Lasers in Surgery and Medicine 33:30–39 (2003)
Nonablative Laser and Light Treatments: Histology
and Tissue Effects—A Review
Murad Alam, MD,1* Te-Shao Hsu, MD,2 Jeffrey S. Dover, MD, FRCPC,2,3,4 David A. Wrone, MD,1
and Kenneth A. Arndt, MD2,3,4,5
1
Section of Cutaneous and Aesthetic Surgery, Department of Dermatology, Feinberg School of Medicine,
Northwestern University, Chicago, Illinois
2
SkinCare Physicians, Chestnut Hill, Massachusetts
3
Department of Dermatology, Dartmouth Medical School, Hanover, New Hampshire
4
Section of Dermatologic Surgery and Cutaneous Oncology, Department of Dermatology,
Yale University School of Medicine, New Haven, Connecticut
5
Department of Dermatology, Harvard Medical School, Boston, Massachusetts
Background and Objectives: Nonablative laser and
light treatments have largely replaced ablative laser
therapy in clinical use for the improvement of the visible
signs of cutaneous photoaging, including rhytides, vascular
lesions, and pigmentation. However, the mechanisms
underlying the reported clinical efficacy of nonablative
treatments are not well-understood. The purpose of this
analysis is to critically evaluate what is known about
histologic and tissue effects of nonablative laser therapy
and suggest future directions for research.
Study Design/Materials and Methods: This is a review
of the English language literature pertaining to nonabla-
tive laser and light treatments available through MEDline
(1995–2002), and unpublished reports presented at major
national meetings. Only studies that included harvesting
and analysis of tissue samples are included.
Results and Conclusions: (a) Thermal injury to the
dermis in association with epidermal cooling most likely
affects the dermal vasculature, which initiates a cascade of
inflammatory events that includes fibroblastic prolifera-
tion and apparent up-regulation of collagen expression; (b)
There is no indication that nonablative treatments are
harmful or able to induce skin cancer; (c) It is possible that
the horizontally distributed collagen reported after non-
ablative treatments is a ‘‘microscar,’’ an enlarged Grenz
sone associated with repetitive photo-induced trauma; (d)
Further research is needed to elucidate the biophysical
mechanisms underlying nonablative treatment, as well as
to distinguish the utility of different wavelengths on
epidermal and dermal improvement. Lasers Surg. Med.
33:30–39, 2003. ß 2003 Wiley-Liss, Inc.
Key words: mechanism; photorejuvenation
INTRODUCTION
Nonablative laser and light treatments (other equivalent
terms include subsurface resurfacing, photorejuvenation,
laser toning) have been used for several years for the
aesthetic improvement of photoaged skin, particularly that
of the face [1–53]. These treatments provide an alternative
ß 2003 Wiley-Liss, Inc.
to traditional full-face laser resurfacing, an ablative
modality in which carbon dioxide and erbium:YAG lasers
are used to remove the entire epidermis and portions of the
dermis. Ablative resurfacing improves skin roughness, fine
periorificial lines, and dyspigmentation by permitting the
growth of new epidermis and superficial dermis to replace
the components of the skin that are vaporized by the laser.
New skin regrowth occurs from hair follicles and via lateral
migration since the bases of the follicles as well as the
germinative bulge region lie below the level of laser
ablation. Nonablative resurfacing is attractive to physi-
cians and patients because it reduces patient inconvenience
and risk and is designed to provide many of the same
benefits of ablative resurfacing. All nonablative treatments
improve skin texture, wrinkles, or surface irregularities,
and some additionally address dyspigmentation as well as
superficial eythema and telangiectasia. The epidermis is
not visibly disrupted in nonablative treatment as only a
relatively modest amount of thermal injury is delivered to
the dermis. Minimal or no healing time is required after
nonablative resurfacing in contrast to the several weeks
required for reepithelialization following ablative resurfa-
cing. Mild erythema and edema do occur following each
treatment, but these sequelae remit within minutes to a
few hours or may be concealed with cosmetics. Patients
typically receive a series of 5–6 nonablative facial treat-
ments separated by 3–4 week intervals. After the standard
course, some patients choose to continue to return every
month for further treatments. Cumulative aesthetic bene-
fits from nonablative resurfacing are similar in type though
less in magnitude than the results of ablative resurfacing.
While nonablative laser treatments have won favor
among patients and physicians as efficacious procedures,
formal studies of efficacy have been limited in scope. Most
*Correspondence to: Murad Alam, MD, Department of Derma-
tology, 675 N. St. Clair St., Ste 19-150, Chicago, IL 60611.
E-mail: murad@alam.com
Accepted 4 April 2003
Published online in Wiley InterScience
(www.interscience.wiley.com).
DOI 10.1002/lsm.10195
 NONABLATIVE LASER AND LIGHT TREATMENTS
attempts to evaluate nonablative therapies have been de-
scriptive, with an emphasis on phenomenology rather than
elucidating mechanism(s) of action.
