Energy Delivery Devices for Cutaneous Remodeling: Title and subTitle BreakLasers, Lights, and Radio Waves

In the 10 years since our group last reviewed this topic,¹ much has changed in cutaneous lasers. Most notably, lasers not previously in routine use for dermatologic interventions have been adapted for treating the skin. Concurrently, the spectrum of potential indications for cutaneous lasers has broadened. A number of subtle alterations have guided this process. Laser experts no longer instinctively believe in a 1-to-1 correspondence between a specific emission wavelength and the desired indication. It is now clear that many different lasers of varying pulse durations can achieve similar effects given the right conditions. Another major trend in cutaneous laser therapy, and in procedural dermatology as a whole, is the proliferation of minimally invasive therapies. Finally, one of the most striking advances in cutaneous laser surgery is that the field has expanded to include nonlaser devices, including intense pulsed light (IPL), light-emitting diodes (LEDs), and radiofrequency (RF) emitters.

Many of the lasers in use in 1993 and before still play important roles in today's therapeutic armamentarium. Vascular lesions still respond to treatment with pulsed-dye lasers (PDLs), as do pigmented lesions and tattoos to Q-switched devices. When cutaneous destruction or ablation is required, the carbon dioxide laser remains without peer.

However, newer lasers and light sources account for much of patient care activity today. Among patients requesting resurfacing, nonablative therapy is chosen dramatically more often than ablative therapy. And laser hair removal, another indication that did not exist a decade ago, is the most requested laser service, although in many cases hair removal is done not in a dermatologist's office but in a laser hair center that is often unaffiliated with a dermatologist or even a physician. Laser treatment of acne, precancers and superficial cancers, psoriasis, and hypopigmentation are small but potentially growing uses for lasers. While accurate estimation is difficult, perhaps half or more of laser services delivered at present are associated with devices or indications that have become available since 1993.

In the following sections, new devices and indications associated with cutaneous laser and laserlike technologies are individually discussed. The most novel emerging technologies are emphasized.

Emitting at a wavelength comparable to that of standard narrowband UV-B radiation, the 308-nm xenon-chloride excimer laser makes possible extremely concentrated UV phototherapy.^{2 - 5} Minimum erythema doses (MEDs) in the 3 to 6 MED range and a series of approximately 2 treatments a week for a total of 3 to 4 weeks provide prolonged remission of a few lesions of localized plaque-type psoriasis. The advantages of this modality over other psoriasis treatments include reduced UV exposure of uninvolved sites (because the laser energy can be precisely directed); the likelihood that patients may avoid completely disrobing before treatment; and an overall brief treatment course of short individual treatments.

However, excimer laser treatment is not appropriate for psoriasis cases with more than a few isolated plaques of body surface involvement because the small handpiece is designed to treat very circumscribed areas. And the laser is less effective for nonplaque psoriasis. Persistent hypopigmentation⁶ after ablative laser resurfacing, striae, some scars, and vitiligo⁷ appear responsive to excimer laser treatment, but initial cosmetically significant gains are not maintained, and repeated retreatment may be necessary.

Focused UV-B energy can be delivered by not only a laser but also a noncoherent light source. The excimer laser has served as the inspiration for an even newer array of light devices that deliver radiation to the skin surface via fiber-optic cables. Intense UV-B energy delivered by means of a mercury vapor arc lamp typically spans the entire UV-B spectrum but peaks at approximately 314 nm and thus is more analogous to narrowband UV-B than to standard UV-B (B-Clear and ReLume, Lumenis Inc, Santa Clara, Calif).^{8 - 10} Apart from this difference, however, it offers many of the same benefits as the excimer laser.

Several intense light devices have emission spectra that commence just above the UV-A range. These blue lights destroy Propionibacterium acnes bacteria in hair follicles by inducing an oxidative photochemical reaction mediated by endogenous porphyrins produced by P acnes.^{11 - 15} Early results with one blue light device that emits at low intensity from 405 nm to 420 nm indicate significant reduction in acne lesion counts. The benefits are typically observed after two 15-minute treatment sessions a week for 4 weeks. While many cases of inflammatory acne respond, acne lesions appear to gradually recur over the subsequent 3 to 12 months. Another blue-light device that may have efficacy for acne has a wider spectrum, from 430 nm to 1100 nm.

Photodynamic therapy (PDT)^{16 - 17} uses light energy to selectively destroy target tissue that has previously been photosensitized to be particularly susceptible to injury. Usually, the initial photosensitization is accomplished by application of a topical photosensitizing agent some hours before treatment. The type of PDT in most common use until recently in the United States is the combination of topical 5-aminolevulinic acid (5-ALA) in 20% solution and blue light with a peak output of 417 nm and 10 J/cm². This regimen was approved by the US Food and Drug Administration (FDA) in 1999 for the "spot" treatment of actinic keratoses (AKs).

