The use of microscopic patterns of injury and sparing described by Manstein et al.1 created a new way of skin resurfacing and “photorejuvenation”. Fractionated laser methods stimulate skin remodeling with rapid post-treatment healing, reducing down-time. Therefore, several varieties of “fractionated” systems suddenly became popular offering a number of different options: there are scanning to stamping mode devices, non-ablative and ablative systems. To date, all fractionated laser treatments utilize water as the primary chromophore, with consequent dermal remodeling. However, it is expected that in future, those devices will evolve to “smarter” versions that would be able to destroy specific targets, much as a “smart bomb” is guided to a target.

Biological pathways and responses involved in the fractionated treatments are not fully understood. Skin tightening has been well described,2,3 but it is not known if fractionated treatments can reduce or expand the tissue. Fractional photothermolysis may, or may not, actually rejuvenate skin by forcing renewal and replacement of senescent tissue. Could fractionated treatments be used to treat or expand other solid organs? Could they be used to regenerate neurons, muscle, liver or any other vital cells? Remarkably, up to 50% of skin can be killed or ablated (vaporized) in a treatment session by fractionated treatment, with no apparent scarring or loss of functionality. It is not impossible that fractionated treatments could promote solid organ “rejuvenation”.

Ablative fractional skin treatment may also provide drug delivery (Fig. 1). This has been described in a small pilot study using fractionated non-ablative laser to enhance photodynamic therapy benefits for skin rejuvenation.4 Potentially, fractionated treatment could help treating any deep skin process including: tumors, recalcitrant hyperkeratotic psoriasis, granulomatous diseases, infections and deep mycosis or delivering vaccines.

Surgical sutures are the most common method for tissue reconstruction and repair. However, both common sutures and staples are not able to prevent fluid leakage, may cause foreign body reactions and scarring, and often require return visits for removal. Synthetic glues and electrical or laser-induced thermal welding may provide immediate tissue bonding but they can also induce scarring or foreign body reactions. Other types of sealants (fibrin and collagen-based) are expensive and not popular among clinicians.

Photochemical tissue bonding (PTB) has recently been created by Irene Kochevar and colleagues using rose-bengal as a photosensitizer and green light for photochemical activation (Fig. 2). The photosensitizer is totally reabsorbed into the body, causes little irritation and has no other known side effects. PTB causes collagen at tissue surfaces to cross-link during about 5 min of light irradiation, yielding a bond with less inflammation or scarring. Preclinical studies for blood vessel, nerve repair,5 cornea,6–8 and skin9,10 have been presented. Interestingly, nerve repair with PTB in combination with human amniotic membrane was shown to be more efficacious than common suture for functional recovery. In comparison to standard sutures, the photochemically sealed amnion wrap also improved histological recovery.5 This novel light-activated method of tissue repair may potentially produce better appearance and functional recovery.

Photodynamic therapy consist of delivering a light-activated drug or precursor, that after light irradiation reacts with oxygen producing free-radicals such as singlet oxygen and other reactive oxygen species (ROS). The ROS damage certain “targets” in tissue, by inducing apoptosis, necrosis, or activating local inflammatory/immune responses.

Many photosensitizers (PS) are currently available for medical use; in dermatology, psoralens, methylene-blue, aminolevulinic-acid (ALA) and its derivatives, porphyrins and porphyrin-derivatives are the most commonly used and studied for various conditions including actinic keratosis, cancer, vascular mal formations, inflammatory diseases, acne, infections, and more. The potential versatility of PDT is impressive.

The use of light with or without combination of a drug was used even by ancient civilizations in Egypt, India and China to treat skin diseases. Since then, photodynamic therapy (PDT) has become a popular modality of treatment in various systems and organs. However, even with increasing promise and many publications, the clinical impact of PDT has been modest. This is likely to change.

In order to increase efficacy and reduce side-effects, different approaches have been described to improve photosensitizer (PS) delivery and accumulation into targeted structures.11 The development of PS that can penetrate easier into the plasma cell membrane is underway, e.g. by changing molecular physico–chemical properties, with consequent increased and faster local drug accumulation.12 An example is the use of alkyl-esters of aminolevulinic acid (ALA) with higher lipophilicity such as the methyl, propyl and hexyl-esters of ALA12; or the use of liposome-encapsulated molecules, oil-dispersions or polymers.13,14 Some of these new molecules are being studied in pre-clinical studies and in phase I and II clinical trials in the US and Europe.

Another strategy for selective PDT is by changing or modulating the target environment. For example, it is possible to inhibit the accumulation of PS in normal surrounding areas while increasing the amount of PS or its photodynamic effect within the targeted structures. When using ALA and ALA-derivatives to produce PDT, the drug has to be metabolized into porphyrins, especially protoporphyrin IX (PpIX). PpIX is the active PS. PpIX accumulation has been demonstrated to be dependant on heme synthesis enzymes, iron stores, and many other variables. By modulating those variables it is possible to control and produce selective targeting (Fig. 3). Table 1 summarizes different methods to modulate porphyrin-induced PDT that can be used to select tissue targeting.

One example is the use of temperature to control tissue targeting. Since most enzymes are temperature labile, Joe et al. demonstrated local inhibition of PpIX accumulation when temperature is lower than about 20°C, and an increase in PS at temperatures above 37°C.20 Thus, a simple temperature gradient in skin could possibly localize photosensitizer in target tissue and spare normal surrounding areas.

Finally, selective-PDT can be produced by a PS that will actively bind to specific cell-targets, for example, by combining a PS with monoclonal antibodies,27 in a method called photoimmunotargeting (PIT).11 PS can be synthetically conjugated to antibodies or aptamers that deliver the PS by binding to specific molecular markers. Those markers can be located on target cells (e.g. cancer), in cells involved in development of the disease, or in the cells effecting immune response. The use of these “new generation PS” could potentially enhance efficacy and reduce side-effects. However, new drugs often take a long time to reach clinical use.

In general, the simple understanding of the mechanisms of action of PDT and pharmacological aspects of PS can be used for selective targeting: by passive methods, by target modulation or by active targeting using conjugated PS into cell markers. The development of these techniques is promising and will create more efficient treatments.

The use of low-level light therapy (LLLT) has been described for pain treatment, anti-inflammatory effect, wound healing, infections and many other indications, amid certain skepticism among scientists and clinicians. Recently, excellent studies have been published suggesting clinical efficacy and explaining some of the molecular biological mechanisms involved. So far, the exact response pathways are not completely known, but evidence points toward photochemical modification of mitochondrial functions. There are many variables involved such as light wavelength, irradiance, pulsing, and delivered light dose. The understanding of these factors is fundamental for choosing appropriate clinical indications and optimal parameters. It is also important to note that different cell types might respond differently to light.

There are many possible primary chromophores identified in the LLLT process, especially in mitochondria28 (Table 2). Several mitochondrial signaling pathways can be changed such as: redox sensitive pathway, cyclic AMP-dependant signaling, nitric oxide control of respiration and other pathways.28,36

In dermatology, LLLT has been used but not yet well developed or optimized for given applications. Hopefully this will ensure based on great evidence.