Clinical evaluations of this therapeutic intervention
have routinely relied on before and after photographs. To
assure some degree of standardization in the evaluation
process, images have been rated by double-blinded obser-
vers, and these ratings supplemented by more objective
noninvasive texture measurement such as profilometry,
ultrasound, and the PRIMOS (Phaseshift Rapid In-Vivo
Measurement of Skin, GF Mestechnik, Teltow, Germany)
3-dimensional in vivo skin imaging system.
The difficulty in comparing outcomes has been exacer-
bated by the proliferation of different laser and light
settings and sources used for nonablative resurfacing.
Fluence, pulse duration, number of passes, and cooling
parameters vary across lasers, and even among the same
devices. When multiple passes and stacked pulses have
been used for nonablative treatment, it has been suggested
that a minimal delay of 3–5 times the thermal relaxation
time of the relevant chromophores be observed between
consecutive pulses to avoid epidermal damage and blanch-
ing [54]. This recommendation may be skin-site dependent,
and is not universally accepted. Peak epidermal tempera-
ture has also been found by some to have an important
influence on the histologic changes after nonablative laser
therapy [55]. With surface Tmax below 458C, very few
histologic changes are seen. With Tmax (¼ 45–488C), dermal
collagen growth and clinical improvements are more likely
to be evident. Above 488C, discernible vesicles emerge as
epidermal/dermal separation occurs. Apparently, an epi-
dermal surface temperature of 40–488C is ideal since this
correlates with a dermal temperature of 708C, which is
required for collagen denaturation [56].
Numerous laser and light devices [57], including the KTP
laser (532 nm), pulsed dye laser (585 nm, 595 nm), intense
pulsed light device (500–1,200 nm), Nd:YAG laser
(1,064 nm Q-switched, 1,064 nm long-pulse, 1,320 nm),
diode laser (980 nm, 1,450 nm), Er:Glass laser (1,540 nm),
and Er:YAG laser (2,940 nm), have been adapted to non-
ablative resurfacing, and recently there has been increased
interest in comparing the relative efficacies of these
machines for this indication. Studies have been undertaken
to: (i) assess long-term results; (ii) isolate the effect of intra-
operative cooling; (iii) evaluate anesthesia options; (iv)
estimate the utility of dyes and carbon lotions used concur-
rently; and (v) evaluate the response to treatment of other
skin surface aberrations, such as acne scarring and neck
lines.
Recently, there has been some attempt to define the
mechanisms underlying the clinical results observed with
nonablative resurfacing. Most invasive investigations of
nonablative resurfacing have compared the histology of
preoperative and postoperative biopsies. A very few
investigators have employed in situ hybridization to dissect
what is occurring at the mRNA level; however, this work
has been limited in scope.
The remainder of this article will review our current
understanding of the effects that nonablative resurfacing
31
has on the skin morphology. Data for each device type will
be discussed separately. General conclusions will then be
drawn, and directions for further study outlined.
RESULTS: REVIEW OF TISSUE EFFECTS
BY LASER TYPE
KTP Laser (With 1,064 nm Nd:YAG)
The KTP laser has traditionally been used for the
treatment of small-caliber focal facial telangiectasia, and
there are no published papers regarding the use of this
device for nonablative resurfacing. A single abstract [58]
briefly describes combined treatment with 532 nm KTP and
1,064 nm Nd:YAG lasers in a large number of subjects from
which biopsies were obtained 1, 2, 3, and 6 months after a
regimen of 3–6 treatments over an indeterminate period.
While the staining and assay methods are not specified, the
author notes that the post-treatment biopsies indicated
new collagen formation at the treated sites.
Pulsed-Dye Laser
The pulsed-dye laser, a workhorse in the treatment of
facial telangiectasia, diffuse erythema, and other super-
ficial vascular lesions, has also been used with intralesional
steroids for the treatment of keloids and hypertrophic
scars. While the laser functions primarily to reduce the
redness associated with scars, it has also been noted to
soften scars. Subsequent anecdotal findings have suggest-
ed that not only scars but also minor skin texture
irregularities improve after repeated laser applications.
This smoothing effect has now been investigated with both
traditional microsecond domain 585 and 595 nm short-
pulse dye lasers. Low energy pulsed-dye lasers (e.g., ‘‘N-
lite’’) as well as long-pulse pulsed-dye lasers (e.g., pulse
durations of 10–40 milliseconds) have also been studied. In
one investigation [59] involving a long-pulse 595 nm device,
3 mm skin biopsies were obtained before treatment, 4–
6 weeks after a series of four treatments, and 3 months
after the treatment cycle. Hematoxylin and eosin (H&E)
staining as well as type I procollagen staining was perform-
ed to assess deposition of collagen and the activity of dermal
fibroblasts. The Grenz zone was moderately thicker in 50%
of patients in both treatment and cryogen only control
groups, but the degree of thickening was greater in the
treatment sites. Similar findings were seen at 3 months,
when an increase in dermal collagen was also observed in
the treated areas.
