Treatment of facial scars is a multispecialty endeavor for optimal patient recovery. One new innovation helping in facial scar treatments are lasers. Fractional laser predictably (tunable) disrupts the barrier of the skin creating deep channels that allow the delivery of drug and cellular materials; this is called laser-assisted drug delivery (LAD). Without exception thus far, LAD has been found to enhance the local uptake of any drug or substance applied to the skin. These zones may be used postoperatively to deliver drugs and other substances to create an enhanced scar therapeutic response to drug or substance applied to the skin.
Key points
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The treatment of disfiguring facial scars has been reinvigorated with recent advances in technology.
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Laser-assisted drug delivery (LAD) is an emerging technology to achieve greater penetration by existing topical medications and drugs to reach desired targets in the skin.
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LADs allows us to alter the stratum corneum, epidermis and/or dermis to facilitate increased penetration of a drug or device to a specific target.
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This emerging concept is bridging medicine with technology; however, the drugs have not been formulated for this type of delivery and so this science is “off-label.”
Introduction
Facial Scars
There are few medical situations as distressing as that of a child or adult whose life has been permanently altered by tragedy. The profound physical, mental, financial, and psychological damage brought on by such calamitous events often are accompanied by significant scarring. When the scarring is on the face, patients have severe physical and psychological stress. The treatment of facial scars is a multispecialty endeavor for optimal patient recovery.
Current Treatments
Scar rehabilitation is the restoring of form and function in scar patients. There are multiple therapeutic approaches have been used in scar management, including surgery (z-plasty), physical therapy, compression, silicone sheeting, corticosteroid therapy, and laser therapy. Leading the way in scar treatments are lasers, which are a scientifically precise and effective treatment modalities to rehabilitate and improve scars. Laser has added a powerful tool to improve scar symptoms and deformities. Given the established benefit of lasers with scars new methods to synergistically improve scars are being studied. At the forefront is laser-assisted delivery (LAD) of drugs, molecules and cells for scar rehabilitation. LAD is a new delivery system (vs oral, intravenous) that enables physician to uniformly distribute drug, cell, or cosmeceutical in microscopic channels to desired depth in cutaneous tissue. Without exception thus far, ablative fractional laser has been found to enhance the local uptake of any drug or substance applied to the skin through any fractional ablative tunnels can be used for LAD systems of a variety of drugs, topical agents, and other living tissue. These zones may be used immediately postoperatively to deliver drugs and other substances to synergistically create an enhanced scar therapeutic response to drug or substance applied to the skin.
History of Laser-Assisted Delivery
Topical drug delivery is essential in the treatment of many cutaneous conditions. The efficacy of topical therapy depends on the penetration of viable skin. However, therapeutic benefit is ultimately limited by absorption of the medication through the skin’s inherent barrier properties. The stratum corneum, the outermost layer of the skin, serves as the rate-limiting step for percutaneous penetration and only 1% to 5% of topically applied drugs absorb into the skin.
Drugs that are semilipophilic (uncharged/nonpolar) and small (<500 Da) may pass through the stratum corneum because the corneocytes are embedded in a lipid matrix. Drugs that are lipophilic and large hydrophilic drugs are not suited for delivery through intact skin. Furthermore, many medications are too large to penetrate and currently require either an injectable or systemic delivery.
Strategies to enhance topical drug delivery include chemical (solvents, surfactants), biochemical (nanoparticle, lipid synthesis inhibitors), and physical methods (tape stripping, sonophoresis, microneedling). The most commonly used in today’s topical drug world is chemical modifications. These approaches are used to remove or alter the stratum corneum and have had variable success with improving drug delivery.
When a drug enters the skin and remains within the skin it is called penetration ; this is how most dermatology drug targets within the skin and function to improve disease. Transdermal delivery and absorption 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 a low molecular mass (<500 Da) and high lipophilicity.
Laser-assisted drug delivery
Laser-assisted drug delivery is an evolving modality first published in 2002, which may allow for a greater precision of depth penetration by existing topical medications and more efficient transcutaneous delivery of drug molecules. Fractional ablative lasers, either carbon dioxide (CO 2 ) or erbium:YAG (Er:YAG), provide a novel way to create a conduit in the stratum corneum, epidermal, and dermal layers in a predictable and controlled pattern resulting in the potential for increased penetration of topically applied molecules. Both CO 2 and Er:YAG are infrared lasers that heat skin tissue to greater than 100°C and cause vaporization. The Er:YAG has an absorption coefficient of 2 × 10 7 /cm and owing to high absorption of water it takes less energy to ablate tissue. The CO 2 has an absorption coefficient 2 × 10 6 cm −1 m −1 and takes higher energies to ablate tissue resulting in increased thermal damage compared with the Er:YAG laser.
