Ultrastructural analysis of 3 hyaluronic acid soft-tissue fillers using scanning electron microscopy.

BACKGROUND: Although hyaluronic acid (HA) specifications such as molecular weight and particle size are fairly well characterized, little information about HA ultrastructural and morphologic characteristics has been reported in clinical literature. OBJECTIVE: To examine uniformity of HA structure, the effects of extrusion, and lidocaine dilution of 3 commercially available HA soft-tissue fillers. MATERIALS AND METHODS: Using scanning electron microscopy and energy-dispersive x-ray analysis, investigators examined the soft-tissue fillers at various magnifications for ultrastructural detail and elemental distributions. RESULTS: All HAs contained oxygen, carbon, and sodium, but with uneven distributions. Irregular particulate matter was present in RES but BEL and JUV were largely particle free. Spacing was more uniform in BEL than JUV and JUV was more uniform than RES. Lidocaine had no apparent effect on morphology; extrusion through a 30-G needle had no effect on ultrastructure. CONCLUSION: Descriptions of the ultrastructural compositions and nature of BEL, JUV, and RES are helpful for matching the areas to be treated with the HA soft-tissue filler architecture. Lidocaine and extrusion through a 30-G needle exerted no influence on HA structure. Belotero Balance shows consistency throughout the syringe and across manufactured lots.

Long-term results for incobotulinumtoxinA in the treatment of glabellar frown lines.

BACKGROUND: IncobotulinumtoxinA has been approved for treatment of glabellar frown lines (GFL) in the United States, all major European markets, South Korea, and Argentina and in Russia and Mexico for the treatment of mimic wrinkles and hyperkinetic facial lines, respectively. OBJECTIVES: Prospective, 2-year, open-label, multicenter, repeat-dose, Phase III trial investigating the safety and efficacy of incobotulinumtoxinA for the treatment of GFL. METHODS: Subjects with moderate or severe GFL on the Facial Wrinkle Scale (FWS), enrolled from previous trials, were treated with 20 U of incobotulinumtoxinA per cycle (up to eight treatment cycles, treatment interval at least 85 days). Efficacy was measured according to the investigator-assessed percentage of responders on the FWS (subjects with a score of 0 or 1) at rest and maximum frown on Day 30 of each cycle, subject assessments, and onset and duration of treatment effect. RESULTS: In 796 subjects, 77% to 88% were responders at rest, and 79% to 90% were responders at maximum frown. Onset was rapid; subjects reported effects in the first few days after treatment. No new tolerability or safety concerns were reported. CONCLUSIONS: IncobotulinumtoxinA injections were well tolerated and resulted in efficacy in the treatment of GFL for up to 2 years.

IncobotulinumtoxinA in esthetics.

IncobotulinumtoxinA (Xeomin®/Xeomeen®/Bocouture®/XEOMIN Cosmetic™) is a botulinum toxin type A that differs from other commercially available botulinum toxin type A preparations in that it is free from complexing proteins ([150 kDa]/NT 201). The proven efficacy of incobotulinumtoxinA in various therapeutic indications preceded its use in the field of esthetic medicine, where it is widely approved for the treatment of glabellar frown lines on the basis of positive efficacy and safety findings from a number of clinical trials. Here, we discuss the characteristics of incobotulinumtoxinA and review the clinical data supporting its use in esthetics.

Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers.

BACKGROUND: Hyaluronic acid (HA) gels have been used as filler material in the aesthetic field. Although the native HA molecule is without specificity of species and organs, synthetic cross-linked gels have differences in chemical composition and three-dimensional structure. Different technologies are employed in cross-linking, and the products have varying rheological properties. OBJECTIVE: To determine whether the gels with differing chemical composition have differing histologic behavior when injected into human skin to determine if the histology changes after 14 days of implantation. MATERIALS AND METHODS: Human volunteers consented to having controlled placement of HA intradermally into forearm or buttock skin. The trials were conducted in a single clinic in association with the Hôpitaux Universitaires de Genève, Geneva, Switzerland. The biopsies were taken immediately after implantation of the product and at day 14. Standard paraffin sections were prepared and stained with hematoxylin and eosin and Alcian blue and examined by an independent pathologist. RESULTS: Results show that each type of HA has a predictable histologic behavior in the skin. Biphasic gel has demonstrated deposition in big pools, often deep in the reticular dermis. The pools compress the collagen fibers. The papillary dermis and superficial reticular dermis are free of HA. Monophasic monodensified gels show large pools of hyaluronans throughout all the thickness of the reticular dermis. This material breaks up the collagen fibers of most of the dermal plane. The papillary dermis is free of exogenous hyaluronans. Monophasic polydensified cohesive gel penetrates into the dermis in a diffuse, evenly distributed manner, except in the papillary dermis, which remains free of exogenous material. CONCLUSION: The different types of cross-linked HA have different behaviors in the dermis immediately after their injection. The patterns are consistent between patients and are predictable. These histologic patterns do not change when biopsies are examined at 2 weeks.

