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Master Case Presentation

Changes in skin physiology and clinical appearance after microdroplet placement of hyaluronic acid in aging hands Stefanie Williams, MD,1,2 Slobodanka Tamburic, PhD,1 Henriette Stensvik, BSc (Hons),1 & Mateja Weber, BSc (Hons)1 1 2

Cosmetic Science Group, School of Management and Science, University of the Arts London, London, UK European Dermatology London, London, UK

Summary

Background Up to now rejuvenating treatment of the hands has been challenging and results often disappointing. Aims To determine whether hyaluronic acid (HA) microdroplet placement into the dorsal hands has an impact on skin physiology and clinical appearance and whether there is any difference between stabilized HA (S-HA) and nonstabilized HA (NS-HA). Patients ⁄ methods The intra-individual comparison in 15 volunteers involved injection sessions at week 0, 4, and 8 with random assignment of left and right hand to either S-HA or NS-HA. Skin physiology parameters cutaneous elasticity, surface roughness, hydration, and transepidermal water loss (TEWL) were measured in vivo at weeks 0 (before treatment), 4 (before subsequent treatment), 12, and 24. Clinical hand assessment was carried out at weeks 0 and 12 by a blinded dermatologist. Results Intradermal injection of S-HA generated significant improvement in skin elasticity and surface roughness at week 12 compared to baseline. On the hands treated with NS-HA, there was a trend for improvement (not significant). While there was no significant difference in hydration and TEWL between both hands before treatment, at week 12 hands treated with S-HA displayed a significantly higher hydration level and lower TEWL compared to NS-HA treatment. Clinically S-HA proved to be significantly superior to NS-HA. At week 24 the observed effects started to return back toward baseline, with S-HA treatment still offering better results compared to the NS-HA. Conclusions Skin revitalization with injectable HA can improve clinical appearance and skin physiology parameters on the back of the hands. It has been shown that S-HA has better effects when compared with NS-HA. Keywords: hand, rejuvenation, hydration, elasticity, roughness

Introduction Since they first became commercially available more than a decade ago, the use of hyaluronic acid (HA) fillers has been mainly confined to the treatment of lines and folds associated with facial aging.1 Reduction in skin Correspondence: Stefanie Williams, 10 Harley Street, London W1G 9PF, UK. E-mail: dr.williams@eudelo.com Accepted for publication June 7, 2009

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elasticity, loss of volumes and visible wrinkle formation are well-characterized features of intrinsic and extrinsic aging of the face.2,3 Although the hands, as the second most exposed skin area of the human body, are subject to similar intrinsic and extrinsic stressors as the face, hand aging is not widely studied nor has it become a focus for cosmetic treatment. While the dorsum of the hand in young individuals typically looks smooth and well hydrated without any pigment irregularities, with increasing age the epidermal

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hydration diminishes, and we see an increase in fine lines and surface roughness and the development of irregular pigmentation such as solar lentigines.4–7 In the young hand, the natural fullness of the subcutaneous tissue effectively masks the appearance of dorsal hand veins and extensor tendons. However, as the skin thins and tissue volume gradually diminishes with time, underlying structures become exposed and, together with bony deformities, create one of the most striking visible features of aging hands.4,8 To date, treatment options for aging hands have focused mainly on reducing pigmentation and include microdermabrasion, chemical peels, intense light sources, and laser therapy.9 Prominent superficial veins can be treated with sclerotherapy.9 Studies looking at restoration of a more youthful fullness are limited and primarily involve autologous fat injections.6,9–11 One of the factors affecting cutaneous aging is the depletion of endogenous HA and its physiological function in the extracellular matrix of the skin. This results in a reduced ability to bind water and contributes to loss of volume, skin wrinkling, and other characteristics of skin aging.1,12 HA also has important antioxidative functions in the skin and can activate dermal fibroblasts and increase production of collagen and other extracellular matrix components.13–16 Supplementing HA in aging skin in order to restore volume and improve skin physiology toward that associated with a younger individual is therefore a logical approach. However, due to its large molecule size, topical application of native HA does not result in sufficient penetration down to the dermis, where most of the processes of skin aging take place. One of the few ways to effectively achieve a significant increase in native HA concentration in the dermis is by injection with a needle. The two main product groups used in this context are nonstabilized HA (NS-HA), also known as native HA, and stabilized HA (S-HA), in which the native polysaccharide is made more resistant against degradation by dermal hyaluronidases through means of chemically cross-linking a small proportion of the polysaccharide chain. There are no data published in the international literature concerning the use of micropuncture placement of HA as part of an intensive revitalization procedure on the dorsum of the hands. A recent study by Kerscher et al.17 highlighted the potential benefits of a non-animal, stabilized HA (NASHA) beyond volume augmentation in a revitalization procedure in the face. By injecting S-HA via a series of micropunctures into the cheek, the authors demonstrated volume restoration, improved skin elasticity, and a reduction in skin surface roughness.17