Ablative fractional resurfacing creates vertical channels of ablation surrounded by thin layers of coagulated tissue known as microthermal zones (MTZ). The creation of these channels theoretically serves as access points for drug delivery and allow for transport of actives deeper into the skin.
LAD is a more efficient transcutaneous delivery of large drug molecules, and potentially a way of delivering systemic medication via a transcutaneous route. Topical drug delivery has many advantages over traditional oral medication. With dermatologic disease, topical administration of therapies directly to the skin limit systemic toxicity. In addition, drug degradation by the gastrointestinal system and first-pass liver metabolism can be avoided with laser cutaneous delivery.
The goals for a cutaneous delivery system include increasing the ability to attain a therapeutic target, decreasing amount of drug needed to deliver, decreasing adverse events to other organs and ease of use for patients. LAD is a new emerging concept bridging medicine with technology to improve health care.
Clinical Applications of Laser-Assisted Delivery
Various dermatologic conditions have been studied with LAD including dysplasia, nonmelanoma skin cancer, psoriasis, inflammatory conditions, local anesthesia, and scars. Studies of LAD have shown without exception that ablative fractional laser pretreatment has been found to enhance the local uptake of any drug or substance applied to the skin.
Investigated dermatologic drugs included lidocaine, 5-aminolevulinic acid (ALA), methyl-5-amnolevulinate (MAL), 5-fluorouracil (5-FU), ascorbic acid, diclofenac, ingenol mebutate, imiquimod, methotrexate, and vaccinations. Specifically in the arena of LAD of scars, compounds studied include corticosteroids, ascorbic acid, 5-FU, platelet-rich plasma, and stem cells.
Which Laser Is the Best Laser-Assisted Delivery?
Haedersdal and colleagues studied a variety of physical techniques that disturbed the stratum corneum to study which modality best enhanced protoporphyrin IX accumulation. Modalities studied included nonablative fractional laser, ablative fractional laser, microneedling, microdermabrasion, curettage, and control. Of all these modalities only ablative laser therapy has the ability to destroy the stratum corneum, epidermal and dermal layers of skin in a predictable and controlled manner, resulting in the potential for increased penetration of topically applied molecules. This study showed the fractional ablative laser was superior enhancing protoporphyrin IX accumulation in the dermis versus the other modalities.
Nonablative lasers do disrupt the dermal epidermal junction, but do not create an opening for larger molecules to gain access to the dermis. This is best understood by histologic differences between nonablative fractional lasers and ablative fractional lasers ( Fig. 1 ).
Laser Dosimetry for Laser-Assisted Delivery
To understand how to best treat facial scars with a LAD system specifically requires an understanding of basic LAD dosimetry strategies. By calibrating laser settings, it is possible to influence drug amount delivered, drug delivery rate, and drug biodistribution. Ablative fractional lasers may be tailored by laser settings including channel density, depth of the channels, as well as the coagulation around the ablated channel to increase drug deposition into targeted cutaneous levels.
Channel Density and Laser-Assisted Delivery
The definition of channel density is the ablated skin surface area. This density can be adjusted via laser spot size or the number of applied channels in a fixed scan pattern. The effect of channel density on rate and extent of drug delivery has been studied for lidocaine and MAL. Bachhav and colleagues studied the effect of channel density on permeation of topical lidocaine in an in vitro porcine model using Er:YAG fractional ablative laser. Their initial hypothesis was that increasing the number of laser channels would increase the overall drug delivery. Channel densities studied included 0 (control),150, 300, 450, and 900 channels per 3 cm 2 with a fixed laser fluence at 24 hours. There was no difference in cumulative permeation between 450 and 900 channels at 6 hours or 300, 450, and 900 pores at 24 hours. Increased permeation of lidocaine occurred with increasing channels up to 450. The authors concluded there is a minimum channel density to achieve maximum increase in drug penetration but that increasing channel density beyond this will not improve permeation. In both literature and experience, there seems to be a plateau around 100 channels/cm 2 . Low density is favored in LAD of drugs. Increasing density may increase the possibility of systemic absorption of that drug.
