A Randomized, Double-Blind, Multicenter Comparison of the Efficacy and Tolerability of Restylane Versus Zyplast for the Correction of Nasolabial Folds

A Randomized, Double-Blind, Multicenter Comparison of the Efficacy and Tolerability of Restylane Versus Zyplast for the Correction of Nasolabial Folds RHODA S. NARINS, MD,PC, n FREDRIC BRANDT, MD, w JAMES LEYDEN, MD, z Z. PAUL LORENC, MD, FACS, MARK RUBIN, MD, z AND STACY SMITH, MD nn n Dermatology and Laser Center, White Plains, New York, w Frederic S. Brandt Dermatology & Assoc., Coral Gables, Florida, z Skin Study Center, Broomall, Pennsylvania, Lorenc Aesthetic Plastic Surgery, New York, z Lasky Clinic, Beverly Hills, California, and nn Therapeutics Inc., La Jolla, California BACKGROUND. Bovine collagen is extensively used for facial soft tissue augmentation but provides only temporary correction and can cause hypersensitivity reactions. Hyaluronic acid derivatives potentially offer improved longevity of correction and a reduced risk of immunogenicity and hypersensitivity. OBJECTIVE. To compare the efficacy and safety of nonanimal stabilized hyaluronic acid gel (Restylane; Q-Med, Uppsala, Sweden) with that of bovine collagen (Zyplast) for treatment of nasolabial folds. METHODS. One hundred thirty-eight patients with prominent nasolabial folds were randomized to treatment with hyaluronic acid gel and bovine collagen on contralateral sides of the face. Treatments were repeated at 2-week intervals, as required, to achieve optimal cosmetic result (baseline). Outcomes were evaluated by a blinded investigator at 2, 4, and 6 months after baseline. RESULTS. Less injection volume was required for optimal cosmetic result with hyaluronic acid gel than with bovine collagen, and patients and investigators judged hyaluronic acid gel to be more effective in maintaining cosmetic correction. The investigator-based Wrinkle Severity Rating Scale and Global Aesthetic Improvement Scale assessments at 6 months after baseline indicated that hyaluronic acid gel was superior in 56.9% and 62.0% of patients, respectively, whereas bovine collagen was superior in 9.5% and 8.0% of patients, respectively. The frequency, intensity, and duration of local injection-site reactions were similar for the two products. CONCLUSION. Nonanimal stabilized hyaluronic acid provides a more durable aesthetic improvement than bovine collagen and is well tolerated. Q-MED GAVE SUPPLIES AND FUNDING FOR THIS RESEARCH. BOVINE COLLAGEN has been used extensively as an injectable biomaterial for facial soft tissue augmentation since its introduction into clinical practice some 20 years ago. 1 Early clinical studies with the injectable bovine collagen Zyderm demonstrated its effectiveness in correcting age-related facial wrinkles, furrows, and other dermal defects. 2 6 However, the temporary nature of the clinical correction 7,8 has prompted the development of more stable biomaterials. Zyplast, a glutaraldehyde cross-linked bovine collagen, allows deeper placement of the implant and provides a more durable aesthetic effect than Zyderm, with maintenance injections being required every 4 to 6 months. 9 Despite the drawbacks of immunogenicity and potential hypersensitivity reactions, 10 bovine collagen has Address correspondence and reprint requests to: Rhoda S. Narins, MD, 222 Westchester Avenue Ste. 300, White Plains, New York, NY 10604, or e-mail: rsnmd@worldnet.att.net. come to be regarded as the gold standard among injectable fillers. 11 Hyaluronic acid derivatives developed for soft tissue augmentation confer less risk of immunogenicity because, unlike collagen, hyaluronic acid is chemically identical across all species. 12 Restylane is a nonanimal, stabilized hyaluronic acid gel that is currently used in Europe and Canada for the correction of moderate facial wrinkles and folds and for lip enhancement. Stabilization (cross-linking) of the hyaluronic acid molecule is achieved through minimal chemical modification, thereby improving its resistance to enzymatic degradation within the dermis without compromising its biocompatibility. Because Restylane is derived from a nonanimal source (it is produced from bacteria by a biofermentation process), there is less likelihood of contamination with antigenic proteins during manufacture; 13 consequently, the risk of hypersensitivity reactions and transmission of potentially harmful infectious agents is reduced. Preliminary r 2003 by the American Society for Dermatologic Surgery, Inc. Published by Blackwell Publishing, Inc. ISSN: 1076-0512/02/$15.00/0 Dermatol Surg 2003;29:588 595