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We initiated a study to evaluate the effects of intradermal HA injections in aging hands of both males and females. The study was designed to show whether injecting HA into the backs of the hands has an impact on clinical appearance and whether there is any change in parameters of skin physiology. The study also looked at whether there is a difference between stabilized HA and nonstabilized (native) HA in both these aspects.

Materials and methods The study was a single-center, prospective, randomized in vivo study involving an intra-individual (left-right) comparison of stabilized (Restylane Vital; Q-Med, Uppsala, Sweden) vs. nonstabilized (Teosyal Meso; Teoxane, Geneva, Switzerland) injectable, nonanimal HA gel in the back of the hands. Treatment effects were compared before and after treatment and also between left and right hands. Fifteen healthy volunteers (12 women, 3 men; mean age 46.53 years ± SD 9.68) with visible signs of aging in the backs of the hands (such as loss of volume and skin elasticity; crinkling and ⁄ or actinic elastosis of the dorsum of the hands) were recruited into the study. Skin phototypes ranged from II to V following the Fitzpatrick classification (4 · type II, 6 · type III, 4 · type IV, 1 · type IV). All subjects provided written, informed consent. The study was approved by a local ethics committee. Volunteers were excluded if they had any active skin disease or had received any minimally invasive rejuvenation procedure on the backs of the hands in the past. Exclusion criteria also included systemic medications affecting skin physiology, blood-thinning medication, autoimmune disorders, neoplastic processes, known hypersensitivity to any of the ingredients used, application of any topical treatment in the study area, and intensive UV exposure 4 months prior to the study. Three sessions of injections were carried out at weeks 0, 4, and 8. At each treatment session, topical anesthetic (5 g Emla) was applied to the backs of the hands and left for 45 min under occlusion. After disinfection of the skin, each hand received approximately 20 serial injections with a 30 GG needle (prefilled, disposable syringes). Microdroplet injection points were randomly distributed (at regular distance, avoiding blood vessels, as illustrated in Fig. 1). Left–right assignment of S-HA and NS-HA was randomized. As recommended by the manufacturers, the S-HA product was injected mid-to-deep dermis, while the nonstabilized product was injected into the superficial dermis. A total of 0.5 mL of product was injected per hand per session.

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Cutaneous elasticity

The elastic properties of the skin were evaluated using a non-invasive suction elasticity meter (Cutometer MPA 580; Courage and Khazaka Electronic GmbH). An 8-mm probe in ‘‘strain-time’’ mode was used at a constant negative pressure to create a standardized vacuum of 450 mbar for 2 s (five repetition cycles). The resistance of the skin to the negative pressure and its ability to return to its original position were displayed digitally as curves, from which the elasticity parameter R2 (gross elasticity, i.e., the ratio between total deformation recovery Ua and total extensibility Uf) was analyzed. Stratum corneum hydration Figure 1 Example of injection points at the dorsal hand (approximately 20 microdroplet injections per hand per session, random distribution of injections points avoiding blood vessels).