Laser Channel Depth Effect on Laser-Assisted Delivery
Laser depth describes the depth of the laser channels and can be adjusted by pulse energy. Higher pulse energies in fractional ablative laser give deeper ablated laser channels. Deeper channels were initially expected to induce a greater dermal uptake of drug; however, inconsistent data on the influence of laser channel depths have been published.
Early studies with lidocaine studied the effect of channel depth on rate and extent of drug delivery. Bachhav and colleagues used an in vitro porcine model with Er:YAG laser with increasing laser fluences from 150 to 200 microns. The greater fluence resulted in greater channel depth. Lower fluences in some cases resulted in removal of stratum corneum without going deeper into the epidermis and higher fluences showed channels through the epidermis and dermis, thus supporting the notion that the laser is tunable to the desired depth but probably needs to be closer to 200 microns to reach the dermis. However, this study was performed in porcine in vitro model not human. Also in this study it was noted that greater fluence did not result in statistically significantly greater cumulative lidocaine permeation with fixed channel numbers. In addition, changing the fluence did not result in greater total lidocaine deposition. The authors concluded that lidocaine delivery is enhanced with LAD, but the transport was independent of fluence, suggesting that even low fluences are sufficient to enhance lidocaine delivery.
In a well-performed porcine LAD study, Oni and colleagues hypothesized that a greater channel depth would lead to greater transdermal absorption. This experiment tested fractional ablative channels at 25, 50, 250, and 500 microns. The result of this study revealed maximum absorption occurred at 250 micron depth. Oni and colleagues concluded this may be owing to vascular plexus between 100 to 300 microns in porcine skin.
Additional research is needed, but it also seems that the drug properties affect the depth of drug delivered, depending on both how charge and hydrophobic versus hydrophilic affects transport in channels.
The optimal depth for scars most likely relates to the thickness of the scar. Scars tend to have abnormal collagen, mainly in the papillary and reticular dermis, lying between 200 and 2000 microns in depth. When treating scars, the authors recommend trying to establish and treat the full depth of the scar. Another study by Sakamoto and colleagues showed no difference in drug penetration for either low channel densities or high channel densities. An in vivo porcine model with CO 2 fractional ablative laser using 100, 200, and 400 MTZ/cm 2 densities for ALA in photodynamic therapy revealed increasing density did not enhance ALA delivery to deeper skin layers, and this may be unique to the chemical properties of ALA.
Coagulation Zone in Laser-Assisted Delivery
The coagulation zone in fractional ablative laser treatment is defined by the thickness of coagulated tissue surrounding the ablative zone. This may be adjusted with some laser systems by the total energy delivered and turning on or off coagulation. The diffusion coefficient of coagulated tissue is less than normal tissue; thus, ablative zones with coagulated tissue have a lower diffusivity. This may have an effect on drug delivery in that a thick coagulation zone may serve as a secondary diffusion barrier and create a drug reservoir in these channels, which we may find to be a positive attribute if we are aiming to delivery drug to the dermis, and do not want systemic delivery. Conversely, no coagulation zone may be better for systemic delivery goals.
Molecular Weight and Drug Diffusion in Laser-Assisted Delivery
An investigation by Haak and colleagues evaluated laser density and molecular weight of polyethylene glycols of increasing molecular weights from 250 to 4000 Da. The polyethylene glycols were applied to the skin after fractional ablative CO 2 laser at densities of 25, 100, 225, and 440 MTZ/cm 2 . Mass spectrometry and nuclear magnetic resonance spectroscopy revealed greater densities resulted in greater transdermal delivery although no statistically significant differences of greater than 100 MTZ/cm 2 . Uptake of the lowest molecular weight was favored. Haedersdal and colleagues studied in vivo LAD of MAL in a porcine model with a CO 2 fractional ablative laser. The experiment studied diffusion distances from the laser channels. They found that MAL diffused 1.5 mm from each laser channel. As more is learned about how far each agent studied diffuses, it will allow for optimal channel density. Of course every drug, cell, and cosmeceuticals diffusion will be based on its inherent properties. Physiochemical properties including size of molecule, diffusion coefficient, skin disease, and other factors affect the ability of different compounds to transverse tissue.
