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.

Performance assessment of an injectable hyaluronic acid/polylactic acid complex hydrogel with enhanced biological properties as a dermal filler.

Injectable hyaluronic acid (HA) hydrogel plays an important role in dermal filling. However, conventional HA dermal fillers mostly lack bio-functional diversity and frequently cause adverse reactions because of the chemical stiffness of highly modified degree and crosslinker residues. In this study, polylactic acid (PLA) was embedded into HA hydrogel as a bioactive substance and 1,4-butanediol diglycidyl ether was used as a crosslinker to prepare the HA/PLA composite hydrogel with enhanced biocompatibility and biological performance. We aimed to investigate the properties of HA/PLA composite hydrogels as dermal fillers by assessing the rheological properties, surface microstructure, enzymolysis stability, swelling ratio, degradation rate, cytotoxicity, and anti-wrinkle effect on photo-aged skin. The results showed that the stability and stiffness of the composite hydrogel decreased with an increasing amount of PLA, while the in vivo safety of the HA/PLA hydrogel was enhanced, showing no adverse reactions such as edema, redness, or swelling. Moreover, the composite hydrogel with 2 wt% PLA exhibited excellent anti-wrinkle effects, showing the highest collagen production. Thus, the PLA-embedded HA composite hydrogel showed potential as a dermal filler with high safety, easy injectability, and excellent anti-wrinkle effects.

Evaluation of Paste-Type Micronized Acellular Dermal Matrix for Soft Tissue Augmentation: Volumetric and Histological Assessment in a Mouse Model.

BACKGROUND: A biological injectable material, paste-type micronized acellular dermal matrix (ADM), has been proven effective in wound healing by filling defects through tissue replacement. This study aimed to compare the efficacy of paste-type micronized ADM on soft tissue augmentation with that of the conventional fillers in animal experiments. METHODS: Two distinct paste-type micronized ADMs, which were mixed with distilled water (mADM) and gelatin (mADM+GEL), respectively, were compared with conventional fillers, hyaluronic acid (HA) and polymethyl methacrylate (COL+PMMA). Thus, four different types of fillers were each injected into the dorsum of nude mice to compare the volume retention and biocompatibility. During the 8-week experimental period, ultrasound and computed tomography (CT) images were obtained for volumetric analysis. Histological evaluation was performed using hematoxylin and eosin and CD 31 staining. RESULTS: According to the CT images at week 8, the mADM and mADM+GEL showed a higher volume persistence rate of 113.54% and 51.12%, compared with 85.09% and 17.65% for HA and COL+PMMA, respectively. The 2-week interval ultrasound images revealed that the mADM showed a volume increase in width rather than in height, and an increase in height for HA did not vary much. Histological analysis showed marked fibrous invasion and neovascularization with the mADM and mADM+GEL compared to that of the conventional fillers. CONCLUSIONS: Paste-type micronized ADM showed soft tissue augmentation with similar effectiveness to that of conventional fillers. Therefore, paste-type micronized ADM has potential as an alternative material for a soft tissue filler in tissue replacement. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Rheological properties and preclinical data of novel hyaluronic acid filler containing epidermal growth factor.

Recently, a novel hyaluronic acid (HA) filler containing the epidermal growth factor (EGF) was developed. The objective of this study was to evaluate the rheological properties, preclinical efficacy and biocompatibility of the EGF-containing HA filler (HA-EGF filler) using a photoaged mouse model. The rheological properties of the new HA-EGF filler were assessed. Twenty-four female hairless mice (SKH1) underwent photoaging induction with 8 weeks of ultraviolet-B irradiation. The mice were randomly divided into four groups and intradermally injected 100 µl of phosphate-buffered saline, HA-EGF filler, HA filler or polynucleotide (PN) into the dorsal region. We examined the effect of fillers on photoaged skin by dermoscopic examination. Furthermore, histological evaluation with immunohistochemical staining was performed to determine the biocompatibility and collagen formation at the 10th week. A real-time quantitative polymerase chain reaction analysis and western blot test assessed the expression of collagen I/III, matrix metalloproteinases (MMPs) and transforming growth factor. The viscosity and elasticity of the HA-EGF filler were lower than those of the HA filler. Histological evaluation revealed no significant differences in the collagen synthesis between the HA-EGF, HA and PN filler groups. No inflammation was observed during the experimental period. The HA-EGF filler induced type I/III collagen production and downregulated the expression of MMP-1, 3 and 9. Our results suggest that the novel HA-EGF filler may be an additional therapeutic option for photoaged skin, which works by inducing collagen synthesis. Based on these preclinical results, further well-controlled clinical studies are required.

