Biostimulating fillers and induction of inflammatory pathways: A preclinical investigation of macrophage response to calcium hydroxylapatite and poly-L lactic acid.

INTRODUCTION: Initial macrophage response to biostimulatory substances is key in determining the subsequent behavior of fibroblasts and the organization of newly synthesized collagen. Though histological studies suggest that calcium hydroxylapatite (CaHA) filler initiates a regenerative healing response with collagen and elastin deposition similar to natural, healthy tissue rather than an inflammatory response with fibrosis, the relative activity of macrophages stimulated by CaHA, as well as how this activity compares to that induced by other biostimulatory fillers, has not been explored. The aim of the study is to characterize the in vitro macrophage response to two biostimulory fillers, CaHA and PLLA (poly-L lactic acid), and to evaluate their inflammatory potential. METHODS: Primary human macrophages were incubated with two dilutions (1:50 and 1:100) of commercially available CaHA or PLLA. After 24 h incubation, an inflammation array was used to screen for the expression of 40 cytokines, released by macrophages. ELISA was used to confirm array results. RESULTS: Four cytokines were significantly upregulated in M1 macrophages incubated with PLLA compared to both unstimulated controls and CaHA: CCL1 (p < 0.001), TNFRII (p < 0.01), MIP-1α (p < 0.05), and IL-8 (p < 0.001). In M2 macrophages, MIP-1α (p < 0.01) and MIP-1ß (p < 0.01) were significantly upregulated by PLLA compared to CaHA and unstimulated controls. CONCLUSION: Together, these findings indicate that the CaHA mode of action is a non-inflammatory response while PLLA initiates expression of several cytokines known to play a role in inflammation. Our study supports the concept that these two "biostimulatory" fillers follow distinct pathways and should be considered individually with regard to mechanism of action.

The Role of Calcium Hydroxylapatite (Radiesse) as a Regenerative Aesthetic Treatment: A Narrative Review.

For decades, a wide variety of natural and synthetic materials have been used to augment human tissue to improve aesthetic outcomes. Dermal fillers are some of the most widely used aesthetic treatments throughout the body. Initially, the primary function of dermal fillers was to restore depleted volume. As biomaterial research has advanced, however, a variety of biostimulatory fillers have become staples in aesthetic medicine. Such fillers often contain a carrying vehicle and a biostimulatory material that induces de novo synthesis of major structural components of the extracellular matrix. One such filler, Radiesse (Merz Aesthetics, Raleigh, NC), is composed of calcium hydroxylapatite microspheres suspended in a carboxymethylcellulose gel. In addition to immediate volumization, Radiesse treatment results in increases of collagen, elastin, vasculature, proteoglycans, and fibroblast populations via a cell-biomaterial-mediated interaction. When injected, Radiesse acts as a cell scaffold and clinically manifests as immediate restoration of depleted volume, improvements in skin quality and appearance, and regeneration of endogenous extracellular matrices. This narrative review contextualizes Radiesse as a regenerative aesthetic treatment, summarizes its unique use cases, reviews its rheological, material, and regenerative properties, and hypothesizes future combination treatments in the age of regenerative aesthetics.

Microtoxin for Improving Pore Size, Skin Laxity, Sebum Control, and Scars: A Roundtable on Integrating Intradermal Botulinum Toxin Type A Microdoses Into Clinical Practice.

BACKGROUND: In aesthetic clinical practice, botulinum toxin type A (BoNT-A) is best known for its use as a neuromodulator for the treatment of dynamic facial lines; however, when injected intradermally as microdroplets, BoNT-A can improve skin quality and overall skin appearance. OBJECTIVES: To discuss key aspects of microtoxin use in clinical practice and provide expert guidance on utilization. METHODS: As part of a continuing medical education lecture series and roundtable, the authors discussed key aspects of microtoxin patient selection, injection technique, and safety. RESULTS: The experiences of expert faculty are shared here. Clinical experience is consistent with reported data. Microtoxin can be used to reduce pore size, sebum production, rosacea, acne, and fine lines, and to improve jawline and neck definition. Intradermal injection can also be employed for the improvement of transverse neck lines as well as for the safe prevention and management of scars and keloids. CONCLUSIONS: Expanding the use of BoNT-A, a predictable, minimally invasive, and affordable treatment to address commonly encountered complaints is appealing. The authors have found that making patients aware of microtoxin as a treatment option results in an increased interest in and utilization of BoNT-A, and high satisfaction among appropriately selected patients.

