Mechanisms of Laser Hair Removal: Could PersistentPhotoepilation Induce Vitiligo or Defects in Wound Repair?
KLAUS SELLHEYER, MD�
BACKGROUND Current laser hair removal modalities achieve a long-term but not persistent (irrevers-ible) hair loss.
OBJECTIVE This review highlights the mechanisms of the current laser hair removal technology andexplores possible side effects.
METHODS The literature is reviewed.
RESULTS The hair shaft plays a key role in the mechanisms underlying current photoepilation proce-dures by acting as a vector for heat transfer. Together with inherent properties of the hair growth cycleand the anatomic specifics of the follicular stem cells located in the bulge, the crucial role of the hairshaft and its lack of complete destruction with present technology are also likely culprits for the non-persistent nature of present laser hair removal. Future persistent photoepilation may be associated withvitiligo or vitiligolike changes. Disturbances in wound repair of previously lasered sites are less likely.
CONCLUSIONS The currently available laser hair removal protocols are safe, not the least because theyachieve long-term but not persistent epilation. The adverse effects of persistent laser hair removaltechnology possibly available in the future are potentially problematic.
Klaus Sellheyer, MD, has indicated no significant interest with commercial supporters.
Laser hair removal is popular and relatively free
of adverse effects.1 A recent evidence-based
meta-analysis, however, from January 2006 of a
total of 30 published trials employing ruby, alex-
andrite, diode, and Nd:YAG lasers as well as intense
pulsed light concluded that there is no evidence of
complete and persistent hair removal with present
technologies.2 Many patients request a persistent
photothermolysis solution for their unwanted hair.
Although such a desire on the patients’ behalf is
understandable, a cautious approach to persistent
hair removal is prudent. Based on recent basic sci-
ence data on the location of the melanocyte stem
cells,3–8 there is a concern that total destruction of
the hair follicle may possibly induce vitiligo or viti-
ligolike changes. There is also a concern with defects
in subsequent wound repair to the sites of previous
laser hair removal should the keratinocyte stem cell
population in the hair follicle bulge9,10 be destroyed.
This review will explore the rationale for these
concerns from a clinical, histopathologic, and basic
science perspective. To that extent, the article will
initially explore the mechanisms of laser-induced
photoepilation, which is permanent but not persis-
tent, and later this review will address these concerns.
Permanent but Not Persistent
The term ‘‘hair removal’’ is understood differently by
the lay public and the scientific community, and even
inside the latter it is often used inconsistently. The US
Food and Drug Administration has adopted a def-
inition for permanent hair removal as a ‘‘significant
reduction in the number of terminal hairs after a
given treatment, which is stable for a period of time
longer than the complete growth cycle of hair
follicles at the given body site.’’11 This definition of
‘‘permanent’’ departs from the original meaning
of its Latin root (‘‘permanentem,’’ preposition of
‘‘permanere’’ = ‘‘endure, continue, stay to the end’’)
& 2007 by the American Society for Dermatologic Surgery, Inc. � Published by Blackwell Publishing �ISSN: 1076-0512 � Dermatol Surg 2007;33:1055–1065 � DOI: 10.1111/j.1524-4725.2007.33219.x
1 0 5 5
�Departments of Dermatology and Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio
and does not imply that the laser-induced hair loss is
irreversible. It is this definition of the term ‘‘perma-
nent’’ which leads to patient misconceptions. In the
following discussion, the term ‘‘persistent’’ (from
Latin ‘‘persistere’’ = ‘‘continue steadfastly’’) will be
used as a reference to hair that does not regrow
subsequent to laser hair removal. So far all laser-
based epilation procedures may be long-term but are
followed by regrowth of hair at one point in time.11
They are therefore permanent in the sense of the
above definition but not persistent.
Mechanisms of Current Permanent Laser Hair
Removal: Primary Damage to the Hair Follicle
Epithelium or Heat Conduction via the
Hair Shaft?
The approach of laser hair removal is less specific
compared to laser therapy of tattoos or telangiec-
tasias in which the target represents a specific
chromophore, absorbing the laser light in a wave-
length- and time-specific manner, which produces
destruction of the target (for review see Goldman12).