Evaluation of Adverse Effects of Resorbable Hyaluronic Acid Fillers: Determination of Macrophage Responses.

Resorbable tissue fillers for aesthetic purposes can induce severe complications including product migration, late swelling, and inflammatory reactions. The relation between product characteristics and adverse effects is not well understood. We hypothesized that the degree of cross-linking hyaluronic acid (HA) fillers was associated with the occurrence of adverse effects. Five experimental HA preparations similar to HA fillers were synthesized with an increasing degree of cross-linking. Furthermore, a series of commercial fillers (Perfectha®) was obtained that differ in degradation time based on the size of their particulate HA components. Cytotoxic responses and cytokine production by human THP-1-derived macrophages exposed to extracts of the evaluated resorbable HA fillers were absent to minimal. Gene expression analysis of the HA-exposed macrophages revealed the responses related to cell cycle control and immune reactivity. Our results could not confirm the hypothesis that the level of cross-linking in our experimental HA fillers or the particulate size of commercial HA fillers is related to the induced biological responses. However, the evaluation of cytokine induction and gene expression in macrophages after biomaterial exposure presents promising opportunities for the development of methods to identify cellular processes that may be predictive for biomaterial-induced responses in patients.

Stem Cell-Derived Extracellular Vesicle-Bearing Dermal Filler Ameliorates the Dermis Microenvironment by Supporting CD301b-Expressing Macrophages.

Hyaluronic acid-based hydrogels (Hyal-Gels) have the potential to reduce wrinkles by physically volumizing the skin. However, they have limited ability to stimulate collagen generation, thus warranting repeated treatments to maintain their volumizing effect. In this study, stem cell-derived extracellular vesicle (EV)-bearing Hyal-Gels (EVHyal-Gels) were prepared as a potential dermal filler, ameliorating the dermis microenvironment. No significant differences were observed in rheological properties and injection force between Hyal-Gels and EVHyal-Gels. When locally administered to mouse skin, Hyal-Gels significantly extended the biological half-life of EVs from 1.37 d to 3.75 d. In the dermis region, EVHyal-Gels induced the overexpression of CD301b on macrophages, resulting in enhanced proliferation of fibroblasts. It was found that miRNAs, such as let-7b-5p and miR-24-3p, were significantly involved in the change of macrophages toward the CD301bhi phenotype. The area of the collagen layer in EVHyal-Gel-treated dermis was 2.4-fold higher than that in Hyal-Gel-treated dermis 4 weeks after a single treatment, and the collagen generated by EVHyal-Gels was maintained for 24 weeks in the dermis. Overall, EVHyal-Gels have the potential as an antiaging dermal filler for reprogramming the dermis microenvironment.

A hyaluronic acid-based filler reduces lipolysis in human mature adipocytes and maintains adherence and lipid accumulation of long-term differentiated human preadipocytes.