In an early study [60] with the 585 nm laser (450 mm pulse
duration), 10 patients with mild to moderate facial wrinkles
and 10 patients with moderate to severe facial wrinkles
each received a single laser treatment. Biopsies were
obtained from over half of patients prior to treatment and
at 6 and/or 12 weeks after treatment. Six and 12-week
biopsy sections stained with H&E revealed a thickened
stratum spinosum and an apparent thickened collagen
layer in the superficial dermis. Increased mucin deposition
was also seen in the superficial dermis. Ultrastructural
evaluation with electron microscopy showed increased
collagen fibers and greater numbers of fibroblasts in the
32 ALAM ET AL.
treated skin. An apparent simultaneous increase in
‘‘normal appearing elastic fibers’’ and a decrease in ‘‘clump-
ing of degenerated elastic fibers’’ were also mentioned.
Evaluations of the standard 585 nm laser in nonablative
resurfacing have been reported in abstracts [61,62]. In one
report, patients received two periorbital treatments with
either pulsed dye laser (PDL) or an intense pulsed light
(IPL) device 6 weeks apart, and biopsies were performed 6
weeks after the final treatment [61]. In-situ hybridization
with mRNA probes for type I collagen and collagenase was
used to analyze both the 585 nm and IPL treated samples.
An 18% increase in type I collagen transcripts in the
papillary dermis was noted after IPL treatment, compared
to 23% increase after PDL, and the increases for collage-
nase transcripts were 32% and 40%, respectively. Zelickson
and Kist [61,62] conclude that the observed increases in
mRNA in fibroblasts indicated stimulation by nonablative
light, most likely resulting in production of extracellular
matrix proteins by dermal fibroblasts. They do not speci-
fically interpret the increase in collagenase transcription,
but possibly this is consistent with increased collagen
turnover, or the removal and replacement of earlier exist-
ing collagen. As an aside, these investigators [62] noted that
localized increased expression of some proteins occurred
near neurovascular bundles and single fibroblasts. No
conclusions were drawn from this incidental finding.
At least two studies have examined the low-energy
585 nm/350 microseconds laser for nonablative treatment
and wrinkle reduction. In one study [63], suction blisters
were raised 72 hours after treatment and blister fluid was
assayed for the aminoterminal propeptide of type III
procollagen (PIIINP; a marker for type III collagen). After
a single laser treatment, PIIINP levels rose from 61.5 mg/L
to 113.5 mg/L, which was highly significant. Interestingly,
two treatments resulted in a concentration of only 95.5 mg/
L, thus suggesting a negative physiologic effect associated
with retreatment. In this same study, pre- and post-
treatment measurements of skin transepidermal water
loss (an estimate of the epidermal barrier function) showed
no change over time, which implies that there was no
compromise in barrier function as a result of these treat-
ments. In a later study [64], pre-treatment and 6 month
post-treatment biopsies were harvested from preauricular
sites, and collagen fiber size was evaluated by electron
microscopy. After 6 months, an increase in both the quan-
tity per unit volume of small collagen fibers consistent with
type III collagen and larger fibers consistent with growth in
type I collagen were observed.
Intense Pulsed Light Device
Intense pulsed light devices have been used for the
treatment of telangiectasia and erythema, reduction of
lentigines, and softening of facial lines and creases. The
multiple skin improving functions of intense pulsed light
have made it a favorite modality for nonablative therapy.
One study [65] with this device obtained 3 mm punch
biopsies from the left malar skin prior to treatment and
1 week after the fifth and final treatment. Microscopic
evaluation entailed rating epidermal atrophy, horny plugs,
loss of polarity, and basal cell necrosis on a normative
scale (0 ¼ nl, þ ¼ slight, þ þ ¼ moderate, þ þ þ ¼ severe).
The dermis was evaluated on changes in elastosis, edema,
telangiectasia, and inflammation, using the same scale
system. Pretreatment epidermis was found to exhibit
moderate to severe atrophy, light to moderate horny plugs,
light to moderate basal cell necrosis, and severe rete ridge
flattening; all of these ratings were found to be improved
slightly to moderately after treatment, but the sample sizes
were insufficient to establish significance. Epidermal thick-
ness, as measured by an optic micrometer, increased to a
range from 0.01–0.03 mm, a statistically significant change
at the level of P < 0.01. Pretreatment dermis was char-
acterized as having moderate to severe elastosis, moderate
edema, moderate telangiectasia, and slight to moder-
ate inflammation; again, after treatment, these features
were slightly to moderately improved, with the greatest
improvement noted in degree of elastosis, which decreased.
