Laser-Assisted Delivery of Therapeutic Agents

Jill S. Waibel

Ashley Rudnick

Peter R. Shumaker

KEY POINTS

The recent increase in the use of ablative fractional laser devices has fostered enthusiasm for laser-assisted delivery (LAD) of medications and other agents. LAD holds enormous promise in the management of scars and a multitude of other disorders.
Medications and other agents have generally not been formulated specifically for this route of delivery and current use in this manner remains predominantly “off-label.”
Extensive future research is required to establish safety, efficacy, dosing, timing, combinations, and other parameters related to LAD.

Survival after severe burns and other trauma has improved dramatically in the United States and elsewhere in the developed world. New strategies are required to manage increasing numbers of patients with functionally and cosmetically debilitating scars. Multispecialty collaboration, innovative therapies, and novel combinations of existing treatments can help ensure optimal patient recovery. Ablative fractional laser-assisted delivery (LAD) of medications and other agents beyond the epidermal barrier is a prime example of one of these innovative combination strategies.

Scar rehabilitation is the attempt to restore form and function to patients. Well-established therapeutic approaches include, but are not limited to, physical therapy, compression, silicone sheeting, corticosteroids, laser therapy, and surgical revision (e.g., Z-plasty, grafts) in severe cases or those refractory to conservative measures (see Chapters 10, 12, 13, and 19). Leading the way in recent years are lasers, which are precise and effective treatment modalities to rehabilitate and consistently improve scars. Evidence for the efficacy of laser treatment alone is accumulating rapidly in the literature,¹,² and new synergistic combinations are being explored.

Topical application of selected medications through intact skin for their local effects or for systemic absorption is routine. However, the epidermis provides an efficient barrier that limits this type of delivery to molecules of a narrow range of specific characteristics including size and fat solubility. LAD, predominantly associated with ablative fractional lasers, is a novel delivery method that enables the treating physician to uniformly distribute larger molecules and even cells through narrow channels to the desired depth in cutaneous tissue. Fractional lasers are the first platforms that allow operators to select the depth of treatment, and as long as the diameter of the channels are below a certain threshold (likely <500 µm),¹ they heal rapidly in 1 to 2 days without scarring. Thus, LAD may provide multiple advantages including delivery of larger quantities of existing topical medications to a precise depth, efficient transcutaneous delivery of large molecules previously not amenable to the transcutaneous route, and even reliable systemic administration for a broader variety of agents. With regard to scars, these channels may be used in the immediate postoperative period to deliver drugs and other substances to synergistically enhance the local therapeutic and remodeling response.

Background

Topical drug delivery is essential in the treatment of dermatologic disease. However, therapeutic benefit is often ultimately limited by the absorption of the medication through intact skin. When a drug enters and remains within the skin it is called penetration. This is how most topically applied drugs function to improve dermatologic disease. Transdermal delivery means a drug has crossed the skin barrier and entered the bloodstream. Transdermal patches have been used since the 1970s, but are limited to drugs with low molecular mass (<500 Da) and high lipophilicity and typically address dermatologic conditions for delivery of medications.³,⁴,⁵ Traditional strategies to enhance topical drug delivery include chemical (solvents, surfactants), biochemical (nanoparticles, liquid synthesis inhibitors), and physical (tape stripping, sonophoresis, microneedling) methods. Chemical modifications are the most commonly utilized today and include approaches to remove or alter the stratum corneum. These have had variable success with improving drug delivery. The stratum corneum, the
outermost layer, serves as the primary rate-limiting barrier for percutaneous penetration and typically only 1% to 5% of topically applied drugs are absorbed.³ Furthermore, many medications are too large to penetrate intact skin and require either intralesional injection or systemic delivery.

LAD is an evolving modality that was first described in the literature in 2002 using full-field ablative devices.⁶ Fractional ablative lasers, typically either the 10,600-nm carbon dioxide (CO₂) or the 2,940-nm erbium:yttrium aluminum garnet (Er:YAG), first emerged around 2007 and provide a novel way to create a conduit in the stratum corneum, epidermal, and dermal layers in a rapid, predictable, and controlled pattern. Both CO₂ and Er:YAG platforms are infrared lasers that target water, heating tissue rapidly to over 100°C and causing vaporization in a precise manner on a micron scale. Ablative fractional resurfacing creates narrow vertical channels of ablation surrounded by thin layers of coagulated tissue (see Chapter 13). These channels serve as access points for drug delivery and allow for transport of actives deeper into the skin. Topical drug delivery has several potential advantages over traditional oral medication. In the management of dermatologic disease, topical administration of therapies directly to the skin may limit systemic toxicity and decrease the amount of drugs required for therapeutic effects. In addition, drug degradation by first pass metabolism through the liver via the gastrointestinal system can be avoided.

