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Animal-Based Hyaluronic Acid Fillers: Scientific and Technical Considerations
Abstract
Successful clinical application of dermal filler products requires an understanding of their physical characteristics and in vivo behavior. This study reviewed the data for hyaluronic acid dermal filler products derived from an animal source--the rooster comb.
A review of the hyaluronic acid literature was performed. Clinical experience with the animal-derived hyaluronic acid products was evaluated.
The source of the hyaluronic acid has not been demonstrated to be a clinically important point of differentiation among filler products. Hypersensitivity reactions are rare and are also present in the products derived from bacteria. Variations that effect the hyaluronic acid products' physical characteristics and clinical performance are more closely related to cross-linking and formulation. Hyaluronic acid gel derived from animal sources is cross-linked by a sulfonyl-bis-ethyl bond and is a soft gel compared with other hyaluronic acid products. There is minimal gel swelling, which results in modest postinjection edema. Optimal clinical application favors patients who desire quick recovery and minimal palpability.
Hyaluronic acid skin filler products derived from an animal source are safe and effective. Successful clinical application should be based on an understanding of the patient's goals and the choice of a hyaluronic acid product with the optimal characteristics.
... It was discovered in 1934 by Karl Meyer and John Palmer, who isolated it from bovine vitreous humour [1,9]. HA has been used for several purposes like wound treatment, ophthalmic surgery, drug delivery and aesthetic treatment [1,2,10]. ...
... HA has been used for several purposes like wound treatment, ophthalmic surgery, drug delivery and aesthetic treatment [1,2,10]. There are currently many different HA dermal fillers, with none of them being universally fitting for every situation [1,7,9,11]. Clinicians should thus be familiarized with HA's rheological and physicochemical properties, as they influence clinical performance [5][6][7][8][9][10][11][12][13]. ...
... There are currently many different HA dermal fillers, with none of them being universally fitting for every situation [1,7,9,11]. Clinicians should thus be familiarized with HA's rheological and physicochemical properties, as they influence clinical performance [5][6][7][8][9][10][11][12][13]. ...
Hyaluronic acid’s water absorption and expansion capacities define a filler’s ability to lift the tissues. Therefore, studying these properties is essential to better understand filler’s clinical performance. The aim of this study was to evaluate and compare water absorption and expansion (bidimensional and three-dimensional) of five Fillmed fillers (Universal, Fine Lines, Volume, Lips and Lips Soft). Water absorption was measured through swelling ratio 24 hours post-hydration. For two-dimensional expansion, samples were analysed quantitatively and qualitatively, using calibrated photographs, before and two hours after hydration. Three-dimensional volume was evaluated before and immediately after injecting the fillers, and 30 minutes, 2 hours and 24 hours post-injection in ex vivo pig skin. The tissue was scanned with the 3Shape TRIOS scanner and resulting STL files were compared. Group comparisons were analyzed with the one-way ANOVA test, and a p-value ≤ 0,05 was established. Lips showed a statistically higher swelling ratio than other fillers (p < 0,05). Fine Lines had the lowest swelling ratio, even if only statistically significant when compared to Universal (p= 0,021). Fine Lines had a significantly higher initial bidimensional width than all fillers (p <0,05) except Lips Soft. 24 hours post-injection, Fine Lines had the highest three-dimensional volume, which was statistically higher than Volume’s (p= 0,049). All fillers absorbed water and expanded, with Fine Lines tending to have the highest three-dimensional expansion, despite its lowest viscosity and water absorption. Further studies with larger sample sizes are needed to investigate the influence of other properties over water absorption and expansion.
... [1][2][3][4] Additionally, HA intervenes in inflammation regulation, drug delivery, angiogenesis, cell migration and proliferation (caused by HA binding itself specifically to proteins that are responsible for these processes, whether they are in the extracellular matrix, on the cell surface, where they're called hyaladherins, or in the cellular cytosol), wound healing (based on its antioxidant properties and ability to eliminate free radicals), and cancer progression (based on its hydrodynamics and ability to interact with tumour cell surfaces and influence the porosity and malleability of extracellular and pericellular matrices, and also based on the fact that an increase in HA links to apoptosis, invasiveness, and drug resistance). [5][6][7][8][9][10][11][12] HA was first discovered in 1934 at Colombia University of New York by two American scientists, Karl Meyer and John Palmer, when they isolated it from bovine vitreous humor. 1,5 HA was then commercialized for the first time by Endre Balazs, who used it as a substitute for egg whites in bakery products. ...
... [5][6][7][8][9][10][11][12] HA was first discovered in 1934 at Colombia University of New York by two American scientists, Karl Meyer and John Palmer, when they isolated it from bovine vitreous humor. 1,5 HA was then commercialized for the first time by Endre Balazs, who used it as a substitute for egg whites in bakery products. More recently, HA has been used for numerous purposes, such as wound treatment, ophthalmic surgery, drug delivery, arthritis treatment (serving as an intra-articularly injected lubricant), and aesthetic treatment. ...
