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Objective: To investigate dermal remodeling effects of crystal-free microdermabrasion on photodamaged skin., Design: Biochemical analyses of human skin biopsy specimens following microdermabrasion treatment in vivo., Setting: Academic referral center., Participants: Volunteer sample of 40 adults, aged 50 to 83 years, with clinically photodamaged forearms. Intervention Focal microdermabrasion treatment with diamond-studded handpieces of varying abrasiveness on photodamaged forearms and serial biopsies at baseline and various times after treatment., Main Outcome Measures: Quantitative polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay were used to quantify changes in inflammatory, proliferative, and remodeling effectors of normal wound healing. Type I and type III procollagen served as the main outcome marker of dermal remodeling., Results: Coarse-grit microdermabrasion induces a wound healing response characterized by rapid increase in induction of cytokeratin 16 and activation of the AP-1 transcription factor in the epidermis. Early inflammation was demonstrated by induction of inflammatory cytokines, antimicrobial peptides, and neutrophil infiltration in the dermis. AP-1 activation was followed by matrix metalloproteinase-mediated degradation of extracellular matrix. Consistent with this wound-healing response, we observed significant remodeling of the dermal component of the skin, highlighted by induction of type I and type III procollagen and by induction of collagen production enhancers heat shock protein 47 and prolyl 4-hydroxylase. Dermal remodeling was not achieved when microdermabrasion was performed using a medium-grit handpiece., Conclusions: Microdermabrasion using a coarse diamond-studded handpiece induces a dermal remodeling cascade similar to that seen in incisional wound healing. Optimization of these molecular effects is likely the result of more aggressive treatment with a more abrasive handpiece.

Objective: To examine clinical and molecular changes after topical fluorouracil treatment of photodamaged human facial skin for actinic keratoses., Design: Nonrandomized, open-label 2-week treatment with fluorouracil cream, 5%, followed by clinical and molecular evaluation., Setting: Academic referral center., Patients: Twenty-one healthy volunteers, 56 to 85 years old, with actinic keratoses and photodamage. Interventions Twice-daily application of fluorouracil cream for 2 weeks and biopsies and clinical evaluation at baseline and periodically after treatment., Main Outcome Measures: Gene and protein expression of molecular effectors of epidermal injury, inflammation, and extracellular matrix remodeling 24 hours after fluorouracil treatment; clinical improvement measured by evaluators, photography, and patient questionnaires., Results: One day after the final fluorouracil treatment, gene expression of the effectors of epidermal injury (keratin 16), inflammation (interleukin 1beta), and extracellular matrix degradation (matrix metalloproteinases 1 and 3) was significantly increased. Types I and III procollagen messenger RNA were induced at week 4 (7-fold and 3-fold, respectively). Type I procollagen protein levels were increased 2-fold at week 24. Actinic keratoses and photoaging were statistically significantly improved. Most patients rated photoaging as improved and were willing to undergo the therapy again., Conclusions: Topical fluorouracil causes epidermal injury, which stimulates wound healing and dermal remodeling resulting in improved appearance. The mechanism of topical fluorouracil in photoaged skin follows a predictable wound healing pattern of events reminiscent of that seen with laser treatment of photoaging.

