LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

0733-8635/99 $8.00

ADVANCES IN MILITARY DERMATOLOGY

+

.OO

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING CDR E. Victor ROSS, MC, USN, and LT Norak Chhieng, MC, USNR

Laser applications in dermatology have recently featured the cosmetic arena, where newer technologies and creative thinking have extended the reach of light to include treatment of wrinkles (water as the laser target), leg veins and facial telangiectasia (hemoglobin as the target), and hair (usually with melanin as the target). Like their civilian counterparts, military dermatologists use the newest generation of lasers for cosmetic ends. These applications have been reviewed in several recent excellent papers.2o,23, 25, 32, 35, 65, 66 Therefore, rather than reporting the present military clinical experience, we examine laser uses in which there are special military significances. Although still largely experimental, some of these diagnostic and therapeutic applications will undoubtedly be implemented by military and nonmilitary office-based dermatologists. The military has traditionally been on the forefront of many well-publicized laser technologies. Applications have included diagnostic strategies such as range finding and submarine detection, and high-powered laser weapons. Various federal agencies within and outside the Department of Defense fund projects that are related to laser technology, many of which are relevant for dermatology. One such project, the medical free electron laser

program (MFEL), involves the use of a free electron laser. These lasers, capable of being tuned over a large range of wavelengths (248 nm to 8 mm), are located at various sites throughout the country. The MFEL program supports qualifying user groups to investigate tissue effects over a wide range of wavelengths that otherwise would be unavailable at most institutions. Topics relevant to dermatology that are presently being explored include tissue welding, wound healing, tissue ablation, and photoacoustic effects. Lee et a137 have shown that laser stress waves can facilitate transdermal drug delivery. A drug is first placed between a black sheet and the skin. Subsequently a Q-switched ruby laser pulse is directed toward the skin surface. The pulse is strongly absorbed by the black sheet, inducing a stress wave that propagates toward the drug, in effect pushing it through the stratum corneum. This system could have tremendous potential in the military for needleless vaccines and possibly in the administration of antiterrorist chemical warfare antidotes. The implementation of such technology in the field will be expedited by emerging diode technology, which should allow for miniaturization of these devices. This scenario underscores the interdependence of engineering and biology in laser -

From the Department of Dermatology, Naval Medical Center San Diego, San Diego, California

DERMATOLOGIC CLINICS

-

-

~

VOLUME 17 NUMBER 1 JANUARY 1999

~

135

136

ROSS & CHHIENG

applications in medicine. Representative laser applications with military relevance are summarized in this article. BURN DEBRIDEMENT

Interestingly, the concept of using short infrared (IR) pulses in the skin for controlled ablation with minimal thermal damage predated the advent of short pulsed CO, laser skin resurfacing (LSR)by several years. Many of the principles used in cosmetic LSR were derived from the early efforts of scientists such as Joseph T. Walsh, PhD. In a series of experiment~,5~-~~ Walsh and colleagues examined laser injuries in skin and showed that thermal damage could be minimized by proper choice of wavelength, irradiance, and pulse duration. The initial in-vivo application of these parameters was burn debridement.29 This was motivated by the sometimes poor results observed after cold steel excision of burn eschars, where blood losses were considerable and contributed heavily to morbidity as well as decreased poor graft take.28Laser burn debridement was first performed with continuous wave (CW) lasers. These devices achieved adequate hemostasis, but the extreme residual thermal damage (400 pm) resulted in delayed healing and decreased graft take. A later experiment of thermal burns showed that approximately 150 pm of residual thermal damage achieved the proper balance of adequate hemostasis and graft surviva1.28The laser used in this study, though developing high peak powers and irradiances, produced too low an average power for rapid ablation of burn eschar. This problem led to Army funding of the development of a high-powered (> 100 W) CW CO, laser coupled with a scanner.24This laser-scanner configuration developed short dwell times and high peak power densities (-9 kW/cm2) so that thermal damage was minimized but still sufficient for hemostasis. The high average power also allowed for delivery of large radiant exposures over short intervals. Fluences were greater than those used in cosmetic laser skin resurfacing (35 J/cm2 versus 7 to 15 J/cm2), resulting in significant eschar ablation (-60 to 80 m per pass). In pig studies, graft take and gross and microscopic wound healing were compared for laser and dermatome debridement of burn eschar. With the exception of increased granulation tissue

in laser wounds in the first 60 days, the dermatomed and irradiated sites were not significantly different. Because of the success of the debridement project in thermal burns, laser treatment of chemical burns has also been investigated, particularly as there are no satisfactory remedies for sulfur mustard-induced skin damage. Smith et a150 have shown that short pulsed CO, lasers are capable of debriding sulfur mustard (HD) wounds with subsequent accelerated healing versus wounds allowed to heal without intervention. HD, an alkylating agent, reacts with DNA to injure cells and the subsequent inflammatory response exacerbates the initial injury. In their study, Smith et a15*used a CO, laser with 60 psec pulse duration in weanling pigs. They found that laser debridement resulted in rapid (14 day) restoration of pretreatment epidermal and dermal architectures, whereas the untreated sites showed epidermal atrophy and disordered epidermal maturation. Also, there was persistent necrobiosis in the untreated sites. It was suggested that the uniform thermal denaturation observed after laser treatment resulted in precise removal of chemically altered dermis, allowing healing to proceed uneventfully (Fig. 1); however, as in cosmetic LSR, it is unclear how thermal damage modulates wound healing. Practically speaking, placement, operation, and maintenance of a high-powered CO, laser in a battlefront medical facility would be complicated; however, since it was shown that debridement could be delayed for as long as 48 hours after injury without compromising the laser effect,50exposed personnel theoretically could be transported from the field to a regional medical facility equipped with a high-powered (or high pulse energy) CO, laser. LASER DECONTAMINATION OF WOUNDS