Clinical Applications

LAD with ablative fractional laser pretreatment has already been reported and evaluated in animal models and clinical studies for a variety of dermatologic conditions including actinic keratosis and nonmelanoma skin cancer, cutaneous infections, inflammatory conditions, anesthetic delivery, scar management, and wound healing. Associated dermatologic drugs and other agents have included lidocaine, 5-aminolevulinic acid, methyl-5-aminolevulinate (MAL), ascorbic acid, diclofenac, ingenol mebutate, imiquimod, methotrexate, minoxidil, diphencyprone, vaccines, 5-fluorouracil (5-FU), triamcinolone acetonide (TAC), platelet-rich plasma, and poly-L-lactic acid (PLLA).⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹,²²,²³,²⁴ The potential applications are enormous and this incomplete list will rapidly grow much longer in the months and years to come.

FIGURE 14-1 A: Histology after 1,550-nm nonablative fractional laser treatment showing dermal coagulation but no corridors. B: Histology after Er:YAG 2,940-nm ablative fractional laser treatment showing open channels creating a pathway for topical penetration of drugs, cells, and cosmeceuticals into the dermal compartment.

Laser Selection for LAD

Ablative lasers are generally considered superior to nonablative lasers for LAD, although studies in this area are limited.²⁵ The general mechanism and rationale is best understood by examining immediate postprocedure histology (Fig. 14-1A and B).

Among the ablative lasers, comparative studies between CO₂ or Er:YAG platforms are lacking. CO₂ platforms are generally associated with a somewhat thicker surrounding rim of coagulated collagen around the ablative columns because of a significantly lower associated absorption coefficient for water and relatively greater degree of heat diffusion compared with Er:YAG. Does the larger coagulated rim associated with CO₂ lasers decrease absorption potential through the channel wall? Does the relative increase in bleeding associated with Er:YAG lasers interfere with the amount of drug placed into the channels? The clinical significance of these and other characteristics are not yet fully known, and future studies are required to match the optimal platform with the desired application.

Technique for Ablative Fractional LAD in Scar Management

Ablative fractional lasers are the first platforms to offer tunable depths of penetration and microcolumn density. The physician may therefore tailor depth and density settings “on the fly” to attempt to optimize treatment for the given clinical application, agent, and location. Initial data on the influence of laser channel depth and density on drug delivery has thus far been counterintuitive. It appears that topical delivery may be optimized by relatively modest energy and density settings, with diminishing returns
above a certain threshold. This has positive implications for the potential tolerability of LAD in the outpatient setting. Studies of the effect of laser parameters on drug delivery in the setting of scars are somewhat limited. Furthermore, the variability of epidermal and collagen thickness and vascularity in scar tissue compared to normal skin may alter these relationships and mandate future studies specifically directed toward scar management. As more is learned about how far each individual agent studied diffuses, it will allow for optimal choice of parameters. Delivery of every drug, cell, and cosmeceutical will vary somewhat based on its inherent properties such as size, diffusion coefficient, skin disease, and other factors.

Laser Parameters: Depth of Treatment

Bachhav et al.²⁶ used an in vitro porcine model to study the effect of Er:YAG laser pretreatment on lidocaine delivery. The authors found that greater fluences did result in greater associated channel depths. However, beyond a threshold of approximately 200 µm of penetration into the dermis, greater fluence did not result in greater lidocaine permeation at a fixed number of channels. The authors concluded that lidocaine delivery is enhanced with LAD, but the transport was independent of fluence once in the dermal compartment. This suggests that even relatively low fluences may be sufficient to enhance lidocaine delivery. In another LAD study involving lidocaine in a porcine model, Oni et al.¹⁸ hypothesized that greater channel depth would lead to greater transdermal absorption. This experiment tested fractional ablative channels at 25, 50, 250, and 500 µm of depth. Results revealed that maximum absorption occurred at a depth of 250 µm. The authors concluded this may be due to the presence of a vascular plexus between 100 and 300 µm in depth in porcine skin. Haak et al.⁷ studied the impact of laser channel depth after fractionated CO₂ laser pretreatment on the delivery of MAL in a porcine model. Test sites included laser channels ranging from 0.3 to 2.1 mm in depth. The authors found that fractional pretreatment accelerates protoporphyrin IX accumulation, but that increasing the depth of dermal penetration did not affect accumulation.

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