Measurement of biophysical parameters Biophysical measurements were taken (prior to subsequent treatments) in an air-conditioned room under standardized conditions, following subject acclimatization for 30 min. Subjects were instructed to maintain their routine skin care regime throughout the entire study period, but not to apply any skin care products in the 12 h prior to measurement. Measurements were carried out prior to the first treatment (baseline, week 0), 4 weeks after the first treatment (week 4), 4 weeks after the last (third) treatment (week 12), and 16 weeks after the last treatment (week 24). In vivo skin physiology parameters evaluated on the dorsum of each hand were cutaneous elasticity, skin surface morphology, stratum corneum hydration, and transepidermal water loss (TEWL). In order to ensure that measurements were taken at the exact same location on the dorsum of the hand at each measurement session, photocopies of the subjects’ hands with identification of exact measurement point were taken prior to the start of the study. Clinical hand assessment (CHA) was carried out by a dermatologist at weeks 0 and 12. Skin surface morphology

Skin roughness was evaluated with a standardized noncontact method using a high-resolution UVA camera (Visioscan VC 98; Courage and Khazaka Electronic GmbH, Cologne, Germany). Digital analysis of the graylevel distribution of the skin’s micro-relief was used to determine the roughness parameter r1 (arbitrary units).

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Stratum corneum hydration (arbitrary units) was measured using Corneometer825 (Courage and Khazaka Electronic GmbH). The device measures the moisture content of the outer 10–20 lm of the stratum corneum by evaluating electric capacitance. At each measurement session, five Corneometer measurements were taken from each hand and a mean value was used for subsequent statistical analyses. Transepidermal water loss

Transepidermal water loss was measured using the EP1 Evaporimeter (Servo Med, Berlin, Germany) which uses an open chamber probe to measure the amount of water evaporated from the skin surface per time in vivo. Readings were taken after 40 s and water loss expressed in units of g ⁄ m2 ⁄ h. Clinical hand assessment

Three clinical parameters were evaluated by a blinded dermatologist through means of macroscopic, dermatoscopic, and tactile evaluation: (A) skin firmness and elasticity after vertical extension; (B) visible skin roughness, skin dryness and atrophic crinkling; (C) subcutaneous volume and skin thickness (‘‘plumpness’’ ⁄ fullness of the dorsum of the hand) and ‘‘skin transparency’’ with visible veins and extensor tendons. Each of the three clinical parameters A–C was assessed on a 7-point scale ()3 = strong worsening, )2 = medium worsening, )1 = mild worsening, 0 = no change, 1 = mild improvement, 2 = medium improvement, 3 = strong improvement). The overall clinical sum score (score A + score B + score C) was then calculated for each hand. Standardized digital photographs were taken at week 0, 4, 8 and 12.

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Statistical analyses

Values are expressed as mean value and standard error of the mean (SEM). Statistical comparisons were made using the t-test for paired samples. Statistical significance was assigned to P-values £0.05 and high significance assigned to P-values £0.001.

Results Patients

Of the 15 subjects recruited, 13 completed the study. One subject had to withdraw due to a femur neck fracture, unrelated to our study. A second subject withdrew due to a mild needle phobia. The mean age of the remaining 13 volunteers was 46.53 years (±SD 10.35 years). Safety

Figure 2 Skin surface roughness r1 (mean ± SEM) before and after revitalization treatment with stabilized and nonstabilized HA (intra-individual comparison, randomized assignment to left and right hand). NS, not significant; **statistically significant (see text for details).

