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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 investigate the efficacy, potential limitations, and biological mechanisms of UV-A1 phototherapy for skin sclerosis due to collagen deposition disorders., Design: Before-and-after trial of UV-A1 irradiation of sclerotic skin; in vivo biochemical analyses after UV-A1 irradiation of normal skin., Setting: Academic referral center., Participants: Patients with morphea/scleroderma or sclerodermoid graft-vs-host disease and volunteers without skin disease. Intervention Sclerotic skin was treated with high-dose (130 J/cm(2); n = 12) or medium-dose (65 J/cm(2); n = 6) UV-A1 phototherapy 3 times per week for 14 weeks; normal skin was treated with UV-A1 irradiation at various doses and frequencies, with biopsies performed afterwards., Main Outcome Measures: In sclerotic skin, induration was clinically assessed using a scoring scale. In normal skin, quantitative polymerase chain reaction was used to assess antifibrotic responses, defined as decreased type I and type III procollagen and increased matrix metalloproteinase levels., Results: In patients with sclerotic skin treated with high-dose UV-A1 irradiation, clinical scores for induration modestly decreased. To investigate what factors prevented further improvement (ie, complete clearance), normal skin with light pigmentation was exposed to UV-A1 irradiation (70-150 J/cm(2)) and was assessed for antifibrotic responses. A single high-dose exposure (110-150 J/cm(2)) elicited substantial antifibrotic responses and induced skin darkening. This skin darkening attenuated responses to subsequent UV-A1 exposures and was dose dependent. Thus, to minimize skin darkening, additional patients with sclerotic skin were treated with medium-dose UV-A1 phototherapy, which was no less effective than high-dose therapy., Conclusion: Clinical responses of sclerotic skin to UV-A1 phototherapy were modest because of UV-A1-induced skin darkening, which is photoprotective and attenuates antifibrotic responses., Trial Registration: clinicaltrials.gov Identifier: NCT00129415.

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: 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 determine the effectiveness of an education theory-based method to teach students to place and tie a simple interrupted stitch., Design: A teaching intervention before-after trial., Setting: Dermatology department, academic university., Participants: Fourth-year medical students and dermatology residents., Main Outcome Measures: Scores on a 12-criterion grading instrument before and after instruction., Results: The scores for medical students and residents in each class showed significant improvement. The mean score for all participants (N = 23) rose by 24% after instruction (P< .001). Scores in 9 of the 12 graded performance areas improved significantly after instruction, including scores in tissue damage/teeth marks (P<.001), needle dulled/bent (P< .001), needle loaded properly and knots square (P = .01), throws done correctly (P = .01), stitch tension and needle entry/exit angle (P = .02), amount of suture used (P = .03), and correct number of throws (P = .04). In addition, participants' confidence increased significantly after instruction (P<.001). No difference was noted between men and women in preinstruction vs postinstruction score improvement., Conclusions: This teaching method can be effectively used to teach students to place and tie a simple interrupted stitch. Once validated and expanded, it may prove useful in shortening and standardizing procedural skill training and in objectively documenting competency.

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.