Dermatol Surg 29:6:June 2003 NARINS ET AL.: RESTYLANE VERSUS ZYPLAST 589 clinical findings indicate that Restylane is well tolerated after intradermal injection and that it provides good initial efficacy in correcting facial wrinkles and folds. 14,15 This evaluator-blinded, controlled study was conducted to compare the efficacy, tolerability, and persistence of cosmetic effect of Restylane and Zyplast over a 6-month period in patients requiring correction of nasolabial folds. Methods Materials Restylane (Q-Medical, Uppsala, Sweden) is a transparent gel that consists of nonanimal, stabilized hyaluronic acid (20 mg/ml) dispersed in physiological saline solution (ph 7.0). The sterile biomaterial (0.7 ml) was provided in a disposable 1.0-mL syringe with a sterilized 30-gauge, 0.5-inch needle for intradermal injection. Zyplast (McGhan Medical Inc., Santa Barbara, CA) is an off-white opaque gel that consists of glutaraldehyde cross-linked bovine skin collagen (35 mg/ml) dispersed in phosphate-buffered physiological saline with 0.3% lidocaine. It is indicated for intradermal injection. Commercially available Zyplast was used in the study and was provided in a 1.0-mL syringe with a sterilized 30-gauge, 0.5-inch needle with or without an adjustable collar to control the depth of insertion. Patient Selection and Study Design This randomized patient- and evaluator-blinded study was conducted at six centers in the United States, and subjects seeking soft tissue augmentation treatment for correction of bilateral nasolabial folds were recruited. For study inclusion, adult outpatients of either gender were required to have moderate or severe nasolabial folds, as determined by the treating investigator using a wrinkle severity rating scale that was developed specifically for the study, and had to be willing to abstain from other cosmetic procedures (e.g., further augmentation therapy, laser or chemical skin resurfacing, botulinum toxin injections, or facelift procedures) for the duration of the study. Subjects who had received facial antiwrinkle therapy or had undergone facial soft tissue augmentation, laser and chemical peeling, or cosmetic facial surgery below the level of the lower orbital rim within the previous 6 months were excluded from the study. The study was performed in accordance with the principles of the Declaration of Helsinki, the International Conference of Harmonization guidelines for Good Clinical Practice, and local regulatory requirements. All patients provided written informed consent before entry to the study. At the initial screening visit, all eligible patients received a collagen test injection (0.1 ml) in the dermis of the volar forearm to assess their sensitivity to bovine collagen. Patients were followed for signs of skin reaction over the next 4 weeks; collagen-naive patients received a repeat collagen test at Week 5, and this injection site was evaluated 1 week later. Patients exhibiting signs of hypersensitivity in these test areas were excluded from the study. Each patient received Restylane in one nasolabial fold and Zyplast on the contralateral side of the face. Treatments were randomly allocated using a computer-generated code. In view of the differences in packaging, appearance, and elastoviscosity between Restylane and Zyplast, treatment assignment could not be concealed from the treating investigator. However, care was taken to ensure that the patient remained unaware of the treatment assignment (by covering the eyes during injection, concealing the syringe, etc.). Moreover, the evaluating investigator, who performed the efficacy assessments, was unaware of the treatment allocation, thus ensuring a doubleblind study design. The response to the initial injection of Restylane or Zyplast was evaluated after 2 weeks, and if the cosmetic result on one or both sides was deemed to be suboptimal by the evaluating investigator, a repeat treatment ( touch-up ) was performed by the treating investigator. Care was taken to ensure that the material used for the touch-up was the same one used for the initial treatment. This touch-up procedure was repeated at 2-week intervals until an optimal cosmetic result was achieved; in this way, a baseline was established against which persistence of correction could be assessed. Patients were then followed at regular intervals over a 6-month period after achievement of the optimal cosmetic result (baseline). Injection Technique Local analgesia (ice, topical analgesics or local infiltration, and/or nerve block with 1% lidocaine solution) was provided before treatment at the discretion of the investigator. Treating investigators were at liberty to use either a linear threading technique, a serial puncture technique, or a combination of the two to place the filler material in the mid to deep dermis. The injection depth and injection volume were selected at the discretion of the individual investigator. Treating investigators were instructed to correct defects fully but not to overcorrect them. Once the injection was completed, the injection site was