The beneficial role of subcutaneous adipose tissue in skin rejuvenation derived from its capacity to fill the under-layer volumes but also from its ability to regulate the extracellular matrix production by dermis fibroblasts. Hyaluronic acid (HA), a major component of the extracellular matrix, is a commonly used injectable dermal filler showing excellent efficiencies to maintain tissue augmentation even after its biodegradation. To improve their stability, the HA molecules can also be "cross-linked" to each other. The effects of cross-linked HA-based fillers on the dermal structure are well known. For safety reasons, most of the physicians prefer to use the blunt cannula for injections. However, evidences showed that the cannula could not be located in the dermis, but it passes through immediate hypodermis and the long-lasting effect of cross-linked HA-based fillers may be related to its effects on adipose tissue. To test whether cross-linked HA has a direct effect on human adipocytes, we treated isolated adipocytes and precursors cells from human skin donors with cross-linked HA. Biochemical and cellular analysis demonstrated that treatment by cross-linked HA showed beneficial effects on differentiated cell adherence and survival as well as reduced basal and induced lipolysis in fully mature adipocytes. Taken together, these data showed that cross-linked HA promoted cell adherence and preserved the adipogenic capacity of preadipocytes during prolonged cell culture, bringing additional evidences of the beneficial role of cross-linked HA-based fillers in maintenance of the subcutaneous fat mass. This first study could defend a preventive approach to facial volume loss during natural aging.

Sodium Alginate as a Potential Therapeutic Filler: An In Vivo Study in Rats.

Filler injection demand is increasing worldwide, but no ideal filler with safety and longevity currently exists. Sodium alginate (SA) is the sodium salt of alginic acid, which is a polymeric polysaccharide obtained by linear polymerization of two types of uronic acid, d-mannuronic acid (M) and l-guluronic acid (G). This study aimed to evaluate the therapeutic value of SA. Nine SA types with different M/G ratios and viscosities were tested and compared with a commercially available sodium hyaluronate (SH) filler. Three injection modes (onto the periosteum, intradermally, or subcutaneously) were used in six rats for each substance, and the animals were sacrificed at 4 or 24 weeks. Changes in the diameter and volume were measured macroscopically and by computed tomography, and histopathological evaluations were performed. SA with a low M/G ratio generally maintained skin uplift. The bulge gradually decreased over time but slightly increased at 4 weeks in some samples. No capsule formation was observed around SA. However, granulomatous reactions, including macrophage recruitment, were observed 4 weeks after SA implantation, although fewer macrophages and granulomatous reactions were observed at 24 weeks. The long-term volumizing effects and degree of granulomatous reactions differed depending on the M/G ratio and viscosity. By contrast, SH showed capsule formation but with minimal granulomatous reactions. The beneficial and adverse effects of SA as a filler differed according to the viscosity or M/G ratio, suggesting a better long-term volumizing effect than SH with relatively low immunogenicity.

Comparative Evaluation of the Effectiveness of Novel Hyaluronic Acid-Polynucleotide Complex Dermal Filler.

HA (Hyaluronic acid) filler, the most commonly used dermal filler, causes several side effects. HA-PN (Hyaluronic acid-Polynucleotide), a new composite filler, has excellent biocompatibility and induces tissue regeneration. In this study, we compare the efficacies and safety profiles of these fillers. The characteristics of HA and HA-PN fillers were compared using scanning electron microscopy and rheometry. No morphological difference was noted between the fillers. However, the latter had higher viscosity and elasticity values. The HA-PN filler induced higher cell migration than the HA filler in a wound healing assay. It was also found to stimulate better collagen synthesis in human and mouse fibroblasts. The HA and HA-PN fillers were injected into SKH1 hairless mice to determine changes in their volume for up to 24 weeks. Increased cell migration and collagen synthesis were observed in mice injected with the HA-PN complex filler. Although the safety and durability of the HA and HA-PN fillers were similar, the latter induced a lower transient receptor potential vanilloid 4 expression and caused less stimulation upon injection. In conclusion, HA-PN complex fillers can stimulate fibroblast growth and facilitate volume growth and skin regeneration.

Practical Guidelines for Hyaluronic Acid Soft-Tissue Filler Use in Facial Rejuvenation.