Although photoepilation also targets pigment, the
targeted pigmentFmelaninFfunctions only as a
mediator of heat dissipation to the surrounding
tissue. Within the anagen hair follicle, melanin is
present in the melanocytes of the hair matrix
(Figures 1 and 2D) and in the hair shaft (Figures 2A
and 3). For epilation to occur, the laser can only
target follicles that are pigmented. Thus, hair folli-
cles that are less pigmented (blond) as well as those
pigmented with pheomelanin-containing (red) in-
stead of eumelanin-containing (dark) hair are less
susceptible to photoepilation procedures.13–19
Laser hair removal based on the theory of selective
photothermolysis20 was first attempted in human
subjects in 1996.21 Multiple clinical studies on a
variety of laser systems followed (for review see
Haedersdal and Wulf,2 Dirieckx,11 Dierickx et al.,22
Anderson,23 Lepselter and Elman,24 and Wanner25).
Unfortunately, histologic data on laser hair removal
are often based on only a few subjects (see below).
Large series with systematic histologic evaluations
over a long time course following laser epilation are
not available. In addition, data are also often difficult
to compare because different laser types and different
treatment parameters are employed. Nevertheless,
two theories of how laser light achieves hair removal
can be crystallized from the published histologic data.
The first theory emphasizes on a direct effect of the
laser light on the viable follicular epithelium, com-
posed of the inner and outer root sheath with the
keratinocyte stem cell–containing bulge, as well as
on the follicular papilla made up of specialized fi-
broblasts (Figure 3). Grossman and colleagues21 re-
ported histologic damage to the follicular epithelium
with increased eosinophilia and nuclear elongation,
leading to follicle rupture in isolated areas, after
normal-mode ruby laser pulses at 270 ms and using a
6-mm beam diameter. Similar changes were noted
Figure 1. The pigmented follicular melanocytes (arrow) arelocated among the hair matrix keratinocytes and transfertheir melanin into the hair shaft. The follicular papilla inva-ginates the epithelial portion of the hair bulb at the bottom.The hair shaft is not depicted in this micrograph. The tan-gentially cut outer root sheath (clear cells in the upper cen-tral portion of the hair follicle) is shown instead. Originalmagnification, �250.
D E R M AT O L O G I C S U R G E RY1 0 5 6
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after Nd:YAG laser radiation of hair.26 In a study
by McCoy and coworkers,15 the ruby laser at dif-
ferent fluences resulted in damage to the hair follicle
specifically in the inner root sheath. Even at the
highest fluences, there was no evidence of total fol-
licular dropout and the follicular papillae remained
viable.15 More extensive damage to hair follicles
after ruby laser application (1-ms pulses, up to
0.9 Hz, 5-mm spot size) with detachment of the
outer root sheath from the surrounding fibrous
root sheath initially and eosinophilic degeneration
of the inner root sheaths later were reported in eight
Japanese patients.27 Three studies, one of which
employing lasered ex vivo scalp skin from face-lift
operations,28 describe damage to the keratinocyte
stem cell–containing bulge region of the hair follicle
after ruby28,29 as well as alexandrite laser.30
The evidence for this claim, however, seems weak
Figure 2. (A) The bulge (arrow), here from a follicle of thebulbous hair peg stage of a human embryo, is typicallymore easily discernible during development compared tothe adult hair follicle. The arrowhead marks the outer rootsheath. Note that the centrally located hair shaft is alreadymelanized (reproduced with permission from Sellheyer K,Bergfeld WF. Histopathologic evaluation of alopecias. Am JDermatopathol 2006;28:236–5947). (B) Melanocytes (arrow-heads) are found in the bulge from this human fetus at ge-stational week 20. They are labeled with an antibody againstthe Bcl-2 protein. The Bcl-2 protein is an antiapoptotic pro-tein protecting the melanocytes from cell death. (C) In thisHMB-45–labeled bulge melanocyte (arrow) from anotherhuman fetus the dendritic nature is apparent (reproducedwith permission from Sellheyer K, Krahl D, Ratech H. Dis-tribution of Bcl-2 and Bax in embryonic and fetal humanskin: antiapoptotic and proapoptotic proteins are differen-tially expressed in developing skin. Am J Dermatopathol2001;23:1–7;64 with permission). (D) The majority of me-lanocytes (arrow), here labeled with HMB-45, are seen in thebulb, as shown here, and not the bulge (compare to B). It isspeculated that the bulbar melanocytes are derived frommelanocytic stem cells located higher up in the hair follicleand located in the bulge. Original magnifications: A, 100 � ;B, 250� ; C, 1000� ; D, 250� .