Objective: To quantitatively examine the epidermal and dermal cellular and molecular changes that occur after photodynamic therapy of photodamaged human skin., Design: Serial in vivo biochemical and immunohistochemical analyses after photodynamic therapy using topical 5-aminolevulinic acid (5-ALA) and pulsed-dye laser treatment., Setting: Academic referral center, Department of Dermatology, University of Michigan, Ann Arbor., Patients: A volunteer sample of 25 adults, 54 to 83 years old, with clinically apparent photodamage of the forearm skin., Interventions: Three-hour application of 5-ALA followed by pulsed-dye laser therapy using non-purpura-inducing settings to focal areas of photodamaged forearms and serial biopsy specimens taken at baseline and various times after treatment., Main Outcome Measures: Immunohistochemical analysis was used to assess levels of markers of epidermal proliferation (Ki67), epidermal injury (cytokeratin 16), and photodamage (p53), as well as various markers of dermal collagen production (including prolyl 4-hydroxylase and heat shock protein 47, and type I procollagen). Real-time reverse transcriptase-polymerase chain reaction technology was used to quantify type I and type III collagen. Type I procollagen protein was quantified with enzyme-linked immunosorbent assay., Results: Epidermal proliferation was stimulated as demonstrated by increases in Ki67 (more than a 5-fold increase; P < .05) and epidermal thickness (more than a 1.4-fold increase; P < .05). Epidermal injury was produced with increased cytokeratin 16 levels demonstrated (to nearly 70-fold of baseline levels; P < .05). Upregulation of collagen production was demonstrated with increases in procollagen I messenger RNA (2.65-fold; P < .05), procollagen III messenger RNA (3.32-fold; P < .05), and procollagen I protein (2.42-fold; P < .05) levels detected. The baseline epidermal p53 level correlated with cytokeratin 16 levels at acute time points, and the latter were found to correlate with peak collagen production., Conclusions: Photodynamic therapy with the specific treatment regimen employed produces statistically significant quantitative cutaneous molecular changes (eg, production of types I and III collagen) that are associated with improved appearance of the skin. Baseline epidermal p53 immunostaining levels may be predictive of dermal responses to this therapy. Comparison with historical data using pulsed-dye laser therapy alone suggests that use of the photosensitizer may enhance dermal remodeling. The quantitative in vivo molecular data presented herein are in keeping with an evolving model to potentially predict the efficacy of new techniques for the treatment of photoaging.

Objective: To evaluate the effectiveness of topical retinol (vitamin A) in improving the clinical signs of naturally aged skin., Design: Randomized, double-blind, vehicle-controlled, left and right arm comparison study., Setting: Academic referral center., Patients: The study population comprised 36 elderly subjects (mean age, 87 years), residing in 2 senior citizen facilities., Intervention: Topical 0.4% retinol lotion or its vehicle was applied at each visit by study personnel to either the right or the left arm, up to 3 times a week for 24 weeks., Main Outcome Measures: Clinical assessment using a semiquantitative scale (0, none; 9, most severe) and biochemical measurements from skin biopsy specimens obtained from treated areas., Results: After 24 weeks, an intent-to-treat analysis using the last-observation-carried-forward method revealed that there were significant differences between retinol-treated and vehicle-treated skin for changes in fine wrinkling scores (-1.64 [95% CI, -2.06 to -1.22] vs -0.08 [95% CI, -0.17 to 0.01]; P<.001). As measured in a subgroup, retinol treatment significantly increased glycosaminoglycan expression (P = .02 [n = 6]) and procollagen I immunostaining (P = .049 [n = 4]) compared with vehicle., Conclusions: Topical retinol improves fine wrinkles associated with natural aging. Significant induction of glycosaminoglycan, which is known to retain substantial water, and increased collagen production are most likely responsible for wrinkle effacement. With greater skin matrix synthesis, retinol-treated aged skin is more likely to withstand skin injury and ulcer formation along with improved appearance.

Objectives: To develop a reproducible photonumeric scale to assess photoprotected skin aging and to determine whether health and lifestyle factors, such as smoking, affect skin aging in photoprotected sites., Design: Using standard photographs of participants' upper inner arms, we created a 9-point photonumeric scale. Three blinded reviewers used the scale to grade the photographs. Participants answered multiple lifestyle questions., Setting: Academic outpatient dermatology clinic., Participants: Eighty-two healthy men and women aged 22 to 91 years. Interventions A professional medical photographer took standardized photographs of each participant's upper inner arm. Participants answered standardized health and lifestyle questions., Main Outcome Measures: (1) Interobserver agreement and reproducibility using the photonumeric scale and (2) health and lifestyle factors most predictive of the degree of aging in photoprotected skin., Results: There was good blinded interobserver agreement as measured by the maximum range of disagreement scores for each participant (mean, 0.91; 95% confidence interval, 0.76-1.06). Results were reproducible. We developed a multiple regression model showing that the best model for predicting the degree of aging in photoprotected skin includes 2 variables: age and packs of cigarettes smoked per day., Conclusions: This photonumeric scale demonstrates good interobserver agreement and good reproducibility. Using this scale, the degree of aging in photoprotected skin was significantly correlated with patient age and a history of cigarette smoking. Additional studies are needed to continue garnering information regarding independent risk factors for aging of photoprotected skin.