BACKGROUND: Hyaluronic acid (HA) fillers are the most commonly used fillers for soft-tissue augmentation. The face is a dynamic structure. Facial rejuvenation by filler products depends on mechanical forces on the region of the face. The successful use of injectable HA fillers requires an understanding of the options available. OBJECTIVE: The purpose of this study is to measure the rheological properties of HA fillers and to clarify how to select these fillers considering their rheological properties. MATERIALS AND METHODS: Rheological characterization was performed on 41 fillers. Physical parameters directly linked to product performance were measured. RESULTS: The properties of the HA fillers varied. These findings provide a basis for selection guideline regarding rheological properties in facial rejuvenation. CONCLUSION: The authors' report is the largest study to determine the rheological properties of HA fillers to date. Understanding the fillers' properties can help physicians select the appropriate fillers for more predictable and sustainable results.

HA-based dermal filler: downstream process comparison, impurity quantitation by validated HPLC-MS analysis, and in vivo residence time study.

The success of hyaluronic acid (HA)-based dermal fillers, with more than 2 million minimally invasive procedures conducted in 2016 in the US alone, is due to their hygroscopic properties of biocompatibility and reversibility. The type and density of HA cross-linkage, as well as the manufacturing technology, may influence not only the in vivo persistence but also the safety profile of dermal fillers. 1,4-Butanediol diglycidyl ether (BDDE) is the cross-linker used in most market-leading HA fillers; 1,4-butanediol di-(propan-2,3-diolyl) ether (BDPE) is the major impurity obtained from the HA-BDDE cross-linking (HBC) process. In this work, a new process to obtain high purity HBC fillers was developed. A new HPLC-MS method was validated for the quantification of BDPE content in HBC dermal fillers. In vitro cytotoxicity of BDPE was evaluated in fibroblasts (IC50 = 0.48 mg/mL). The viscoelasticity was monitored during the shelf-life of the HBC-10% hydrogel and was correlated with in vitro hyaluronidase resistance and in vivo residence time in a rabbit model. This analysis showed that elasticity is the best parameter to predict the in vivo residence time. Finally, a series of parameters were investigated in certain marketed dermal fillers and were compared with the results of the HBC-10% hydrogel.

Hyaluronan-based hydrogels as dermal fillers: The biophysical properties that translate into a "volumetric" effect.

Biophysical and biochemical data on hyaluronan (HA)-based dermal fillers strongly support their optimal use and design to meet specific requisites. Here, four commercially available (in Europe) HA "volumetric" fillers, among the most used in the clinical practice, have been characterized in vitro. Analyses revealed the highest amounts of water-soluble HA reported so far and provided hydrodynamic data for these soluble polymeric fractions. Volumetric gels exhibit a wide range of rigidity with most of them showing G' values around 200-300Pa. They greatly differ in cohesivity. 1mL of gel hydrates up to 2.4-3.2mL. The products completely solubilize due to Bovine Testicular Hyaluronidase (BTH)'s action, thus predicting in vivo complete resorption. For the first time, filler degradation due to reactive oxygen species (ROS) was studied by rheological measurements and a rank in stability was established. Studies using Human Dermal Fibroblasts (HDF) indicated a positive biological response to the HA networks. Further, gel capacity to prompt collagen I, elastin and aquaporin3 synthesis was demonstrated, thus suggesting a positive effect on skin elasticity and hydration, besides the physical volumetric action. The findings are the first wide assessment of features for the volumetric class of HA-fillers and include first data on their resistance to degradation by ROS and biological effects on HDF. The study represents a valuable contribution to the understanding of HA-fillers, useful to optimize their use and manufacture.

Hyaluronic acid-cross-linked filler stimulates collagen type 1 and elastic fiber synthesis in skin through the TGF-ß/Smad signaling pathway in a nude mouse model.