Although it has been suggested that laser wounds are more susceptible to infection than mechanically induced wounds of similar depths,4l lasers have been shown to temporarily decrease bacterial counts. Because most battlefield wounds are contaminated, making primary closure inappropriate, laser sterilization is attractive as a means of rendering wounds suturable. Bacterial neutralization may be photothermal or photochemical, de-

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

pending on the laser configuration. In a representative study, Bartels et a16 showed that indocyanine green (ICG) and 808-nm diode laser light induced rapid sterilization in rabbit skin wounds inoculated with bacteria. The experiment was carried out as follows. A fresh skin incision was inoculated with S. intermedius at a concentration of lo8 colony forming units (CFU) per gram of tissue. After 1 day, the wounds were irradiated after incubation with indocyanine green (ICG), a photoactive dye strongly absorbed by 808-nm light. Presumably this process resulted in localization of tissue heating so that collateral damage was minimized. Although this laser/ dye combination was shown to decrease bacterial counts within hours of surgery, there was a relative increase in CFU 2 days postoperatively compared with inoculated wounds without laser therapy. The authors speculate that bacteria proliferated in the thermally denatured tissue. Also, nonuniformities in dye and light distribution might have allowed for shielding of bacteria by dye particles. Existing light/dye combinations have been most effective against gram-positive bacteria, suggesting that the polysaccharide wall in gramnegative species might offer some protection from photothermal laser injury. Improvements in beam delivery and dye distribution may result in enhanced bacterial killing with further minimization of collateral thermal damage. These advances should result in fewer hot and cold spots, and it follows that under these conditions lower fluence rates should be more effective in bacterial killing. Although wavelengths other than 800 nm have been used in laser wound decontamination experiments, rapid advances in diode laser technology have allowed for miniaturization of these devices. This makes diode lasers particularly attractive to military medical planners who envision these tools as part of the medic’s backpack arsenal. Accordingly, a Navy medic in the future might sterilize a shrapnel wound with a pen-sized diode laser with or without photoactive dyes. That same medic then could appose the wound using the same laser configuration (although with higher power densities) through a process known as tissue welding (vide infra). Moreover, a topical anesthetic gel could be administered to the injured servicemember through use of a laser stress wave (vide supra) for rapid onset of analgesia. This stress wave would propel the compound through the stratum corneum. Newer investigations of wound decontami-

137

nation have focused on a 490-nm laser coupled with sodium fluorescein dyes. Alternatively, a Nd:YAG laser with India ink has been used; unfortunately this results in permanent black tattooing of the wound. Another potential bactericidal modality for antibacterial action is photodynamic therapy (PDT), combining a photosensitizer with light. In contrast to the photothermal effects produced by the diode/ICG combination, PDT relies on singlet oxygen formation to destroy cells. Certain light-dye combinations are being investigated for antibacterial eff e c t ~ An . ~ ~optimal system would combine low tissue dark toxicity (toxicity of the photosensitizer without light), increased uptake by the pathogen, and compatibility with practically priced laser or nonlaser light sources. A promising drug is aminolevulinic acid (ALA), a naturally occurring amino acid, that, in excess in tissues, leads to protoporphyrin IX formation. ALA has been shown to be photoactive against s. a u ~ e u sAlso, . ~ ~ ALA is highly practical, because it is effective when administered topically, and photosensitivity normally lasts for only 24

LASER TATTOO REMOVAL

Although today tattooing has become fashionable among people from all walks of life, within certain groups in the military, the tattoo is a rite of passage. Although the tattoo and military service are compatible, there is a tremendous demand for tattoo removal, particularly as the servicemember ages or assumes new responsibilities. Many members request removal of only the most conspicuous tattoos (i.e., forearm or calf), where casual clothes are inadequate for coverage. This is especially true among older soldiers and sailors who were tattooed in a more male-oriented military, where, for example, a tattoo of a well-endowed woman on the forearm might be overlooked (or even applauded). Today this type of tattoo is not consistent with military core values. More commonly, the servicemember desires tattoo removal simply to conform to the norms of his or her community as part of society. This typically occurs during transition from one job to another (i.e., enlisted to officer corps or military police to the FBI). There are special circumstances in which administrative action may be taken against a servicemember who is tattooed with a potentially offensive design. For example,

138

ROSS & CHHIENG

Figure 1. A, Skin injury 1 day after exposure to sulfur mustard (HD). €3, Chemically injured skin after 14 days, no laser treatment. Note the atypicality of keratinocytes and dermal necrobiosis and dermal inflammation (original magnification x 200). Illustration continued on opposite page

swastika tattoos obviously might decrease unit cohesiveness and morale and would not be tolerated. Also, some tattoos are usually disqualifying for entry into military service, for example, a tattoo associated with the skinhead movement.55In this case, the military clinic will not remove the tattoo, but the pro-

spective member can have it treated at their own cost at a civilian facility. For the past 10 years, dedicated tattoo removal lasers have been available commercially. These Q-switched lasers achieve short pulses (10 to 100 nsec) so that thermal damage and possibly mechanical damage are con-

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

139

Figure 1 (Continued). C, Chemically damaged skin after 14 days. This site was treated with a CO, laser 1 day after HD exposure. Note restored normal skin architecture in laser-treated site. Site without laser treatment shows atypical keratinocytes and dermal necrobiosis. (Courtesy of Kathleen Smith, MD, National Naval Medical Center, Bethesda, MD).

