Integrating skin color assessments into clinical practice and research: A review of current approaches.

Skin color classification can have importance in skin health, pigmentary disorders, and oncologic condition assessments. It is also critical for evaluating disease course and response to a variety of therapeutic interventions and aids in accurate classification of participants in clinical research studies. A panel of dermatologists conducted a literature review to assess the strengths and limitations of existing classification scales, as well as to compare their preferences and utilities. We identified 17 skin classification systems utilized in dermatologic settings. These systems include a range of parameters such as UV light reactivity, race, ethnicity, and degree of pigmentation. The Fitzpatrick skin type classification is most widely used and validated. However it has numerous limitations including its conflation with race, ethnicity, and skin color. There is a lack of validation data available for the remaining scales. There are significant deficiencies in current skin classification instruments. Consensus-based initiatives to drive the development of validated and reliable tools are critically needed.

Efficacy and Safety of a New Resilient Hyaluronic Acid Filler in the Correction of Moderate-to-Severe Dynamic Perioral Rhytides: A 52-Week Prospective, Multicenter, Controlled, Randomized, Evaluator-Blinded Study.

BACKGROUND: The perioral region is highly mobile and subject to multifactorial changes during aging. Resilient Hyaluronic Acid Redensity (RHAR), an RHA filler, was developed with the aim of optimizing outcomes in dynamic facial areas. OBJECTIVE: This randomized, blinded, multicenter clinical study aimed to demonstrate superiority of RHAR over no-treatment control for correction of moderate-to-severe dynamic perioral rhytides. MATERIALS AND METHODS: Blinded live evaluator assessments of efficacy included improvement in perioral rhytides severity using a proprietary scale (Perioral Rhytids Severity Rating Scale [PR-SRS]) and the Global Aesthetic Improvement Scale. Subjects self-assessed their results with FACE-Q, a validated patient-reported outcome measure, and satisfaction scales. Safety was monitored throughout the study based on common treatment responses (CTRs) and adverse events (AEs). RESULTS: The primary efficacy end point was achieved, with the treatment group showing statistically significant superiority over the control group at Week 8 (80.7% vs 7.8% responder rate by PR-SRS, p < .0001). Most patients (66%) were still responders at Week 52 (study completion). Most AEs were CTRs after perioral injection of a dermal filler, and none was a clinically significant treatment-related AE. CONCLUSION: Resilient Hyaluronic Acid Redensity is effective and safe for the correction of dynamic perioral rhytides in all Fitzpatrick phototypes, with marked durability.

Aspiration Revisited: Prospective Evaluation of a Physiologically Pressurized Model With Animal Correlation and Broader Applicability to Filler Complications.

BACKGROUND: Aspiration testing before filler injection is controversial. Some believe that aspiration can help prevent inadvertent intravascular injection, whereas others cite false-negative results and question its value given that the needle position always changes somewhat during injection procedures. OBJECTIVES: The authors sought to test the relation of false-negative results to the viscosity of the material within the needle lumen and determine whether a less viscous material within the needle lumen could decrease the incidence of false-negative results. METHODS: In vitro aspiration tests were performed utilizing 30-G and 27-G needle gauges, 2 cross-linked hyaluronic acid fillers, normal saline bags pressurized at 140 and 10 mmHg to mimic human arterial and venous pressures, and 3 needle lumen conditions (normal saline, air, and filler). Testing was repeated 3 times under each study condition (72 tests in total). For in vivo correlation, aspiration tests were performed on femoral arteries and central auricular veins in 3 rabbits (4-5 aspirations per site, 48 tests in total). RESULTS: In vitro and in vivo testing utilizing 30-G needles containing filler both showed false-negative results on aspiration testing. In vitro and in vivo testing utilizing needles containing saline or air showed positive findings. CONCLUSIONS: False-negative results from aspiration testing may be reduced by pre-filling the needle lumen with saline rather than a filler. The pressurized system may help overcome challenges of animal models with intravascular pressures significantly different from those of humans. The adaptability of this system to mimic various vessel pressures may facilitate physiologically relevant studies of vascular complications.

The First of Two One-Year, Multicenter, Open-Label, Repeat-Dose, Phase II Safety Studies of PrabotulinumtoxinA for the Treatment of Moderate to Severe Glabellar Lines in Adult Patients.