The Emerging Field of Regenerative Aesthetics-Where We Are Now.

BACKGROUND: Regenerative aesthetics is an emerging branch of regenerative medicine with therapies aimed at recapturing youthful structure and function using the body's own systems. OBJECTIVE: To introduce the field of regenerative aesthetics, and to explore themes and evidence surrounding current and emerging therapies in the field. MATERIALS AND METHODS: A review of the literature was performed for each of the 3 pillars of regeneration; namely, stem cells, biochemical cues, and scaffolds. RESULTS: Herein, we provide an overview of the field of regenerative aesthetics, a discussion surrounding the 3 pillars of regeneration, and an overview of the evidence supporting current and emerging therapeutic modalities that could play a pivotal role in the future of aesthetic treatments. CONCLUSION: An enhanced understanding of this field can serve to further enhance our awareness about the regenerative effects of therapies we already offer, in addition to providing inspiration for future innovation.

Pan-Asian Consensus on Calcium Hydroxyapatite for Skin Biostimulation, Contouring, and Combination Treatments.

BACKGROUND: Several usage guidelines for calcium hydroxylapatite (CaHA), a dermal filler material, exist for non-Asian patients, making it necessary to determine whether their findings and consensuses are applicable to Asian patients who have distinct anatomies, cultural preferences, and aesthetic requests. OBJECTIVE: We sought to develop a Pan-Asian consensus on CaHA use in skin biostimulation, contouring, and combination treatments for face and body indications. METHODS: A survey on CaHA usage for contouring and biostimulation indications in Asian patients was conducted, followed by discussions to establish consensus statements and topics for examination. RESULTS: Several aspects of facial shaping and contouring or skin biostimulation with CaHA were agreed on, including that dilution is not a key consideration, that microfocused ultrasound with visualisation precedes CaHA in same day or session treatments, and that cannulas should be used. Among the many agreements on interventions in specific facial and body areas, there were also disagreements due to the diverse Asian patient presentations, requests, and access to tools or products; for example, CaHA should be placed in the interfascial layer for temple contouring, CaHA should not be injected directly into the infraorbital area for safety, and diluted CaHA should be injected subdermally for nonfacial or whole-face biostimulation and contouring. CONCLUSION: Our disagreements highlight the diversity of Asian facial morphotypes and desired aesthetic outcomes and underscore the need for customized aesthetic strategies to accommodate the heterogeneity of Asian anatomies, cultural preferences, and aesthetic ideals. Establishing consensus statements on critical aspects of Asian patient considerations, efficacy and safety, is crucial. This document provides strategic guidance on the use of classic, diluted CaHA for biostimulation or undiluted Radiesse®(+) (Merz Pharma GmbH & Co. KGaA, Frankfurt, Germany) for lifting and contouring to ensure consistent CaHA delivery for successful patient outcomes.

Aesthetic Delusions: An Investigation into the Role of Rapid Visual Adaptation in Aesthetic Practice.