There were no serious adverse events during the study and no subject withdrew from the study as a result of an adverse event. Three volunteers experienced mild hematomas following injection, which resolved within a week. Visible weals seen after injection of nonstabilized HA resolved within 24–48 h. Occasional lumps seen after injection of stabilized HA were massaged out immediately in order to avoid longer-lasting problems. No patient experienced visible or palpable bumps or lumps lasting longer than 48 h.

improvement in gross elasticity seen with stabilized HA between week 0 (before treatment) and week 12 (4 weeks after the last treatment) was statistically significant (0.533 ± 0.037 vs. 0.658 ± 0.022, P = 0.006). NS-HA also increased skin elasticity compared to baseline between weeks 0 and 12 but the difference was not statistically significant (0.571 ± 0.052 vs. 0.621 ± 0.043, P = 0.337). There was still a trend for improved skin elasticity at week 24 compared to baseline, especially on the S-HA-treated hand (P = 0.078 for S-HA; P = 0.664 for NS-HA).

Skin roughness

Hydration

The mean skin surface roughness r1 decreased in both hands after treatment with injectable HA (Figs 2 and 3). The reduction in skin roughness seen with S-HA, from an average of 73.16 ± 3.37 (before treatment) to 62.62 ± 3.76 (week 12), was statistically significant (P = 0.006). NS-HA showed a trend for reduced skin roughness compared to baseline over the same period, however the difference was not statistically significant (80.46 ± 4.85 vs. 75.38 ± 5.11, P = 0.370). Roughness returned to approximate baseline level in the NS-HA group by week 24 (P = 0.963 compared to baseline), while a trend for improvement was still evident in the S-HA group at this point (P = 0.213 compared to baseline).

Stratum corneum hydration increased with both S-HA and NS-HA after skin revitalisation with HA. However, while statistical analysis confirmed that both hands had similar stratum corneum hydration before treatment (33.26 ± 2.72 on the site randomized for subsequent S-HA treatment and 32.50 ± 2.65 for NS-HA; P = 0.724), at week 12 the hands treated with S-HA had developed a significantly higher hydration compared to the side treated with NS-HA (35.73 ± 1.82 vs. 32.92 ± 2.65; P = 0.046; Fig. 5). A small increase in hydration remained at week 24 on the stabilized site but dropped to below baselines levels in the nonstabilized site. Transepidermal water loss

Skin elasticity

Mean gross elasticity R2 gradually increased in both hands after treatment with injectable HA (Fig. 4). The

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Transepidermal water loss was reduced, i.e., improved, in both treatment groups (Fig. 6), but reduction was greater with stabilized HA than NS-HA at week 12.

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Figure 3 (a–d) Visioscan examples of a 35-year-old female subject before and after revitalization treatment with stabilized (a = before; b = after 12 weeks) and nonstabilized (c = before; d = after 12 weeks) hyaluronic acid on the back of the hands.

Figure 4 Gross skin elasticity R2 (mean ± SEM) before and after revitalization treatment with stabilized and nonstabilized hyaluronic acid (intra-individual comparison, randomized assignment to left and right hand). NS, not significant; **statistically significant (see text for details).

Figure 5 Stratum corneum hydration (mean ± SEM) before and after revitalization treatment with stabilized and nonstabilized hyaluronic acid (intra-individual comparison, randomized assignment to left and right hand). NS, not significant; *statistically significant (see text for details).

While both hands had a similar TEWL before treatment (8.135 ± 0.67 vs. 8.55 ± 0.55; P = 0.474), at week 12 TEWL was statistically significantly better in the S-HA-treated hand (6.64 ± 0.45 vs. 7.44 ± 0.51;

P = 0.014). By week 24, the difference between the two treatments was no longer statistically significant (P = 0.85), but TEWL remained slightly better than before treatment.

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Clinical hand aging score (CHA)

Treatment with injectable HA did improve the clinical appearance of aging hands on both sites (Figs 7–10). The mean improvement in CHA was 6.15 (±SEM 0.56) and 2.92 (±SEM 0.31) with stabilized and NS-HA, respectively (blinded dermatologist assessment). The difference in clinical improvement at week 12 between S-HA-treated hands and NS-HA-treated hands was clinically and statistically highly significant (P = 0.0001). CHA did not include a formal evaluation of skin color, but anecdotal changes with markedly brighter appearing skin were noted in almost all subjects following treatment (see Figs 8–10).