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin type A produced by Clostridium botulinum. OBJECTIVES: The authors sought to investigate the safety of prabotulinumtoxinA for treatment of glabellar lines. METHODS: This was a multicenter, open-label, repeat-dose, 1-year phase II safety study. Adults with moderate to severe glabellar lines at maximum frown, as assessed by the investigator on the validated 4-point photonumeric Glabellar Line Scale (0 = no lines, 1 = mild, 2 = moderate, 3 = severe), were enrolled. On day 0, patients received an initial treatment of 20 U prabotulinumtoxinA (4 U/0.1 mL freeze-dried formulation injected into 5 target glabellar sites). On and after day 90, patients received a repeat treatment (RT) if their Glabellar Line Scale score was ≥2 at maximum frown by investigator assessment. Safety was evaluated throughout the study. RESULTS: The 352 study patients received a median total dose of 60 U, that is, 3 treatments per year. Fifty-one patients (14.5%) experienced adverse events (AEs) assessed as possibly study drug related; 11.1% experienced study drug-related AEs after the initial treatment. With each RT, progressively lower percentages of patients experienced study drug-related AEs. Six patients (1.7%) experienced study drug-related AEs of special interest: 3 eyelid ptosis (0.9%), 2 speech disorder (0.6%), and 1 blepharospasm (0.3%). Seven patients (2.0%) experienced serious AEs; none were study drug related. Of the 2393 samples tested, 2 patients (0.6%) tested positive for antibotulinum toxin antibodies at a single postbaseline visit. CONCLUSIONS: The safety of RTs of 20 U of prabotulinumtoxinA for moderate to severe glabellar lines was first established in this early phase II study based on a broad range of outcomes.

Prospective, Randomized, Investigator-Blinded, Split-Face Evaluation of a Topical Crosslinked Hyaluronic Acid Serum for Post-Procedural Improvement of Skin Quality and Biomechanical Attributes.

BACKGROUND: This split-face, controlled study investigated the ability of a topical crosslinked hyaluronic acid formulation (RHA serum) to enhance clinical results from fillers, microneedling, or chemical peeling of aging skin. Previous comparative skin explant studies demonstrated greater efficacy of RHA serum than topical non-crosslinked high or low molecular weight hyaluronic acid in decreasing trans-epidermal water loss, increasing epidermal hydration, and improving corneocyte microstructure. METHODS: 24 female subjects aged 35 to 55 were enrolled. 8 received intradermal hyaluronic acid filler injection, 8 received microneedling, and 8 received superficial mandelic acid chemical peeling. Subjects initiated twice-daily, standardized application of RHA serum to one side of the face 2 days after the procedure. Topographical imaging, bioinstrumental, and blinded clinical evaluations were performed at days 0, 14, and 28. RESULTS: Areas treated with RHA serum showed statistically significant improvements in skin surface topography and hydration compared to untreated areas. Blinded investigator scoring showed greater improvement of RHA serum-treated skin in moisture, tone/complexion, radiance, texture, uniformity, and global appearance. Subjects' questionnaire responses correlated with these findings. Subjects expressed greater satisfaction with appearance of the treated hemiface. No adverse events were observed during the study. CONCLUSIONS: When initiated post-procedurally, topical RHA serum was well-tolerated and enhanced biomechanical properties, quality, and clinical appearance of the skin. Based on these data, RHA serum may be of value in improving patient outcomes and satisfaction following minimally invasive aesthetic procedures. The availability of the same hyaluronic acid technology also as a cohesive, tissue-integrating injectable filler enables synergistic, multi-level treatment plans to be devised.

J Drugs Dermatol. 2018;17(4):442-450.

The Mechanisms and Potential Impact of Stem Cell Activation in Skin Rejuvenation: An Evidence-Based Analysis.

Stem cells can propagate indefinitely in an undifferentiated state; or, with appropriate signals, differentiate into various types of mature cells. Strong interest in stem cell therapies for degenerative diseases has extended to skin aging, itself a degenerative process. This article reviews mechanisms of skin aging, and enables an evidence-based approach to topical skin rejuvenation - specifically, to formulations labeled as stem cell products.

J Drugs Dermatol. 2017;16(4):378-384.

Pilot Comparative Study of the Topical Action of a Novel, Crosslinked Resilient Hyaluronic Acid on Skin Hydration and Barrier Function in a Dynamic, Three-Dimensional Human Explant Model.