As much as been learned to date about laser dosimetry for LAD of drugs the interaction of the laser parameters will need to be studied and customized for each individual drug or device.
Laser-Assisted Delivery Facial Scar Technique
The majority of treatments are performed in office using topical anesthetic preparations under occlusion for 1 hour or more before treatment. Selected pulse energies are proportional to the scar thickness. Higher pulse energy settings recommend lower treatment densities of 5% to 10%. The treatment area includes the entire scar sheet and a 1- to 2-mm rim of normal skin. Within 2 minutes of stopping the laser, the drug or device is applied topically or injected in the needed area. Then, immediately after ablative fractional treatments and laser-assisted drug delivery is completed, petrolatum or a petrolatum-based ointment is applied and continued several times daily until the site is fully epithelialized, usually within 3 or 4 days. Patients may resume showering the following day and begin gentle daily cleansing with mild soap of the area at least twice a day. Patients are allowed to resume essentially normal activity after treatment. Oral antibiotics and antivirals are commonly used for prophylaxis starting 1 day before treatment and continuing for up to 1 week. Antifungal agents may be entertained on a case-by-case basis or if the patient develops localized pain or pruritus after laser treatment. When treating facial areas, viral prophylaxis should be considered. Photoprotection should be advocated, including avoidance in the early posttreatment period and application of bland sun blocks (zinc or titanium dioxide) once epithelial integrity is restored and for 12 weeks after laser therapy.
As discussed, scar therapy takes a multidisciplinary, multimodal approach for optimal success. Before, during, and after LAD therapy, other specialists including reconstructive surgeons, physical therapists, occupational therapists, and psychiatrists also treat the patient. In cases of scar contracture, participation in physical and occupational therapy is highly recommended to take full advantage of the laser effects. Compression therapy while healing from LAD with either silicone gel sheets, tight athletic wear, and/or medical compression garments.
Agents for Laser-Assisted Delivery Systems for Treatment of Facial Scars
In scars, laser ablated zones may be used immediately to deliver drugs and other substances to synergistically create an enhanced therapeutic response. Ablative channels are generally 100 to 4000 microns in depth for targeted cutaneous drug delivery. By combining laser therapy with drugs, molecules, or devices simultaneously we may achieve a more optimal clinical result in scars.
Introduction
Facial Scars
There are few medical situations as distressing as that of a child or adult whose life has been permanently altered by tragedy. The profound physical, mental, financial, and psychological damage brought on by such calamitous events often are accompanied by significant scarring. When the scarring is on the face, patients have severe physical and psychological stress. The treatment of facial scars is a multispecialty endeavor for optimal patient recovery.
Current Treatments
Scar rehabilitation is the restoring of form and function in scar patients. There are multiple therapeutic approaches have been used in scar management, including surgery (z-plasty), physical therapy, compression, silicone sheeting, corticosteroid therapy, and laser therapy. Leading the way in scar treatments are lasers, which are a scientifically precise and effective treatment modalities to rehabilitate and improve scars. Laser has added a powerful tool to improve scar symptoms and deformities. Given the established benefit of lasers with scars new methods to synergistically improve scars are being studied. At the forefront is laser-assisted delivery (LAD) of drugs, molecules and cells for scar rehabilitation. LAD is a new delivery system (vs oral, intravenous) that enables physician to uniformly distribute drug, cell, or cosmeceutical in microscopic channels to desired depth in cutaneous tissue. Without exception thus far, ablative fractional laser has been found to enhance the local uptake of any drug or substance applied to the skin through any fractional ablative tunnels can be used for LAD systems of a variety of drugs, topical agents, and other living tissue. These zones may be used immediately postoperatively to deliver drugs and other substances to synergistically create an enhanced scar therapeutic response to drug or substance applied to the skin.
History of Laser-Assisted Delivery
Topical drug delivery is essential in the treatment of many cutaneous conditions. The efficacy of topical therapy depends on the penetration of viable skin. However, therapeutic benefit is ultimately limited by absorption of the medication through the skin’s inherent barrier properties. The stratum corneum, the outermost layer of the skin, serves as the rate-limiting step for percutaneous penetration and only 1% to 5% of topically applied drugs absorb into the skin.