The significance of these changes was not assessed. The
overall significance of these apparently global improve-
ments in epidermal and dermal morphology are not
interpreted by the authors, who focus principally on the
decrease in elastosis, and a corresponding anecdotal
increase in collagen deposition, which was not an explicitly
measured outcome of this study. It is not clear whether the
reported significant increase in epidermal thickness is a
real effect, or an illusory finding deriving from more
marked curvature of some rete ridges after treatment.
A histologic study [66] evaluated templar skin biopsies
3 weeks after a series of five treatments spaced 3 weeks
apart. Following treatment, significant collagen deposi-
tion was observed on H&E stained samples within 300 mm
of the skin surface. The authors report that with ‘‘immu-
nostaining,’’ types I and type III collagens were visible. A
different study [67] compared skin biopsies taken from the
forehead prior to and 4 weeks after four full-face treat-
ments. New collagen was noted in both the papillary dermis
and the full-thickness reticular dermis in treated speci-
mens. A resolution in the superficial dermal inflammatory
infiltrate and papillary dermal melanophages was also
observed.
A more extensive histologic study [68] obtained 2 mm
punch samples from treated and control areas before
treatment, 1 week, 3 months, and 12 months after a series
of 6 IPL sessions at monthly intervals. The tissue was
stained with H&E, as well as Masson trichrome (collagen),
von Gieson (elastic tissue), and reticulin (new collagen
fibers). Specimens were also analyzed by electron micro-
scopy. Pretreatment skin showed mild to moderate sun
damage, characterized by solar elastosis. In most of the
pretreatment biopsies at least one follicle displayed de-
modex with a perifollicular lymphoid infiltrate and focal
spongiosis (seborrheic dermatitis). One week after treat-
ment, no perifollicular infiltrate was evident; however, at 3
and 12 months, demodex and an associated lymphoid
infiltrate were again observed. There was no evidence of
differing amounts or quality of collagen, elastin, or reticulin
before or after treatment. Ultrastructural analysis reveal-
ed no significant alteration in collagen or elastin fibers, and
 NONABLATIVE LASER AND LIGHT TREATMENTS
the basement membrane zone remained normal. In several
samples, slightly more compact collagen was found in the
papillary dermis, but this was not a marked change. The
authors were thus not able to corroborate the collagen
changes noted by other investigators, and they proposed a
novel mechanism to explain the reported clinical efficacy of
nonablative therapy—the possible transient therapeutic
effect of the coagulative necrosis of demodex organisms. In
view of the substantial evidence from other investigations,
documenting collagen changes after nonablative treat-
ment, these authors’ finding that collagen is unchanged
but that demodex may be causally responsible for the
therapeutic effect of laser treatment represents a contrary
opinion. While demodex may possibly mediate a secondary
effect in nonablative resurfacing, the potential role of the
organism must at present be regarded as interesting but
highly speculative.
Diode Laser (980 nm)
The diode laser has been used most extensively for hair
removal, and there is limited information on its utility as
a means of nonablative resurfacing. In a single study [69],
the 25 W, 980 nm diode laser was used to irradiate
in vitro skin samples obtained from breast skin (reduction
mammoplasties) and eyelid skin (blepharoplasties), as well
as the in vivo eyelid skin of two patients. Tissue shrinkage
and a zone of denatured collagen were noted immediately
after treatment in the in vitro samples. At laser settings
which resulted in no gross epidermal damage, the investi-
gators reported immediate skin shrinkage of up to an
astonishing 16%, which they considered comparable to that
induced with CO2 laser. Additionally, eyelid skin of two
patients was treated in vivo and biopsied 6 and 21 days,
respectively, after treatment. On day 6, the tissue demon-
strated few inflammatory cells, trace denatured collagen,
and a modest amount of new collagen, with no clear line of
demarcation between newly organizing collagen and
mature collagen; the epidermis, including the epidermal
papillae, remained intact. At 21 days, tissue stained with
Masson’s trichrome showed a nearly normal dermis with
clearly discernible collagen bundles.
Nd:YAG Laser (1,064 nm), Q-Switched
The Q-switched Nd:YAG laser was developed for the
treatment of skin pigments, including those present in
lentigines and tattoos, but has been used by some practi-
tioners for nonablative resurfacing. In a single study [70],
infraauricular skin treated with two passes of this laser was
biopsied before treatment and 3 months after treatment.
Four of six biopsies specimens obtained after treatment
demonstrated decreases in solar elastosis and a mildly
thickened upper papillary collagen zone. Increased ‘‘orga-
nization’’ of the collagen manifested as collagen bundles in
parallel alignment with the epidermal surface. These col-
lagen changes were of a similar type but less extensive than
those observed after ablative carbon dioxide laser resurfa-
cing. The authors [70] do not address the significance of the
perceived changes in collagen. For instance, we would sug-
33
gest the possibility that the horizontal fibrous arrays seen
post-treatment in the dermis may have been evidence of a
scarring process caused by thermal damage rather than an
improvement in collagen deposition.
