Different types of laser have been used for LADD. Each type is more or less effective, although it is also important to know the individual safety profile. In practical terms, we can divide the lasers used in LADD into 4 groups: (1) Fully ablative lasers, such as the carbon dioxide (CO2) laser (10 600nm) or the erbium-doped yttrium aluminum garnet (Er:YAG) laser (2940nm), whose main chromophore is water and which lead to heating and total vaporization of the skin; (2) AFLs, which are the same as the previous group, although when used fractionally, they lead to columns of thermal injury, which are microscopic treatment zones (MTZs); (3) NAFL, which are similar to the previous group and include lasers such as the erbium fiber laser (1550nm). These also produce MTZs, although in the columns, only heating of the skin is observed, with no ablation of the dermal-epidermal junction; and (4) Nonablative dermal remodelling lasers. This group includes all lasers with chromophores other than water but which have been used to induce greater drug absorption. They also include lasers for the treatment of vascular anomalies, such as the 585/595-nm pulsed dye laser or the neodymium-doped YAG laser (1064nm).15 The characteristics of AFL have led it to be the most widely studied in LADD, followed by NAFL (Fig. 1).

Figure 1.

Various types of laser used in laser-assisted drug delivery. A, Fully ablative lasers, mainly CO2 (10 600nm) and Er:YAG (2940nm). These perform full, not fractional ablation, of the epidermis, thus enabling the drug to reach the dermis. B, Ablative fractional lasers. These are a fractional version of the ablative lasers described in A. They generate microscopic ablation channels through which the drugs reach the dermis. C, Nonablative fractional lasers, such as Er:Glass 1550nm, which generate microscopic columns of coagulated tissue without ablating the epidermis. D, Nonablative dermal remodelling. This subtype includes all those lasers with chromophores other than water, which deposit energy in the area of the chromophore, generally in the dermis, as, for example, with lasers used to treat vascular anomalies, such as the 585/595-nm pulsed dye laser or Nd:YAG (1064nm). gr1.

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While the risk of adverse effects such as erythema, vesiculation, crusting, or even scarring are lower with fractional lasers than with conventional ablative lasers, these effects may appear when high fluences and densities are applied.16–18 If AFLs are used for LADD, the settings must be optimized to achieve the best results possible with the minimum risk.

The density of fractional lasers refers to the amount of tissue covered by the MTZs. The total density depends on both the number of channels and on the size of the laser beam. Initial studies with MAL, which were subsequently corroborated with other agents (diclofenac, tretinoin), showed that the concentrations of the product in skin increased with increases in density up to a maximum of 5%, at which point the concentrations stabilized.19–22 Thus, densities higher than 5% in treatment with AFL carry no clear benefits but do carry a greater risk of adverse events.

Another key parameter is the depth of the channel itself, which depends directly on laser fluence. As a general rule, we should apply higher fluences in order to reach the deeper layers of the dermis if we wish to treat conditions such as alopecia or scarring. The most superficial layers of the dermis would be appropriate for treatment of photodamage, melasma, or superficial scarring. In patients with melasma, vitiligo, or superficial nonmelanoma skin cancer, ablation restricted to the epidermis could be sufficient.23

In the case of AFLs, drug absorption is affected by the coagulation zone (CZ) surrounding the channels, as well as by total ablation depth. The area of the CZ ranges from around 50mm to 150mm, depending on fluence and, in particular, laser wavelength, and is greater for CO2 lasers (10 600nm) than for Er:YAG lasers (2940nm).24,25 The greater affinity of Er:YAG for water leads to “purer” ablation, with almost no heat given off around the MTZs, whereas in the case of CO2, a wider CZ is generated owing to the reduced affinity for water. The presence of CZs implies even greater absorption of the drug delivered across the channels, thus also explaining the superiority of AFL over modalities that do not involve the generation of heat around the channels, as is the case in microneedling.12 However, it is important to remember that the presence of CZs only reflects transmission of heat to the surrounding dermis, which may be associated with undesirable local reactions.26

Given that lipophilic substances have a greater intrinsic ability to cross an intact epidermis, the more marked effect of LADD is observed with hydrophilic substances.4 Other relevant factors that affect absorption include the vehicle used, the type of preparation, and the presence of additives or excipients. Liquid and gel formulations cross the channels produced by AFL with greater affinity than more oily formulations in the form of creams or ointments.27 This observation should be taken into account owing to the greater efficacy and the greater risk of adverse effects when these formulations are used.4

There is also some disparity between hydrophobic and hydrophilic substances and their association with penetration via the laser channels. In the case of hydrophilic substances, such as 5-fluorouracil or methotrexate, greater absorption has been detected in direct relation to AFL fluence and, therefore, the depth of the channels. However, this finding has not been confirmed in studies with hydrophobic substances such as imiquimod and lidocaine.8,9,23,28

Various considerations must be taken into account with respect to the suitability of applying topical drugs directly to the dermis. First, we must ask whether the substances and excipients we intend to use are suitable for subcutaneous application. Local hypersensitivity has been reported with the application of vitamin C serum delivered via microneedling, which led to the formation of histologically confirmed granulomas or even systemic hypersensitivity reactions.29 Under ideal conditions, we would use only highly sterile products, although not all topical products are available as such. AFL itself carries some risk of bacterial infection owing to direct exposure of the dermis, and this risk increases when we apply drugs such as 5-fluorouracil, corticosteroids, and MAL.14,17,30,31 It is important to insist on aseptic conditions for application of LADD procedures.