Objective: Nonablative laser therapy is widely practiced for cutaneous rejuvenation. We sought to quantify dermal molecular changes after exposure of photodamaged skin to nonablative laser energy., Methods: Nonablative laser therapy of forearm skin using either a 585-nm wavelength pulsed dye laser or a 1320-nm wavelength neodymium:yttrium-aluminum-garnet laser was performed. Serial biopsy specimens were obtained at baseline and various times after treatment., Results: Statistically significant increases in type I procollagen messenger RNA expression occurred after exposure of photodamaged skin to each laser. Induction was 47% (P < .05) and 84% (P < .05) above baseline levels 1 week after laser therapy among those treated with the pulsed dye and neodymium:yttrium-aluminum-garnet lasers, respectively. Substantial induction of type III procollagen, various matrix metalloproteinases, and primary cytokines was also demonstrated. Responses with respect to all molecules studied were highly variable., Limitations: This study addresses molecular changes after a single laser exposure whereas clinically, serial treatments are often provided., Conclusions: Nonablative laser therapy may result in quantifiable alterations in molecules associated with remodeling of the dermal matrix, although responses vary greatly among patients.

Background: Risk of photocarcinogenesis and the relevance of collagen in wrinkle effacement are two issues related to prolonged use of retinoic acid (RA) that have not been fully addressed., Objective: Our purpose was to investigate the degree of epidermal cellular atypia and the thickness of papillary dermal collagen in photoaging after long-term use of RA., Methods: Thirty-four subjects with photoaged skin were treated daily with 0.05% RA for at least 6 months. Epidermal cellular atypia was graded by means of a semiquantitative scale. Thickness of collagen band was measured by using image-analysis software., Results: Compared with pretreatment findings, melanocytic and keratinocytic atypia was significantly reduced and the collagen band thickness doubled., Limitations: This was an open-label study., Conclusion: Improvement in epidermal cellular atypia is consistent with the ability of RA to act as a chemopreventive agent in epithelial carcinogenesis. Prolonged use also significantly increased collagen matrix deposition in dermal repair zones, which most likely contributes to wrinkle effacement by RA.

Background: Tretinoin is often prescribed before laser resurfacing in an attempt to enhance results., Objective: We sought to assess the clinical and biochemical effects of preoperative tretinoin use before laser resurfacing., Methods: Patients were randomized to apply tretinoin to one forearm and placebo to the other for 3 weeks. Patients' photodamaged forearms were focally treated by carbon-dioxide laser resurfacing. Biopsy specimens were obtained at baseline and various times posttreatment. Real-time polymerase chain reaction technology was used to quantify messenger RNA levels of types I and III procollagen and matrix metalloproteinases-1, 3, and 9. Wounds were assessed for degree of re-epithelialization using a computer graphics-generated template. A colorimeter was used to quantify postoperative erythema., Results: No substantial differences in either biochemical markers or clinical end points were identified between tretinoin and placebo pretreated forearms., Conclusions: We found no evidence of enhanced collagen formation, accelerated re-epithelialization, or quicker resolution of postoperative erythema with tretinoin pretreatment before laser resurfacing.

Objective: To quantitatively examine the dynamics of molecular alterations involved in dermal remodeling after carbon dioxide (CO(2)) laser resurfacing of photodamaged human skin., Design: Serial in vivo biochemical analyses after laser therapy., Setting: Academic referral center, Department of Dermatology, University of Michigan, Ann Arbor. Subjects Volunteer sample of 28 adults, 48 to 76 years old, with clinically evident photodamage of the forearms. Intervention Focal CO(2) laser resurfacing of photodamaged forearms and serial biopsies at baseline and various times after treatment., Main Outcome Measures: Reverse transcriptase real-time polymerase chain reaction technology and immunohistochemistry were used to assess levels of type I and type III procollagens; matrix metalloproteinases (MMPs) 1, 3, 9, and 13; tropoelastin; fibrillin; primary cytokines interleukin 1beta and tumor necrosis factor alpha; and profibrotic cytokine transforming growth factor beta1., Results: Production of type I procollagen and type III procollagen messenger RNA peaked at 7.5 and 8.9 times baseline levels, respectively, 21 days after treatment and remained elevated for at least 6 months. Increases in messenger RNA levels of several cytokines (interleukin 1beta, tumor necrosis factor alpha, and transforming growth factor beta1) preceded and/or accompanied changes in collagen levels. Marked increases in messenger RNA levels of MMP-1 (39 130-fold), MMP-3 (1041-fold), MMP-9 (75-fold), and MMP-13 (767-fold) were noted. Levels of fibrillin and tropoelastin rose in a delayed fashion several weeks after treatment., Conclusions: The biochemical changes seen after CO(2) laser resurfacing proceed through a well-organized and highly reproducible wound healing response that results in marked alterations in dermal structure. These quantitative changes may serve as a means for comparison as other therapeutic modalities meant to improve the appearance of photodamaged skin are evaluated.

