Principles and clinical applications of transcutaneous laser-assisted drug delivery: A narrative review

Introduction

Transdermal penetration of locally applied compounds can be enhanced by external chemical or physical sources. Research on laser-assisted drug delivery (LADD) is increasing and is geared towards enhancing transdermal drug delivery (TDD).^1,2 Other techniques that enhance TDD include curetting, dermabrasion, ion electrophoresis, pressure waves, vacuum, and Radio frequency (RF). ³ Using these modes, many drugs have been successfully delivered through the skin, including triamcinolone acetonide, 5-aminolevulinic acid (5-ALA), 5-fluorouracil (5-FU), and methotrexate.^4–7 LADD is an emerging field of dermatology. In general, LADD bypasses the cuticle and many other barrier mechanisms, thereby enhancing the penetration and intradermal diffusion of locally applied substances. ⁸ Transdermal administration is when a drug passes through the skin barrier to the bloodstream or its target compartment. External physical or chemical sources can be used to enhance TDD. Laser-assisted administration is an increasingly widely used method that uses ablative or non-ablative lasers to remove or weaken cuticle and epidermal areas in order to access the subdermis. ⁹ In 1991, Nelson et al. ¹⁰ used the mid-infrared erbium-yttrium-scandium gallium garnet laser to promote the transdermal delivery of hydrocortisone and interferon gamma. They applied an energy density of 1 J/cm2 on isolated pig skin and observed the tissue sections to find a linear relationship between laser penetration depth and pulse number. In vitro the Franz cell box was used to measure cumulative drug penetration. The laser exfoliated 12.6% of the cuticle region and increased the penetration of hydrocortisone and interferon gamma by 2.8 and 2.1 times. ¹⁰ The results of this study have inspired subsequent research.

LADD involves controlled, selective epidermal and dermal disruption to allow penetration and absorption of topical drugs and macromolecular drugs. ⁹ In dermatological clinics, LADD has been used to treat a variety of conditions, including light damage, scarring, tumors, vitiligo and other numerous indications.^11,12 However, most studies on LADD have come from animal or in vitro models. There is still much to learn about the applicability of LADD in humans, and practitioners may face new safety concerns associated with this form of treatment. Challenges in predicting efficacy and safety of LADD include the unpredictability of drug dose and possible systemic toxicity, variability in absorption, induction of local and systemic hypersensitivity reactions, and inconsistencies in treatment regimen. ¹³

The main mechanism of lattice LADD is the focal photothermal effect: laser is used to punch vertical channels deep into the dermal layer of the skin to promote drug transdermal absorption. ⁹ This characteristic can be used to treat many skin diseases with unsatisfactory effect of single external drugs. Not only can it be used to assist the transmission of some immunosuppressants and reduce adverse reactions brought by systemic absorption, but the degree of laser-assisted drug transport can also be controlled by adjusting energy and density. According to the absorption of moisture to laser wavelength and whether the skin tissue undergoes vaporization or stripping., the laser can be divided into ablative fractional laser (AFL) and non-ablative fractional laser (NAFL).^14,15 This characteristic can be used to treat many skin diseases that have had unsatisfactory results with single external drugs.

Background information

Administering drugs through the dermal route is frequently challenging because of the skin's external barrier. This barrier consists of the cuticle and the tight junction.^16,17 In the 1990s, investigators demonstrated that the transdermal bioavailability of topical drugs was approximately 1–5% of the applied dose. Some drugs faced challenges penetrating the skin to reach deeper targets, limiting their effectiveness and leading to unsatisfactory therapeutic outcomes.^10,18 On the other hand, although systematic administration may be more easily utilized by the body, it comes with the drawback of potential side effects and the mentioned influence on the skin through dose factors. It is essential to carefully consider the balance between therapeutic benefits and potential adverse effects when choosing a method of medication administration. For a topical substance to penetrate the skin, there are three pathways: intercellular movement through intercellular space, intracellular movement and intracellular movement through cellular water pores, as well as infiltration through follicular and glandular structures.^13,19