Figure 3. Schematic of hair follicle anatomy.
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S E L L H E Y E R
based on the published histologic pictures and the
pathologic description. One of the figures published
by Liew and colleagues28 showed a cytokeratin
19–labeled immunohistochemically processed sec-
tion.28 Cytokeratin 19 is a putative hair follicle stem
cell marker.31 The depicted slide, however, revealed a
full array of labeled stem cells in the bulge region
whereas the hair shaft was thermally damaged.
Damage to the hair bulb encircling the follicular
papilla was not described.
Bencini and colleagues14 claim complete disappear-
ance of hair follicles in three biopsies taken from a
total of 208 patients 3 months after the last treat-
ment with a long-pulsed low-potency Nd:YAG laser.
In biopsies from these three patients 6 hours after the
first treatment, they observed extensive necrosis of
the hair follicle and sebaceous gland epithelium. Five
to twenty minutes after application of a long-pulsed
Nd:YAG laser, Chui and coworkers32 reported
nuclear elongation and cytoplasmic degeneration at
the outermost portion of the outer root sheath at the
level of the hair bulb.
The second theory of how laser light achieves hair
removal focuses more on hair shaft damage as the
key feature. This is not surprising, as the hair shaft,
especially of darker hair, contains melanin as a laser-
susceptible chromophore, transferred from the viable
hair matrix melanocytes located in the deep portion
of the hair follicle (Figures 1 and 2A). According to
this mechanism of laser hair removal, known as
the ‘‘hair conduction theory,’’33 the hair shaft func-
tions as a conduction tube that transmits the ab-
sorbed energy as heat to the surrounding viable
portion of the hair follicle, thereby leading to
‘‘collateral damage.’’ Laser-induced destruction of
the hair shaft is even reported by several of the
above-mentioned proponents of hair removal due
to direct damage of the follicular epithelium,
albeit not viewed as the main mechanism of
hair removal.15,17,21,29,30
Support for a key role of targeting hair shaft melanin
comes from the observation that laser-induced
damage to the follicular epithelial sheaths was found
only in those follicles with damaged hair shafts.34 In
an experimental study employing a thermal imaging
system, Topping and colleagues34 demonstrated that
histologic changes of the hair follicle epithelium
were found to a greater depth and extent in those
hair follicles reaching higher temperatures, corre-
sponding with either an increased photon energy
conversion and/or combustibility of the hair shaft.
Thermally damaged hair shafts revealing charred
material around the periphery and cracking and
distortion of the shaft matrix were observed histo-
logically.35 The accompanying histologic damage to
the hair follicles appeared to concentrate around the
periphery of hair shaft keratin.35 In a more recent
article, the hair shafts were described as thermally
altered, exhibiting a thinned or shriveled appear-
ance, after exposure to an 800-nm-wavelength diode
laser or a 1,064-nm-wavelength Nd:YAG laser.36 In
many cases the hair follicles were entirely devoid of
hair shafts. Damage to the surrounding follicular
epithelium, including the bulge, was minimal,
rendering the viable portion of the hair follicle
structurally intact.36
It seems likely that the inherent thermal conductivity
of the hair shaft rather than direct laser light pen-
etration of the viable follicular epithelium is the
main underlying mechanism of the currently em-
ployed laser hair removal modalities. The key role of
the hair shaft as a heat vector is also likely to be one
of the reasons why photoepilation is only permanent
but not persistent and why the current laser hair
removal techniques do not induce vitiligo or wound
repair defects.
Why Do the Current Laser Modalities Not
Achieve Persistent Hair Removal?