... More recently, HA has been used for numerous purposes, such as wound treatment, ophthalmic surgery, drug delivery, arthritis treatment (serving as an intra-articularly injected lubricant), and aesthetic treatment. 1,2,13 The first biocompatible gel (hylan B gel, Hylaform) was created in 1980 by Balaz, 5 and the first HA filler (Restylane) was approved in the United States in December 2003 for the correction of deep wrinkles and folds. [14][15][16][17] In 2006, the American Society of Aesthetic Plastic Surgeons declared HA dermal fillers to be the fastest noninvasive aesthetic procedure in the United States. 1 Currently, there is a wide panoply of different HA-based dermal fillers, each of them manufactured in a distinct way and with different characteristics, with none of them being a universally fitting filler for every situation. ...
Synopsis Hyaluronic acid’s (HA) main functions are absorbing water into the tissues and structuring the skin. It is mostly used in dermal fillers, treatments for certain diseases, and wound healing. This study intends to review current literature of HA’s rheology and its physicochemical properties as an injectable filler. Data were acquired from articles concerning HA-based biomaterials published within the last 25 years in PubMed and ScienceDirect. The MeSH terms “hyaluronic acid” and “dermal fillers,” were used either alone or combined with “rheology,” “physicochemical concepts,” “cross-linking reagents,” “viscoelastic substances,” “cohesivity,” and “cosmetic techniques.” Some articles not found during the initial search were chosen from the reference lists of previously selected publications. All articles that fit in the theme were considered valid regardless of study type. Available literature describes intrinsic properties of HA as a glycosaminoglycan. As an injectable filler, its rheology (viscoelasticity and cohesivity) and its physicochemical properties (cross-linking, hydrophilia, particle size, and HA concentration) define its clinical behavior by influencing its longevity, lifting capacity, resistance to external forces, and needle extrusion force. HA is promising as a dermal filler and healing agent. Understanding its properties is essential, as each patient benefits from different products. Future research should continue to explore these propertie
... Hyaluronic acid (HA) is increasingly utilized for a number of medical device applications, including FDA-approved use in ophthalmic surgery, 1-3 dermal augmentation, 4,5 and treatment of osteoarthritis. 6,7 Numerous other applications are contemplated, 8 including skin rejuvenation, 9,10 drug delivery, 11,12 cancer therapy, 13 resorbable scaffolds in tissueengineered products, 11,14,15 peritoneal dialysis therapy, 16 and cell encapsulation. ...
... 17,18 Since the chemical structure of animal or nonanimal-derived HA is identical to that in humans, it should be the ideal biomaterial provoking no reaction. 4,5,19 However, short term acute but transient inflammatory reactions are common, 20,21 while rare longterm adverse events may correlate with subclinical chronic inflammation. 6,22 The cause of observed inflammatory reactions has been a matter of debate. ...
... 20,21,23 As endotoxin contamination and protein content have been reduced, inflammatory reactions in patients have decreased in incidence but have not been eliminated. 4,5 Concern has focused on low molecular weight (LMW) components or degradation fragments from implanted HA-containing devices to account for observed inflammatory reactions. 19,24 A large body of literature exists supporting the conclusion that high molecular weight HA (HMW-HA) is generally antiinflammatory while low molecular weight HA (LMW-HA) may function as an alarm signal to the immune system, particularly for monocyte/macrophages. [25][26][27] However, many of the studies claiming effects by LMW fragments of HA did not rigorously exclude the possibilities that those effects were actually due to nanomolar concentrations of contaminating bacterial endotoxin or other biologically active molecules contaminating HA preparations. ...
Hyaluronic acid (HA) is increasingly used for a number of medical device applications. Since the chemical structure of HA is identical no matter its bacterial or animal origin, it should be the ideal biomaterial. However, short term transient inflammatory reactions are common, while rare long-term adverse events may correlate with subclinical chronic inflammation. Concern has been raised that low molecular weight components or degradation fragments from implanted HA may directly stimulate inflammatory reactions. This study examined a panel of HA molecular weights from the unitary disaccharide up to 1.7 x 10(6) Dalton lengths, in which endotoxin was assayed at a very low level (less than 0.03 EU/mg). The murine cell line RAW 264.7, rat splenocytes, and rat adherent differentiated primary macrophages were assayed for nitric oxide production under a variety of inflammatory conditions plus or minus HA. Under the highest inflammatory states, nitric oxide production was mildly suppressed by HMW-HA while slightly augmented by LMW-HA at mg/mL concentrations. However, at micromolar concentrations fragments below 5000 Daltons, thought to have drug-like qualities, were without effect. These data support the hypothesis that if endotoxin is reduced to an extremely low level, LMW-HA may not directly provoke normal tissue macrophage-mediated inflammatory reactions.