Enhancing drug delivery: Insights into common AFL

Laser activated drug penetration technology is divided into complete ablation technology and partial ablation technology. In addition to ablative mechanisms that promote drug absorption, non-ablative lasers also help improve skin drug delivery. Laser modes using surface skin ablation as a drug osmotic enhancement mechanism include excimer (193 nm), Nd: YAG (355,532,1064, or 1320 nm), Er: YAG (2940 nm), and CO2 laser (10,600 nm). YAG and CO² laser are the most popular laser drug delivery methods. ⁸ Common AFL mainly include Er: YAG laser (wavelength 2940 nm) and CO² laser (wavelength 10 600 nm), whose wavelength can be highly absorbed by water. Traditional exfoliating laser is used to exfoliate the epidermis in a continuous manner, but it is easy to cause postoperative scar, erythema and abnormal pigment. ⁵ AFL strips the epidermis in the form of a dot array. It divides a laser beam into tiny laser beams (the size of the laser spot is measured in microns) that penetrate the cuticle of the epidermis and reach the dermis, instantly removing dead tissue and creating tiny vertical channels corresponding to the beam. Surrounding it are thin layers of thermally solidified tissue that form microscopic treatment zones (MTZs). The structure provides a channel for the transport of external drugs. MTZs are surrounded by healthy skin tissue, which greatly reduces the time (1–2 days) required for the skin to return to normal barrier function after dot laser treatment. ¹² Hsiao et al.²⁰ used conventional CO² laser and lattice CO² laser, respectively, to assist the transdermal transmission of amino potassium cyclitic acid, and compared their transdermal permeability. It was found that the two laser treatments promoted the transdermal penetration of amino potassium to a similar degree. ²⁰ However, under the same energy, dot matrix CO² laser has much less damage to skin than conventional CO² laser. ²⁰ In laser-skin interactions, three mechanisms are involved in enhancing drug delivery: direct ablation, light-wave mechanism and photothermal effect. ²¹ Partial ablation breaks the skin barrier through the formation of micropores. The drug delivery molecule is then released from the carrier into the microchannel. These drugs mainly accumulate in microchannels, forming reservoirs for further diffusion. The formation of microchannels increases the diffusion area and makes the infiltration efficiency higher. The drug spreads vertically into the deeper layers of the skin. This delivery into deeper layers of the skin results in increased healing ability. In addition to vertical diffusion, drugs can also spread laterally to surrounding tissues. Light waves, which are unipolar compression waves, can be generated by various methods, not limited to lasers. The wave can penetrate the epidermis temporarily without stratum corneum (SC) ablation. ²² Photomechanical wave induced intracellular lipid destruction and lacunar dilation allow drugs to enter the deep layer of the skin. The intensity of the laser absorbed by water can be converted into heat. This phenomenon is especially important for carbon dioxide lasers. ²³ The photothermal effect destroys the skin barrier performance, allowing the drug to easily permeate the skin.

Enhancing drug delivery: Insights into common NAFL

Common NAFL wavelengths include 1440 nm, 1550 nm and 1565 nm. NAFL can also provide channels for drug delivery by producing MTZs similar to AFL. The difference is that the water uptake of the laser wavelength is less, so the MTZs are not caused by vaporizing strips of cuticle, but by normal cascading corneous layer forming in the thermal damage of columns, producing the microscopic epidermal necrosis, dermal collagen degeneration and severely damaged skin barrier function. ¹⁴ Compared with AFL, NAFL significantly reduced patients’ discomfort and shortened postoperative recovery time. Lim et al.⁵ investigated the transdermal absorption of amino acid after pretreatment with a wavelength of 1550 nm erbium glass laser. The results showed that ALA penetration was significantly increased in NAFL-treated skin compared to untreated areas.