BACKGROUND: To date, the process of adaptation in the setting of aesthetic medicine has not been investigated. The combination of complex advanced feedback in the current intense social media milieu, in conjunction with easily accessible and effective aesthetic treatments, has produced pockets of overtreated patients and over-zealous practitioners. We examine whether aesthetic assessments of attractiveness and what appears natural can be distorted by the cognitive process of adaptation. METHODS: Forty-eight female participants were exposed to photographs of female faces in whom lip fullness had been strongly under- or over-exaggerated, while remaining within the bounds of natural appearing lips. Before and after evaluation of the exaggerated images, participants were asked to rate an alternative set of faces in terms of attractiveness (reflecting direct assessment of effective beauty impression) and naturalness (reflecting indirect assessment of beauty norms). The evaluation set consisted of six base faces that had been digitally altered to create a systematically varying 11 step set of lip sizes from extremely thin, to the original version, to very full. RESULTS: Second-order polynomial fits indicated clear shifts of the subjects' facial aesthetic assessments towards the specific lip fullness of the adaptors. In contrast, such adaptions were not found for ratings of face naturalness. In contrast to research demonstrating mathematical foundations and unchanging rules governing perceptions of beauty, we show that simple viewing of exaggerated feature morphologies can rapidly result in recalibration of a person's assessment of attractiveness. CONCLUSION: This paper provides evidence that facial attractiveness is fluid, and that there are psychological mechanisms that cause an aesthetic bias. Over-exposure to exaggerated features can lead to significant changes to a person's ideas of attractiveness.

Consensus on the Use of Hyaluronic Acid Fillers from the Cohesive Polydensified Matrix Range: Best Practice in Specific Facial Indications.

BACKGROUND: As the treatment indications for the Cohesive Polydensified Matrix® hyaluronic acid (CPM-HA) portfolio continue to expand and diversify, injectors new to the range or those who are expanding the treatments they offer may be unsure of the optimal product and injection technique for specific facial areas. Each product in the CPM-HA portfolio has been intentionally designed to provide the best physical properties for a specific indication and target tissue. This document has been developed to provide a comprehensive, one-stop reference for clinicians using the portfolio. METHODS: An international panel of experts in the field of aesthetic medicine convened to develop guidelines on effective and safe injection technique when performing treatments with the CPM-HA range of soft-tissue fillers. RESULTS: Consensus members considered treatment indications in the upper, middle and lower face. Landmark deficiencies and anatomical considerations are described for each indication and consensus recommendations provided on the optimal product, injection depth and treatment technique. This is supplemented by the experts advice on avoidance of complications. Throughout, an evidence-based approach to selection of products and injection techniques is provided. The result is a fully tailored approach to a range of indications covering the full portfolio of CPM-HA products, including the newest addition for skin revitalization. CONCLUSION: The recommendations in this consensus document are provided to assist clinicians in the selection of CPM-HA products, administration techniques and depths of injection with the aim of providing seamless and natural treatment results, enhanced safety and patient satisfaction.

Skin Quality - A Holistic 360° View: Consensus Results.

INTRODUCTION: Skin quality is an important component of human attractiveness. To date, there are no standardized criteria for good skin quality. To establish a consensus for good skin quality parameters and measurement and treatment options, a virtual skin quality advisory board consisting of a global panel of highly experienced aesthetic dermatologists/aesthetic physicians was convened. METHODS: A total of 10 dermatologists/aesthetic physicians served on the advisory board. A modified version of the Delphi method was used to arrive at consensus. Members accessed an online platform to review statements on skin quality criteria from their peers, including treatment and measurement options, and voted to indicate whether they agreed or disagreed. Statements that did not have agreement were modified and the members voted again. Consensus was defined as: strong consensus = greater than 95% agreement; consensus = 75% to 95% agreement; majority consent = 50% to 75% agreement; no consensus = less than 50% agreement. RESULTS: There was strong consensus that good skin quality is defined as healthy, youthful in appearance (appearing younger than a person's chronological age), undamaged skin and that skin quality can be described across all ethnicities by four emergent perceptual categories (EPCs): skin tone evenness, skin surface evenness, skin firmness, and skin glow. The EPCs can be affected by multiple tissue layers (ie, skin surface quality can stem from and be impacted by deep structures or tissues). This means that topical approaches may not be sufficient. Instead, improving skin quality EPCs can require a multilayer treatment strategy. CONCLUSION: This global advisory board established strong consensus that skin quality can be described by four EPCs, which can help clinicians determine the appropriate treatment option(s) and the tissue or skin layer(s) to address. Skin quality is important to human health and wellbeing and patients' perception for the need for aesthetic treatment.

The perception bias of aesthetic providers.