Nd:YAG Laser (1,320 nm)
A substantial number of studies have examined histology
following treatment with the 1,320 nm Nd:YAG laser. In
one study [56,71], 3 mm punch biopsies were obtained from
the left postauricular areas before, 1 month, and 6 months
after the fourth and final treatment. Pretreatment biopsies
in all subjects demonstrated some degree of solar damage,
with thinned epidermis and elastotic changes in the dermis.
One month after the fourth treatment most patients
showed some evidence of new collagen, which was evident
in all patients 6 months post-treatment. In other studies
[72,73], 1 mm punch biopsies were obtained from the pre-
auricular region before treatment, and 2 weeks and 6 weeks
after the 8th treatment. Before treatment, biopsies showed
a thin epidermis, flat dermal-epidermal junction, an elas-
totic dermis with wide spaces between the collagen bundles,
and random deposition of collagen fibers. Six weeks after
the last treatment, a thicker epidermis with more undulat-
ing rete pegs at the dermal-epidermal junction, increased
density of collagen fibers, decreased interfibrillary spaces,
and linear orientation of collagen fibers parallel to the
dermal–epidermal junction was noted.
Another abstract [74] is significant for describing the
effects of a remarkable 28-treatment series, administered
as two treatments a week over the course of 3 months.
Comparison of preauricular biopsies from before treatment
to those removed 6 months after treatment demonstrated
post-treatment collagen that was more eosinophilic and
homogeneous, interstitial spaces between fibers that were
reduced, and dermal thickness and density that were
increased.
Some studies have attempted a more in-depth analysis of
histologic and tissue features. Postauricular biopsies taken
pretreatment, and 1 and 3 months after three treatments
were stained with H&E and Masson’s trichrome to assess
collagen in the papillary and upper reticular dermis as well
as the amount of elastic fibers [75]. Amount of collagen,
homogenization of collagen (collagen horizontally arranged
in upper papillary band), inflammation, and amount of
elastic fibers were rated on a 0–5 scale. At 1 month, a 1 point
increase in collagen homogenization was noted in half of the
patients. However, collagen homogenization returned to
baseline levels by 3 months. Of the minority of patients who
showed wrinkle reduction at 3 months, half showed in-
creased collagen and homogenization of collagen, and the
remainder showed either collagen increase alone or no
change in parameters.
At least one study (CoolTouch I, CoolTouch Corporation,
Roseville, CA) [55] has examined the effects of differing
numbers of laser passes immediately after treatment.
The laser device provided a train of three pulses (300 micro-
seconds each) with a spot size of 5.5 mm, and 20–
30 milliseconds of epidermal cooling followed 10–20 milli-
seconds later by the laser. One hour after 3 passes using
34 ALAM ET AL.
these parameters, intraepidermal edema and acantholysis
occurred near the basal layer, and this result was less
noticeable in the tissue subjected to 2 passes, and absent
after 1 pass. Three days later, the 3 pass treated skin
displayed microthrombosis, widened vessels, sclerosis of
vessel walls, infiltration of neurophilic granulocytes, and
no intact mast cells; 2 passes were associated with mild
epidermal changes and superficial vascular changes, which
were correlated with subjective improvement, and 1 pass
was associated with no histologic or clinical alterations.
Biopsies obtained at the same intervals and number of
passes at control sites where only cryogen spray was
delivered revealed no histologic changes beyond slight
epidermal edema.
This is an important study because it focuses on the early
histologic changes after nonablative laser treatment. The
conclusion is drawn that immediate vascular damage,
recruitment of inflammatory cells, and release of mediators
may be the responsible for the clinical improvements
associated with nonablative resurfacing. While epidermal
edema and inflammation likely resolve over weeks to
months, the changes in collagen that are reported in other
studies are likely due to inflammation.
Diode Laser (1,450 nm)
The 1,450 nm diode laser has been used both for
treatment of facial rhytides and for treatment of active
acne. Acne treatment can be considered an extension of the
nonablative applications of this laser since the mechanism,
directed dermal injury, appears to be the same. Very little
published research is available regarding the nonablative
efficacy of this laser, which is marketed as a nonablative
device.
Several studies are apparently in preparation. Tanzi and
Alster [76–79] describe studies in which they have found
randomized patients to receiving treatment to either the
left or the right sides of their faces, with the contralateral
side serving as a control. In a study of 20 patients with
transverse neck lines, the treated sides apparently had
clinical and histologic improvement of rhytides, but perio-
bital rhytides improved more. For the treatment of atrophic
facial scars, 1,450 nm diode laser has been compared to
1,320 nm Nd:YAG laser. Possibly, the 1,450 nm laser may
be superior to the 1,320 nm Nd:YAG device for nonablative
treatment of atrophic facial scars, although no specific
histologic data is yet available.
