for both the clinicians and their patients. A further advantage is the solid state nature of LEDs. There are no filaments to be heated up, and no flashlamps are required to produce light or to pump the laser medium: LEDs thus run much cooler than their extremely higher-powered cousins, so less is required in the way of dedicated cooling systems, again helping to reduce the cost. However, some cooling of LEDs is still required, especially when LEDs are mounted in multiple arrays, because as the temperature of an LED increases, its output will move away from the rated wavelength. When wavelength cell- or target-specificity is required, this could be a major problem. The solid state nature of LEDs also makes them much more robust than either lasers or IPL systems, so they tend to be able to take the sometimes not-so-gentle handling which is part of a busy clinical practice without causing either output power loss or alignment problems. Finally, LEDs can be mounted in flat panel arrays, which may in turn be joined together in a treatment head which can be adjustable to fit the contour of the large area of tissue being treated, whether it is the face, an arm, the chest or back, or a leg. Compare this potentially very large treatment area of some 100 of square centimeters with that of a laser, usually a very few millimeters in diameter, or that of an IPL treatment head, typically 1 cm × 3 cm, and the clinician-intensive nature of the latter two is quickly evident when large areas are to be treated such as the entire face. Multiple shots are required, and the handpiece has to be manually applied and controlled by the user. The LED-based treatment head can be attached to an articulated arm to make individual adjustment even easier. Heads with different wavelengths can be designed to be easily interchangeable, controlled by the same base unit. With ‘set-it-and-forget-it’ microprocessor-controlled technology, the clinician simply sets the head up over the area to be treated, following the manufacturer’s recommendations, turns the system on, and he or she can then leave the patient for the requisite treatment time and attend to other patients or tasks. Moreover, in many cases a suitably trained nurse can carry out the treatment once the clinician has prescribed it, because LED systems are much more inherently safe for the patient than lasers or IPLs.

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, phototherapy plays a very important role. If we consider the typical beam pattern of a surgical CO₂ laser in tissue, we see the range of temperature-dependent bioeffects as illustrated schematically in Fig. 5, ranging from carbonization above 200°C, vaporization above 100°C, through coagulation around 60–85°C, all the way down to photobiomodulation, which occurs atraumatically when there is no appreciable rise in the tissue temperature 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 photodamage, and athermal, atraumatic photobiomodulation. The zones are also shown in a typical CO₂ laser specimen stained with hematoxylin and eosin (Fig. 5).

Laser surgery involves all zones, but the importance of the photobiomodulative 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 better healing with less inflammation and much less postoperative pain. IPL systems, and so-called nonablative lasers, produce areas of deliberate but controlled coagulative damage beneath a cooled and intact epidermis (Fig. 6), however they also produce the photobiomodulative zone to help achieve the desired effect of neocollagenesis and neoelastinogenesis through the wound healing process in the dermal extracellular matrix (ECM). LED-based phototherapy systems, on the other hand, deliver only athermal and atraumatic effects, but are still capable of inducing the wound healing process almost as efficiently as IPLs and nonablative lasers, as will be shown in detail in a later section.

The first law of photobiology, the Grotthus-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 simply converted 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 photons, but their wavelength, 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 chromophore, but it must also penetrate deeply enough to reach enough of the target chromophores with a 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. On the contrary, penetration of light into living tissue is, however, extremely important in phototherapy, and very frequently displays characteristics which are often in discord with results produced by mathematical models, a point often totally ignored by some researchers. A favorite, but photobiologically false, axiom beloved of phototherapy opponents, is that ‘all light is absorbed within the first millimeter of tissue’. Anyone who has shone a red laser pointer through their finger, transilluminating 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. Figure 7 is based on a transmission photospectrogram of a human hand captured in vivo over the waveband from 500 nm (visible blue/green) to 1,100 nm in the near infrared.7 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 penetration depth into the tissue. It must also be remembered that the OD is not an arithmetic but a logarithmic progression, so that the difference between an OD of 4 and one of 6 is not simply 2, but 2 orders of magnitude, i.e. a factor of 100.

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 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 two wavelengths. Visible yellow at 595 nm is at the peak of the oxyhemoglobin absorption curve, and is also much higher absorbed in epidermal melanin than 633 nm, which is why the yellow light in the spectrogram did not penetrate at all well into the tissue due to competing chromophores of epidermal melanin and superficial dermal blood. Accordingly, cellular and other targets in the mid to deep reticular dermis are inaccessible to yellow light with sufficient photon intensities to achieve multiple photon absorption in the target cells. The deepest penetration was achieved at 820–840 nm in the near infrared. At this waveband, pigment is not a primary chromophore with proteinous targets 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, or low level laser therapy (LLLT) as it was also known, delivered a wavelength of 830 nm for this very reason,8 and was shown to penetrate living hands, and even bone, very successfully.9 After around 1,000 nm, water absorption once again starts to play a significant role, and in the curve in Fig. 2 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 systems at wavelengths already tried, tested and proven in the more than three decades of laser therapy application and research, so LED systems delivering 633 nm or thereabout in the visible red and 830 nm in the near infrared, and at high enough photon densities, have been reported as having significant effects on their target tissues at a good range of depths well into the mid and even the deep reticular dermis. 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. 7. From the standpoint of photobiological theory, yellow light has very good potential specificity in a number of subcellular and haematological targets, such as cytochrome-c oxidase, however its poor penetration into the intermediate and deeper dermis, where cellular targets such as fibroblasts lie, limits the practical efficacy of yellow light in living tissue. Blue light at around 415 nm has very interesting properties regarding the eradication of the bacterium Propionibacterium acnes (P. acnes) although the photoreaction is different and will be discussed later in the chapter. LED systems with many other wavelengths have been produced, but basically they have very little or no published work to back up the claims of the manufacturers. ‘Any old LED will not do’ is an axiom which must be borne in mind by the dermatologist wishing to incorporate LED phototherapy into his or her practice.