BACKGROUND: Hyaluronic acid (HA) is a popular ingredient in topical formulations for cosmetic improvement of the skin. Most formulations contain linear, non-crosslinked HA oligomers, low molecular weight (LMW) HA, and/or high molecular weight (HMW) HA. Crosslinking of HA enhances its clinical longevity and mechanical characteristics. The objective of this study was to characterize the topical effects of a new, crosslinked resilient HA (RHA) that is also available as a cohesive, tissue-integrating injectable filler, compared with non-crosslinked HMW HA and LMW HA. Living human skin explants that preserve the 3-dimensional structure of in vivo skin were used to maximize clinical relevance. METHODS: Standardized doses of each HA product were applied daily for 9 days to human skin explant surfaces. Untreated explants served as controls. Water content of the stratum corneum and entire epidermis was analyzed by Raman spectroscopy. Transepidermal water loss (TEWL) was measured to assess skin barrier function. Explant morphology and microrelief were evaluated by optical and scanning electron microscopy. RESULTS: Crosslinked RHA achieved a significant increase in epidermal water content (7.6%) over the control. Spectral cartography confirmed a higher epidermal water content with RHA than with HMW HA or LMW HA. TEWL was reduced by 27.8% with RHA, and by 15.6% with HMW HA, but increased by 55.5% with LMW HA. Cutaneous microrelief improved with RHA. Corneocyte cohesion improved with RHA and HMW HA. CONCLUSIONS: This comparative, multimodal study demonstrated greater benefits of topical crosslinked RHA over linear HMW HA or LMW HA in reducing TEWL, retaining and redistributing water within the epidermis, maintaining skin integrity, and improving skin barrier structure and function. RHA was a more efficacious humectant than LMW HA, and a more efficacious occlusive moisturizer than HMW HA. These integrative epidermal repair activities are of significant value for addressing primary deficits of aging skin, improving tolerance to retinoids and other topical agents, and optimizing procedural outcomes. A combination of topical and injectable HA provides an elegant model of synergistic, multi-level skin restoration.

Pilot, Multicenter, Open-Label Evaluation of Safety, Tolerability and Efficacy of a Novel, Topical Multipotent Growth Factor Formulation for the Periorbital Region.

BACKGROUND: This multicenter, open-label pilot study evaluated safety, efficacy and tolerability of a topical formulation containing a multipotent growth factor resignaling complex (MRCx), when applied to infraorbital and lateral canthal skin. METHODS: Thirty-nine female subjects with mean age of 56.8 years who had periorbital lines and wrinkles, uneven skin texture, puffiness, and lack of skin firmness were enrolled, and 38 completed the study. All subjects applied the multipotent growth factor formulation bilaterally to the periorbital area, twice daily for 60 days. Efficacy and treatment-related adverse events were evaluated at Baseline and days 14, 30, and 60. Investigators rated the periorbital areas based on 10-point scales. RESULTS: Subjects' self-reported compliance with treatment was greater than 99% throughout the study. At day 60, all subjects had improvement in infraorbital brightness (≥ 2 points), moistness (≥ 2 points), wrinkles (≥ 1 point), sallowness (≥ 1 point), crepiness (≥ 1 point), smooth texture (≥ 1 point), skin tightness (≥ 1 point), and skin tone (≥ 1 point). Investigator-rated assessments showed ≥ 1-point improvement for lateral canthal wrinkles, dyschromia/mottled pigmentation, skin tone, overall brightness, and moistness. Investigator-rated scoring on the Global Aesthetic Improvement Scale (GAIS) demonstrated that 67.6% of subjects were much improved/improved at day 14, and 63.1% remained improved at day 60. Overall, 76.2% and 79.0% of subjects were very pleased/pleased/mostly pleased with the appearance of their infraorbital and lateral canthal areas at day 60. Adverse events comprised one case of mild canthal erythema, and one case of mild eye irritation, both of which were respectively resolved. CONCLUSIONS: This pilot study demonstrated that the topical multipotent growth factor formulation was safe, effective and well tolerated for periorbital skin rejuvenation.

The potential of topical and injectable growth factors and cytokines for skin rejuvenation.

Growth factors and cytokines (referred to collectively hereafter as GFs) control cell growth, proliferation, and differentiation via a network of inter and intracellular signaling pathways. There are striking parallels between the pathways involved in skin wound healing and those implicated in photoaging of the skin. In recent years, topical and injectable GFs have emerged as an intriguing therapeutic modality that can be harnessed for aesthetic and medical purposes. This article provides a review of available evidence for the role in skin regeneration of topical GFs, and of injectable GFs contained in autologous platelet-rich plasma (PRP). It presents data from recent studies of GFs, offers a discussion of their potential to serve as antiaging actives, and includes safety considerations. As studies of injectable GFs typically assume preexisting familiarity with PRP protocols and the theory behind them, explanatory notes are provided. An assessment is provided of the evidence gaps that exist currently between experimental observations regarding GFs and their proven clinical benefits. Data of evidence levels II and III support the use for skin rejuvenation of topical GFs derived from sources including secretions or lysate of human dermal fibroblasts, and secretions of the snail Cryptomphalus aspersa. GFs with associated stem cell proteins, secreted by human dermal fibroblasts under hypoxic stress, can accelerate skin healing after laser resurfacing. In vitro and animal studies, small case series of PRP-treated patients and one prospective clinical study of its variant, platelet-rich fibrin matrix (PRFM), suggest the value of injectable GFs for skin rejuvenation. However, data of higher power are required to expand this proof of concept into an evidence-based paradigm. The clinical applications of topical and injectable GFs are promising, and remain to be fully defined. With continued study, data of higher evidence level can be accrued and formulations can be developed that offer optimal clinical efficacy, safety, tolerability, and stability. Better understanding of the mechanism of action of GFs can potentially advance our general understanding of dermal signaling pathways, and hence of hyaluronic acid and other alloplastic fillers; and allow the development of protocols for synergistic combination of GFs with other skin rejuvenation modalities.