Topical 5-ALA, which diffuses into the skin and accumulates preferentially in tumors and dysplastic cells after application, is enzymatically converted into the endogenous photosensitizer protoporphyrin IX. Clinically, after the 5-ALA is applied to the target areas of the skin, patients are instructed to avoid significant light exposure for up to 14 to 18 hours, after which the pretreated skin is exposed to a light source. More recently, it has been shown that preapplication of 3 to 6 hours, or even as little as 1 to 3 hours is sufficient to effectively treat various lesions, including nonhypertrophic AK. A type of 5-ALA available in Europe, 5-ALA-methylester, appears to be relatively faster acting and may further reduce pretreatment duration before irradiation.

Many light sources have been used in PDT. Red light (630-640 nm) and blue light (400-420 nm) are commonly used to photoactivate protoporphyrin IX and thus induce an oxygen-dependent cytotoxic reaction that destroys the target lesions. Additionally, red laser pointers, argon lasers, slide projectors, and other broadband intense light devices and PDLs have been used.

Alexiades-Armenakas and colleagues,¹⁸ in this issue of the ARCHIVES, demonstrate that PDT can be accomplished with PDLs in lieu of blue light. This substitution is possible because the emission wavelengths of PDLs coincide with an absorption peak of protoporphyrin IX, the photoactive metabolite of 5-ALA. Pulsed-dye laser's suitability for PDT also derives from other relevant features, including the rapidity of treatment and the comfort and protective epidermal effects associated with cryogen spray cooling. Furthermore, long-pulse-width 595-nm PDL of the type used in the study enables purpura-free treatment, a major improvement over PDT with short-pulsed 585-nm PDL, which can leave dark bruising that regresses over weeks. The long-term remission noted by the authors is marked, with over 90% of presumed lesions of AK remaining completely cleared 8 months after treatment cessation. The provided control group of PDL alone is useful in demonstrating the efficacy of the PDT/PDL combination. In later studies, the authors may consider comparison groups of conventional blue-light PDT and wide-area cryotherapy; it would be interesting to compare the efficacies and tolerabilities of these therapies side by side.

In the treatment of AK with PDT, nonresponding lesions larger than 5 mm in diameter are recommended for biopsy because a large proportion of these may be squamous cell carcinomas. Even when there is diligent counting of thousands of presumed AKs before treatment, there is no way to be sure that the pretreatment lesions were in fact AKs unless biopsy specimens from each are evaluated, but this problem is virtually universal among therapeutic studies of AK.

Topical PDT can induce erythema, edema, scaling, crusting, and pigmentary change, as well as photosensitivity for 48 hours after treatment. Therapeutic efficacy is diminished for hyperkeratotic lesions, and the time required for a treatment can dissuade potential patients.

Photodynamic therapy has been shown to be an effective treatment for nonhypertrophic AKs. It also has potential as a means of minimally nonablative or minimally ablative skin rejuvenation, with a number of treatments with 5-ALA, in combination with PDL or IPL showing efficacy in improving skin texture and reducing dyspigmentation. A promising frontier for PDT is removal of light-colored hair because the concentration of pigment may be a lesser determinant of the efficacy of PDT than it is of conventional laser and light-based approaches.

The advent of IPL devices in the early 1990s signaled a revolutionary change in the treatment of cutaneous lesions with light sources. No longer was it de rigeur to use a laser of a specific wavelength and pulse duration to treat a particular skin complaint. Rather, a variety of lesions could be effectively reduced with an intense, pulsed, broad-spectrum, noncoherent flashlamp that used a variable filter to modulate short wavelengths. Intense pulsed light has now been shown to be effective in the treatment of vascular lesions,¹⁹ including facial telangiectasia,²⁰ rosacea-associated erythema, pigment-related lesions such as lentigines,^{21 - 22} and unwanted hair.²³ Anecdotal unpublished reports suggest that that IPL, like PDL, may be used to boost the efficacy of 5-ALA–mediated PDT for the treatment of AKs as well as photoaging.

In the initial days of IPL, the therapy was underutilized owing to the number and complexity of parameters that needed to be adjusted before treatment. Over time, early adopters of the technology became expert at calibrating IPL machines, which are now commonly available with reliable preprogrammed settings made possible by the hard work of these pioneers. Increasing ease of use coupled with the multiple beneficial effects of broadband light have collectively led to IPL's dominant position in the nonablative therapy revolution. The term photorejuvenation^{24 - 25} was coined to describe the simultaneous improvement in brown spots, red spots, and fine facial rhytids that could be achieved after a series of 5 or 6 monthly treatments with this device. While less dramatic than ablative resurfacing, photorejuvenation has much milder adverse effects, normally only transient edema and erythema and, very infrequently, mild crusting or purpura. Patients receiving photorejuvenation treatments can return to social activities or work within hours.