Compared to pure hyaluronic acid filler, cross-linked hyaluronic acid (HAc) exhibits superior biocompatibility and longevity as a dermal filler. We previously developed composite HAc-hydroxyapatite (HAp) fillers. Herein, we systematically compared the protein-level increase and gene expression between HAc-micro-HAp and HAc-nano-HAp in mice and determined the mechanisms underlying the biological responses to HAc and HAp. Five-week-old female BALB/c-nude mice were classified into five groups: normal skin, Radiesse, Restylane, HAc-nano-HAp, and HAc-micro-HAp. Fillers (200 µl) were injected to evenly fill the back of mice. Skin biopsies were performed to investigate collagen and elastic fiber synthesis after filler injections. Western blot analysis, real-time polymerase chain reaction analysis, and immunohistochemistry were performed to investigate protein and gene expression changes. Organ (liver, lung, spleen, and kidney) toxicity of HAc-nano-HAp was determined by hematoxylin and eosin staining after 12 weeks. Protein and gene expression analyses indicated that, compared with pure fillers, HAc-nano-HAp and HAc-micro-HAp hydrogels preferentially promoted collagen and elastic fiber formation through the TGF-ß pathway. The composite fillers also exhibited no evidence of organ toxicity. HAc-HAp filler might play an important role in collagen and elastic fiber regeneration. HAc filler stimulates collagen type 1 and elastic fiber synthesis through the TGF-ß/Smad pathway. The role of HAc-HAp composite fillers in photoaging in animal models and their effects on skin, including elasticity and tensile strength, should be investigated.

Comparative Evaluation of the Biodegradability and Wrinkle Reduction Efficacy of Human-Derived Collagen Filler and Hyaluronic Acid Filler.

BACKGROUND: The development of fillers for wrinkle prevention is growing to meet rising demands to reduce the aging of skin. OBJECTIVE: In this experiment, we confirmed the effects of human collagen and hyaluronic acid filler biodegradation for wrinkle reduction using a photo-aging mouse model. MATERIALS AND METHODS: A total of 10 hairless mice (SKH1-Hrhr) were randomly divided into two groups and injected with hyaluronic acid and human-derived collagen filler. At 0, 2, 4, 8, and 12 weeks, PRIMOSlite®, folliscope, and MRI were used to evaluate the biodegradability of the fillers after the injections. We also studied the photo-aging mouse model for skin roughness and histological evaluation and confirmed that the filler injection had excellent anti-wrinkle effects. RESULTS: Human-derived collagen fillers had excellent biodegradability compared to that of hyaluronic acid fillers. The skin surface roughness in the photo-aging mouse models was significantly reduced after injections of human-derived collagen filler. CONCLUSION: Our results showed that the human-derived collagen filler had excellent biodegradability and effectively reduced wrinkle formation in a photo-aging mouse model. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

An objective method to assess the improvements of skin texture roughness after botulinum toxin type a treatment of crow's feet.

BACKGROUND: Photo-numeric scales could lack precision and objectivity on evaluating the improvements on wrinkles after a treatment with botulinum toxin type A. The authors suggest a new digital evaluation method to analyze its effectiveness. OBJECTIVES: This study aims to investigate retrospectively the effect of intramuscular injection of botulinum toxin type A on skin texture in the lateral peri-orbital region with a new objective method. METHODS: Skin texture roughness (STR) in the lateral peri-orbital region is evaluated with a multi-directional light beam by light emitting diodes of different wavelengths (Antera 3D® ), before and after injections of 12 units of botulinum toxin type A. The wrinkles and lines deeper than 0.5 mm are filtered to measure accurately skin texture. RESULTS: We observed an improvement of STR in all cases treated with botulinum toxin type A. A significant decrease of STR was recorded as follows: 17.08% (P < .0001) at 4 weeks and 12.14% at 4 months (P = .001). CONCLUSION: Botulinum toxin type A treatment of crow's feet was able to improve STR. The Antera® device and software are a valuable, objective, easy and reproducible method to assess the effects of the toxin.

Nonsurgical Rhinoplasty: Nasal Grid Analysis and Nasal Injecting Protocol.