Drugs that are semilipophilic (uncharged/nonpolar) and small (<500 Da) may pass through the stratum corneum because the corneocytes are embedded in a lipid matrix. Drugs that are lipophilic and large hydrophilic drugs are not suited for delivery through intact skin. Furthermore, many medications are too large to penetrate and currently require either an injectable or systemic delivery.
Strategies to enhance topical drug delivery include chemical (solvents, surfactants), biochemical (nanoparticle, lipid synthesis inhibitors), and physical methods (tape stripping, sonophoresis, microneedling). The most commonly used in today’s topical drug world is chemical modifications. These approaches are used to remove or alter the stratum corneum and have had variable success with improving drug delivery.
When a drug enters the skin and remains within the skin it is called penetration ; this is how most dermatology drug targets within the skin and function to improve disease. Transdermal delivery and absorption 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 a low molecular mass (<500 Da) and high lipophilicity.
Laser-assisted drug delivery
Laser-assisted drug delivery is an evolving modality first published in 2002, which may allow for a greater precision of depth penetration by existing topical medications and more efficient transcutaneous delivery of drug molecules. Fractional ablative lasers, either carbon dioxide (CO 2 ) or erbium:YAG (Er:YAG), provide a novel way to create a conduit in the stratum corneum, epidermal, and dermal layers in a predictable and controlled pattern resulting in the potential for increased penetration of topically applied molecules. Both CO 2 and Er:YAG are infrared lasers that heat skin tissue to greater than 100°C and cause vaporization. The Er:YAG has an absorption coefficient of 2 × 10 7 /cm and owing to high absorption of water it takes less energy to ablate tissue. The CO 2 has an absorption coefficient 2 × 10 6 cm −1 m −1 and takes higher energies to ablate tissue resulting in increased thermal damage compared with the Er:YAG laser.
Ablative fractional resurfacing creates vertical channels of ablation surrounded by thin layers of coagulated tissue known as microthermal zones (MTZ). The creation of these channels theoretically serves as access points for drug delivery and allow for transport of actives deeper into the skin.
LAD is a more efficient transcutaneous delivery of large drug molecules, and potentially a way of delivering systemic medication via a transcutaneous route. Topical drug delivery has many advantages over traditional oral medication. With dermatologic disease, topical administration of therapies directly to the skin limit systemic toxicity. In addition, drug degradation by the gastrointestinal system and first-pass liver metabolism can be avoided with laser cutaneous delivery.
The goals for a cutaneous delivery system include increasing the ability to attain a therapeutic target, decreasing amount of drug needed to deliver, decreasing adverse events to other organs and ease of use for patients. LAD is a new emerging concept bridging medicine with technology to improve health care.
Clinical Applications of Laser-Assisted Delivery
Various dermatologic conditions have been studied with LAD including dysplasia, nonmelanoma skin cancer, psoriasis, inflammatory conditions, local anesthesia, and scars. Studies of LAD have shown without exception that ablative fractional laser pretreatment has been found to enhance the local uptake of any drug or substance applied to the skin.
Investigated dermatologic drugs included lidocaine, 5-aminolevulinic acid (ALA), methyl-5-amnolevulinate (MAL), 5-fluorouracil (5-FU), ascorbic acid, diclofenac, ingenol mebutate, imiquimod, methotrexate, and vaccinations. Specifically in the arena of LAD of scars, compounds studied include corticosteroids, ascorbic acid, 5-FU, platelet-rich plasma, and stem cells.
Which Laser Is the Best Laser-Assisted Delivery?
Haedersdal and colleagues studied a variety of physical techniques that disturbed the stratum corneum to study which modality best enhanced protoporphyrin IX accumulation. Modalities studied included nonablative fractional laser, ablative fractional laser, microneedling, microdermabrasion, curettage, and control. Of all these modalities only ablative laser therapy has the ability to destroy the stratum corneum, epidermal and dermal layers of skin in a predictable and controlled manner, resulting in the potential for increased penetration of topically applied molecules. This study showed the fractional ablative laser was superior enhancing protoporphyrin IX accumulation in the dermis versus the other modalities.
Nonablative lasers do disrupt the dermal epidermal junction, but do not create an opening for larger molecules to gain access to the dermis. This is best understood by histologic differences between nonablative fractional lasers and ablative fractional lasers ( Fig. 1 ).