Factors affecting laser-assisted drug transdermal delivery

Application of laser-assisted transdermal drug delivery

Other applications

In addition, LADD is not only widely used in the above fields, but also shows excellent application prospects in other aspects. ⁴² Firstly, it has shown potential for enhancing wound healing by delivering growth factors, antimicrobial agents, or other wound healing-promoting substances directly to the site of the wound. It can also be used for the treatment of hyperpigmentation conditions, such as melasma or post-inflammatory hyperpigmentation. ⁴³ By delivering depigmenting agents, such as hydroquinone or kojic acid, directly to the affected skin, LADD can help reduce the appearance of dark spots or patches. Furthermore, it can aid in the treatment of nail fungal infections (onychomycosis) by enhancing the delivery of antifungal medications to the nail bed. This approach can improve the penetration of the drugs and increase their efficacy in combating the infection. ⁴⁴ LADD has shown promise in the treatment of pruritus, a common symptom associated with various skin conditions. By delivering anti-itch medications directly to the affected areas, LADD can provide targeted relief and reduce itching sensations. ⁴⁵ In addition, Junsuwan was treated patients with botulinum toxin type A (BTX-A) for primary palmar hyperhidrosis.^13,46 Thus, Fractional CO² laser enhanced transmission of BTX-A, resulting in a reduction in sweat volume. The results show that the method has a good clinical effect.

LADD safety: Systemic reactions and toxicity

LADD has been used to deliver analgesics, antineoplastic drugs and even bone marrow stem cells into systemic circulation.^18,47 Correspondingly, drug delivery enhancement of pores or channels created by the laser raises concerns about systemic toxicity, especially when treating larger skin areas. Laser preconditioning purposefully destroys the epidermis and cuticle, thereby facilitating drug entry into the dermis and its vascular system. According to Fick's diffusion law, the rate of diffusion of a substance is directly proportional to its concentration gradient. Therefore, careful consideration of drugs and dosages is essential for effective diffusion. Marra et al. ⁴⁸ reported a case of lidocaine poisoning of the face and neck pretreated with 30% lidocaine after fractional photothermal decomposition using a 1550 nm diode pumped erbium fiber laser. Subsequent clinical studies showed that no systemic toxicity was found after 6% lidocaine was applied to the whole face with CO² or Er: YAG laser, although serum lidocaine levels were detected. ⁴⁹ In addition, Tian and colleagues⁵⁰ studied the application of fractional Er: YAG laser pretreatment in increasing the analgesic effect of compound lidocaine cream and noted positive results without systemic toxicity. But only 3-4 cm² of skin were treated. ⁵⁰ These studies showed that lidocaine was toxic after fractional photothermal decomposition.

Potential hazards and limitations

In the process of determining the safety and efficacy of transdermal drug delivery, there are still many unknown factors worth further exploration. Therefore, it is prudent to retain LADD in the topical body surface area, use drugs or products suitable for topical injection, or use topical compounds of as pure a formulation as possible. It is also prudent for physicians to use a dose not higher than the intradermal dose, bearing in mind that even intradermal injections can produce systemic side effects, such as Cushing's reaction after steroid treatment in cicatricial lesions. ⁵¹ Finally, clinicians should be aware of the systemic side effects and toxic doses of all drugs used for LADD. Therefore, in a known therapeutic area and assuming 100% absorption at a standard dose, clinicians can confidently apply the drug and any systemic absorption will be within the therapeutic and safety range of the drug. Currently, some drugs, especially hydrophilic molecules and macromolecules, have limited skin penetration problems, which can be solved with laser aid. This effect has led to the wider use of local administration. As laser can significantly increase the accumulation of drugs in the skin, it is expected to improve the treatment efficiency of skin diseases. Most LADD studies have focused on in vitro or animal platforms. Most patients who require laser-assisted intervention have skin lesions with impaired barrier function. The penetration enhancement effect of laser on skin lesions can be reduced. How lasers can still effectively enhance drug penetration of diseased skin should be understood in the near future. Of course, many clinical trials have demonstrated the effect of laser-assisted drug administration on the treatment of skin diseases, however, some clinical studies lack appropriate controls and the number of patients is limited. In order to determine the efficacy of laser-assisted drugs, it is urgent to design clinical trials carefully in the future.

The introduction of compact, portable laser devices has revolutionized the field of LADD, enabling widespread use in outpatient clinics. These portable devices have overcome the inconvenience associated with larger lasers, making it easier to administer LADD treatments in non-hospital settings. With the combined efforts of biomedical and mechanical engineering experts, it is necessary to further develop small devices that are convenient for application. Non-ablative laser enhanced drug delivery is rarely used in clinical studies. Non-ablative laser has obvious advantages because it has little damage to skin surface.