Botulinum toxin: examining duration of effect in facial aesthetic applications.

Patient satisfaction with botulinum toxin treatment is a key success factor in aesthetic procedures and is governed by the interaction of numerous variables. Duration of effect is important because it influences retreatment intervals as well as affecting cost and convenience to the patient. In order to review the evidence on the duration of benefit associated with various commercial formulations of botulinum toxin, MEDLINE was searched using the following terms: 'botulinum' and 'duration'/'retreatment' (limits: 'clinical trials,' 'meta-analyses,' 'English'). I also searched my existing reference files, reference lists of identified articles, and meeting/conference abstracts to ensure completeness. The focus was on clinical medicine and aesthetic trials. To be eligible for the analysis, studies had to include efficacy assessments at multiple timepoints. To estimate duration of benefit, the following outcomes were examined and summarized: responder rates, mean wrinkle severity scores at various timepoints (with or without changes from baseline), and relapse rates. Duration at both repose and maximum attempted muscle contraction was considered when provided. Where possible, duration was assessed by formulation and dose. The initial search yielded 164 articles. Of these, 35 included an adequate measure of duration in aesthetic indications. The majority of these (22) were on the glabellar area. Study designs and endpoints were highly heterogeneous, and duration of effect varied between studies. Several studies with the BOTOX Cosmetic (onabotulinumtoxinA; Allergan, Inc., Irvine, CA, USA) formulation of botulinum toxin type A (BoNTA) included relapse rates, defined conservatively as return to baseline levels of line severity for two consecutive visits approximately 30 days apart (at repose and maximum contraction). In these studies, duration of effect ranged from 3 to 5 months in female patients and from 4 to 6 months in male patients. Individual patients had longer durations of response. Across all studies providing relapse rates, most patients relapsed by 6 months. In studies assessing patient satisfaction, satisfaction remained high throughout the duration of the studies ( approximately 4 months). With the Dysport formulation (abobotulinumtoxinA, clostridium botulinum type A toxin-hemagglutinin complex; Ipsen Biopharm Ltd, Wrexham, England), retreatment intervals were estimated at a mean of 3.9 months (median = 3.3 months). These results were consistent with responder rates from another Dysport study in which the active treatment differed from placebo at 3 but not 4 months. A single comparative study demonstrated that the proportion of patients relapsing at week 16 was 23% (95% CI 11.5, 41.6) in the BOTOX Cosmetic group as compared with 40% (95% CI 25.2, 60.1) in the Dysport group. Myobloc (rimabotulinumtoxinB, botulinum toxin type B; Solstice Neurosciences, Inc., South San Francisco, CA, USA) was associated with shorter durations of action (2-3 months). Data from facial areas other than the glabella, although more limited, supported a duration of at least 3-4 months. The addition of BoNTA to dermal fillers or light/laser therapy appeared to increase the degree of effect. Repeated BoNTA treatments may prolong duration of effect or potentiate the effect. In conclusion, patients can expect treatments to last > or =3 months but often as many as 4-5 months depending on the facial area, dose, and formulation. Additional research should help clarify the impact of age, baseline rhytid severity, patient sex, repeated treatments, and combination treatment on longevity of effect.

Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A in the treatment of glabellar frown lines.