Since there is no universal standard of beauty, each aesthetic provider's definition may shape his/her practice of aesthetic procedures. Beauty and attractiveness are commonly defined by both mathematical and cultural influences and are shaped by our surroundings and what is most familiar to us. Therefore, we thoroughly explored the literature to better elucidate these variables and biases that affect the perception of beauty, in order to better provide appropriate and customized aesthetic procedures that preserve each individuals' own unique beauty. Understanding how each provider's own bias and aesthetic preferences differs from that of his/her patients may go a long way to improving communication in the consultation process and patient satisfaction with the outcomes achieved. We know that clinicians many times superimpose their biases onto their patients, so it is important that each practitioner accounts for bias in aesthetic medicine when consulting with patients and colleagues.

Delayed Inflammatory Reactions to Hyaluronic Acid Fillers: A Literature Review and Proposed Treatment Algorithm.

BACKGROUND AND OBJECTIVES: There is a wide diversity of opinions regarding the management of delayed inflammatory reactions (DIRs) secondary to hyaluronic acid (HA)-based fillers. The plethora of approaches has led the authors to conduct a review regarding management and treatment of DIRs as well as establish therapeutic guidelines for this purpose. MATERIALS AND METHODS: A review of the literature was performed through databases such as PubMed using keywords including HA-fillers and complications, delayed HA filler sequelae and therapy, soft tissue and dermal filler reactions and management. Additionally, a survey comprised of questions regarding the management and treatment of DIRs was sent to 18 physicians highly experienced with soft-tissue filler injections in 10 countries. Their answers and recommendations were analyzed and debated amongst these panelists. RESULTS: Sixteen panelists favored antibiotic therapy as first-line treatment for DIRs, specifically dual antibiotic therapy consisting of a fluoroquinolone along with a tetracycline or macrolide for a period of 3-6 weeks. The majority refrained from the use of intralesional (IL) or systemic steroids except in the case of disfiguring or recalcitrant reactions. IL hyaluronidase was recommended by 13 panelists; however, some preferred a watchful waiting approach for a period of 48 hours to 2 weeks prior to IL hyaluronidase, and in cases where antibiotics did not lead to improvement. CONCLUSION: A consensus was reached and summarized to propose a clear, easy-to-follow, stepwise algorithm for the treatment of DIRs.

Managing intravascular complications following treatment with calcium hydroxylapatite: An expert consensus.

BACKGROUND: Inadvertent intra-arterial injection of dermal fillers including calcium hydroxylapatite (CaHA) can result in serious adverse events including soft tissue necrosis, permanent scarring, visual impairment, and blindness. When intra-arterial injection occurs, immediate action is required for optimal outcomes, but the infrequency of this event means that many physicians may never have experienced this scenario. The aim of this document is to provide evidence-based and expert opinion recommendations for the recognition and management of vascular compromise following inadvertent injection of CaHA. METHODS: An international group of experts with experience in injection of CaHA and management of vascular complications was convened to develop a consensus on the optimal management of vascular compromise following intra-arterial CaHA injection. The consensus members were asked to provide preventative advice for the avoidance of intravascular injection and to produce a treatment protocol for acute and delayed presentation. To ensure all relevant treatment options were included, the recommendations were supplemented with a PubMed search of the literature. RESULTS: For prevention of intra-arterial CaHA injection, consensus members outlined the importance of a thorough knowledge of facial vascular anatomy and patient history, as well as highlighting potential risk zones and optimal injection techniques. Individual sections document how to recognize the symptoms of vascular occlusion leading to vision loss and tissue necrosis as well as detailed treatment protocols for the management of these events. For impending tissue necrosis, recommendations are provided for early and delayed presentations with treatment protocols for acute and follow-up treatment. A separate section details the treatment options for open and closed wounds. CONCLUSIONS: All physicians should be prepared for the eventuality of intra-arterial injection of a dermal filler, despite its rarity. These consensus recommendations combine advice from aesthetic experts with the latest reports from the published literature to provide an up-to-date office-based protocol for the prevention and treatment of complications arising from intra-arterial CaHA injection.

Validated Assessment Scales for Cellulite Dimples on the Buttocks and Thighs in Female Patients.