Objective: To quantitatively examine changes in p53 tumor suppressor gene immunostaining after carbon dioxide (CO(2)) laser resurfacing of photodamaged skin to assess the potential value of this treatment in reducing the risk of progression to cutaneous carcinoma., Design: Serial in vivo immunohistochemical analyses after laser therapy., Setting: Academic referral center, Department of Dermatology, University of Michigan, Ann Arbor., Other Participants: Volunteer sample of 11 adults, 51 to 76 years old, with clinically evident photodamage of the forearms., Intervention: Focal CO(2) laser resurfacing of photodamaged forearms and serial biopsies at baseline, 3 weeks, and 6 months after treatment., Main Outcome Measures: Because keratinocytes with mutations in p53 or altered p53 expression stain via immunohistochemical techniques, image analysis of immunohistochemically stained sections was used to quantify p53 expression., Results: Positive immunostaining for p53 in the interfollicular epidermis was noted in 8 of 11 subjects at baseline, with an average staining density of 250 cells/mm(2). Average staining decreased to 3 cells/mm(2) 3 weeks after treatment. This decrease was sustained at 5 cells/mm(2) 6 months after resurfacing., Conclusions: There was a consistent decrease in p53 immunostaining in the interfollicular epidermis lasting for at least 6 moths after CO(2) laser resurfacing of photodamaged skin. Since p53 mutation or overexpression is observed in a majority of cases of cutaneous carcinoma, the posttreatment repopulation of the epidermis with p53-negative keratinocytes should theoretically decrease the risk of malignant progression. Further study of laser resurfacing as a prophylactic procedure in patients at high risk for skin cancer development appears warranted.

A 0.1 percent tretinoin cream applied to the skin may eliminate liver spots in some individuals. Liver spots are pigmented areas on the skin that are believed to be caused by long-term exposure to sunlight. Of 58 individuals with liver spots on their faces and arms, 28 applied the cream to affected areas every night, and 30 applied a cream that did not contain tretinoin. The appearance of their liver spots was assessed visually after two and four weeks of treatment and every month thereafter. A skin biopsy of a liver spot was performed in each individual before and after 10 months of treatment. After 10 months of treatment, significantly more patients in the tretinoin group experienced some lightening of their liver spots, compared with patients in the control group. Analysis of skin biopsies showed individuals using tretinoin had decreased pigmentation in the area of the liver spot.

Photoaging of the skin refers to cumulative damage from sun exposure. There is limited evidence so far that 0.1 percent tretinoin applied directly to the skin can improve the characteristics and appearance of photodamaged skin. In this study, six women (age range, 36 to 55 years) applied tretinoin to one forearm and an inactive placebo cream to the other forearm daily for four months. At the beginning and end of the study, skin biopsies were taken and the structure of the skin was examined using an electron microscope. Specifically, the number of anchoring fibrils in the epidermal-dermal junction were counted; these structures contain the protein collagen. It was theorized that during sun damage, exposure to UV light increases the production of collagenase, the enzyme that breaks down collagen in the skin, and that the collagenase degrades the anchoring fibrils. Tretinoin is believed to inhibit this process, preserving the anchoring fibrils. The anchoring fibrils may literally anchor the layers of skin to one another, straightening out the tiny wrinkles caused by sun damage. Treatment with tretinoin doubled the density of anchoring fibrils as compared with the placebo cream; the increased number of these anchoring fibrils may be responsible for the improved appearance of photoaged skin when treated with tretinoin. (Consumer Summary produced by Reliance Medical Information, Inc.)