fined to the immediate area of the target particle?, 27, 35 Despite the overall success of short pulsed laser treatment, there is a basic lack of knowledge regarding how tattoo lightening occurs. The initial step, the generation of high temperatures and pressures within the ink particles from absorbed laser light, is well established. What follows is less clear. Suggested mechanisms have include fragmentation of ink particles (with simultaneous release from the macrophage and reuptake by scavenger cells, some of which migrate to the lymphatics), intrinsic optical property changes in the particles, transepidermal elimination, and increased light scattering in the dermis from subsurface scarring.51The fragmentation model has received the most support, as it is intuitively attractive (like pounding rocks), and some studies suggest that particles decrease in size after treatment;67 however, other studies have shown no change in particle size or even increases in average particle size for certain ink types.12,48 Optimally, laser treatment should spare the epidermis, where some melanosomes are invariably destroyed during high-energy short pulse laser tissue exposures for 532-nm, 694nm, and to a lesser degree, 755-nm wave-

lengths. Surface cooling devices have been successfully used in other laser applications for epidermal preservation (i.e., port wine stain and telangiectasia);however, the physics of heating with Q-switched lasers (very rapid and extreme temperature rises within the melanosome) mitigates their effectiveness in decreasing unwanted epidermal damage. As noted previously, laser tattoo removal has been compromised by inadequate characterization of the physical and biologic cascade of events that follow irradiation. Study of laser tattoo interactions is further undermined by the wide variability in ink formulas used for particular colors. Each artist typically concocts his or her own compounds so that likecolored tattoos often respond differently to identical sets of laser parameters." 35 Initially it was felt that tattoos could be removed if the proper wavelength, pulse duration, and fluence were used because almost all tattoos will absorb specific bandwidths according to absorption spectra (Fig. 2);"3however, even with strong light absorption, some tattoos have proved resistant. This may be related to early rephagocytosis of particles by fibroblasts, excessive amounts of ink, depth of particles, failure of temperature and pressure '

140

ROSS K t CHHIENG

Wavelength (nm)

Figure 2. Representative absorption spectrum from a green tattoo. (Note maximum at 720 nm; this is between ruby and alexandrite wavelengths.)

stresses to alter particles so that they appear lighter, and electrochemistry (changes in the valence state of inorganic dyes when subjected to high-powered laser irradiation). Each of these might be overcome theoretically as described later in text. Rephagocytosis may be prevented by topical or intradermal application of compounds that alter the inflammatory response.16 For example, LTB4 selectively recruits neutrophils. If this is applied before or just after laser irradiation, these transient cells might be more likely to transport particles from the dermis than mononuclear cells, which are more likely to rephagocytize particles and remain in the dermis. In some tattoos, ink is located deep in the dermis (1-2 mm) so that particles remain unaffected even after multiple treatments. This is because of the rapid attenuation of subsurface energy density with increasing depth. Strategies for driving the photon density deeper in the dermis include the following: 1. Using ultrashort (picosecond versus

nanosecond) pulses, which are more likely to achieve the high subsurface power densities sufficient to cause chemical or physical changes in the particles (Fig. 3).48 Using larger spot diameters, which result in overall deeper beam penetration for equivalent surface f l ~ e n c e s . ~ ~ Using high fluences (10 to 15 J/cm2), which in turn result in increased subsurface energies. (This is only practical for the 1064-nm wavelength, as shorter wavelengths will create severe epidermal damage). Making the dermis more transparent. The optical properties of the dermis can be altered, for example, by the intradermal injection of glycerin, which has an index of refraction similar to dermis. This effectively couples light transmission between collagen and dermal water, allowing for enhanced penetration. In short, the dermis becomes more transparent, analogous to placing a drop of immersion oil on the skin surface to

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

141

containing ferric oxide. Therefore, if inks containing these inorganic metals were avoided, a type of permanent but laser-removable tattoo could be marketed. The development of new technologies will allow for progressively smaller and more powerful lasers for tattoo removal. Also, tunable pulsed lasers will be available so that the optimal wavelength for a specific tattoo color might be dialed in on the control panel. Selection of this wavelength could be based on absorption spectra of the tattoo using a lowpriced compact spectrophotometer built into the laser case. Despite these technical improvements, as long as particle responses to high-power exposures are not better characterized, resistant tattoos will be commonplace. A first step would be some degree of standardization in ink manufacturing, so that at least certain colors might respond predictably to identical sets of laser parameters. Also, future studies should examine ways to modulate the subsequent posttreatment inflammatory infiltrate response to expedite pigment removal. PSEUDOFOLLICULITIS BARBAE

Figure 3. A, Tattoo pretreatment. B, After 4 treatments with Nd:YAG laser (fluence of 0.65 J/cm2). The left lower third section was treated with 20-nsec pulses, the right lower portion was treated with 35-psec pulses. Note improved clearing with psec exposures. The upper half was treated with 20-nsec pulses at conventional high fluences (7 J/crn2).

enhance visualization of blood vessels (the oil matches the index of refraction for stratum corneum). Another consideration in laser tattoo removal is electrochemistry. It has been shown that titanium and iron are reduced by the excitation from high-powered laser tissue interactions. Inks containing these compounds often become darker with short-pulse laser exposures? A pilot study was done at the Wellman Laboratories of Photomedicine (Boston, MA) that showed a higher incidence of titanium dioxide in tattoos resistant to serial laser treatments. This was most commonly observed in green tattoos, a color for which the artist will often add titanium dioxide as a brightener. Also, irradiation of inks in Petri dishes showed darkening in those samples

Another laser application with potential high impact in the military is hair removal for men with Pseudofolliculitis barbae (PFB). Normally this inflammatory condition is caused by sharp, very short hairs that curl over to re-enter the skin (extrafollicular).Hair can also directly penetrate (transfollicular)the epidermis without externalizing itself first. The end result is an inflammatory response to pseudofollicles with subsequent development of papules and pustules. Frequent shaving, as is common practice, or improper treatment will exacerbate the condition and may lead to bacterial infection, pigmentation problems, and scarring including keloid formation.',11, 15, 18, 21 As a result, affected individuals have traditionally been given temporary no-shaving chits to facilitate treatment. PFB is prevalent in any ethnic group predisposed to having tightly curved or coiled hair. In the Armed Forces the great majority of patients are African-American men, a group for which the exact prevalence of PFB is not known. Anecdotal reports have estimated it at anywhere from loo%to 83Y0.l The wide disparity implies that PFB cases have been poorly tracked. Informal interviews with staff physicians at the Naval Hospital San