BACKGROUND: Use of botulinum toxin for esthetic purposes has rapidly expanded over the last 20 years. IncobotulinumtoxinA, also known as NT 201, is a new botulinum toxin type A (150 kDa) that is free from complexing proteins. OBJECTIVES: A prospective, multicenter, randomized, rater- and patient-blind, international Phase III trial to investigate the noninferiority of incobotulinumtoxinA to another botulinum toxin type A, onabotulinumtoxinA, in the treatment of glabellar frown lines. METHODS: A total of 381 patients were randomized in a 3:1 (incobotulinumtoxinA:onabotulinumtoxinA) ratio to receive 24 U incobotulinumtoxinA of or onabotulinumtoxinA. Efficacy end points included the percentage of responders (patients with an improvement of ≥1 point on a 4-point facial wrinkle scale) at maximum frown at weeks 4 and 12 as assessed by the investigators, and a panel of independent raters based on standardized digital photographs. RESULTS: Four weeks after injection, response rates at maximum frown were 96.4% in the incobotulinumtoxinA group and 95.7% in the onabotulinumtoxinA group as assessed by independent raters. Analysis of the data confirmed the noninferiority of incobotulinumtoxinA. Response rates at rest were lower for both products. The rate of adverse events was low. CONCLUSION: IncobotulinumtoxinA is equally as effective as onabotulinumtoxinA in the treatment of glabellar frown lines. Both preparations were well tolerated.

Use of intraoperative botulinum toxin in facial reconstruction.

BACKGROUND: Botulinum toxin is a potent neuromodulator that temporarily relaxes muscles and can improve wound healing. OBJECTIVE: This retrospective analysis assessed the use of intraoperative botulinum toxin type A or B in patients undergoing surgical reconstruction after Mohs micrographic surgery for treatment of skin cancer. The primary effect of intradermal botulinum toxin on wound healing was also studied. METHODS & MATERIALS: Charts of patients who received intraoperative botulinum toxin type A (n=9) or B (n=9) in conjunction with reconstructive surgery after Mohs micrographic surgery were reviewed. Three volunteers also underwent dermal injections of botulinum toxin type A followed by erbium laser resurfacing. RESULTS: Outcomes did not differ in patients treated with botulinum toxin type A and type B. Patients had excellent apposition of wound edges and smooth skin overlying soft tissue; no significant complications were noted. Healing of erbium laser ablation did not differ between botulinum toxin type A-treated skin and control skin. CONCLUSIONS: Administration of botulinum toxin type A or B after reconstruction after Mohs micrographic surgery aided wound healing; botulinum toxin type A and botulinum toxin type B were equally effective. Intradermal botulinum toxin type A demonstrated no primary effect on healing of erbium laser-resurfaced skin.

A validated grading scale for forehead lines.

BACKGROUND: As with other facial wrinkles, the gradual loss and disorganization of collagen fibers and elastin, connective tissues that provide underlying support for skin, cause horizontal forehead rhytides in large part. OBJECTIVES: To develop the Forehead Lines Grading Scale for objective quantification of horizontal forehead rhytides at rest and with expression and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: The Forehead Lines Grading Scale is a 5-point photonumeric rating scale that was developed to objectively quantify resting (static) and hyperkinetic (dynamic) forehead lines. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was highly significant. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the severity of forehead lines for which patients commonly seek correction. The scale is well stratified for consistent rating.

A validated brow positioning grading scale.

BACKGROUND: One of the first areas to show facial aging is the periorbital region, where brow malposition contributes to the overall appearance of aging. Movement and positioning of the brows are also sex specific. Men may desire a low brow, whereas women may prefer high, arched brows. OBJECTIVES: To develop the Brow Positioning Grading Scale for objective quantification of eyebrow position and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify positioning of eyebrows at rest. Nine experts rated photographs of 35 subjects twice with regard to positioning of the eyebrow in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. The test-retest correlation coefficients were acceptable for each expert. CONCLUSION: The 5-point photonumeric scale generated spans the positioning of the eyebrow for which patients commonly seek correction. The scale is well stratified for consistent rating.

A validated lip fullness grading scale.

OBJECTIVES: To develop the Lip Fullness Grading Scale for objective quantification of lip volume for a reliable assessment and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify fullness of upper and lower lip separately. Nine experts rated photographs of 35 subjects, twice, separately for upper and lower lip. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: Agreement between the experts was high. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the fullness of the upper and lower lip for which patients commonly seek correction. This scale is well stratified, with low intra- and interrater variability.

A validated grading scale for marionette lines.

BACKGROUND: Melomental folds, or marionette lines, are one of the consequences of facial aging. The curvilinear wrinkles formed because of facial movements and the aging process extend downward from the oral commissures. OBJECTIVES: To develop the Marionette Lines Grading Scale for objective quantification of the severity of melomental folds and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify the severity of melomental folds. Nine experts rated photographs of 35 subjects, twice, with regard to marionette lines in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was high. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the severity of marionette lines for which patients commonly seek correction. The scale is well stratified for consistent rating.