Acne treatment with the 1,450 nm device has been
reported in studies that have targeted back acne. Paithan-
kar et al. [80] delivered four treatments spaced 3 weeks
apart to the entire treatment sites, rather than to just
where acneiform papules had been marked. The investiga-
tors found a statistically and clinically significant reduction
in acne lesion counts after treatment. Histologic findings
were epidermal preservation but rupture of the pilosebac-
eous unit and thermal coagulation of the sebaceous lobule
and follicle. Given the low density of sebaceous glands on
the back, these changes were not observed in many biopsy
samples. Long-term follow-up biopsies of similarly treated
back and face skin showed no difference from baseline in
adnexal structures, including sebaceous glands and folli-
cles. Significantly, research with shorter pulse (810 nm)
diode lasers used in combination with indocyanine green
(ICG) dye has indicated similar transient necrosis of
sebaceous glands followed by long-term improvement of
acne [81]. The underlying mechanism of epidermal sparing
and dermal injury is consistent with the nonablative
paradigm and different from aminolevulinic acid (ALA)-
photodynamic therapy (PDT) and other laser/light based
acne treatments that achieve their effect by depopulating p.
acnes. Further studies of the treatment of facial acne using
the 1,450 nm laser are under way, but at present it is not
clear to what extent sebaceous gland necrosis underlies the
efficacy of nonablative laser treatments in patients who do
not have active acne.
Er:Glass Laser
The erbium:glass laser has few applications in cutaneous
laser surgery beyond nonablative resurfacing, which
introduced this device to many practitioners. In an early
study, domestic pigs, a frequently used model for wound
repair, were treated with an Er:Glass laser [82]. Following
treatment, the epidermis was preserved in all cases.
Additionally, reproducible bands of denatured collagen
were observed in the superficial and deep dermis of this
model animal. Significant wound shrinkage (>2% by area)
was seen immediately after treatment, but only when
accompanied by complete collagen denaturation. When
collagen denaturation did occur, it was localized deep (400–
1,200 mm) within the dermis. The induced basophilic
staining (an indicator of collagen denaturation) persisted
from day 14 for superficial wounds (400–800 mm) to a month
for deeper wounds (800–1200 mm). Pitted scarring did occur
in areas of significant collagen alteration. This pitted scar-
ring may be the clinical sequela of the collagen alterations
that are the major changes in many studies. Collagen
remodeling may culminate in a ‘‘microscar’’ that results
from inflammatory-driven fibrosis.
Human studies with the Er:Glass laser included one [82]
in which seven preauricular sites on each of nine subjects
were irradiated at various energies and number of passes.
A punch biopsy was taken from one treatment site in each
patient immediately post-treatment and at 2 months.
Among the sites where no gross epidermal damage was
observed, immediate post-treatment biopsies revealed
clumping of basophilic collagen and elastotic material,
and loss of birefringence. Slight changes in collagen stain-
ing were noted at a depth of 400–1,300 mm. Depth of injury
increased with laser fluence and number of passes. The
dermis contained clumped basophilic collagen and elastotic
material, and thermal damage to follicular structures and
sebaceous glands was observed at the same depth. Mean
depth of injury was 703 mm, and the average thickness of
the band of altered collagen was 513 mm. After 2 months,
some biopsies showed dermal fibroplasia that was approxi-
mately 760 mm thick. Increased numbers of fibroblasts
were observed at depths equivalent to those at which the
heat-related damage had been documented. Some skin
swelling persisted over time, but a significant increase in
 NONABLATIVE LASER AND LIGHT TREATMENTS
glycosaminoglycans was not observed by routine mucin
stains. Overall, it was found that greater epidermal contact
cooling through a chilled sapphire window during laser
treatment resulted in protection of a relatively greater
portion of the epidermis and superficial dermis from gross
thermal injury; therefore, greater cooling induced deeper
dermal injury.
Another investigation [83] collected biopsies before, and
7 days, 3 weeks, and 2 months after a single treatment.
Orcein and H&E staining of 3 mm preauricular biopsies
revealed a thin epidermis, superficial collagen bands in the
papillary dermis, and a disordered solar elastotic appear-
ance in the dermis prior to treatment. Post-treatment, a
loss of orcein-stainable material within 7 days suggested
that the elastosis was becoming altered. After 2 months,
few elastotic fibers were observed even in the reticular
dermis. The superficial collagen band in the upper dermis
was thickened, with the collagen fibers arranged more
horizontally, suggestive of a microscar.