590 NARINS ET AL.: RESTYLANE VERSUS ZYPLAST Dermatol Surg 29:6:June 2003 manually massaged to allow the implanted material to conform to the contours of the adjacent tissues. Evaluation Clinical efficacy assessments were conducted independently by the evaluating investigator and the patient at 2, 4, and 6 months after baseline. Tolerability assessments were performed by the patient (using a daily diary to record adverse events) for 2 weeks after each treatment session and by the treating investigator at 2, 4, and 6 months after baseline. Adverse events were assessed by the treating investigator for severity and relationship to the study treatment. Clinical efficacy was assessed using Wrinkle Severity Rating Scale (WSRS) and a Global Aesthetic Improvement Scale (GAIS). The WSRS is a photograph-based outcome instrument that is designed specifically for quantifying facial folds. Scoring of fold severity is based on visual assessment of the length and apparent depth of the nasolabial fold without reference to baseline or pretreatment appearance (Table 1). Unlike the WSRS, the GAIS is a relative rather than absolute scale: The investigator grades the overall improvement in each nasolabial fold by comparing the patient s appearance at follow-up against a high-magnification photograph taken before treatment (Table 2). The primary efficacy endpoint comprised the investigator-assessed WSRS score at 6-months postbaseline; secondary endpoints included investigatorand patient-assessed WSRS scores at 2- and 4-months postbaseline, GAIS ratings at baseline and at 2-, 4-, and 6-months postbaseline, and the number of treatment sessions required to achieve an optimal cosmetic result. Table 1. The Wrinkle Severity Rating Scale Score Description 5 Extreme: Extremely deep and long folds, detrimental to facial appearance; 2- to 4-mm visible V-shaped fold when stretched; unlikely to have satisfactory correction with injectable implant alone 4 Severe: Very long and deep folds; prominent facial feature; less than 2-mm visible fold when stretched; significant improvement is expected from injectable implant 3 Moderate: Moderately deep folds; clear facial feature visible at normal appearance but not when stretched; excellent correction is expected from injectable implant 2 Mild: Shallow but visible fold with a slight indentation; minor facial feature; implant is expected to produce a slight improvement in appearance 1 Absent: No visible fold; continuous skin line Table 2. The Global Aesthetic Improvement Scale Rating Very much improved Much improved Improved No change Worse Statistics Intrapatient comparisons of the change in WSRS score (from pretreatment) with Restylane and Zyplast were performed using McNemar s test. Categorical variables ( Restylane is superior to Zyplast. Restylane is equivalent to Zyplast, and Zyplast is superior to Restylane ) were derived from the change in WSRS score, the GAIS rating, and the number of treatment sessions for each patient and were expressed as frequencies. The null hypothesis of equal treatment effect was tested against a two-sided alternative of treatment difference using McNemar s test on the derived categorical variables. All statistical tests were two sided, and a probability value of less than 5% was considered statistically significant. Results Patient Demographic Characteristics Of 152 subjects who were initially screened, 138 were randomized to study treatment and treated with both study products (safety population). The intent-to-treat population comprised 137 patients (128 women and 9 men). Patients ranged in age from 27 to 78 years (mean 54.3) and were predominantly White (89%); 59 patients (43.1%) had previously received collagen injections. Of this population, 134 patients completed 6 months of follow-up, whereas 4 patients withdrew from the study prematurely because of consent withdrawal (2), protocol violation (1), or loss to follow-up (1). Efficacy Description Optimal cosmetic result for the implant in this patient Marked improvement in appearance from the initial condition, but not completely optimal for this patient. A touch-up would slightly improve the result Obvious improvement in appearance from the initial condition, but a touch-up or retreatment is indicated The appearance is essentially the same as the original condition The appearance is worse than the original condition Before treatment, nasolabial folds were rated by the evaluating investigator as being mild in 4% of patients