... Clinicians use HA's hygroscopicity in multiple clinical roles, including as expanding fillers for plastic surgery [159]. This is possible in humans because post-translational modification of hyaluronic acid is limited between species, allowing for HA transplantation from bovine, bacterial, and poultry sources with incredibly limited immune response (mostly due to incomplete purification) [160,161]. Degradation is controlled over seven to nine months, whilst degradation products have been shown to be both non-toxic and can be metabolised with ease. Romagnoli and Belmontesi [162] list a number of HA products currently used within the filler market, including the Allergan system, Qmed, and FDP. ...
... Given the identical molecule manufacture capacity of multiple organisms representing three kingdoms, HA (as previously mentioned) has historically been isolated from a number of organisms, including bovine eye, rooster wattle, or human umbilical tissue [160,161]. Although these sources have generally been successful, renewed scrutiny due to zoonotic infection and incomplete purification methods have led to renewed interest in bacterial fermentation as a route for the manufacturing of HA [175,176]. ...
Plastics have found widespread use in the fields of cosmetic, engineering, and medical sciences due to their wide-ranging mechanical and physical properties, as well as suitability in biomedical applications. However, in the light of the environmental cost of further upscaling current methods of synthesizing many plastics, work has recently focused on the manufacture of these polymers using biological methods (often bacterial fermentation), which brings with them the advantages of both low temperature synthesis and a reduced reliance on potentially toxic and non-eco-friendly compounds. This can be seen as a boon in the biomaterials industry, where there is a need for highly bespoke, biocompatible, processable polymers with unique biological properties, for the regeneration and replacement of a large number of tissue types, following disease. However, barriers still remain to the mass-production of some of these polymers, necessitating new research. This review attempts a critical analysis of the contemporary literature concerning the use of a number of bacteria-derived polymers in the context of biomedical applications, including the biosynthetic pathways and organisms involved, as well as the challenges surrounding their mass production. This review will also consider the unique properties of these bacteria-derived polymers, contributing to bioactivity, including antibacterial properties, oxygen permittivity, and properties pertaining to cell adhesion, proliferation, and differentiation. Finally, the review will select notable examples in literature to indicate future directions, should the aforementioned barriers be addressed, as well as improvements to current bacterial fermentation methods that could help to address these barriers.
... Hyaluronic acid fillers are currently used for their good biocompatibility, however their short durability is a problem [14][15][16][17][18][19][20][21]. To achieve longer-lasting effect of fillers, cross-linked dextran-based and PMMA mixed novel materials have recently been developed [22,23]. ...
... The allergy test is not required because HA is identical in structure among species [19]. However, enzymes such as hyaluronidase and free radicals can rapidly degrade HA polymers [20,21]. In an effort to achieve a longer-lasting effect, DiHM and PDiHM were introduced and recently attracted attention as novel materials for soft tissue augmentation [22][23][24][25][26][27]. ...
This study was conducted for evaluation of the ability to maintain efficacy and biocompatibility of cross-linked dextran in hydroxypropyl methylcellulose (DiHM) and cross-linked dextran mixed with PMMA in hydroxypropyl methylcellulose (PDiHM), compared with hyaluronic acid (HA) filler. Saline and HA solution was administered in the negative and positive control groups, and DiHM and PDiHM were administered in the test groups (n = 10 in each group). The site of cranial subcutaneous injection was the mid-point of the interpupillary line, and the site of intraoral submucosal injection was the ridge crest 2 mm below the cervical line of the mandibular left incisor. Before and immediately after filler injection, intraoral photos and lateral cephalometric radiographs were taken for analysis and comparison of the effect of the filler on the injection sites. The filler injected areas were converted into sequential size changes (%) of the baseline. Histomorphologic examination was performed after 12 weeks. The smallest value in the filler injected area was observed during the experimental period in the normal saline group (p < 0.001), which was almost absorbed at 4 weeks (7.19% ± 12.72%). The HA group exhibited a steady decrease in sequential size and showed a lower value than the DiHM and PDiHM groups (saline < HA < DHiM, PDHiM, p < 0.001). DiHM and PDiHM tended to increase for the first 4 weeks and later decreased until 12 weeks. In this study on DiHM and PDiHM, there was no histological abnormality in cranial skin and oral mucosa. DiHM and PDiHM filler materials with injection system provide an excellent alternative surgical method for use in oral and craniofacial fields.
... HA is not only a biologic and naturally occurring filler, but it also has a variety of different biological effects that depend on its molecular size. 26 Small fragments are proinflammatory whereas long chains inhibit inflammation. [27][28][29] For its use as a filler, it has to be stabilized and the way and degree of stabilization are also important for the tolerability of HA. 30 The more HA is cross-linked and thus stable the more its tolerability is reduced. ...