Er:YAG Laser
The Er:YAG laser has traditionally been used for ablative
resurfacing, but protocols have been developed for ‘‘partly
ablative’’ and ‘‘subablative’’ treatments. In one combination
approach [84], the epidermis is first removed at ablative
settings and then the laser is reprogrammed for a sub-
ablative mode. Preoperative, immediately postoperative,
and 2 months post-treatment biopsies were obtained from
preauricular sites in patients undergoing this treatment
and tissue sections were stained with H&E and Masson
trichrome. Histology before resurfacing revealed poor
collagen compaction and elastotic tissue. Immediately after
treatment, H&E-stained epidermis contained a residual
carbonized layer and some blood deposition associated with
the partly ablative effect of the Er:YAG laser treatment
settings. Additionally, immediately post-treatment, der-
mal collagen fibers in the upper papillary area were dis-
ordered. Two months later, the epidermis and dermal-
epidermal junction appeared normal, with a well-oriented
band of collagen observed below and parallel to the dermal-
epidermal junction.
Another use of the Er:YAG laser entails avoiding
significant epidermal damage through low-fluence treat-
ments [85]. Such treatments can be delivered as a single
pulse per unit area, or as a train of mild pulses. Concurrent
use of cryogen spray cooling with repetitive Er:YAG pulses
may affect the heat available for dermal coagulation, thus
creating a temperature curve analogous to that generated
by a lower-pulsed laser without cooling. In short, it appears
difficult to use the Er:YAG laser to obtain a significant deep
dermal effect while adequately protecting the epidermis.
However, repetitive Er:YAG treatments can yield dermal
collagen coagulation and neo-collagen formation at depths
similar to those observed with carbon dioxide laser re-
surfacing while avoiding complete epidermal ablation [86].
Acute dermal coagulation in the aftermath of such treat-
ment has been noted to a depth of 250 mm, and 4 weeks later,
neocollagen formation was observed to a depth of greater
than 100 mm.
35
Studies of the Er:YAG laser have also been conducted
with laboratory animals. Male hairless rats were pulse-
train irradiated (i.e., treated with stacked pulses) with
sufficiently low fluences to ensure epidermal preservation,
and biopsied at 24 hours, 3 days, and 7 days. Sections were
stained with H&E, Masson trichrome (collagen), orcein
(elastic fibers), alcian blue (mucopolysaccharides), and
periodic acid Schiff (fibrin) [87]. On day 1, the epidermis
was intact, the dermis showed homogenized changes with
thin and rarefied elastic fibers, and hair follicles were
intact. On day 3, the epidermis remained intact, and at
those sites receiving high temperature, slight muscular
atrophy, dermal homogenization, fibroblastic proliferation
in the deep dermis, and lipocyte disorganization were ob-
served. On day 7, the epidermis and hair follicles were
intact, and homogenized changes with fibroblastic pro-
liferation were seen throughout the dermis. Dermal
wounds were found to be ovoid with a thickness of
200 mm. In another study [88], partially ablative treatment
was delivered to the skin of Sprague–Dawley rats. Four
millimeters punch biopsies were obtained from laser and
control sites 1 hour after treatment. Collagen coagulation
(hyalinization, glass-like appearance) was used as the
principal marker for depth of thermal damage. Frequent
nonhomogeneous and patchy areas of collagen were observ-
ed, possibly because of laser ‘‘hot spots’’ where more intense
radiation was delivered. The demarcation between the
coagulated and the intact dermis was poor, even with the
use of polarized microscopy. As the number of laser pulses
in a sequence was increased, the amount of thermal damage
increased nonlinearly, but epidermal thickness decreased
linearly. The greatest coagulative injury was seen around
hair follicles. With 3–10 stacked pulses, collagen coagula-
tion was observed up to 300 mm below the dermal-epidermal
junction.
DISCUSSION
As can be seen from the above detailed review, there is an
abundance of small studies examining post-treatment
histology after nonablative resurfacing, but the informa-
tion that can be distilled from these investigations is
surprisingly limited. In part, this paucity of knowledge may
be attributed to limited analytic methodologies employed.
Most studies have entailed a subjective comparison of pre-
and post-treatment histology using H&E or special stains,
with the post-treatment biopsies usually obtained at a few
time points. Much of the data have been anecdotal, and
many of the conclusions are unsubstantiated. Conse-
quently, only a few generalizations can be drawn about
tissue effects associated with nonablative laser treatment:
(1) It appears that laser treatments that are delivered
in combination with epidermal pre- or post-cooling can
protect the epidermis from ablation yet deliver a
thermal injury to the dermis. The depth of the dermal
injury may be increased if greater epidermal cooling is
applied concurrently.
(2) Thermal injury to the dermis most likely affects the
vasculature, which initiates a cascade of inflammatory
36 ALAM ET AL.
events that includes fibroblastic proliferation and
apparent up-regulation of collagen expression.
(3) Weeks to months after a series of nonablative treat-
ments, collagen deposition is increased and assumes a
horizontal orientation parallel to the plane of the
epidermis. There are some reports of overall dermal
and even epidermal thickening.
(4) Several different laser and light devices appear
capable of inducing similar histologic changes follow-
ing nonablative resurfacing.
Some specific areas need be addressed in future studies.
In particular, a high degree of rigor and standardization
may help overcome the problem of a small n in each study.