The PDL was the first device created in response to the theory of selective photothermolysis. Replacing the argon laser, which destroyed vascular lesions via nonselective thermal effects, the early PDL selectively targeted hemoglobin. The modern PDL, by allowing the use of longer pulse durations, can be used without the induction of disfiguring purpura, often persistent for weeks, that originally curtailed patient acceptance of this laser. Current devices generate higher peak fluences, which make feasible treatment with extended pulse durations that deliver energy slowly enough to avoid disrupting vessels and inducing bruising.

The longer pulse duration that is achieved actually entails a train of 3 or 4 discrete micropulses, the exact configuration and duration of which vary across devices from different manufacturers. Diffuse erythema and small-caliber telangiectasias appear amenable to purpura-free PDL treatment.²⁶ Treatment with repeated pulses, or pulse-stacking, has been found to increase the effectiveness of purpura-free treatment of facial telangiectasia.²⁷ Nose and cheek telangiectasias are more responsive to 3 or 4 overlapping pulses than to single nonoverlapping pulses. Treatment of thicker vessels and vascular malformations such as port-wine stains still require induction of purpura for speedy resolution in a reasonable number of treatments. Manipulation of the extended pulses and pairing of them with different cooling sources can provide a range of therapeutic options.^{28 - 29} For instance, histologic damage to the epidermis is minimized by longer pulses and more cooling.²⁹

At the opposite end of the PDL spectrum, 585-nm lasers with lower energy output have been recently developed for nonablative therapy.³⁰ Repeated treatments with such lasers may induce modest improvements in skin texture as well as acne scarring. One such device (N-Lite; ICN Pharmaceuticals Inc, Costa Mesa, Calif) has also recently been approved by the FDA for treatment of active inflammatory acne.

The availability of the millisecond-pulsed Nd:YAG laser has been a boon for the treatment of resistant vascular lesions and for hair removal. More penetrating than the PDL or IPL, the Nd:YAG is able to treat deeper, larger-caliber vessels without causing purpura. There is now a considerable body of data confirming the efficacy of one or a few treatments of Nd:YAG laser for 1- to 3-mm lower extremity and periocular reticular veins,^{31 - 35} which are less susceptible to clearance by other lasers and light sources. Fine telangiectasias and diffuse erythema on the face and the legs can also be treated with Nd:YAG laser.^{32 - 34}

Topical anesthesia should be applied for an hour or more before Nd:YAG laser treatment because this laser tends to elicit moderate pain, especially when thicker, deeper vessels are targeted. Intense epidermal cooling is essential and may be achieved via either contact with a chilled window, cryogen spray, or icy pressurized air.

While the emissions of the Nd:YAG laser are only moderately absorbed by melanin, long-pulsed variants of this laser have been successfully used to remove hair in patients with darker skin (types IV-VI) without the postinflammatory hyperpigmentation or hypopigmentation that may be associated with use of alexandrite and diode lasers.^{36 - 37} Pseudofolliculitis barbae and acne keloidalis are relieved by hair removal at the affected sites, with subsequent diminution of inflammation and regression of papulonodules.³⁷ Eye protection during Nd:YAG treatments is crucial for both operators and patients³⁸ because (1) this laser emits radiation beyond the visible spectrum, and users may consequently forget it is on; and (2) the generated laser light can penetrate deeply enough to cause retinal injury and permanent optical field defects.

Relatively new to dermatology, the mid-infrared lasers are least absorbed by melanin and most deeply penetrating.³⁹ Used primarily for nonablative resurfacing of photodamaged skin, the mid-infrared lasers have demonstrated efficacy for the improvement of active acne and acne scars, as well as fine to moderate facial rhytids.⁴⁰ Periocular wrinkles respond better than perioral ones. Infrared lasers, although quite uncomfortable during treatment, are associated with only a few hours of posttreatment redness and swelling, while adverse effects and longer-duration tissue effects are routine with other nonablative devices. Adequate cooling is essential in the use of all of these devices. Research is continuing on decreasing the intraoperative discomfort associated with mid-infrared devices through the use of topical anesthesia, anesthesia peels, adequate epidermal cooling, and other mechanisms.

In terms of provenance, the mid-infrared lasers are different from each other: The 1320-nm laser is an Nd:YAG, the 1450-nm is a diode, and the 1540-nm is an erbium:glass device. Recent studies have indicated that the 1450-nm and 1320-nm lasers are effective in the treatment of active acne, which they can markedly reduce by shrinking sebaceous glands. The 1319-nm device is a new machine that delivers a scanned infrared beam through a contact cooling window. Studies have just began to evaluate its efficacy, which presumably is similar to that of the 1320-nm Nd:YAG.