Discussion Injections of HA into the back of the hands increases cutaneous elasticity and stratum corneum hydration while reducing skin surface roughness and TEWL. These noninvasively measured in vivo changes in parameters of skin physiology are consistent with the endogenous mode of action of HA in the skin. HA can hold up to 500–1000 times its own weight of water in the extracellular matrix of the dermis. This increases skin turgor and creates volume.1 A HA-induced increase in de novo biosynthesis of collagen over 12 weeks is also likely to be a contributing factor behind the observed gradual increase in skin elasticity.13,14,16,18 The role of increased biosynthesis of dermal components by injected HA has recently been explored in vivo and in vitro by Wang et al.16 The authors demonstrated that deposits of NASHA into the dermal matrix enhanced stimulation of de novo synthesis of type I collagen possibly mediated by

Figure 6 Transepidermal water loss (mean ± SEM) before and after revitalization treatment with stabilized and nonstabilized hyaluronic acid (intra-individual comparison, randomized assignment to left and right hand). NS, not significant; *statistically significant (see text for details).

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mechanical stretching and consequent activation of collagen-producing fibroblasts in the dermis.16 In vivo measurement of biophysical parameters provided an objective assessment of comparative efficacy of the two different HA gels. S-HA was found to be superior to NS-HA according to all parameters at week 12 (4 weeks after the last treatment). S-HA also seemed to exhibit a longer duration of effect; as with all biophysical parameters measured, the return to baseline levels occurred more rapidly with NS-HA gel. A mild degree of improvement above baseline could still be seen with S-HA in all parameters at 24 weeks, i.e. 16 weeks after the last injection. As with all dermal filler and skin revitalization treatments, timing of repeat treatment is important in order to maintain a good effect. The data obtained in our study suggest that a top-up treatment of S-HA on the hands should initially be scheduled every 4 months to maintain the effect. However, our data also suggest that for NS-HA more frequent maintenance treatments are needed. Longer term studies using this approach should provide some insight as to whether treatment intervals for both HA types might extend over time reflecting the structural changes in the dermis described by Wang et al.16 An anomaly of effect was observed with stratum corneum hydration in our study; after showing a small increase up to week 12 in hands treated with NS-HA, it dropped to below baseline by week 24. A potential explanation for this effect could be the warmer temperatures experienced at week 24 of this study, which may have caused some degree of dehydration. However, the drop to below baselines levels was not observed with S-HA despite identical climatic influences.

Figure 7 Clinical sum score (mean ± SEM) after revitalization treatment with stabilized and nonstabilized hyaluronic acid (week 12, intra-individual comparison, randomized assignment to left and right hand). ***Statistically highly significant difference.

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Figure 8 (a–d) Clinical example before and after revitalization treatment with stabilized (a = before; b = after 12 weeks) and nonstabilized (c = before; d = after 12 weeks) hyaluronic acid (female aged 61 years).

Figure 9 (a–d) Clinical example before and after revitalization treatment with stabilized (a = before; b = after 12 weeks) and nonstabilized (c = before; d = after 12 weeks) hyaluronic acid (female aged 60 years).

The main reason for the stronger and longer-lasting effects observed on the S-HA-treated site is most likely the fact that the cross-linking achieved in the stabilization process prevents a quick degradation of injected

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HA by physiological hyaluronidases in the skin. Under physiological circumstances native HA in the skin has a half-life of just a few days, but it is significantly higher following stabilization.1 It has been shown that

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Figure 10 (a–d) Time series photographs: Male subject aged 57 years (a) before (week 0), (b) 4 weeks after the first treatment (week 4), (c) 4 weeks after the second treatment (week 8), (d) 4 weeks after the third treatment (week 12) with stabilized hyaluronic acid.