Another key factor in LADD is the interval between use of the laser and application of the product to the skin. It is important to remember that the microscopic channels close with time owing to debris such as fibrin, inflammatory mediators, and keratinocytes.32–34 One study showed that topical application 6hours after use of the laser increases absorption, which is most successful during the first 30minutes. However, no increase in absorption is observed when the product is applied after 24hours.35Figure 2 shows the appropriate steps for LADD and the considerations to be taken into account for each one.

Figure 2.

Laser-assisted drug delivery: steps and aspects to be taken into account. PDT indicates photodynamic therapy. gr2.

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As is the case with topical treatments, absorption of drugs using LADD depends on many characteristics that are intrinsic to the patient, the skin disease treated, and the area affected by the disease. Thus, absorption is more potent in cases of inflamed or eroded skin. Similarly, more hydrated skin exhibits greater affinity for the absorption of oily substances. Furthermore, the patient's age is important, given that atrophy, erosion, and ulceration are more likely to affect older people, who are also at greater risk of infection and take longer to recover.36 Therefore, the ideal approach would be to make a correct evaluation of the patient's skin type, since there may be some atrophy due to solar elastosis in patients with low skin types, even younger patients. In such cases, laser fluence should be reduced, and in CO2 AFL devices that allow it, pulses with a lower heat deposit should be administered to prevent pathological scarring. As for location, the drug is absorbed mainly across the transappendageal pathway through the follicles in hairy areas; therefore, the parameters for using LADD should be applied with greater caution.

Some studies report enhanced absorption of aminolevulinic acid and methyl 5-aminolevulinate assisted by various types of laser, and there are even studies that use devices such as pulsed dye lasers as light sources. In the present analysis, we are interested in those studies that use lasers to deliver photosensitizers to the dermis and thus ensure greater effectiveness with PDT. Thus, studies of the usefulness of LADD in the context of PDT—both for treatment of actinic keratosis and for superficial basal cell and squamous cell carcinoma—have reported greater rates of effectiveness, but also more adverse effects (eg, crusting, pruritus, pain, and erythema).51–60 Haedersdal et al.56 demonstrated absorption rates for MAL that were 13.8 times greater with continuous-wave Er:YAG and up to 7.3 times greater with the fractional version. Similar results have been reported from animal models based on CO2 lasers.

Triamcinolone acetonide (TCA) is one of the most widely used intralesional or subcutaneous corticosteroids in various skin diseases owing to its sustained release. The main adverse effects include atrophy, ecchymosis, telangiectasia, infection, and even ulceration at the injection site.30 Application of this agent using LADD has mainly been investigated in the treatment of pathologic scarring (hypertrophic and keloid scars) and in the sequelae of burns. While this drug has been investigated in several studies, that of Waibel et al.6 on hypertrophic scars causing functional restriction is noteworthy. The authors administered TCA using LADD (fractional CO2 laser), with 3-5 treatments every 2-3 months. Improvement was recorded not only in texture and thickness, but also for dyschromia and scar functionality. Several studies have reported similar results.37,38,61,62 Of particular interest is a study comparing effectiveness and tolerability in the treatment of hypertrophic scars using fractional Er:YAG followed by intralesional corticosteroid injections (TCA 10%) or topical corticosteroids (desoximetasone 0.25% under occlusion), with 4 sessions every 6 weeks. The results show the topical corticosteroid to be slightly more effective than the intralesional drug, although the difference was not statistically significant. The authors also reported much better scores for pain and patient preference.

Our experience shows that the combination of CO2 laser and TCA 10% applied with smooth massage during the 15minutes following application of the laser yields very good results both for hypertrophic and keloid scars and for the sequelae of burns (Fig. 3). In addition, the simple application of topical anesthetic before laser treatment ensures better tolerance than combining laser treatment with subsequent TCA injections. In the case of very vascularized erythematous scars, this technique can be combined with a previous vascular approach based on techniques such as pulsed dye laser or intense pulsed light. For this purpose, we generally use pulsed dye laser (595nm) with pulses of 0.5-6ms and fluence of 5-7J/cm2, followed immediately by AFL.

Figure 3.

Example of delivery of triamcinolone acetonide assisted by ablative fractional CO2 laser in a patient with sequelae of a facial burn. A, Before treatment. B, Pass of CO2 laser with a fractional scanner over the whole surface of the facial burn; a smoke extractor is used alongside the treatment. C, Application of injectable triamcinolone acetonide 10% solution: the solution is applied topically over the area treated with the laser. D, Extension of the corticosteroid over the whole area of the burn. E, Smooth massage to ensure better penetration of the product. gr3.

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