Proteogenomic analysis of Mycobacterium tuberculosis by high resolution mass spectrometry.

The genome sequencing of H37Rv strain of Mycobacterium tuberculosis was completed in 1998 followed by the whole genome sequencing of a clinical isolate, CDC1551 in 2002. Since then, the genomic sequences of a number of other strains have become available making it one of the better studied pathogenic bacterial species at the genomic level. However, annotation of its genome remains challenging because of high GC content and dissimilarity to other model prokaryotes. To this end, we carried out an in-depth proteogenomic analysis of the M. tuberculosis H37Rv strain using Fourier transform mass spectrometry with high resolution at both MS and tandem MS levels. In all, we identified 3176 proteins from Mycobacterium tuberculosis representing ~80% of its total predicted gene count. In addition to protein database search, we carried out a genome database search, which led to identification of ~250 novel peptides. Based on these novel genome search-specific peptides, we discovered 41 novel protein coding genes in the H37Rv genome. Using peptide evidence and alternative gene prediction tools, we also corrected 79 gene models. Finally, mass spectrometric data from N terminus-derived peptides confirmed 727 existing annotations for translational start sites while correcting those for 33 proteins. We report creation of a high confidence set of protein coding regions in Mycobacterium tuberculosis genome obtained by high resolution tandem mass-spectrometry at both precursor and fragment detection steps for the first time. This proteogenomic approach should be generally applicable to other organisms whose genomes have already been sequenced for obtaining a more accurate catalogue of protein-coding genes.

Aesthetic applications of calcium hydroxylapatite volumizing filler: an evidence-based review and discussion of current concepts: (part 1 of 2).

BACKGROUND: Calcium hydroxylapatite filler (CaHA; Radiesse) is a synthetic, non-animal derived product composed of minerals that occur naturally in bone and teeth. Following its development in the US, initial approval by the US FDA for non-aesthetic indications and CE marking in Europe, it was used off FDA-labeling for aesthetic purposes. Its use has grown further since its FDA approval in 2006 for long-lasting correction of moderate to severe wrinkles and folds. It is a popular filler for volume restoration to the face, and also to nonfacial areas such as the dorsum of the hands. METHODS: The first article of this two-part series provides an evidence-based review of study data pertaining to the mechanism of action and biocompatibility of CaHA filler, and its safety, efficacy and tolerability when used for aesthetic purposes. The review includes data from a number of prospective, controlled comparative studies, from several retrospective studies, and from a meta-analysis of reported complications from alloplastic filler procedures over a 20-year period. The study methodology and number of study subjects are sufficiently robust to provide a high Evidence Level for much of the data. RESULTS: CaHA has good safety, efficacy and tolerability profiles that are comparable to those of hyaluronic acid (HA) fillers. It provides an initial, immediate volume replacement for up to 12 months followed by longer term correction due to biostimulation, resulting in collagenesis. Evidence Level II studies show longevity of 30 months or more after nasolabial fold implantation. Other studies demonstrate the appropriateness of CaHA filler for volume restoration to areas including the mid face, lower face and hands. CaHA is classified as an adjustable filler, whereas HA is fully reversible by hyaluronidase digestion. For this reason, and also because of CaHA's high viscosity and elasticity, evidence-based and experiential consensus suggests its avoidance in highly mobile areas (e.g. lips) or in anatomically unforgiving areas (e.g. the periocular region), where there may be increased incidence of nodules. CONCLUSION: CaHA filler is safe, efficacious and well-tolerated when used appropriately. It is increasingly recognized that many patients require pan-facial volume restoration, and that many can benefit from combined treatments. Therefore, CaHA and HA fillers may be considered complementary rather than competitive to each other. The second article of this series offers a discussion of product characteristics, scientific principles and injection techniques to optimize treatment with CaHA filler, including special considerations for avoidance and management of complications.