142

ROSS & CHHIENG

Diego reveal that PFB remains a common problem in the Navy and Marine Corps. Moreover, according to one investigator ”Pseudofolliculitis barbae has now become the most significant dermatologic disease in the US Army.”’O The military has a need to keep PFB under control not only to maintain a uniform, cleanshaven appearance, but also for the safety of the individual in a combat environment. The ever-present threat of chemical weapons requires that gas masks fit properly, and more than 1/8 inch of beard growth may interfere with the This relatively minor medical problem has become a major social issue and has in some cases led to racial tension. In the 1970s, the military’s approach to PFB incited public demonstration and frank mutiny by disgruntled African-American enlisted members.’O The novice military physician typically suspects that PFB patients asking for no shave chits simply do not want to shave, and he or she may be skeptical of the earnestness of the patient’s participation in therapy; however the authors’ experience is that most men with PFB in the military desire a clean-shaven face; they have simply been unable to find a strategy for effective treatment. Because of the need for uniform treatment strategies among medical officers, the Navy has developed a specific protocol for management of PFB. The protocol involves three phases of escalating treatment regimens, depending on the severity and refractoriness of disease. For example, Phase I includes the use of simple topical remedies such as tretinoin and Vioform HC (CIBA, Summit, NJ),

whereas Phase I1 includes the application of sometimes irritating chemical depilatories. If the servicemember fails all phases of treatment, the following instruction from the Chief of Naval Personnel may apply. If the commanding officer determines that a permanent no-shaving status is detrimental to good order and discipline or affects the member’s ability to perform military duties, he or she may submit a recommendation to the Bureau of Naval Personnel for Administrative Separation by Reason of Pseudofolliculitis b a ~ b a e . ~ ~ In practice, most commanding officers are flexible if the servicemember has made a good-faith effort to participate in the treatment program and failed, typically that member is allowed to clip the hair to approximately 1 / 8 inch long rather than be separated. The Marine Corps, however, places an extremely high emphasis on appearance, from weight to grooming standards, and is less accommodating. One report demonstrated an attrition rate of 1807 among African-American Marines who were serving on their first enlistment between 1977 to 1979.54 Treatment for PFB remains unsatisfactory. Most therapies simply do not work, or if they do, usually only offer short-term improvement after which they become ineffective. Agents that have been used with variable success include but are not limited to depilatories, topical and oral antibiotics, glycolic acid, topical steroids, vitamin A derivatives (such as tretinoin), electrolysis, and laborious shaving regimens. The only reliable cure for PFB is not shaving. By allowing the hair to grow, tension will automatically release the ingrown hair by spring action in about 3 to 4

Figure 4. Typical pseudofolliculitis barbae (PFB) follicle and course of laser beam.

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

weeks (Fig. 4).", 14,l9 Alternatively, removing the hair follicle completely could also provide a potential cure for PFB. Present modalities like electrolysis are generally prohibitive because the entire face would have to be treated; moreover, incomplete destruction has resulted in keratin granulomas. Lasers may offer a field therapy that would be practical for a widespread condition such as PFB (Fig. 4). It has been shown to be effective in at least delaying hair regrowth in recent studies.15,26, 30, 34, 43 With further refinement (and the development of low-cost compact systems that would be widely available), laser hair removal could be a feasible option for members afflicted with PFB in the Armed Forces. By eliminating this condition, one could expect improvement of morale among troops, increased battle effectiveness, and significant savings to the US Government. Laser hair removal is simultaneously facilitated and compromised by the anatomy of the follicle as well as the physics of the initial laser tissue interaction. On one hand, even in darkly pigmented patients, the greatest concentration of melanin is the cortex and matrix of the follicle, so that there is contrast between the melanin concentration in the epidermis and hair shaft. This contrast allows for some selectivity in laser hair removal systems with melanin as a target (this represents the great majority of available technologies). On the other hand, this contrast may be minimal in darker people with dark hair. Also, in all patients, the relative depth of the hair bulb and bulge (one or both of which must probably be destroyed for permanent follicle death) is an obstacle to treatment. The ultimate goal in laser hair removal is permanent painless destruction of the follicle, but even temporary removal (where the patient would be treated every 2 to 3 months) might prove acceptable. Most PFB patients are injured only when the sharpened shaft re-enters the skin, so that temporary arrest of hair growth should improve the condition. It is unclear which specific structure within the follicle must be destroyed for permanent removal. Potentially important units are the bulb, roughly 2 to 3 mm deep to the skin surface, and the bulge, comprised of stem cells near the insertion of the arrector pili muscle (roughly 1 to 1.5 mm Melanin is the initial laser target in most hair removal strategies. The bulb and bulge (or other follicular structures) are then damaged by heat conduction (and possibly pres-

143

sure waves) from the heavily melanized shaft and matrix. The challenge is to combine adequate energy delivery to the deeper follicle with simultaneous preservation of the epidermis. There is an optical window in skin (about 600 to 1200 nm) where light penetration is enhanced by a combination of decreased melanin absorption, little interference from other chromophores (although there is some HbO, absorption from 730 to 1100 Fm), and intrinsically greater beam penetration (decreased scattering losses in the dermi~).~, The optimal wavelength for maximal beam penetration, significant melanin absorption, and relative epidermal sparing (without surface cooling) is unknown but probably lies between 700 and 850 nm?6 This is the wavelength that the ratio of dermal to epidermal energy density deposition is maximal for depths equal to the bulge or bulb (Fig. 4). Because an action spectrum (which may not parallel the absorption spectrum for melanin) has not been performed for laser hair removal, other wavelengths (or broad-band devices) might be more active biologically. Laser light in general is attenuated from the surface down (backscattering actually results in subsurface energy hot spots-still these will typically be superficial to the hair bulge and bulb), so that the epidermis will almost always endure more energy density than the deeper follicle. Surface cooling devices can overcome some of the limitations of the top to bottom nature of the light delivery. Also, epidermal damage can be decreased by lengthening the laser pulse so that melanosomes (roughly 1 m in diameter) are gently heated (the larger surface to volume ratio allows for more conductive and radiational cooling), whereas the deeper follicle structures (200 to 300 Fm in diameter-which take longer to cool) are heated cumulatively during the same period. Theoretically, pulses should be designed to match the thermal relaxation time for the hair follicle (roughly 40 to 100 m ~ e c ) .l6~This , results in maximal heating of the follicle without collateral damage in the dermis. There are other considerations in selective destruction of follicular structures besides pulse duration. For example, the bulb may be selectively heated by its position in the hypodermis during anagen. The fat insulates the bulb so that temperatures are higher and sustained versus more superficial follicular structures, which reside in the less insulating If not for epidermal melanin, a strong argument can be made for 694 nm (ruby) as the