BACKGROUND: New treatment methods for cellulite require globally accepted scales for aesthetic research and patient evaluation. OBJECTIVE: To develop a set of grading scales for objective assessment of cellulite dimples on female buttocks and thighs and assess their reliability and validity. MATERIALS AND METHODS: Two photonumeric grading scales were created and validated for dimples in the buttocks in female patients: Cellulite Dimples-At Rest, and Cellulite Dimples-Dynamic. Sixteen aesthetic experts rated photographs of 50 women in 2 validation sessions. Responses were analyzed to assess inter-rater and intra-rater reliability. RESULTS: Overall inter-rater reliability and intra-rater reliability were both "almost perfect" (≥0.81, intraclass correlation efficient and weighted kappa) for the At Rest scale. For the Dynamic scale, inter-rater reliability and intra-rater reliability were "substantial" (0.61-0.80). There was a high correlation between the cellulite scales and body mass index, age, weight, and skin laxity assessments. CONCLUSION: Consistent outcomes between raters and by individual raters at 2 time points confirm the reliability of the cellulite dimple grading scales for buttocks and thighs in female patients and suggest they will be a valuable tool for use in research and clinical practice.

Validated Assessment Scales for Skin Laxity on the Posterior Thighs, Buttocks, Anterior Thighs, and Knees in Female Patients.

BACKGROUND: The demand for noninvasive skin-tightening body procedures is increasing. OBJECTIVE: To develop a set of grading scales for the objective assessment of skin laxity and assess their reliability and validity. MATERIALS AND METHODS: Two photonumeric grading scales were created and validated for skin laxity in female patients: Skin Laxity-Posterior Thighs/Buttocks, and Anterior Thighs/Knees. Fifteen aesthetic experts rated photographs of 50 women in 2 validation sessions. Responses were analyzed to assess inter-rater and intra-rater reliability. RESULTS: Overall inter-rater reliability according to intraclass correlation efficient (ICC) 2.1 and weighted kappa was at least "substantial" for both scales in both sessions, and "almost perfect" (≥0.81) for the Anterior Thighs and Knees scale in session 2. Intra-rater reliability was "almost perfect" for both scales (ICC 2.1) and "substantial" to "almost perfect" by weighted kappa. A correlation between the skin laxity scales and body mass index, age, weight, sun exposure, and cellulite severity was observed. CONCLUSION: The skin laxity photonumeric grading scales are valid and reliable instruments for assessing laxity on the posterior thighs and buttocks, and anterior thighs and knees. The scales will be of value for standardizing clinical evaluations and quantifying outcome measurements in research and clinical practice.

Global Consensus Guidelines for the Injection of Diluted and Hyperdiluted Calcium Hydroxylapatite for Skin Tightening.

BACKGROUND: Calcium hydroxylapatite (CaHA) is approved to correct moderate-to-severe wrinkles and folds and soft-tissue volume loss in the face and hands. More recently, subdermal injection using diluted CaHA has been used to improve skin laxity. OBJECTIVE: To review evidence for the safe and effective use of diluted CaHA in the face and body and provide best practice recommendations. METHODS: A global panel of expert aesthetic physicians convened to develop consensus-based guidelines for treating laxity and superficial wrinkles using diluted (ratio of 1:1) and hyperdiluted (≥1:2) CaHA. RESULTS: Diluted and hyperdiluted CaHA stimulates targeted neocollagenesis in the injection area to improve laxity and skin quality in the mid- and lower face, neck, décolletage, upper arms, abdomen, upper legs, and buttocks. Treatment can be used as an adjunct to volume augmentation or combined with additional modalities for optimal results. Adverse events are related to the injection and include bruising, swelling, mild pain, and induration. In thinner and darker skin, too-superficial injections of less diluted CaHA can lead to more adverse events. CONCLUSION: This report provides preliminary guidelines for the novel off-label use of CaHA for biostimulation in the face and body. Further trials will provide additional clarity regarding treatment paradigms for optimal outcomes.