NASHA can retain volume in the skin for several months.1,12 As the NASHA gel dissipates, each HA molecule progressively binds more water, which means that the volume is maintained until the HA is almost fully degraded (‘‘isovolaemic degradation’’). This ‘‘isovolaemic degradation’’ of NASHA might also have enhanced the stability of the observed increase in stratum corneum hydration. An additional reason for the weaker effect of NS-HA in our study might be the slightly lower concentration of HA compared to the stabilized HA product (15 mg ⁄ mL vs. 20 mg ⁄ mL, respectively). These two products were specifically chosen for our study; to the best of our knowledge they are the most commonly injected HA preparations ⁄ concentrations for skin revitalization. In addition to objective assessment of change in biophysical parameters, graded assessment of clinical appearance by a blinded dermatologist, according to identified criteria, allowed comparisons of visually significant changes before and after treatment and between the two types of HA used. Our study demonstrated unambiguously that injectable HA can significantly improve the clinical appearance of aging hands in men and women. S-HA was highly significantly superior to NS-HA according to clinical assessment by week 12. These findings may have more direct relevance to patients as improvements in clinical appearance rather than biophysical

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measurements of aging may prompt them to seek rejuvenating treatment. According to Butterwick,9 many patients believe that hands are more indicative of their true age and may adopt hand postures that minimize the appearance of aging hands. The informally observed increase in skin brightness after treatment is likely due to changes in light reflection by increased volume and a subsequently more convex skin surface on the back of the hands. This remains an interesting field of clinical research for future in vivo studies. Although participating volunteers were recruited as convenience sample in our study, randomization of treatment to the right or left hand removed any possibility of bias due to handedness. There is reported to be a slight difference in appearance between the dominant and nondominant hand, although Jakubietz et al.8 only described a slight increase in venous engorgement in the dominant hand, and no difference in onset or pattern of wrinkle formation. In our study, the greatest clinical improvements were seen in slim, physically fit and active subjects with rather ‘‘bony’’ hands and visible dorsal hand veins, whereas the difference in subjects with preserved dorsal hand volume was less prominent, as expected. This underlines the importance of adequate patient selection and direction of patients’ expectations for this treatment, as for all cosmetic dermatology procedures.

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There was no formal assessment of injection pain conducted as part of our study, but anecdotal feedback suggested that treatment with S-HA was consistently and slightly less uncomfortable than the more superficial injections with NS-HA. A low level of discomfort was reported overall due to the topical anesthesia offered. In a retrospective study, Redaelli19 looked at injection treatment for hand rejuvenation with poly-lactic acid into the subcutaneous layer and metacarpal spaces. Although they found that this treatment overall improved the appearance of aging hand, results were inconsistent, mainly due to the nonstandardized treatment regime in this retrospective study.19 Man et al. described the successful use of S-HA and collagen in volume restoration in the dorsal hands.20 Blinded clinical assessment of vein clearance showed HA to be superior in efficacy to collagen 12 weeks after treatment and associated with greater patient satisfaction.20 Until now the limited cosmetic use of HA in the hands has mainly been aimed at purely reproducing the volume effect previously created by procedures such as fat augmentation.1,6,11 Micropuncture placement of HA aimed at restoring volume and changing skin physiology to reflect that of younger skin (skin revitalization) is a new concept and has not yet been formally evaluated on the backs of the hands. Our study closes that gap and demonstrates, to our knowledge for the first time, that injectable HA can not only improve the clinical appearance of aging hands, but also its physiological functions. The findings of our hands study reflect those of a facial study of Kerscher et al., who found that intradermal micropuncture placement of NASHA generated improvements in elasticity and clinical appearance on the face.17 However, in their study, the greatest improvements were seen 16 weeks after the last treatment session. In our study the greatest effects were observed 8 weeks after the last treatment, with benefits still apparent with S-HA at week 24. This might be due to differences in skin physiology between the face and the hands and ⁄ or differences in external influences such as more frequent water and detergent contact of the hands. This also confirms the immense importance of testing in loco. Both studies suggest that microdroplet placement of S-HA in the dermis may result in biosynthesis of new dermal components that influence biophysical parameters.