The (pigmented) hair shaft as the prime target of the
laser beam is the product of the pilosebaceous unit. It
is produced by apoptosis of matrix keratinocytes
within the hair bulb, which itself interacts with the
hair bulge located at the lower end of the permanent
portion of the hair follicle (Figure 3). For persistent
D E R M AT O L O G I C S U R G E RY1 0 5 8
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hair removal to occur, the viable structures produc-
ing the hair shaft have to be destroyed. Is it likely
that laser-induced heat transfer via the hair shaft can
be controlled in a manner that induces complete and
selective destruction of all the surrounding viable
follicular structures involved in the production of the
hair shaft? The histologic observations discussed
above do not favor an affirmative answer and the
nonpersistent nature of laser hair removal today is
not in support of it either.2 One would think that
electrolysis would be able to induce persistent hair
removal, and an early histologic study37 seems to
support this notion. Despite being praised as the gold
standard of irreversible hair removal,38,39 it is only
partially effective40 and hair regrowth occurs at a
rate of 15 to 50%.41
The laser effects of hair removal treatments appear
to be random: damaged hair follicles are seen dis-
persed among intact ones.17,35 The latter would al-
low for subsequent hair regrowth. The histologically
observed random nature of hair follicle damage may
correlate with the heterogeneous rise in temperature
within the lasered individual pilosebaceous units.
Experimentally, Topping and colleagues34 described
a range of temperature increase between 2 and 321C
for the total of 80 measured hairs.34
In addition to the difficulty in selectively confining
the dissipated heat energy from the lasered hair
shafts to the surrounding follicular structures and the
random distribution of the laser effects in hair-bear-
ing skin, there are several inherent characteristics of
hair follicle anatomy and physiology that erect
stumble stones in our pursuit of persistent hair
removal.
The first is the cyclical nature of hair growth itself.
Laser pulses destroy the hair follicles in their anagen
stage whereas those in telogen and catagen are un-
affected.13,16,18,42 Therefore, follicles cycling
through telogen and catagen will be missed and give
rise to new anagen follicles. With subsequent and
multiple treatments, spaced out at appropriate in-
tervals, the influence of the hair growth cycle on the
treatment result can be minimized, however,43–45
albeit not entirely excluded. This is documented
by studies reporting merely an induction of a pro-
longed telogen phase, independent from the use of
a Q-switched or a long-pulsed laser regimen, but not
an irreversible morphologic destruction of the ana-
gen follicle.15,16,18 The influence of the hair growth
cycle is also highlighted by reports showing minia-
turization rather than complete loss of the hair fol-
licles.26,30,46 This is likely a response of the internal
biologic clock of the hair follicle by which it evades
destruction and retains the possibility of later re-
growth, comparable to androgenetic alopecia.47
Closely associated with the difficulties imposed upon
by the cyclical nature of the hair growth cycle is the
association of the melanogenesis with the anagen
phase. Hair is actively pigmented only when it
grows, whereas in catagen melanogenesis it is
switched off and in telogen it is absent throughout.48
This leaves no optimal target for the commonly
employed lasers to remove unwanted hair.
Most importantly, the bulge harboring the follicu-
lar keratinocyte stem cells9,10 is not pigmented
(Figure 2A) and therefore difficult to target by
currently employed laser modalities. In agreement
with others,13,17,21,23,30,33,34,49,50 I strongly favor the
notion that it is the bulge with its central role in hair
growth which needs to be destroyed, for laser hair
removal to become persistent and not only perma-
nent. In addition to the lack of melanin pigment, the
bulge forms a lateral protuberance pointing away
from the hair canal (Figures 2A and 2B), which may
protect it from the dissipation of heat from the
lasered hair shaft. In analogy, it is this anatomic
feature that led Cotsarelis and coworkers9 to spec-
ulate that the keratinocyte stem cells of the bulge are
safeguarded against accidental loss due to plucking.
In contrast, the bulb is subjected to the damage in-
duced by plucking the hair shafts.51 Moreover, it is
worthwhile to mention that the bulge is rather well
vascularized52,53 allowing for rapid heat dissipation.
In addition to the above features, the bulge kerati-
nocytes are rapidly dividing only during late telogen
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in preparation of the subsequent anagen phase.54,55
Grossman and associates21 speculate that this may
affect their susceptibility to injury. As mentioned
above, hair follicles are not particularly sensitive to
laser destruction when cycling through the telogen
phase during which melanogenesis is at its low point.
Because the follicular stem cells are otherwise slow-
cycling, they may be less sensitive to laser light injury
compared to the highly mitotically active matrix
keratinocytes of the bulb.
Knowing these facts of hair biology allows us to
understand why current laser modalities do only
induce permanent but not persistent hair loss. They
also make us understand why presently used laser
photoepilation procedures are safe.