Finally, the different wavebands, visible light and invisible infrared light, have different primary mechanisms. Absor­ption of visible light photons at appropriate levels induces a photochemical reaction, and a primary photochemical cascade occurs within the cell, usually instigated by specific components in the respiratory chain of the mitochondria, the adenosine triphosphate-producing power-houses of the cell.10 Infrared photons, on the other hand, are primarily involved in photophysical reactions which occur in the cell membrane, changing the rotational and vibrational characteristics of the membrane molecules. Through subsequent activation of the various membrane-located transport mechanisms, such as the Na⁺⁺/Ca⁺⁺ and Na⁺⁺/K⁺⁺ pumps and changes in the cell permeability, changes occur in the chemical and osmotic balance in the cytosol, finally resulting in the induction of a secondary chemical cascade which gives more or less the same endpoint as the visible light photons, namely cellular activation or proliferation.11 These photoreactions are illustrated schematically in Fig. 8.

To sum up, the wavelength of a therapeutic source therefore has a double importance, namely to ensure absorption of the incident photons in 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. Wavelength is thus probably the single most important consideration in LED phototherapy, because without absorption, there can be no reaction.

Light energy travels in the form of photons. It is obvious that the more photons are incident per unit area of tissue, the greater will be the bioeffect. This incident photon intensity is called the power density, or irradiance, of a beam of light. The power density (PD) is an extremely important factor, following wavelength, and is calculated using the following formula:
where OP is the output power incident on the target in watts (W) and TA is the irradiated 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 2, where a laser with a constant incident output power of 2 W targets tissue with a range of spot sizes. 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 πr ², 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 to achieve the desired degree of multiple absorption 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 photobiomodulation. 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. 9)8 ’ 12 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 maximum 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 used on its own, will not achieve anywhere near a clinically useful photon intensity in the target tissue (Fig. 10a). When multiple LED’s are mounted close together in a planar array, however, (cf Fig. 3) and precisely positioned 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 phenomenon of interference, particularly with the physical forward- and backward scattering characteristics of red and near IR light which result in the greatest photon intensity being beneath the surface of the skin, exactly where it should be to achieve the optimum therapeutic effect (Fig. 10b). If the distance between the LEDs is too great, however, then the intensity will drop off dramatically because of the lack of interaction between the individual LED beams (Fig. 10c).

So far, 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 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 phototherapy is the energy density (ED), also known as the spectral fluence. ED is calculated as follows:
where OP is the output power incident on the target 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 phototherapy, 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 bioreaction, and this is illustrated in Table 3 where a constant dose of approximately 25 J/cm² can achieve the entire gamut of bioeffects from pure athermal photobiomodulation to severe photodestruction. The total uselessness of joules as a meaningful parameter is also illustrated: the greatest amount of energy in the table, 2,000 J, produced a phototherapeutic effect, whereas the smallest, 8 mJ (0.008 J), produced a photosurgical effect. 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 1,800 J/cm² (30 min exposure). Tissue was examined macroscopically and microscopically immediately after irradiation for any signs of damage: none was found. The wounds were closed and followed up at different 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 specimens. In pharmaceutical science, the medicine 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.

The temporal profile of a beam of light energy simply means the output mode in which the light is delivered to the target. There are two modes, continuous wave (CW) and pulsed. 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. 11a, left pane). 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. 11a, right pane). 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 ‘frequency modulation’, because an exogenous frequency (the on-off sequence) is being superimposed on the inherent frequency of the beam which is predetermined by the wavelength, each wavelength having a fixed frequency. For example, near infrared at 830 nm, visible red at 633 nm and visible blue at 415 nm have ‘built in’ frequencies of approximately 3.6 × 10⁸, 4.7 × 10⁸, and 7.2 × 10⁸ MHz. 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 photochemical cascade. At very high ev values, such as those associated with ultrashort wavelengths, such as 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.

In a true pulsed beam, from a high-powered laser, an extremely high peak power is reached in a spike-like waveform, with a very short pulsewidth, 1 ms or even in ns. The peak power may be in mega- or even gigawatts.(Fig. 11b, left pane) 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. 11b, right pane). No current LED system is capable of delivering a true pulsed beam.

PDT can be exogenous or endogenous, the better known form of which is exogenous.

Basically the majority of the information in subsections 1 and 2 has been based on the concept of photon absorption therapy

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