A two-center, open-label, randomized, split-face study to assess the efficacy and safety of one versus three intradermal injection sites of abobotulinumtoxinA in the treatment of lateral periocular rhytides.

BACKGROUND: Lateral canthal rhytides partly result from repetitive muscular actions of the orbicularis oculi. OBJECTIVE: To determine the efficacy of one versus three injection sites of AbobotulinumtoxinA (ABO) in the treatment of lateral canthal rhytides. METHODS: This was a two-center, evaluator-masked, 120 day study in which 40 patients with moderate to severe hyperdynamic lateral canthal rhytides at maximal contracture were randomized to receive one injection of 36 Units of ABO into the middle of the lateral orbital rhytides on one side, with the contralateral side treated with the same total dose of ABO, divided into three intradermal injections of 12 Units each, along the lateral canthal area. A blinded evaluator assessed lateral orbital rhytides at rest and maximal contraction at baseline, 7, 42, 90, and 120 days post treatment. Standardized digital photography and subject self- assessment were performed at each visit. RESULTS: No statistically significant difference was seen at any visit between sides treated with one injection and those treated with three injections in any evaluation category. There was no difference in adverse events between the two sides. CONCLUSION: Sites treated with three injections of ABO showed no statistically significant difference from those treated with one injection.

New and emerging concepts in soft tissue fillers: roundtable discussion.

In the years since the U.S. FDA approval in 2003 of the first hyaluronic acid (HA) filler, a number of other HA products have become available for use in the U.S., in addition to products composed of calcium hydroxylapatite (CaHA), poly-L lactic acid (PLLA) and polymethyl methacrylate (PMMA). This roundtable discussion between two US-based dermatologists, a European plastic surgeon, and a US-based plastic surgeon provides an overview of commonly used alloplastic filler products and examines how new strategies for soft tissue augmentation are developing as filler options continue to expand.

Hyaluronic acid fillers on the horizon: roundtable discussion.

In this roundtable discussion, the physicochemical properties and potential clinical applications of two new ranges of hyaluronic acid fillers are reviewed. These fillers display enhanced tissue integration after implantation due to novel manufacturing processes, and one of the ranges is customized for specific clinical applications by variation of filler gel calibration and cross-linking.

Blunt-tipped microcannulas for the injection of soft tissue fillers: a consensus panel assessment and recommendations.

As blunt injection microcannulas increase in popularity, clinicians may find it of value to have a systematic review of their current uses. This consensus document is derived from a roundtable discussion between a multi-specialty faculty comprising two U.S.-based dermatologists, one U.S.-based plastic surgeon, and one European cosmetic surgeon, all of whom were early adopters of blunt microcannulas for alloplastic fillers. The purpose of this consensus document is to provide an overview of the utility and clinical applications of blunt microcannulas, guidelines for their safe and efficacious use, and recommendations for the further evidence that needs to be accrued to substantiate the claims that have been made in regard to their superior safety profile and other benefits.

Rheological evaluation of the physical properties of hyaluronic acid dermal fillers.

BACKGROUND: Hyaluronic acid (HA) gels are commonly injected into the skin to lift rhytides and to improve facial appearance. The different processes used in their manufacture and formulation yield products with unique physical characteristics that play an important role in predicting their clinical performance. OBJECTIVE: The following rheologic evaluation was performed to objectively measure the physical characteristics of HA dermal filler products derived from similar bacterial sources and containing the same butanediol diglycidyl ether cross-linker, but formulated using different manufacturing techniques. The objective of this study was to evaluate the physical characteristics of two distinct families of HA products, thereby providing clinicians with a greater understanding of these products' attributes and the ability to optimize their use in the treatment of patients seeking facial rejuvenation. MATERIALS AND METHODS: The physical properties of commercially-available dermal fillers containing HA were evaluated using rheologic testing methods under clinically-relevant conditions. Additionally, light microscopy was used to assess the particulate nature of each product. RESULTS: The gels tested demonstrated a broad range of elasticity, firmness and viscosity. Light microscopy confirmed the particulate nature of each product and revealed HA particles of varying size and distribution. CONCLUSION: This rheologic evaluation demonstrates that differences exist among the HA products tested including gel elasticity, viscosity, and the range and distribution of gel particle sizes. Understanding the distinct physical characteristics of different HA dermal fillers and how these characteristics may predict their clinical behavior can assist clinicians in achieving the desired results in patients seeking facial rejuvenation.