The gold standard for efficacy in ablative laser resurfacing remains the carbon dioxide laser, which was the first device used for this indication. In this issue of the ARCHIVES, Batra et al⁴¹ present the first long-term prospective evaluation of patient outcomes after laser resurfacing. Two and a half years after full-face resurfacing with carbon dioxide and erbium:YAG (Er:YAG) laser, 88% of patients receiving facial resurfacing continued to note an overall improvement in appearance, with this being rated as "good" (1.8 on a 0-3 scale). Interestingly, there was a modest decline in satisfaction from 3 to 30 months. The authors speculate that this may be attributed to the wrinkle-combating effect of residual edema (which eventually receded), unrealistic expectations that the rapid rate of postoperative improvement would be maintained indefinitely, or possibly real declines in rhytid improvement over time. This study offers insights into patient satisfaction in the short term as well. In particular, the mean duration of discomfort immediately after treatment (12.1 days) was skewed by outliers, with the duration being only half as long for three fourths of the patients.

Since the mid-1990s, the trend toward minimally invasive produres has encouraged laser practitioners to develop interventions that produce results like those of traditional laser resurfacing but with much diminished recovery time. Deriving from this process, the early Er:YAG lasers offered more rapid reepithelialization and less posttreatment erythema than carbon dioxide lasers, but with a corresponding reduction in clinical efficacy and less intraoperative convenience due to the lack of laser-associated vascular coagulation.⁴² During the past half decade, a newer generation of modified Er:YAG lasers has enabled the surmounting of some of these technical obstacles. Normal-mode erbium lasers were first packaged with low-intensity carbon dioxide lasers that permitted the concurrent hemostasis and tissue shrinkage characteristic of carbon dioxide devices while preserving the quick recovery properties of erbium. Similar results can be achieved also by another modern hybrid in which multiple variable pulse duration erbium lasers are channeled through a unified handpiece.^{43 - 44} A device in this latter category is presently the best-regarded means for combining coagulative effect with quick recovery time using Er:YAG technology.

Radiofrequency and microwave radiation are electromagnetic radiation in the spectrum from 3 kHz to 300 GHz.^{45 - 46} In 1 convention, microwave radiation is considered a portion of the RF band. Alternatively, microwaves are discretely defined as emissions within the range 300 MHz to 300 GHz, and radio waves as emissions from 3 kHz to 300 MHz. Neither radio waves nor microwaves have sufficient energy (<10 eV) to have ionizing effects on biologically active tissue. In the skin, RF radiation can be used to induce a thermal effect at particular depths.

Radiofrequency devices impact skin by emissions of high-frequency radio waves that mimic many of the effects of lasers and intense light sources. In the late 1990s, RF devices were adapted to ablate skin by generating a plasma at various depths within the skin surface.⁴⁷ This so-called cold ablation procedure (or coblation) in fact was neither achieved at particularly low temperatures nor truly ablative of the epidermis. Marketed as a minimally invasive ablative device, coblation was purported to be easily tolerated under local anesthetic but became commercially available just as ablative resurfacing was being largely replaced by nonablative treatment.

More recently, RF technology has been reconfigured for nonablative use.^{45 - 46} Unlike lasers, which induce heat by selectively targeting particular chromophores, nonablative RF devices generate heat as a result of tissue resistance to the movement of electrons within an RF field. Like nonablative lasers, the RF modality spares the epidermis and has its primary effect within the dermis. One new device produces a 6-MHz alternating RF current that reaches the skin via a treatment tip equipped with cryogen cooling. In terms of machine function and hardware, there are some major differences compared with laser: An internal computer receives information from the RF tip about contact temperature, application force, and impedance, and a coupling fluid is required to ensure electrical contact with the skin surface. Even heating reaches the deep dermis, with the volume and depth of this heat zone controlled by the human operator. Copious topical anesthesia, injection anesthesia, and/or sedation is needed before treatment initiation because the correction of skin laxity and sagging can elicit significant deep pain.

With this technique, tissue tightening has been reported to be dramatic, perhaps even more notable than with carbon dioxide ablation.⁴⁸ Eyebrows can be lifted through skin shrinkage.⁴⁹ As noted by Jacobson et al⁵⁰ in their preliminary report in this issue of the ARCHIVES, dramatic improvements of nasolabial folds, jowls, and marionette lines can also be achieved with the nonablative application of RF. Hypothetically, the superficial musculoaponeurotic system, the deep fascia that is pulled and tacked in surgical face-lifts, may be modified by such deep treatments. If this is occurring, it will be important to establish long-term safety. And while "color blind" nonablative RF therapy is potentially suitable for a range of skin types, more information is needed to better understand why RF wrinkle reduction is highly effective in some patients and ineffective in others. Over the next few years, some of the following questions will be answered based on data now being collected: Are 3 treatments, performed once a month, better than a single treatment? Should more than 1 pass be done at each treatment session? and Does the delivery of higher energies produce even more tightening?