A validated hand grading scale.

BACKGROUND: Following the popularity of facial cosmetic procedures to reverse the signs of aging, cosmetic procedures that rejuvenate the hand are being sought. Irregular surface pigmentation, prominence of superficial veins and tendons, thinning of the dermis, and loss of subcutaneous fat typically characterize aging of the hand. OBJECTIVES: To develop the Hand Grading Scale for objective quantification of the severity of hand aging and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: The Hand Grading Scale is a 5-point photonumeric rating scale that was developed to objectively quantify the severity of aging of the hand. Nine experts rated photographs of 35 subjects, twice, with regard to the aspect "hand aging" in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was considerably high. Bubble plots (bivariate scatter plots) demonstrated linearity in judgment by the experts. CONCLUSION: The 5-point photonumeric scale generated spans the severity of hand aging for which patients most commonly seek correction. The scale is well stratified for consistent rating.

A validated grading scale for crow's feet.

OBJECTIVE: To develop the Crow's Feet Grading Scale for objective quantification of the severity of lateral canthal lines and to establish the reliability of this photonumeric scale for clinical research and practice. MATERIALS AND METHODS: A 5-point photonumeric rating scale was developed to objectively quantify the severity of lateral canthal lines at rest and at maximum contracture of the orbicularis oculi. Nine experts rated photographs of 35 subjects, twice, with regard to the aspect crow's feet in comparison with morphed images. Inter- and intrarater variability was assessed by computing intraclass correlation coefficients. RESULTS: The agreement between the experts was significantly high. Furthermore, the test-retest correlation coefficients were high for each expert after an overnight interval, demonstrating low inter- and intraevaluator variability. CONCLUSION: The 5-point photonumeric scale generated spans the severity of the type of crow's feet for which patients most commonly seek correction. The scale is well stratified for consistent rating.

Botox in men.

Men have a growing interest in cosmetic dermatologic treatments. Botulinum toxin type A (BTX-A) treatment offers a minimally invasive approach to improving facial lines and is often the first cosmetic procedure chosen by male patients. In general, men can be treated with the same techniques as women, but often require more units of BTX-A. Glabellar lines in the male have been the most well-studied with a recommended starting dose of 40 U. Some men may require up to 80 U in the glabellar complex. The most common cause of an inadequate result in male patients is under-dosing. Forehead lines require care, as many men with horizontal lines have low-positioned eyebrows, and excessive relaxation of the lower frontalis muscle can drop their brows further. Special consideration should be given to the male brow when treating men. Lateral orbital lines can be treated with a starting dose of 15 U per crow's foot. Men may need additional injections to the orbicularis oculi muscle as many men have a broad circumferential orbicularis. The lower face is amenable to BTX-A treatment in men. BTX-A can be used to reduce axillary sweating and improve armpit odor. BTX-A shows promise in treating benign prostatic hyperplasia, and may in the future become a first-line treatment.

Update on botulinum toxin.

Botulinum toxin for facial enhancement is currently the most popular aesthetic procedure performed in the United States. New developments have occurred within the last few years. Patients prefer having multiple areas of the upper face treated which increases patient satisfaction. Treatment of the forehead is now being accomplished with fewer units of botulinum toxin. This helps preserve the natural look of some movement of the forehead. Men require more units of botulinum toxin than women. Combination therapy using botulinum toxin along with lasers or filler substances is ideal. Aesthetic medicine knowledge has progressed, contributing a greater understanding of botulinum treatment for advanced areas of the face. The orbicularis oris, mentalis, and depressor anguli oris are now routinely treated and help improve overall facial appearance. Other forms of botulinum toxins (additional type A or type B toxins) are available, each with advantages and disadvantages.

Update on botulinum toxin.

Botulinum toxin for facial enhancement is currently the most popular aesthetic procedure performed in the United States. New developments have occurred within the last few years. Patients prefer having multiple areas of the upper face treated which increases patient satisfaction. Treatment of the forehead is now being accomplished with fewer units of botulinum toxin. This helps preserve the natural look of some movement of the forehead. Men require more units of botulinum toxin than women. Combination therapy using botulinum toxin along with lasers or filler substances is ideal. Aesthetic medicine knowledge has progressed, contributing a greater understanding of botulinum treatment for advanced areas of the face. The orbicularis oris, mentalis, and depressor anguli oris are now routinely treated and help improve overall facial appearance. Other forms of botulinum toxins (additional type A or type B toxins) are available, each with advantages and disadvantages.