Dermatol Surg 29:6:June 2003 NARINS ET AL.: RESTYLANE VERSUS ZYPLAST 591 Figure 1. Mean change (from pretreatment value) in WSRS score over a 6-month period after optimal cosmetic correction (Week 2) with Restylane or Zyplast. (these patients were rated moderate by the treating investigator, who was responsible for judging study eligibility), moderate in 62% of patients, or severe in 34% of patients. At optimal cosmetic result, similar improvements were obtained on the Restylane- and Zyplast-treated sides of the face, with the great majority (approximately 90%) of the patients showing a one- or two-grade change in WSRS score with either treatment; nasolabial folds were rated as absent or mild in 89.6% of patients. Restylane showed significant superiority over Zyplast with respect to the change (from pretreatment) in WSRS score at all postbaseline time points (Po0.0001) (Figure 1). Thus, at 6 months postbaseline, Restylane was superior to Zyplast in 56.9% of patients, whereas Zyplast was superior to Restylane in 9.5% of patients (Po0.0001) (Table 3). By this time, 67.2% of Zyplast-treated folds had returned to their pretreatment condition compared with only 29.9% of Restylane-treated folds. Likewise, Restylane produced a significantly better (Po0.0001) GAIS rating than Zyplast at all time points after baseline. At 6 months after baseline, Restylane proved superior to Zyplast in this regard in 62.0% of patients, whereas Zyplast was superior to Restylane in 8.0% of patients (Po0.0001) (Table 4). Patient evaluations of treatment efficacy were consistent with those of the investigators (Tables 5 and 6). The number of treatment sessions required to achieve an optimal cosmetic result with Restylane and Zyplast ranged from 1 to 3 (a mean of 1.4 for both products) and did not differ significantly between the two products (P 5 0.56). However, the total injection volume needed to produce this effect was lower for Restylane (mean, 1.0 ml; range, 0.3 to 2.8 ml) than for Zyplast (mean, 1.6 ml; range, 0.1 to 5.0 ml). Serial photographic images of nasolabial folds before and after treatment with Restylane and Zyplast are presented in Figure 2. Tolerability After the initial treatment session, local injection-site reactions (as recorded in patients diaries) occurred at Table 3. Evaluating Investigator s Assessment of Change in WSRS Score From Pretreatment to Various Times Postbaseline: Categorical Outcomes Categorical Outcome (Percentage of Patients) Months After Optimal Cosmetic Result Restylane Is Superior Restylane Is Equivalent Zyplast Is Superior To Restylane P Value 2 33.6 59.1 7.3 o0.0001 4 51.1 38.7 10.2 o0.0001 6 56.9 33.6 9.5 o0.0001 Table 4. Evaluating Investigator s Assessment of GAIS Rating at Various Times Postbaseline: Categorical Outcomes Categorical Outcome (Percentage of Patients) Months After Optimal Cosmetic Result Restylane Is Superior Restylane Is Equivalent Zyplast Is Superior To Restylane P Value Baseline n 3.6 89.0 5.1 Not applicable 2 38.7 52.6 8.0 o0.0001 4 56.9 34.3 8.8 o0.0001 6 62.0 29.9 8.0 o0.0001 n Baseline represents the optimal cosmetic result and corresponds to 2 weeks after the last treatment session.

592 NARINS ET AL.: RESTYLANE VERSUS ZYPLAST Dermatol Surg 29:6:June 2003 Table 5. Patient s Assessment of Change in WSRS Score From Pretreatment to Various Times Postbaseline: Categorical Outcomes Categorical Outcome (Percentage of Patients) Months After Optimal Cosmetic Result Restylane Is Superior Restylane Is Equivalent Zyplast Is Superior To Restylane P Value 2 27.0 62.0 11.0 0.0023 4 35.0 53.3 11.7 o0.0001 6 52.6 41.6 5.8 o0.0001 Table 6. Patient s Assessment of GAIS Rating at Various Times Postbaseline: Categorical Outcomes Categorical Outcome (Percentage of Patients) Months After Optimal Cosmetic Result Restylane Is Superior Restylane Is Equivalent Zyplast Is Superior To Restylane P Value Baseline n 11.7 75.9 9.5 Not applicable 2 34.3 55.5 9.5 o0.0001 4 43.1 47.4 9.5 o0.0001 6 55.5 36.5 8.0 o0.0001 n Baseline represents the optimal cosmetic result and corresponds to 2 weeks after the last treatment session. 