What Are the Two Most Important Adverse
Effects of Persistent Laser Hair Removal?F
A Speculation
Because current laser hair removal technology results
only in long-term but not persistent hair loss, a dis-
cussion of this question remains naturally theoretical
and speculative. I believe, however, that an early
discourse may channel future scientific development
in this arena, allows further exploration into basic
trichologic aspects, and gives us a tool to explain to
our patients why the current permanent laser hair
removal technology may be the better alternative
over possibly persistent future photoepilation. I raise
two concerns and both are based on the stem cell
theory, specifically the theory of melanocyte
stem cells and the theory of follicular keratinocyte
stem cells.
Could Persistent Laser Hair Removal Induce
Vitiligo or Vitiligolike Changes?
Hypopigmentation is variably described as a side
effect of current laser hair removal modali-
ties.1,11,15,22,44,56,57 But as laser hair removal is not
persistent, so is the hypopigmentation. It is typically
only of a transitory nature. It is also likely
not follicular in origin but due to secondary effects
of the laser beam on pigmented basal keratinocytes
of the interfollicular epidermis58 because ultrastruc-
tural studies have confirmed melanosome disinte-
gration in that compartment following laser hair
removal.17
Scarring alopecias, on the other hand, most impor-
tantly discoid lupus erythematosus of the scalp and
beard area, can be associated with irreversible hypo-
pigmentation, resembling vitiligo (Figures 4A and
4B).47 All scarring alopecias have in common the
destruction of the follicular bulge (Figure 4C).47
Could it be that the underlying basis for the viti-
ligolike changes observed in discoid lupus erythe-
matosus of hair-bearing areas is rooted in the
destruction of melanocytes located in the hair follicle
and more specifically in the hair bulge? If that is the
case, then one could reasonably conclude in analogy
that the necessary prerequisite for persistent laser
hair removal, namely, the destruction of the hair
bulge, would also lead to vitiligo or vitiligolike
changes.
It is long known that repigmentation of patches of
vitiligo originates from the hair follicles (Figure
5).59–61 In vitiligo, active (dopa-positive) mela-
nocytes within the epidermis are destroyed, whereas
repigmentation occurs from inactive (dopa-negative)
melanocytes located in the outer root sheath.59 The
melanocytes are anatomically more specifically
localized to the bulge area, which is part of the outer
root sheath.62,63 Melanocytes in the bulge can
already be seen during the bulbous hair peg stage of
the developing human embryo.64 In 1996, Slominski
and coworkers65 postulated the existence of a
melanocyte stem cell population in the bulge area in
analogy to the keratinocyte stem cell population
described earlier by Cotsarelis and coworkers.9 They
were not able, however, to prove their claim.
Finally, in 2002, Nishimura and associates3 charac-
terized a melanocytic stem cell population located in
the bulge area. They employed elegantly conducted
transgenic mice experiments and found all the fea-
tures in these bulge melanocytes that characterize
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stem cells, being immature, slow cycling and self-
maintaining. These melanocyte precursors were also
capable of regenerating progeny on activation at a
stage of the hair growth cycle, when the follicle is
most susceptible to laser hair removal, namely, the
early anagen.48 Subsequent studies by others con-
firmed the existence of a melanocyte stem cell pop-
ulation in the follicular bulge.4,5
The above experiments employed a murine model
and although a human analog of melanocytic
stem cells residing in the follicular bulge has yet
to be found, it is quite likely that the human
hair follicle has a similar system at its disposal. In
view of the basic science data discussed, I reiterate
my concern that a persistent hair removal laser
system may be associated with vitiligo or
vitiligolike changes similar to those described in
scarring alopecias, as it would require the destruc-
tion of the bulge with the melanocytic stem cell
population.
Arguments can be found, however, that may amelio-
rate such a concern. First, within the murine system
employed by the above authors, the C57BL6 mice
strain, truncal melanocytes are only present in the hair
follicle but not in the interfollicular epidermis.66,67 In
vitiligo, the interfollicular melanocytes are destroyed,
Figure 4. (A) In patients with discoid lupus erythematosus of the scalp or beard area persistent hypopigmentation (arrow) isoften observed. (B) This transverse section through a hair follicle reveals the lymphocytic infiltrate (arrow), which is re-sponsible for the destruction of the hair follicle. (C) In this longitudinal section from another scarring alopecia, lichenplanopilaris, the bulge (arrow) is completely destroyed and the hair follicle is replaced by scar tissue (B and C reproducedwith permission from Sellheyer K, Bergfeld WF. Histopathologic evaluation of alopecias. Am J Dermatopathol 2006; 28:236–5947).Original magnifications: B, 100� ; C, 100� .