144

ROSS & CHHIENG

optimal wavelength for laser hair removal; however, despite the intrinsically higher efficiency of ruby light, most clinicians restrict ruby laser treatment to skin types I to III.9, l5,I7 In darker skin types dyspigmentation has been reported even with surface cooling. In designing a system for the prospective PFB patient, most likely a longer wavelength would be superior. Because melanin absorption decreases significantly with increasing wavelength, often larger surface fluences (30 to 60 J/cm’) are required to achieve adequate light doses in the deeper parts of the hair follicle for wavelengths greater than 750 nm. Recently, 755 nm and 810 nm have been studied.43Additionally, 1064-nm lasers (Nd:YAG) have been used with and without exogenous chromophores for hair There is a strong appeal for diode lasers, as they combine smaller sizes and typically are more reliable than their solid-state counterparts. For example, new high-powered diode arrays allow for fluences of 30 to 60 joules/cm, with spotsizes as large as 9 mm. Some preliminary studies support treating darker skin types with longer wavelengths (> 750 nm).43N a r ~ r k a showed r~~ that darker skin could be treated with a long pulsed (20 msec) alexandrite laser, but epidermal sideeffects were acceptable only with smaller fluences (8 to 15 J/cm2). Larger fluences and shorter pulse durations produced blistering and pigmentation alterations. Efforts continue to better understand the physics and biology of laser hair removal. Kreindel and Ladin36have recently studied the optical and thermal properties of hair. They emphasized that the location of the bulb (dermis or hypodermis) should play a role in determination of the laser parameters. This is related to the biology of the follicular cycle. Early anagen hair bulbs are located more superficially but are still pigmented, therefore shorter pulses and lower fluences should be used. In contrast, normal anagen bulbs are in fat, requiring larger fluences for removal but also tolerating longer pulse durations because fat protects peripheral tissue. TISSUE WELDING

Tissue welding has long been fancied as a replacement for s u t u ~ e sThe . ~ central feature of tissue welding is denaturation of collagen, which allows for annealing of apposed collagen fibers (Fig. 5). This temporarily secures

Figure 5. Electron micrograph showing cut collagen fibrils. A, before and 17,after heating. The heated fibrils are able to bind to adjacent heated fibrils. (Courtesy of George Naseef, MD, Wellrnan Laboratories of Photornedicine, Boston, MA).

wound edges while natural tissue remodeling restores wound strength much like traditional suture wounds. Often a protein solder or photoactive dye is used to assist in the initial closure. The greatest drawback to tissue welding has been the lack of reproducible strong welds. Advances have included protein glues (solders) and laser-absorbing chromophores that confine heating to the area of injury.49 Temperature feedback systems (remote) have been devised to enhance reproducibility and provide meaningful endpoints for the surg e ~ n Current . ~ ~ endpoints such as tissue blanching serve as rather primitive visual feedback signals.46Other real-time assessments of collagen denaturation may increase the reproducibility and, therefore, the acceptance of tissue welding. For example Lin and Anderson have used fluorescence dyes as molecular reporters of local temperature changes and collagen d e n a t ~ r a t i o n By . ~ ~using dyes that bind to collagen and assessing changes in fluorescence with heating, wound temperatures can be reported noninvasively (Fig. 6). Advantages of tissue welding include closure rates of up to 1 mm/s; this is 50% faster

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

145

I00 Excitation @ 460 nrn CollagexFITC = 44 FITC = Fluorescein ITC

50

0

0

I

I

30

I

50

40

.

60

I

70

80

Temperature (C) Figure 6. Spectrum showing change in fluorescence of sodium fluorescein with increasing temperature. The upper line is control (unbound) fluorescein, showing native fluorescence. The lower line represents fluorescein bound to collagen. Note that as the collagen is heated, the fluorescein disassociates from collagen, and native fluorescence is restored at -65" (the melting temperature of collagen).

than most surgeons are capable of suturing.4'j Also, clinical experience has shown a reduced foreign body response and less susceptibility to leakage versus sutured or stapled wounds. A water-tight seal is important, for example, in urinary tract closures to prevent infection or fistula formation7 The skin serves as an easily accessible model for tissue welding. The challenge is to achieve a relatively small zone of lateral thermal damage that allows for rapid healing, minimal scarring, and comparable wound strength to more traditional suture wounds. Presently several laser systems have been used for tissue welding. One appealing configuration combines a Nd:YAG laser and India ink (the ink strongly absorbs the irradiation so that collateral thermal damage is minimized). A recent presentation showed that this wavelength and ink, combined with 50 to 100 msec laser exposures, achieved welding depths that extended half the depth of the dermis; still, lateral thermal damage was limited to <200 pm.21These welds were applied to full-thickness incisions made on the backs of guinea pigs. India ink was used to localize the heating and restrict thermal damage. By 21 to 28 days postinjury, there was equivalence between wound tensile strength in the laser-welded wounds and their control sutured counterparts (Fig. 7).