For example, if studies used similar treatment methods
(e.g., same number of passes, same fluences), interpreta-
tion of the post-treatment changes would be more compar-
able and hence more meaningful. To this end, efforts should
be made to:
(1) Subtype patient populations to determine whether
skin type, degree of photodamage, anatomic site, or
other demographic or skin morphologic features
influence the degree of nonablative laser efficacy.
(2) If practical, institute appropriate controls, including
biopsies of untreated skin sites in the same patients at
various intervals, to differentiate the specific effects of
nonablative therapy versus untreated skin.
(3) When histologic or other operator-dependent evalua-
tions are performed, use at least two independent
observers, and document interobserver agreement
(4) Acquire tissue samples early during the course of a
series of treatments. Tissue evaluations should not be
restricted to just pre- and post-biopsy times.
(5) Standardize the parameters for fluence, number of
passes, number of treatments, intertreatment inter-
val, and treatment technique now that these are
known for many laser devices.
Additionally, we would hope for better studies correlat-
ing clinical efficacy with tissue effects. At present, there is
wide disagreement on the extent to which histologic
findings correlate with clinical appearance after treatment.
Many investigators report a weak correlation, some report
a near perfect correlation and others see none at all. As
studies are better defined and methodologies become more
standardized, more clarity may emerge on this issue.
Although causality is inherently difficult to establish,
consistently obtained findings may provide insight into
which tissue processes are necessary for efficacy.
Previous investigations on photoaged human skin have
noted that while the epidermis is altered during the aging
process, the most significant differences between chron-
ologic and photoaged skin manifest in the dermis [32,89–
93]. Unlike chronologically aged dermis, which contains
reduced eosinophilic and Hales stainable material (marker
for glycosaminoglycans) and small fibroblasts, photoaged
dermis includes a broad swath of eosinophilic material
(Grenz zone) immediately under the epidermis. Ubiquitous
horizontally arrayed bundles of normal collagen fibers in
the papillary dermis of photoaged skin stain positively for
reticulin, thus confirming the presence of new collagen in
the context of a healing wound. The entire enlarged Grenz
zone associated with photoaged skin has been compared to
a ‘‘microscar’’ resulting from repetitive photo-induced skin
trauma. Interestingly, the histologic descriptions of the
horizontally distributed collagen in this photodamage-
associated Grenz zone closely approximate the histologic
findings observed by many investigators weeks to months
after a series of nonablative laser treatments. These simi-
larities suggest a repetitive photo-insult may induce
microscopic changes in laser-treated subjects that are ana-
logous to the dermal scarring associated with ultraviolet-
associated photodamage. Dermal thickening interpreted as
‘‘increased’’ and ‘‘organized’’ collagen (see generalization #3
under ‘‘Discussion’’) may in fact be a vestige of trauma and
inflammation caused during remodeling after thermal or
light injury to the dermis. Whether the alterations pro-
duced by nonablative laser are as persistent as typical
photodamage, and the extent to which they are comparable
to photodamage, is not known. It should also be noted that
the lasers used for nonablative resurfacing do not emit at
ultraviolet wavelengths. At present, there is no evidence to
indicate that nonablative laser treatments are deleterious.
The few studies of nonablative resurfacing that have
focused on immediately postreatment histologic effects
suggest that further investigation of early events may
clarify the mechanism of action even further. Specifically,
thermal injury to the dermis after laser treatment may
induce an inflammatory response. Recruitment of inflam-
matory cells and their liberation of cytokines may result in
remodeling of the dermal compartment. Characterization
of the inflammatory process at several time points begin-
ning hours and days after treatment may provide a series of
sequential histologic snapshots that will aid in elucidat-
ing this mechanism. Skin biopsies obtained at daily in-
tervals during the early phase of healing may be especially
informative.
There is increasing evidence to support the clinical
efficacy of nonablative laser and therapy of various wave-
lengths, and the associated patient satisfaction. Addi-
tionally, some investigators are beginning to report
circumstances in which nonablative laser therapy may be
variably effective [94]. But this is not enough. As scientists
[95], we aspire to a greater degree of understanding about
the underlying mechanisms. Only more research focused
on the histologic changes that ensue after irradiation can
clarify the relevant microscopic events. Improved charac-
terization of the cellular effects associated with nonablative
resurfacing would also be directly valuable to clinicians.
Further studies should also evaluate the comparative
efficacy of different wavelengths and devices on epidermal
and dermal improvement. As physicians, we are obligat-
ed to ensure that patient-directed procedures, especially
aesthetic and elective procedures, are both efficacious and
safe. More knowledge about nonablative resurfacing will
increase our confidence that we are helping patients
without inducing undesirable side-effects.
 NONABLATIVE LASER AND LIGHT TREATMENTS
ACKNOWLEDGMENTS
We thank Robert M. Lavker, Ph.D., for his generosity in
critically and repeatedly reading earlier drafts of this
manuscript.
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