Research into the efficacy of nonablative RF is in early stages. In November 2002, the FDA-approved RF devices device for the treatment of periorbital rhytids. Another emergent RF technology is a hybrid of IPL and RF. This has been promoted as a means of removing light-colored and white hair and may also have nonablative skin-tightening effects. Initial data clarifying the scope of efficacy of this combined device are expected to be available soon.

Another use of RF technology is for the occlusion of large leg veins and treatment of duplex ultrasound–verified saphenous vein reflux not amenable to standard sclerotherapy.⁵¹ Under ultrasound guidance, an RF catheter can be inserted into the target vein, and the device is activated as the catheter is withdrawn. Veins collapse and are permanently closed in about 90% of cases. Not only are the general anesthesia and recovery time associated with traditional vein stripping avoided, but RF endovenous occlusion is more efficacious and less likely to cause extravasation than a similar process in which naked laser fibers are used.

Light-emitting diodes are small robust devices that emit a narrow band of electromagnetic radiation ranging from the UV to the visible and infrared wavelengths.^{46 ,52 - 53} Physically, LEDs are configured on small chips or connected to small lamps (usually 3-5 mm in diameter). Once so assembled, individual LEDs generate light of low intensity, in the milliwatt domain. For medical applications, many LEDs can be placed together into panels to collectively generate higher-intensity energies, though achieved at the cost of decreased operational lifetime. Generally, however, good durability, including resistance to temperature, shock, particulate matter like dust, and other environmental disturbances, renders the LED a practical device for routine use. Power and maintenance needs are minimal, and a typical lamp may have a working life of as long as 100 000 hours. From the patient perspective, treatment with LEDs is painless and quick, lasting a few minutes for the entire face.

The mechanism of action of LEDs in nonablative therapy is not entirely elucidated owing to the novelty of the application. However, it is believed that specific LED light parameters, or "codes," photomodulate certain cellular and subcellular receptors.⁵² Photomodulation can thus inhibit, activate, or leave unchanged intracellular cascades that culminate in tissue effects. It is believed that LEDs may exert their actions on skin cells in a manner more precise than typical laser and light-based therapies, with, for instance, only some cell types being affected by a given emitted code.

Producing narrowband light within a 10- to 20-nm range around a peak emission wavelength, LED sources are intermediate between lasers and broadband intense light in terms of emission bandwidth. Preliminary investigations of mechanism suggest that LEDs may instigate fibroblast up-regulation and collagen remodeling similar to that seen after nonablative laser and light therapies. Clinically, periorificial rhytids may be improved. Research findings remain speculative, but one promising feature of LEDs compared with conventional laser and light therapies is that tissue effects are achieved without preceding thermal injury or visible erythema and edema. Unlike conventional therapies, LED photomodulation does not appear to require inflammation to affect cellular function.

Lasers require space for storage, and laser maintenance is costly. To mitigate these problems and increase sales, manufacturers are choosing to place multiple laser units within a single enclosure. It remains to be seen whether the commoditization of lasers is complete; that is, is a laser by any manufacturer the same as any other device founded on the same principles, or are there qualitative differences among brands? Additionally, it has not been established that bundling devices is cost-effective over the long run. While maintenance and space costs may be lower for a combined device, such a device can be used only on 1 patient at a time, and when it is out of service, an entire practice may be paralyzed.

A comparable innovation that has more unequivocally extended the reach of extant devices is the addition of handpieces and treatment modes. For instance, the 532-nm potassium-titanyl-phosphate (KTP) laser is now available in larger spot sizes and scanning handpieces that permit rapid full-face treatment. Similarly, laser hair removal has been incrementally accelerated by the introduction of wider-diameter tips. Consistent reliable delivery of greater energy over wider areas in less time has been made possible by the increasing robustness of laser technology and the growing power of individual lasers.

Historically, ablative resurfacing lasers have been used to smooth depressed scars from resolved acne. More recently, lasers and light therapies have been developed to alleviate active acne vulgaris. The first proposed therapeutic mechanism is predicated on affecting the skin population of the anaerobic pleomorphic diphtheroid P acnes, which is significant in the pathogenesis of acne in that it promotes local inflammation through a variety of biochemical reactions.^{12 - 15} P acnes also releases porphyrin, and when porphyrin absorbs light of particular wavelengths, a photochemical reaction generates free singlet oxygen. This potent oxidizing agent in turn destroys tissues and organisms, including P acnes, through its effect on cellular membranes. The intense light machines that have been used for this purpose are the blue lights, discussed above.