Fried21 were able to achieve their promising results by combining relatively short laser exposures and larger spot sizes; this allowed for deep penetration while limiting collateral damage. Shallow heating, leading to inadequate tensile strengths and dehiscence, has compromised many past efforts in tissue welding. Presently the Army is funding research at Oregon Medical Laser Center using elastin from pigs as patch welds. This patch and sew kit can be used to fuse human tissue. The material can be fabricated into custom shapes to seal broken blood vessels and repair damaged organs. The weld is enhanced by a dye that uses a diode laser at 800 nm for photoactivation. The Army is planning on eventual compaction and battery operation of the laser source so that these patch kits might be deployed along with medical personnel at the f r ~ n t - l i n e In . ~ ~the future this type of hightech bandage could be used in skin. SUBSURFACE IMAGERY

Another area of importance for lasers in the military is subsurface imagery. Various subsurface imaging strategies may allow, for example, the identification of nonradio-

146

ROSS & CHHIENG

Figure 7. A, Guinea pig skin just after welding with 1064-nm laser (power = 16W; spotsize = 4 mm; pulse duration = 100 msec). Note near full-thickness extension (1 mm) of thermally altered collagen with limited lateral spread (200 km) 6, Shown 21-28 days after weld. Note nearly fullthickness zone of fibroplasia with limited lateral spread of thermal damage. Black areas are retained India ink granules (hematoxylin-eosin stain, bar = 400 km). Illustration continued on opposite page

opaque projectiles from land mines (i.e./ leather pieces). These technologies may offer future alternatives to standard histopathology. Among the techniques that show promise are confocal scanning microscopy (CFM), optical coherence tomography (OCT), and la-

ser-induced fluorescence (LIF).22,45, 64 These modalities, enhanced by the rapid progress in computer technology, permit real-time characterization of subsurface structures. This allows for the possibility of an optical biopsy performed over large skin surface areas with

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

147

Figure 7 (Continued). Gross wound 21-28 days after suturing. D, Gross wound 21-28 days after laser weld; again black color is due to retained India ink. (Courtesy of Nathaniel Fried, PhD, Northwestern University, Evanston, IL.)

no risk of scarring. The confocal microscope has already been shown to noninvasively identify melan~cytes;~~ further refinements in technology may reliably distinguish benign from malignant pigmented lesions. CFM works by rejecting all light except that from a focal plane (Fig. 8);63a pinhole is used as the filter. Finally, a scanner links all of these small point images so that a horizontal optical section is created. Unfortunately, CFM is intrinsically limited to superficial dermal structures so that high-quality images have only been described to about 300 Frn deep in the dermis. OCT offers the potential for deeper imaging than CFM (1 to 2 mm vs. 300 Fm). This technique uses interference patterns to create images. OCT provides information about subsurface structures based on time of flight delays between the reflective boundaries and backscattering sites in the skin (Fig. 9). Photons that are scattered once in tissue can be detected at very small levels by using an interferometer. In brief, light from a noncoherent source (either light emitting diode or laser running multimode) is directed toward the skin surface and to a reference mirror. When photons are returned simultaneously, there is constructive interference and the light signal is increased at the detector. By scanning the interference patterns, an im-

age is constructed. Like CFM, OCT has limitations compared to standard excision specimens. One cannot stain for structural antigens (i.e., 5100); also, resolution is only on the order of 10 Fm versus 1 km, and depth is limited. Other potential newer methods of skin imaging include range gating and hyperspectral imaging. Range gating is a kind of optical radar, where photons are emitted from a source (i.e., laser probe on the skin surface) after which a detector captures reflected photons only after a specific elapsed time. The characteristic time can be used to determine the depth of the reflecting object (i.e., a foreign body in the skin). Hyperspectral imaging consists of taking surface spectral patterns and resolving them into very small dimensions so that irregularities not identifiable by the naked eye are exposed. Medical applications already include identification of chromosomes. Future applications of this technology might allow for diagnosis of skin conditions based on unique surface spectra. CONCLUSION

To the practicing dermatologist who is bombarded by bold advertisements in meeting exhibit halls, recent advances in laser

148

ROSS 81 CHHIENG

Figure 8. Principle of confocal scanning microscopy (CFM). The object (small structure in dermis) is selectively imaged by the pinhole, which blocks light rays from structures just deep and lateral to the object.

Light source

A-

Detector *-=

Beam splitter

X

I

Figure 9. Principle of optical coherence tomography (OCT). When the distances X and Y are equal there will be constructive interference at the detector; by scanning over the skin axially and laterally, an image is formed.

LASERS IN THE MILITARY FOR CUTANEOUS DISEASE AND WOUND HEALING

technology must appear to be driven only by cosmetic applications. Certainly, new techniques such as laser skin resurfacing and laser hair removal have reinvigorated the field of laser dermatology. More cosmetic applications will almost certainly follow as there are still virtually untapped targets (i.e., sebum and fat) in the skin. On the other hand, the clinician should realize that behind the scenes there is a great deal of basic science research relevant to laser-tissue interactions, tissue optics, and laser engineering. Some of these projects are and will continue to be funded by the Department of Defense as well as civilian federal agencies. Eventually, many of the basic science breakthroughs will be converted to clinically useful devices that should find their way onto the battlefield and into the dermatologist's office of the future. It is not premature to say that within 10 years, an invivo biopsy could be performed on the skin (particularly helpful in children) followed by selective laser treatment. Subsequently, test of cure treatment progress could be performed by a follow-up noninvasive optical biopsy. Therefore the entire series of diagnostic and therapeutic interventions will be performed without physically violating the stratum corneum. With each technological advance and creative idea relevant to lasers in dermatology, there is a progressive blurring of the traditional boundaries of physics, biology, medicine, and engineering. This has lead to greater collaboration than ever between scientists with different backgrounds, and recent interdisciplinary efforts will undoubtedly accelerate human mastery over light and its interactions with the skin. As D. A. Benaron, PhD concluded in a recent issue of Science in his discussion on Tissue Optics, "we are now leaving the dark ages of biology and medicine."y References 1. Alexander AM, Delph W I Pseudofolliculitis barbae in the military: A medical, administrative and social problem. J Natl Med Assoc 66:459-464, 1974 2. Alster TS: Q-switched alexandrite laser treatment (755 nm) of professional and amateur tattoos. J Am Acad Dermatol 33:69-73, 1995 3. Anderson R Laser-tissue interactions. In Goldman M, Fitzpatrick R (eds): Cutaneous Laser Surgery: The Art and Science of Selective Photothermolysis. St. Louis; Mosby; 1994, pp 1-18 4. Anderson RR, Geronemus R, Kilmer SL, et a 1 Cosmetic tattoo ink darkening: A complication of Qswitched and pulsed-laser treatment. Arch Dermatol 129:lOlO-1014, 1993