93.5% of Restylane- and 90.6% of Zyplast-treated sites, but these were predominantly mild or moderate in intensity and short lasting (7 days or less). The most frequent symptoms with Restylane and Zyplast were swelling (87.0% vs. 73.9% of sites), redness (84.8% vs. 84.8%), tenderness (77.5% vs. 64.5%), pain (57.2% vs. 42.0%), and bruising (52.2% vs. 48.6%) (Table 7). The incidence of most reactions was lower after the touch-up sessions than after the initial treatment session. During the 6-month follow-up phase, treatmentrelated adverse events were reported in 38.4% of patients in the safety population. These were almost exclusively local injection-site reactions, which affected 26.8% of Restylane- and 39.1% of Zyplasttreated sites. Among these reactions, the most frequent were redness and swelling (Table 8). Local injection site reactions were predominantly of mild or moderate intensity (97.1% of total) and were attributed to Restylane (26.8%), Zyplast (39.4%), or the injection procedure (33.8%). Delayed-onset reactions (occurring 14 days or more after the last treatment) were seen in 12 patients (8.7%) and occurred with equal frequency at Restylane- and Zyplast-treated sites (10 and 11 events, respectively); however, none of these reactions were considered by the investigator to be a hypersensitivity response to the implant. All delayed-onset reactions, of which redness was the most common, were mild or moderate in intensity and resolved within 2 to 3 months without treatment. Discussion The results of this randomized comparative study extend earlier findings obtained from noncontrolled studies regarding the efficacy and tolerability of Restylane in facial soft tissue augmentation. Both Restylane and Zyplast were equally effective in producing aesthetic correction of the nasolabial folds and were similarly well tolerated. Importantly, however, Restylane provided a more durable aesthetic correction than Zyplast, as indicated by significant treatment differences in favor of Restylane that were evident as early as 2 months after treatment and were maintained for at least 6 months after treatment. Results from previous noncontrolled studies of Restylane have also shown a considerable degree of correction persisting for more than 6 months after treatment. 14,15 It is reported that after treatment with bovine collagen, the majority of patients require touch-up injections every 4 to 6 months. 9 The results of this study suggest that less frequent treatments may be required with Restylane and that a smaller volume of Restylane than Zyplast is required to achieve a similar cosmetic result. This latter observation may be

Dermatol Surg 29:6:June 2003 NARINS ET AL.: RESTYLANE VERSUS ZYPLAST 593 Figure 2. Photographic images of nasolabial folds of a representative patient (A) before treatment, (B) on achievement of optimal cosmetic result, and (C) at 6 months after achievement of optimal cosmetic result with Restylane and Zyplast. Treatments were administered to contralateral sides of the face: Restylane on the patient s left side and Zyplast on the patient s right side.

594 NARINS ET AL.: RESTYLANE VERSUS ZYPLAST Dermatol Surg 29:6:June 2003 Table 7. Incidences of Local Injection-Site Reactions, as Assessed From Patient Diaries, After the Initial Treatment Session: Results Are Expressed as a Percentage of Patients (N 5 138) Restylane Zyplast Swelling 87.0 73.9 Redness 84.8 84.8 Tenderness 77.5 64.5 Pain 57.2 42.0 Bruising 52.2 48.6 Itching 30.4 23.9 Other 24.6 23.9 Includes injection-site stiffness, nodules, and pimples. Table 8. Incidences of Local Injection-Site Reactions During 6 Months of Follow-Up: Results Are Expressed as a Percentage of the Total Number of Events (N 5 142) Restylane Zyplast Redness 19.0 24.6 Swelling 6.3 7.0 Bruising 4.2 2.8 Pruritus 2.8 5.6 Skin induration 2.8 5.6 Tenderness 2.8 4.9 Skin discoloration 0.7 3.5 Pustular rash 0.7 0.7 Pain 0 0.7 Other n 2.8 3.5 Total 40.8 59.2 n Papules and nodules. explained by the substantial water reabsorption that occurs from the collagen suspension during the first 24 hours after injection. 16 Stabilized hyaluronic acid, however, binds significant amounts of water, allowing a more durable cosmetic improvement with little or no early loss of correction. The hyaluronic acid derivative therefore offers potential advantages over the current standard in augmentation treatment (Zyplast) both in terms of reduced volume of injection (and presumably reduced cost) and improved patient convenience. Furthermore, in contrast to the situation with bovine collagen, for which skin testing is mandatory because of potential allergic and hypersensitivity reactions, 16 hyaluronic acid gels confer little, if any, risk of such reactions and have been available commercially (in Europe and Canada) for several years without the requirement for skin testing. Tolerability evaluation indicated a profile of local reactions similar to that previously reported for Restylane in clinical studies and postmarketing surveys, and no hypersensitivity responses were identified. Although the overall incidence of local reactions may appear high to U.S. clinicians who are familiar with injectable