Additionally, selective thermal destruction of sebaceous glands has been demonstrated to have some efficacy in the treatment of active acne.^{39 ,54 - 57} Randomized trials of back acne in which 4 treatments with the 1450-nm diode laser were performed a month apart have revealed postlaser sebaceous gland rupture and thermal necrosis associated with significant reduction in numbers of acne lesions. Long-term studies are ongoing and indicate some persistence of effect. In addition to the low-energy PDL (N-Lite), 1320-nm Nd:YAG, and 1450-nm diode lasers, each now approved for the treatment of inflammatory acne, nonablative RF technology⁵⁸ appears promising for this indication. These fast, easily implemented approaches have displaced earlier more cumbersome technologies, such as the 810-nm diode laser with concurrent topical application of the photosensitizing dye indocyanine green. Topical 5-ALA PDT may be a highly effective means for reducing acne via simultaneous bacteriocidal action and sebaceous gland necrosis. While FDA approval for the treatment of acne by PDT has not been given, encouraging studies validating efficacy are under way.

New treatment regimens for AK include novel topical medications alone as well as topical treatments in conjunction with laser and intense light.⁵⁹ Topical 5-ALA PDT has progressed significantly in recent years and has become the most widely used light-based combination therapy for AK. Indeed, the adverse effects and complexity of this treatment for AK have led to limited use, given the simple alternative treatments, like cryotherapy. Topical 5-ALA PDT for AK is explained in the section on red light and PDT.

Aminolevulinic acid–based PDT has been attempted for superficial basal cell carcinoma in a manner identical to that used for AKs.⁶⁰ Skin biopsy specimens 4 and 8 weeks after treatment have shown persistent basal cell carcinoma in 50% or more of treated lesions. A randomized prospective study comparing topical methyl aminolevinulate and red-light irradiation with excisional surgery for nodular basal cell carcinoma showed 91% of patients treated with PDT experienced complete response (vs 98% with surgery), with a better cosmetic response.⁶¹

Soon after the inception of selective hair follicle ablation by ruby laser in 1996, laser hair removal became a routine dermatologic intervention.⁶² Recently, the introduction of Nd:YAG lasers has enabled hair removal in dark-skinned patients with minimal postinflammatory hyperpigmentation. A new hybrid technology combining RF pulses with intense light purportedly has efficacy for all hair types, including light-colored and white hair, but these claims have not yet been substantiated.

Unlike postinflammatory hyperpigmentation, hypopigmentation induced by laser treatment does not always spontaneously resolve. Intense versions of UV-B therapy have been developed during the past several years that have some ability to repigment artifactually lightened⁶ and vitiligo affected⁷ skin. The degree of improvement of hypopigmentation after intense light treatment can be highly cosmetically significant, with both patients and physicians observing nearly normal color after treatment cessation. Duration of remission may vary with different patients and lesion types, but benefit after a single treatment course can last many months or more. If the long-term efficacy of intense UV-B and excimer laser for vitiligo is verified by follow-up studies, this treatment will be a potentially exciting addition to the interventions available for this disfiguring disease.

The treatment of leg veins, particularly reticular and varicose veins, remains a challenging assignment for lasers and light sources. Sclerotherapy is still the first-line treatment,^{63 - 64} and while laser and light are more effective than they used to be, they are nonetheless reserved for resistant cases, including patients with needle phobia, sclerosant allergy, or telangiectatic mats composed of vessels too narrow for needle insertion.⁶⁵ Several devices, including the PDL and IPL, have some efficacy for fine telangiectatic leg veins too small for sclerotherapy. Medium-caliber blue reticular veins have recently been shown to respond to Nd:YAG laser treatment, the first laser successful for this indication. Large incompetent leg veins can now also be treated by endovenous therapy using laser or RF energy.

Nonablative laser and light treatments (also called subsurface resurfacing, photorejuvenation, and laser toning) have been used since the late 1990s for the aesthetic improvement of photoaged skin, particularly of the face.^{46 ,66 - 67} These treatments provide an alternative to traditional full-face laser resurfacing, an ablative modality in which carbon dioxide and/or Er:YAG lasers are used to remove the entire epidermis and portions of the dermis. In nonablative treatment, the epidermis is not visibly disrupted, and posttreatment effects typically include only mild erythema and edema. Nonablative resurfacing is attractive to physicians and patients alike because, in contradistinction to ablative resurfacing, there is little if any downtime. All nonablative treatments may improve skin texture and tone, some improve wrinkles or surface irregularities including scarring, and some additionally address dyspigmentation and/or erythema and telangiectasia. Cumulative aesthetic benefits from nonablative resurfacing are similar in type though smaller in magnitude than the results of ablative resurfacing. Good candidate patients for nonablative resurfacing tend to be relatively young (usually aged 25-65 years) and have minimal sagging of the face.