Hyperdilution of CaHA fillers for the improvement of age and hereditary volume deficits in East Asian patients.

With their high elasticity and viscosity, calcium hydroxylapatite (CaHA) fillers are now widely used to treat age-related or hereditary facial soft tissue volume deficits. CaHA filler volume augmentation is further enhanced by its ability to stimulate neocollagenesis and improve skin quality. However, its high viscosity and cohesivity may hinder its spread and distribution, while its injection by cannula or needle may require moderate extrusion force and lead to uneven distribution or focal accumulation in tissues. Thus, new or modified delivery techniques and tools have emerged, particularly from East Asian physicians. One such technique is hyperdilution with diluents such as lidocaine or normal saline. CaHA hyperdilution appears to be more frequently used by experienced injectors who have varying methodologies. Here, we demonstrate the precise delivery of diluted filler to treat indications related to hereditary volume deficits, volume loss, or aging in the periorbital, nasolabial and submalar regions, marionette lines, and hollowed mid-facial areas. Regardless of age or indication, dilution eases filler delivery for the injector, while using lidocaine as the diluent decreases patient discomfort and minimizes pain. Increasing injection diluent volumes reduces filler thickness (viscosity) and facilitates its even spread, encouraging skin stimulation through more direct contact with tissues and minimizing unevenness. Our results effectively demonstrate that hyperdilution is an innovative and positive evolution in CaHA filler delivery.

Consensus Recommendations for Combined Aesthetic Interventions Using Botulinum Toxin, Fillers, and Microfocused Ultrasound in the Neck, Décolletage, Hands, and Other Areas of the Body.

BACKGROUND: The popularity of aesthetic procedures in the face has led to greater disparity between treated areas and those that still show evidence of true age. Although many areas of the body often require multiple treatment procedures for optimal rejuvenation, combination therapy for specific areas is not yet well defined. OBJECTIVE: To develop recommendations for the optimal combination and ideal sequence of botulinum toxin (BoNT), hyaluronic acid, calcium hydroxylapatite (CaHA), and microfocused ultrasound with visualization in nonfacial areas across all skin phototypes. METHODS: Fifteen specialists convened under the guidance of a certified moderator. Consensus was defined as approval from 75% to 94% of all participants, whereas agreement of ≥95% denoted a strong consensus. RESULTS: Recommendations have been provided for the neck, décolletage, and hands and include the timing and sequence of specific procedures when used concurrently or over several treatment sessions. Position statements are offered in lieu of consensus for the upper arms, abdomen, buttocks, and knees. CONCLUSION: Nonfacial rejuvenation often requires multiple procedures for optimal results in individuals with significant age-related changes. Further clinical studies are recommended to raise awareness of non-facial indications and provide clinicians with the best evidence for best treatment practices.

Consensus Recommendations for Combined Aesthetic Interventions in the Face Using Botulinum Toxin, Fillers, and Energy-Based Devices.

BACKGROUND: The aging process is a complex interplay of intrinsic and extrinsic factors across multiple layers of the face. Accordingly, combining aesthetic interventions targeting different manifestations of aging often leads to better results than single modalities alone. However, no guidelines for a pan-facial approach using multiple interventions have been published to date. OBJECTIVE: To develop consensus recommendations for the optimal combination and ideal sequence of botulinum toxin (BoNT), hyaluronic acid, calcium hydroxylapatite, and microfocused ultrasound with visualization (MFU-V) in persons of all Fitzpatrick skin types. METHODS AND MATERIALS: Fifteen specialists convened under the guidance of a certified moderator. Consensus was defined as approval from 75% to 94% of all participants, whereas agreement of ≥95% denoted a strong consensus. RESULTS: Optimal aesthetic treatment of the face begins with a thorough patient assessment and an individualized treatment plan. Spacing consecutive treatments 1 to 2 weeks apart allows for resolution of side effects and/or to assess results. For same-day treatments, BoNT and fillers may be performed together in either sequence, whereas MFU-V is recommended before injectable agents. CONCLUSION: Expert consensus supports a combination approach using multiple modalities in specific sequence for the safe and effective treatment of the aging face.