filler materials, it should be remembered that patients were encouraged to record all signs and symptoms in daily diaries. The incidences reported here are therefore likely to be higher than those reported in routine clinical practice. The higher incidence of injection-site pain seen with Restylane after the initial treatment session could possibly be attributed to the absence of local anesthetic from this preparation (Zyplast, in contrast, contains lidocaine) and its more viscous nature. Most importantly, Restylane showed a similar or reduced frequency, intensity, and duration of local injection-site reactions compared with bovine collagen. The ideal injectable filler material would be biocompatible, readily prepared, easy to inject, long lasting in its cosmetic effect, and free of injection-site pain and other complications. Restylane brings us closer to such an ideal filler by offering improved durability and efficiency (less injection volume required), with similar or superior tissue compatibility to alternative fillers, and avoids the need for skin testing before use. In recent years, numerous drugs and devices have been introduced onto the market, only to be withdrawn subsequently because of adverse effects, interactions, or issues of clinical performance. Restylane has been used for several years in Europe and Canada and has demonstrated a favorable safety and efficacy profile in clinical practice. With this demonstration of equal or better tolerability, combined with the superior longevity of cosmetic correction to that obtained with the current standard filler material, Restylane should be considered the new standard in injectable filler materials. Acknowledgment The authors thank Stephen Baker, MD, FACS (Clinical Instructor Plastic Surgery, Volunteer Clinical Faculty, University of Miami School of Medicine), Doris J. Day, MD (Department of Dermatology, New York University Medical Center), Andrew Frankel, MD (Division of Head and Neck Surgery, University of California at Los Angeles, Los Angeles, CA), Scott Gottlieb, MD (Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA), Curt M. Littler, MD (SHARP Rees-Stealy Medical Group Inc., San Diego, CA), and Richard W. Swift, MD (Department of Plastic Surgery, Manhattan Eye, Ear and Throat Hospital, New York) for their contribution as evaluating investigators in this study. References 1. Knapp TR, Kaplan EN, Daniels JR. Injectable collagen for soft tissue augmentation. Plast Reconstr Surg 1977;60:389 405.

Dermatol Surg 29:6:June 2003 NARINS ET AL.: RESTYLANE VERSUS ZYPLAST 595 2. Cooperman LS, MacKinnon V, Bechler G, Pharriss BB. Injectable collagen: six years clinical investigation. Aesthetic Plast Surg 1985;9:145 51. 3. Kaplan EN, Falces E, Tolleth H. Clinical utilization of injectable collagen. Am J Plast Surg 1983;10:437 51. 4. Watson W, Kay RL, Klein AW, et al. Injectable collagen: a clinical overview. Cutis 1983;31:543 6. 5. Nicolle FV. Correction of age and disease related contour deficiencies of the face. Aesthetic Plast Surg 1985;9:159 62. 6. Stegman SJ, Tromovitch TA. Implantation of collagen for depressed scars. J Dermatol Surg Oncol 1980;6:450 3. 7. Burke KE, Naughton G, Cassai N. A histological, immunological, and electron microscopic study of bovine collagen implants in the human. Ann Plast Surg 1985;14:515 22. 8. Rapaport MJ, Salit R, Rivkin L. Collagen injections for aging skin lines (wrinkles). J Am Acad Dermatol 1984;11(2 Pt 1):250 2. 9. Matti BA, Nicolle FV. Clinical use of Zyplast in correction of ageand disease-related contour deficiencies of the face. Aesthetic Plast Surg 1990;14:227 34. 10. Stegman SJ, Chu S, Armstrong R. Adverse reactions to bovine collagen implant: clinical and histologic features. J Dermatol Surg Oncol 1988;14(Suppl 1):39 48. 11. Klein AW, Elson ML. The history of substances for soft tissue augmentation. Dermatol Surg 2000;26:1096 105. 12. Larsen NE, Pollack CT, Reiner K, Leshchiner E, Balazs EA. Hylan gel biomaterial: dermal and immunologic compatibility. J Biomed Mater Res 1993;27:1129 34. 13. Friedman PM, Mafong EA, Kauvar ANB, Geronemus RG. Safety data of injectable nonanimal stabilized hyaluronic acid gel for soft tissue augmentation. Dermatol Surg 2002;28:491 4. 14. Olenius M. The first clinical study using a new biodegradable implant for the treatment of lips, wrinkles, and folds. Aesthetic Plast Surg 1998;22:97 101. 15. Duranti F, Salti G, Bovani B, Calandra M, Rosati ML. Injectable hyaluronic acid gel for soft tissue augmentation: a clinical and histologic study. Dermatol Surg 1998;24:1317 25. 16. Cheng JT, Perkins SW, Hamilton MM. Collagen and injectable fillers. Otolaryngol Clin North Am 2002;35:73 85.