Discussion

Cuticle barrier is the main barrier to percutaneous absorption of topical drugs. There have been many studies using various methods to destroy the cuticle to enhance the penetrating effect of topical drugs, including ionization, low-frequency ultrasound, point-like acupuncture, repeated adhesive tape, etc. However, these methods have a variety of disadvantages, such as uncontrollable depth, poor repeatability, unknown side effects.^24,52 By adjusting different parameters, dot array laser can point strip tissues at different depths. Using laser that penetrates only the cuticle and superficial epidermis can increase the transdermal absorption of drugs and avoid other side effects. ³⁷ Because the penetration depth is shallow and the repair speed is fast, skin trauma will not be caused. There are no visible erythema, edema and other inflammatory reactions at the treatment site, and no other side effects will be caused.

Lattice laser parameters, including laser wavelength, laser energy, MTZ density and aperture radius, have a great impact on the efficiency of drug transdermal absorption. In addition, the physical and chemical properties of the drug itself, including molecular weight, lipophilicity, ionization properties and whether there is a nanoparticle carrier in the spatial structure, also have an impact on the drug transdermal efficiency. To optimize this parameter and find a higher and more stable laser-assisted drug transdermal system is worth further exploring and expanding its advantages.

The waveform of a laser pulse is generally not as important as its wavelength in determining its effectiveness for a particular application. However, the waveform can affect the way that energy is delivered to the target and can have an impact on the efficiency of the laser. Superpulsed lasers can emit several thousand bursts of power per second, with each burst lasting only a few nanoseconds. The waveform of these lasers is typically described as a “sharktooth” pattern. While this waveform has been associated with an increased risk of burns in some applications, it may be more effective for other applications such as cancer treatment. In terms of ablative works, such as cancer treatment, the waveform of the laser pulse may be less important than other factors such as the fluence (energy per unit area) and pulse duration. LADD is an increasingly studied and applied methodology for drug delivery. It has been used in a wide variety of clinical applications.

Most studies on dot-matrix laser-assisted drug transdermal penetration focus on in vitro or on animals, and generally use complete and healthy skin to evaluate the effect of laser assisted dermal penetration. However, in clinical practice, most skin patients requiring dot-matrix laser-assisted drug administration have various functional disorders in the skin lesions, and the effect of dot-matrix laser-assisted drug transdermal penetration may be changed in these skin lesions. At present, many clinical studies have demonstrated the therapeutic effect of LADD on skin diseases, but there are also problems such as low total number of patients (less than 100) and lack of appropriate control group. In addition, the cellular and molecular mechanisms of the laser-assisted drug osmosis mode remain unclear, and further efforts are needed to elucidate the effect of dot matrix laser irradiation on cuticle and keratinocytes.

Compared with other methods, dot array laser has more advantages in assisting the transdermal absorption of macromolecules in a less invasive way. Compared with traditional laser, dot array laser causes less damage to the skin and can restore the skin barrier function more quickly, so it is increasingly used to assist drug delivery. At present, many basic studies have proved the effectiveness and safety of dot array LADD, and this method needs to be further applied in clinical treatment of diseases in the future.

Conclusions

The prospect of topical application of therapy, bypassing the gastrointestinal and venous pathways, is an attractive approach that may have fewer systemic side effects. However, when administered through its intended route, clinicians can expect to be relatively reliable in dose and effect, thanks to the rigorous pharmacological studies and oversight that lead to the continued production of drugs and their vectors. This consistency between patient and doctor is a luxury for LADD, not a necessity. The efficacy and safety of LADD depend on the type of laser, the laser setting, the size of the treatment area, the biology of the treatment area, and the nature and concentration of the drug used. The clinician must have a firm grasp of the expected adverse effects of laser ablation, as well as the local and systemic effects of the drug or compound. For LADD to make a seamless transition from the laboratory to clinical practice, further research is needed to illuminate nuances and knowledge gaps.

BL, RS, FZ, WL, DZ conceptualized the literature search; BL, FW, LS conducted the literature search, screened titles and abstracts, and retrieved texts; XQ resolved conflicts within clusion and exclusion; BL,FW,LS.XQ extracted the data; BL, RS, FZ drafted the manuscript; all authors revised the manuscript.