Periocular botulinum toxin.

Botulinum toxin type A (BOTOX, Dysport) has revolutionized treatment of wrinkles around the eyes. Since the first publications of its cosmetic benefit by Drs. Jean and Alastair Carruthers, hundreds of articles have been published about its cosmetic use. BOTOX holds U.S. Food and Drug Administration approval in the United States for treatment of glabellar lines. BOTOX is in widespread use worldwide and is currently the most popular cosmetic treatment in the United States.

Myobloc.

Myobloc is the currently available commercial formulation of type B botulinum toxin. Released in the United States in 2000, it is approved by the Food and Drug Administration for the treatment of cervical dystonia. The most commonly used botulinum toxins, the type A toxins (Botox and Dysport), affect the SNAP-25 protein, whereas the type B toxin (Myobloc) affects vesicle-associated membrane protein, also known as synaptobrevin. Both type B and type A are antigenically distinct. This article explains the difference between Myobloc and type A toxins, reviews equivalency and other published studies, and describes practical uses for this product in facial aesthetics.

Molecular weight analyses and enzymatic degradation profiles of the soft-tissue fillers Belotero Balance, Restylane, and Juvéderm Ultra.

BACKGROUND: In this study, the authors sought to determine the molecular weight distribution of three hyaluronic acids-Belotero Balance, Restylane, and Juvéderm Ultra-and their rates of degradation following exposure to hyaluronidase. Lot consistency of Belotero Balance also was analyzed. METHODS: Three lots of Belotero Balance were analyzed using liquid chromatography techniques. The product was found to have high-molecular-weight and low-molecular-weight species. One lot of Belotero Balance was compared to one lot each of Juvéderm Ultra and Restylane. Molecular weights of the species were analyzed. The hyaluronic acids were exposed to ovine testicular hyaluronidase at six time points-baseline and 0.5, 1, 2, 6, and 24 hours-to determine degradation rates. RESULTS: Belotero Balance lots were remarkably consistent. Belotero Balance had the largest high-molecular-weight species, followed by Juvéderm Ultra and Restylane (p < 0.001). Low-molecular-weight differences among all three hyaluronic acids were not statistically significant. Percentages of high-molecular-weight polymer differ among the three materials, with Belotero Balance having the highest fraction of high-molecular-weight polymer. Degradation of the high-molecular-weight species over time showed different molecular weights of the high-molecular-weight fraction. Rates of degradation of the hyaluronic acids following exposure to ovine testicular hyaluronidase were similar. All hyaluronic acids were fully degraded at 24 hours. CONCLUSIONS: Fractions of high-molecular-weight polymer differ across the hyaluronic acids tested. The low-molecular-weight differences are not statistically significant. The high-molecular-weight products have different molecular weights at the 0.5- and 2-hour time points when exposed to ovine testicular hyaluronidase and are not statistically different at 24 hours.

Advances in the use of botulinum neurotoxins in facial esthetics.

AIM: To present the latest findings and future developments in the cosmetic use of botulinum neurotoxin. METHODS: Review of recent literature and new scientific developments. RESULTS: Botulinum neurotoxin type A preparations onabotulinumtoxinA (BOTOX(®) Cosmetic/Vistabel(®), Allergan Inc.) and abobotulinumtoxinA (Dysport(®) /Azzalure(®) /Reloxin(®) , Ipsen Pharma,) have been used for many years and are effective and well tolerated for facial esthetic procedures. However, advances are continually made in the esthetics field. New formulations that may exhibit reduced antigenicity are becoming available, such as incobotulinumtoxinA (Xeomin(®) /Xeomeen(®) /Bocouture(®); formerly known as NT 201, Merz Pharma), which is a botulinum neurotoxin type A free from complexing proteins. In addition, lower facial procedures using botulinum toxin combined with fillers are becoming increasingly popular. Injection techniques and patterns are also evolving, with the aim of creating a more natural result and avoiding a "frozen" appearance. Moreover, the diversity of individuals requesting esthetic procedures is increasing, with growing interest from men and patients with a variety of skin types and colors. CONCLUSIONS: The uses of botulinum toxins for facial esthetics procedures continue to expand, with new techniques and formulations. The availability of products such as incobotulinumtoxinA may reduce the risk of neutralizing antibody development while maintaining the good efficacy and safety of existing formulations.