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S E L L H E Y E R
whereas the follicular melanocytes are preserved.59
Therefore, the experimental model and the human
disease may not be comparable. Second, it is possible
that melanocyte stem cells in the human are organized
not only in the bulge of the hair follicle but also
present within the epidermis, comparable to epidermal
stem cells.68 Obviously, the presence of epidermally
located melanocyte stem cells could theoretically be
responsible for the repopulation of the epidermis with
mature melanocytes, should the follicular counterparts
be wiped out by laser hair removal techniques. The
therapeutical success of epidermal grafting in
vitiligo69–72 may support the possible existence of
epidermal melanocyte stem cells. Third, selective
apoptosis of melanocytic stem cells, which occurs in
Bcl-2–deficient mice, leads to premature hair gray-
ing.73 Correspondingly, human gray hairs reveal a
decreased number of quiescent melanocytes within the
hair follicle.74 Thus, the destruction of the entire bulge
in a hypothetical persistent laser hair removal system
may be of no consequence for the melanocyte popu-
lation of the epidermis.
In sum, however, our current lack of knowledge does
not allow us to preclude the possibility of the in-
duction of vitiligo or vitiligolike changes, should
persistent laser removal become a future possibility.
Could Persistent Laser Hair Removal Induce
Defects in Wound Repair?
The second concern I have regarding persistent laser
hair removal systems is also based on the stem cell
theory. The focus this time is on the follicular kera-
tinocyte stem cells and their possible contribution to
wound repair.
As vitiligo patches repigment from the hair follicle,
so does wound healing make use of the preserved
adnexal structures, for example, in partial thickness
wounds or after CO2 and Er:YAG laser resurfac-
ing.10,75,76 Although it is now known that there is a
subset of epidermal stem cells relevant for the
maintenance of the epidermis,68,77,78 the stem cells
located in the bulge contribute to the epidermis
during wound healing.76 According to most recent
data, the bulge stem cells are recruited to the center
of the wound after epidermal injury, thereby con-
tributing to epidermal wound healing.76
Is it possible that persistent laser hair removal de-
stroying the bulge may have an effect on the wound-
healing capacity of the skin, should a subsequent
injury occur to the previously lasered site? The an-
swer to this question must remain entirely specula-
tive, because there is no adequate clinical or
experimental model to explain the consequences
of a complete destruction of the bulge. Although
scarring alopecias are characterized by bulge
injury, wound healing studies are difficult to perform
and ethically not justifiable in this subset of
patients. Because the epidermis is organized in
epidermal proliferative units76 with the possible
crucial role of the central basal keratinocyte as an
epidermally located stem cell,79,80 I agree with Ito
Figure 5. In vitiligo repigmentation after PUVA therapy of-ten starts from the hair follicles, as depicted in the center ofthe thigh.
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and colleagues76 that persistent laser hair removal
may not have a detrimental effect on subsequent
future wounding to the site. The redundancy of the
biologic system, organized in epidermal and follic-
ular stem cells, may prevent that. Only the actual
capability to eventually perform persistent photo-
epilation, however, will give us an answer to this
question.
Conclusion
It is obvious from the above review that there are
more questions than answers. I agree with Goldberg
that it is ‘‘only with a better understanding of hair
biology and the histologic evidence of laser induced
changes that we will begin to truly understand the
mechanism of laser induced hair removal’’81 andF
I addFof potential serious consequences of future
persistent photoepilation. I believe that such an ap-
proach ties one aspect of cosmetic dermatology into
the broad field of clinical dermatology.
Acknowledgment The author thanks Mitchel P.
Goldman, MD, for his review of the manuscript.
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Address correspondence to: Klaus Sellheyer, MD, TheCleveland Clinic Foundation, Department of AnatomicPathology L25, Section of Dermatopathology, 9500 EuclidAvenue, Cleveland, OH 44195, or e-mail: [email protected]
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