149

5. Anderson RR, Parrish JA: The optics of human skin. J Invest Dermatol 7713-19, 1981 6. Bartels K, Morton R, Dickey D, et al: Use of laser diode energy (808 nm) for selective photothermolysis of contaminated wounds. Proc Society of Photo-instrumentation Engineers 2395:602-606, 1995 7. Bass LS, Treat MR Laser tissue welding: A comprehensive review of current and future clinical applications. Lasers Surg Med 17:315-349, 1995 8. Benaron D, Cheong W, Stevenson D: Tissue Optics. Science 276:2002-2003, 1997 9. Bjerring P, Zachariae H, Lybecker H, et al: Evaluation of the free-running ruby laser for hair removal: A retrospective study. Acta Derm Venereol 78:48-51, 1998 10. Brauner GJ, Flandermeyer KL: Pseudofolliculitis barbae: Medical consequences of interracial friction in the US Army. Cutis 23:61-66, 1979 11. Brown Jr LA: Pathogenesis and treatment of pseudofolliculitis barbae. Cutis 32373-375, 1983 12. Chen H, Diebold G: Chemical generation of acoustic waves: A giant photo-acoustic effect. Science 270:963, 1995 13. Conte MS, Lawrence JE: Pseudofolliculitis barbae. No 'pseudoproblem'. JAMA 241:53-54, 1979 14. Coquilla BH, Lewis CW: Management of pseudofolliculitis barbae. Mil Med 160963-269, 1995 15. Dierickx C: Comparison between a long pulsed ruby laser and pulsed, infrared laser system for hair removal. Lasers Surg Med lO(suppl):199,1998 16. Dierickx C, Farinelli W, Flotte T, et al: Effect of delayed type hypersensitivity (type IV) immune reaction on the laser treatment of tattoos (abstract). Lasers Surg Med Suppl8:33, 1996 17. Diercikx C, Farinelli W, Grossman M, et al: Longpulsed ruby laser hair removal: Comparison between two pulse widths (0.3 and 3 msec). Lasers Surg Med Suppl 736, 1998 18. Draper W: Pseudofolliculitis barbae. US Navy Medicine 72:29-33, 1981 19. Dunn Jr JF: Pseudofolliculitis barbae. Am Fam Physician 38:169-174, 1988 20. Fitzpatrick RE: Laser resurfacing of rhytides. Dermato1 Clinics 15:431447, 1997 21. Fried N Dye-assisted laser skin welding with pulsed radiation: In vivo wound healing results. Lasers Surg Med lO(suppl:230, 1998 22.Fujimoto JG, Brezinski ME, Tearney GJ, et al: Optical biopsy and imaging using optical coherence tomography. Nat Med 1:970-972, 1995 23. Garden JM, Bakus AD: Laser treatment of port-wine stains and hemangiomas. Dermatol Clinics 15:373383,1997 24. Glatter R, Goldberg J, Schomacker KT, et a1 Carbon dioxide laser ablation with immediate autografting in a full thickness porcine burn model. Ann Surg 228257-265, 1998 25. Goldberg DJ: Laser treatment of pigmented lesions. Dermatol Clinics 15:397407, 1997 26. Goldberg DJ, Littler CM, Wheeland RG: Topical suspension-assisted Q-switched Nd:YAG laser hair removal. Dermatol Surg 23:741-745, 1997 27. Goyal S, Arndt KA, Stern RS, et al: Laser treatment of tattoos: A prospective, paired, comparison study of the Q-switched Nd:YAG (1064 nm), frequencydoubled Q-switched Nd:YAG (532 nm), and Qswitched ruby lasers. J Am Acad Dermatol 36:122125,1997 28. Green H, Burd E, Nishioka N, et a1 Mid-dermal wound healing: A comparison between dermatomal excision and pulsed carbon dioxide laser ablation. Arch Dermatol 128:639-645, 1992