BACKGROUND: Nonsurgical rhinoplasty using injectable fillers improved skin quality and texture, cost-effectiveness, and quick recovery. The aim of this study was to provide a valid and customized protocol for injecting the nose with the aid of a nasal grid. METHODS: From January of 2016 to October of 2017, 150 consecutive patients entered the trial. The mean patient age was 36 years (range, 16 to 60 years). The patients were divided into two arms: primary nasal defects (no previous surgery, n = 109) and secondary nasal defects (previous surgery, n = 41). The primary defect group included 43 male patients and 66 female patients, and the secondary nasal defect group included 14 male patients and 27 female patients. Within each arm, patients were stratified into three age group tiers: younger than 30 years, 30 to 45 years, and older than 45 years. RESULTS: The grid became the reference for quantity and sequence of injection records. The overall complication rate was 1.82 percent, and a visual analogue scale ranging from 1 to 10 was implemented (with 10 being the most accurate correction). Of the patients evaluated, 98.350 percent scored 8 to 10, 0.825 percent scored 6 to 8, and 0.825 percent scored below 6. CONCLUSIONS: Fillers can be either alternatives or complementary to plastic surgery. Nonsurgical rhinoplasty, with its avoidance of general anesthesia, splints, swelling, and bruising, represents a distinct advantage, allowing the patient to return to work as quickly as the same or the next day. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

An in vitro and in vivo study on the properties of hollow polycaprolactone cell-delivery particles.

The field of dermal fillers is evolving rapidly and numerous products are currently on the market. Biodegradable polymers such as polycaprolactone (PCL) have been found to be compatible with several body tissues, and this makes them an ideal material for dermal filling purposes. Hollow PCL spheres were developed by the Council for Scientific and Industrial Research (CSIR) to serve both as an anchor point and a "tissue harbour" for cells. Particles were tested for cytotoxicity and cell adherence using mouse embryo fibroblasts (MEF). MEFs adhered to the particles and no significant toxic effects were observed based on morphology, cell growth, cell viability and cell cycle analysis, suggesting that the particles are suitable candidates for cell delivery systems in an in vivo setting. The objective of providing a "tissue harbour" was however not realized, as cells did not preferentially migrate into the ported particles. In vivo studies were conducted in BALB/c mice into whom particles were introduced at the level of the hypodermis. Mice injected with PCL particles (ported and non-ported; with or without MEFs) showed evidence of local inflammation and increased adipogenesis at the site of injection, as well as a systemic inflammatory response. These effects were also observed in mice that received apparently inert (polystyrene) particles. Ported PCL particles can therefore act as a cell delivery system and through their ability to induce adipogenesis, may also serve as a dermal bulking agent.

Biochemistry, Physiology, and Tissue Interactions of Contemporary Biodegradable Injectable Dermal Fillers.

BACKGROUND: Injectable dermal fillers are becoming increasingly popular for soft tissue augmentation and rejuvenation. Most contemporary biodegradable products are derived from hyaluronic acid, calcium hydroxylapatite, or poly-L-lactic acid. Achievement of desired cosmetic outcomes is largely dependent on selection of the optimal injectable product based on the chemical composition, the physiologic interactions with surrounding tissue, product longevity, and a thorough understanding of potential adverse reactions. OBJECTIVE: To review and describe the biochemistry, physiology, and tissue interactions of the most commonly used contemporary biodegradable dermal fillers. METHODS: A thorough review of the literature was performed with additional review of pertinent clinical cases and corresponding histopathology. RESULTS: This article provides a comprehensive review of the biochemistry, physiology, and potential tissue interactions of the most commonly used biodegradable dermal fillers. The underlying biochemical properties of each product and how they contribute to specific physiologic and adverse tissue reactions is described. CONCLUSION: Understanding of the innate differences in the physical properties, and physiologic responses to soft tissue fillers allows clinicians to achieve desired aesthetic outcomes with fewer adverse events.