Conclusion This is the first study demonstrating unequivocally that injectable HA can not only improve the clinical

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appearance of aging hands but also change parameters of skin physiology on the backs of the hands for the better. Our study also demonstrates that skin revitalization with S-HA produces better and longer-lasting effects compared with NS-HA.

Acknowledgments We thank all volunteers for taking part in our study. We also thank Q-med, Sweden, for donating the study products and the University of the Arts London for funding our study.

References 1 Matarasso SL, Carruthers JD, Jewell ML; Restylane Consensus Group. Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane). Plast Reconstr Surg 2006; 117: S1–43. 2 Ogden S, Griffiths TW. A review of minimally invasive cosmetic procedures. Br J Dermatol 2008; 159: 1036–50. 3 Williams S, Reuther T, Krueger N, Kerscher M. Bioengineering studies into cutaneous elasticity in 2023 probands. J Eur Acad Dermatol Venereol 2005; 19: 54. 4 Bains RD, Thorpe H, Southern S. Hand aging: patients’ opinions. Plast Reconstr Surg 2006; 117: 2212–8. 5 Meyer LJM, Stern R. Age-dependent changes of hyaluronan in human skin. Invest Dermatol 1994; 102: 385–9. 6 Coleman SR. Hand rejuvenation with structural fat grafting. Plast Reconstr Surg 2002; 110: 1731–44. 7 Ortonne JP. Pigmentary changes of the ageing skin. Br J Dermatol 1990; 122(Suppl. 35): 21–8. 8 Jakubietz RG, Kloss DF, Gruenert JG, Jakubietz MG. The ageing hand. A study to evaluate the chronological ageing process of the hand. J Plast Reconstr Aesthetic Surg 2008; 61: 681–6. 9 Butterwick KJ. Rejuvenation of the aging hand. Dermatol Clin 2005; 23: 515–27. 10 Butterwick KJ. Lipoaugmentation for aging hands: a comparison of the longevity and aesthetic results of centrifuged versus noncentrifuged fat. Dermatol Surg 2002; 28: 987–91. 11 Butterwick KJ, Bevin AA, Iyer S. Fat transplantation using fresh versus frozen fat: a side-by-side two-hand comparison pilot study. Dermatol Surg 2006; 32: 640–4. 12 Matarasso SL. Understanding and using hyaluronic acid. Aesthetic Surg J 2004; 24: 361–4. 13 Doillon CJ, Silver FH, Berg RA. Fibroblast growth on a porous collagen sponge containing hyaluronic acid and fibronectin. Biomaterials 1987; 8: 195–200. 14 Fisher GJ, Varani J, Voorhees JJ. Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol 2008; 144: 666–72.

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15 Foschi D, Castoldi L, Radaelli E, Abelli P, Calderini G, Rastrelli A, Mariscotti C, Marazzi M, Trabucchi E. Hyaluronic acid prevents oxygen free-radical damage to granulation tissue: a study in rats. Int J Tissue React 1990; 12: 333–9. 16 Wang F, Garza LA, Kang S et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol 2007; 143: 155–63. 17 Kerscher M, Bayrhammer J, Reuther T. Rejuvenating influence of a stabilized hyaluronic acid-based gel of

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nonanimal origin on facial skin aging. Dermatol Surg 2008; 34: 720–6. 18 Yoneda M, Yamagata M, Suzuki S, Kimata K. Hyaluronic acid modulates proliferation of mouse dermal fibroblasts in culture. J Cell Sci 1988; 90: 265–73. 19 Redaelli A. Cosmetic use of polylactic acid for hand rejuvenation: report on 27 patients. J Cosmet Dermatol 2006; 5: 233–8. 20 Man J, Rao J, Goldman M. A double-blind comparative study of nonanimal-stabilized hyaluronic acid versus human collagen for tissue augmentation of the dorsal hands. Dermatol Surg 2008; 34: 1026–31.

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