150

ROSS & CHHIENG

29. Green HA, Domankevitz Y, Nishioka NS: Pulsed carbon dioxide laser ablation of burned skin: In vitro and in vivo analysis. Lasers Surg Med 10:476484, 1990 30. Grossman M: Removal of excess body hair with an 800 NM pulsed diode laser. Lasers Surg Med lO(suppl):201,1998 31. Grossman MC, Dierickx C, Farinelli W, et al: Damage to hair follicles by normal-mode ruby laser pulses. J Am Acad Dermatol 35:889-894, 1996 32. Herd RM, Dover JS, Arndt KA: Basic laser principles. Dermatol Clinics 15:355-372, 1997 33. Hodersdal M, Bech-Thomsen N, Wulf HC: Skin reflectance-guided laser selections for treatment of decorative tattoos. Arch Dermatol 132:403407, 1996 34. Kilmer S: Hair Removal Study Comparing the QSwitched Nd:YAG and Long Pulse Ruby & Alexandrite Lasers. Lasers Surg Med lO(supp):203,1998 35. Kilmer SL: Laser treatment of tattoos. Dermatol Clinics 15:409417, 1997 36. Kreindel M, Ladin 2: Optical and thermal properties of hair (abstract). Lasers Surg Med 1998; Suppl 10(abstract):2 37. Lee S, McAuliffe D, Flotte T, et al: Laser stress waves can facilitate in vivo transdermal drug delivery. Lasers Surg Med Suppl 10:62, 1998 38. Lin T, Anderson R: Dye-mediated monitoring of type I collagen denaturation (abstract). Lasers Surg Med Suppl 10:50, 1998 39. Lui H, Salasche S, Kollias N, et al: Photodynamic therapy of nonmelanoma skin cancer with topical aminolevulnic acid: a clinical and histologic study [letter]. Arch Dermatol 131:737-738, 1995 40. Lytle D Laser-fused patch could mend wounds. Biophotonics International 4:54-55, 1997 41. Madden J, Edlich R, Custer J, et al: Studies in the management of cutaneous wounds. IV. Resistance to infection of surgical wounds made by knife, electrosurgery, and laser. Am J Surg 119:222-224, 1970 42. Nanni CA, Alster TS Optimizing treatment parameters for hair removal using a topical carbon-based solution and 1064-nm Q-switched neodymium:YAG laser energy. Arch Dermatol 133:1546-1549, 1997 43. Narurkar V: The safety and efficacy of the long pulse alexandrite laser for hair removal in various skin types. Lasers Surg Med lO(suppl):189,1998 44. Poppas DP, Stewart RB, Massicotte JM, et a1 Temperature-controlled laser photocoagulation of soft tissue: In vivo evaluation using a tissue welding model. Lasers Surg Med 18:335-344, 1996 45. Rajadhyaksha M, Grossman M, Esterowitz D, et al: In vivo confocal scanning laser microscopy of human skin: Melanin provides strong contrast. J Invest Dermatol 104:946-952, 1995 46. Reiss S: Prospects look brighter for laser tissue welding. Biophotonics International 26-27, 1997 47. Ross E, Farinelli W, Skrobal M, et al: Spotsize effects on purpura threshold with the pulsed dye laser (abstract). Lasers Surg Med Suppl 754, 1995 48. Ross E, Naseef G, Kelly M, et al: Comparison of picosecond and nanosecond 1064 nm laser pulses in

49. 50.

51.

52. 53. 54. 55. 56.

57. 58.

59. 60. 61. 62.

63. 64. 65. 66. 67.

the treatment of tattoos. Arch Dermatol 134:167-171, 1997 Small IV W, Heredia N, Maitland D, et al: Experimental and computational laser tissue welding using a protein patch. J Biomed Optics 3:96-101, 1998 Smith KJ, Skelton HG, Martin JL, et al: CO, laser debridement of sulphur mustard (bis-2-chloroethyl sulphide) induced cutaneous lesions accelerates production of a normal epidermis with elimination of cytological atypia. Brit J Dermatol 137:590-594, 1997 Taylor CR, Anderson RR, Gange RW, et al: Light and electron microscopic analysis of tattoos treated by Qswitched ruby laser. J Invest Dermatol 97131-136, 1991 US Army: Pseudofolliculitis of the beard. Washington DC, United States Department of the Army, TB Med 287, January 1, 1983 US Navy: Bupers Instruction 1000.22: Management and Disposition of Navy Personnel with Pseudofolliculitis Barbae (pFB). 1993, p Pers-23 US Navy: Pseudofolliculitis Barbae (report on attritioin rate) [letter]. :6310-6313, 1979 US Navy: Skin and Cellular Tissues: Manual of the Medical Department; Section XVII vd Meulen F, Sterenborg H, Ibrahim A, et al: Photodynamic destruction of Huemophilus pnrninfluenzue and Staphylococcus uureus by endogenously produced porphyrins (abstract). Lasers Surg Med lO(suppl):28, 1998 Walsh J: Pulsed laser ablation of tissue: analysis of the removal process and tissue healing. Medical Engineering Cambridge, MIT, Thesis 312, 1988 Walsh Jr JT, Deutsch TF: Er:YAG laser ablation of tissue: Effect of Pulse Duration and Tissue Type on Thermal damage. Lasers in Suraerv .,, and Medicine. 9:314-326, 1989" Walsh Tr IT, Deutsch TF: Er:YAG laser ablation of tissue: Measurement of tissue ablation rates Lasers Surg Med 9:3-337, 1989 Walsh Jr JT, Deutsch T F Pulsed CO, Laser ablation of tissue: Effect of tissue mechanical properties. IEEE Trans Biomed Eng 36:1195-1201, 1989 Walsh Jr JT, Deutsch TF: Pulsed COz laser tissue ablation: Measurement of the ablation rate. Lasers Surg Med 8:264275, 1988 Walsh Jr JT, Flotte TJ, Anderson RR, et al: Pulsed CO, laser tissue ablation: Effect of tissue type and pulse duration on thermal damare. Lasers Sum Med 8:108118, 1988 Webb R Confocal optical microscopy. Rep Prog Phys. 1996;59:427471 Welzel J, Lankenau E, Birngruber R, et al: Optical coherence tomography of the human skin. J Am Acad Dermatol 37958-963, 1997 West TB: Laser resurfacing of atrophic scars. Dermato1 Clin 1997; 15:449457 Wheeland RG. Laser-assisted hair removal. Dermatol Clin 15:469477, 1997 Zelickson BD, Mehregan DA, Zarrin AA, et al: Clinical, histologic, and ultrastructural evaluation of tattoos treated with three laser systems. Lasers Surg Med 15:364-372, 1994 I

I

1

Address reprint requests to CDR E. Victor Ross, MC, USN Naval Hospital San Diego 34800 Bob Wilson Drive Box 324 San Diego, CA 92134 e-mail: vross@[email protected]