The PDL was initially found to induce dermal fibroblasts to produce a zone of new collagen after 1 or 2 purpuric treatments to photoaged periocular skin.⁶⁸ Since then, it has been determined that a number of wavelengths of both visible and infrared radiation have the ability to induce this very same change. In histologic analyses, the resultant dermal thickening has been interpreted as "increased" and "organized" horizontally arrayed bundles of normal collagen fibers in the papillary dermis.⁶⁹

Numerous laser and light devices, including the KTP laser (532 nm), PDL (585 nm and 595 nm),⁷⁰ IPL (515-1200 nm), Nd:YAG (1064-nm Q-switched, 1064-nm long-pulse, 1319 nm, and 1320 nm), diode (980 nm and 1450 nm), Er:glass (1540 nm), and LEDs, have been adapted to be effective in, or specifically developed for, nonablative resurfacing. The mid-infrared devices, including 1319-/1320-, 1450-, and 1540-nm devices, appear most effective for wrinkle and acne scar reduction. Coarse wrinkles and skin laxity may also be reduced by a series of treatments with the standard 1064-nm Nd:YAG.⁷¹ Intense pulsed light devices, by virtue of their broad emission spectrum, appear the most effective for simultaneous treatment of red patches and brown patches.

Differences in the relative benefits of particular wavelengths notwithstanding, the overall clinical efficacy of nonablative laser therapies remains poorly elucidated.⁷² There are few well-controlled studies of individual devices and laser wavelengths, exceedingly rare comparative studies of different wavelengths, and a lack of understanding as to why certain conditions or patient subpopulations may respond differently to certain types of treatments.^{67 ,72} In comparing nonablative laser treatment with traditional ablative resurfacing, it appears that there is a substantial efficacy advantage for the more invasive resurfacing technique, with some nonablative therapies administered by certain practitioners having a quite marked clinical effect and others in other studies eliciting little discernible improvement.⁷³ The lack of consistent data about clinical effectiveness is paralleled by an equal dearth of mechanistic understanding regarding how nonablative devices work, the relevant tissue effects that are induced, and the long-term sequelae of nonablative radiation within the skin.⁶⁹

The proliferation of devices with varying efficacy profiles and tissue effects suggests that synergistic benefits may be attained by using several devices in combination. In this issue of the ARCHIVES, Min-Wei Lee⁷⁴ demonstrates that nonablative therapy with combined KTP (532-nm) and Nd:YAG (1064-nm) laser may be superior to therapy with either laser alone. Her study is notable for the large number of patients enrolled, including 50 receiving a series of treatments with each laser alone and 50 receiving a series with both lasers together. The sample size greatly increases the credibility of the conclusions that sequential treatment with the KTP and Nd:YAG provides all of the redness and pigmentation reduction achievable by just the KTP plus more skin texture, tone, and rhytid improvement than is possible with either laser alone.

Interestingly, the Nd:YAG is minimally efficacious as a sole nonablative modality for the face, but it augments the topographic effects of the KTP. As with many single-device nonablative approaches, tissue effects are transient, with mild erythema and edema. Lee⁷⁴ continues to enroll more patients in this protocol in an ongoing study in her private practice; the long-term outcomes of this enlarging cohort will be interesting to see. Significantly, like many investigators, Lee is not able to provide a compelling elucidation of the histologic changes or tissue effects mediating the visible benefits. To extend the clinical logic of this study, the effects of other vascular devices such as PDLs and IPL may be similarly amplified by concomitant use of the Nd:YAG.

Nonlaser technologies may provide many of the same nonablative benefits as lasers and light sources. The efficacies of these technologies are summarized in the sections on PDT and RF and LED technology.

Pseudofolliculitis barbae and acne keloidalis, painful, persistent problems deriving from ingrown and abscessed hairs, disproportionately affect dark-skinned and African American patients. As described in the section regarding the Nd:YAG laser, a variety of "razor bumps" are now highly responsive to treatment.

The ubiquity and intractability of psoriasis have made it a desired target of laser devices for many decades. The PDL has again been touted as efficacious for long-term remission of psoriasis, but this therapy is not widely used at present. Intense UV-B light and the 308-nm excimer laser are both recently introduced extensions of traditional UV-B phototherapy, which is a known means for inducing psoriasis remission.

A major barrier to the use of new high-energy devices is patient discomfort during treatment. Topical anesthetics are sometimes applied before therapy, but these can be messy and ineffective. More invasive anesthesia may not be feasible or appropriate, given the relatively noninvasive nature of the primary procedure.

In this issue of the ARCHIVES, Kilmer et al⁷⁵ provide a significant contribution to the literature on pretreatment topical anesthesia by codifying what others have implied. Namely, extremely fastidious application of topical anesthesia in combination with oral analgesia and sedation can yield excellent pain control. The authors demonstrate this in the extreme case of full-face carbon dioxide laser resurfacing, a potentially very painful procedure that entails epidermal and partial-thickness dermal ablation. Their treatment protocol includes pretreatment face washing and warm compresses, presumably to enhance anesthesia penetration. Moreover, in addition to 30 g of topical anesthetic under occlusion, oral hydrocodone/acetaminophen, diazepam, and intramuscular ketorolac are concurrently administered. There appears to be enough redundancy in this anesthesia protocol to ensure a high level of patient comfort, but the process is laborious and difficult to implement for minor procedures such as repeated nonablative laser or light treatments. Modifications may be required for less invasive procedures, and the EMLA used may likely be replaced by other still available topical anesthetics without any loss of efficacy ("EMLA" is a proprietary acronym for eutectic mixture of local anesthetics previously manufactured by AstraZeneca Pharmaceuticals LP, Wilmington, Del).

Interestingly, Kilmer et al⁷⁵ note that, compared with control skin, the skin receiving topical anesthesia "displayed nonconfluent thermal damage." While they ascribe the low incidence of adverse effects to this uneven damage, it is reasonable to wonder to what extent, and in what manner, the effects of laser, light, and RF treatment may be changed by the presence of topical anesthesia. Another question is whether topical anesthesia efficacy varies with sex, skin type, or ethnicity.

Also in this issue of ARCHIVES, Baron and associates⁷⁶ investigate a different approach to enhanced topical anesthesia when they pretreat with Er:YAG laser pulses to facilitate absorption of anesthetic. The combination of laser and 4% lidocaine is found to be about 60% more effective in reducing needle insertion pain than either laser with placebo or lidocaine without laser. This is an intriguing result, but one that needs to be more carefully delineated. It is unclear why the initial Er:YAG pulse would be "painless" if it in fact disrupted the stratum corneum (and would this painlessness change if larger area were treated?), and the fact that the topical lidocaine was only applied for 5 minutes is a significant undertreatment that deviates from standard protocols. To be most convincing, and to justify the additional step of laser pretreatment, the combined anesthetic method should next be shown to relieve discomfort during ablative or uncomfortable nonablative facial treatments.

The concurrent study by Guerra and colleagues⁷⁷ also uses the Er:YAG laser as a delivery system, one permitting treatment with autologous cultured epidermal grafts for stable vitiligo. The laser is used to prepare the vitiliginous skin surface to receive the grafts. Deepithelialization with laser is faster than with other methods, and for larger areas and higher fluences, topical anesthetic under occlusion for 2 hours is used prior to laser treatment. Transplanting about 100 cm² per patient in 21 patients, the authors note at 18 months an overall repigmentation rate of 75%, which rises to 90% when 3 nonresponding patients are excluded. While the procedure is expensive, it appears effective, and large areas can be treated using only a small biopsy specimen from the patient. Upper extremity sites are treatment resistant. Protracted pretreatment patient tracking may be required to restrict this modality to patients with stable vitiligo because cases of unstable disease may worsen after treatment.

The excitement of technological developments⁷⁸ should not obscure the significant challenges that must be broached if the medical promise of lasers, light sources, and similar devices are to be realized. First and probably most importantly, the molecular and biophysical mechanisms underlying the tissue effects of these technologies must be clarified.^{69 ,79} Translational, near-basic research will be required to understand what is occurring, so that the desired effects can be magnified and the adverse effects minimized. Research into mechanism will also reassure dermatologists that the procedures we are performing are inherently safe.

Second, epidemiologic studies would be useful to clarify the link between treatment efficacy and patient-specific features. Certain therapies may be most useful for patients with particular skin texture, Fitzpatrick skin type, age, or sex. Individual interventions appear to have different effects in different patients, and if those most likely to succeed can be determined before treatment commences, overall response rates may be higher and patient disappointment reduced. To distinguish minor variations in relative efficacy across different subpopulations, it will be important to create ever-better measures for objectively and validly assessing the degree of clinical change.⁸⁰

Third, the efficacy of current treatments notwithstanding, even the same devices can be configured to be more effective. Continual experimentation with new and different treatment regimens and treatment parameters, some involving multiple different devices, should be encouraged so that there is a steady march toward the maximum potential efficacy of a given device.

Fourth, while there is no reason to believe that any of the procedures described above are inherently unsafe, long-term studies of outcome should be undertaken to confirm and verify safety and delineate the practice patterns that are most likely to minimize risk and avoid adverse effects.^{81 - 82} Presumably, multiple laser treatments over a long period do not induce photodamage because of the omission of UV wavelengths from the delivered frequency ranges, but this probable state of affairs has not been definitively proven.

Finally, physicians should separate the emotional overlay associated with patients' desire for laser procedures, like nonablative therapy, from the scientific evidence regarding the treatment benefits. While this moral hazard must be avoided in all branches of medicine, it may be particularly acute in cutaneous laser surgery, a field in which interventions culminate in the modification of physical appearance and, often, self-image.