Filler injections belong to the most frequently performed noninvasive beautifying procedures. When done correctly they are generally well tolerated. However, a number of factors, such as poor filler quality, and particularly host as well as user dependent filler reactions may lead to unwanted effects. These may be early, late, or delayed events with characteristics for each of them. Temporary fillers almost invariably cause temporary side effects whereas those of permanent fillers may last forever. Some fillers are notorious for their poor safety profile; for example, silicone is banned in the European Union and the United States but nevertheless used by many practitioners and beauticians. Many fillers can be identified in histopathologic sections allowing specific measures to be instituted.
... Additionally, abdominal fat is associated with a reduction in lung function and poorly asthma control, although only a few studies have considered the role of abdominal fat and BF. Thus, anthropometric evaluation should therefore use other markers, such as waist circumference (WC) and BF measures (7,(14)(15)(16) . ...
Background
The role of abdominal fat and body fat (BF) in the evaluation of nutritional status in asthma has been considered recently. The present study aimed to evaluate the association between different anthropometric markers and asthma control, pulmonary function and quality of life. A secondary objective was to determine the agreement between the anthropometric markers with respect to assessing obesity in adults with asthma.
Methods
This cross‐sectional study enrolled adult asthma patients attending an outpatient asthma clinic in southern Brazil. Patients were evaluated regarding sociodemographic data, lung function, asthma control, nutritional status and health‐related quality of life (Asthma Quality of Life Questionnaire; AQLQ). Nutritional status was classified by body mass index (BMI), waist circumference (WC) and BF.
Results
The mean (SD) age of the 198 patients was 56.2 (14.8) years. The prevalence of uncontrolled asthma among subjects who were overweight as diagnosed by their BMI was 64.6% higher than in those who were normal weight. An increase in a measure of BMI (1 kg m⁻²) decreases approximately 44–59% of symptoms, activity limitations and emotional function domains of the AQLQ, whereas an increase in a measure in WC (1 cm) decreases approximately 24–30% of the same domains. Agreement between BMI and BF was 0.566 and that between BMI and WC was 0.597 by Kendall's Tau‐b test.
Conclusions
The prevalence of uncontrolled asthma is greater in overweight subjects than in normal weight subjects. WC and BMI were negatively associated with symptoms, activity limitations and emotional function domains of the AQLQ. BMI appears to be sufficient to diagnose the nutritional status of subjects with asthma in this population.
... For example, the gel strength as measured by rheology has been said to relate to the lifting capacity and tissue integration. It has been suggested that firm gels have a better ability to resist deformation, 3,8,13,16,17 whereas softer gels have been said to better integrate into the tissue because they deform more easily. 9 There have also been some suggestions on how the cohesion affects the clinical performance. ...
Background:
There are several published articles on characterization of fillers, describing methods for both chemical and physicochemical characterization. Recently a lot of focus has been on the development of methods for measuring cohesion of hyaluronic acid (HA) fillers.
Objective:
The aim of this study is to investigate and compare the drop-weight method and the correlation between cohesion and other physicochemical properties using a variety of HA fillers.
Materials and methods:
HA fillers covering several product families and manufacturing techniques were used. The HA fillers also covered a range of HA concentrations from 12 to 24 mg/mL. Cohesion was determined using sensory evaluation and the drop-weight method. Other physicochemical properties evaluated were rheology and the swelling factor.
Results:
In this study, it was verified that values obtained by the drop-weight method reflect the perceived cohesion very well. The correlation with rheology is affected by the HA concentration in the products. A remarkably good correlation between swelling factor and cohesion was found.
Conclusion:
Cohesion correlates with other physicochemical methods. It could be discussed whether there is a need for a separate cohesion method because other already established physicochemical methods such as rheology and swelling factor can describe the underlying properties that affect cohesion.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
... In particolare, la superfamiglia TRP è composta da sette famiglie, la più interessante delle quali è quella dei "vanilloi-di" (TRPV), la quale può essere attivata da una serie di "sensori di pericolo" (quali ambiente acido, diversi tipi di temperature, alterazioni osmotiche, alcuni lipidi, prostaglandine, endocannabinoidi), con conseguente possibilità di scatenamento di prurito e dolore a livello cutaneo 31 . Anche alcuni mediatori "classici" del prurito, quali eicosanoidi, istamina, bradichinina, ATP e diverse neurotrofine, sono in grado fisiologicamente di attivare TRPV1, e vengono dunque definiti "endovanilloidi" [32][33][34] . Tale attivazione di TRPV1, che in un primo momento è in grado di eccitare le terminazioni afferenti sensoriali 35 , in un secondo tempo, al contrario, può desensibilizzarle, se eccessiva: vengono poste, in tal modo, le basi per una potenziale applicazione terapeutica di tale effetto funzionale 19 , come si vedrà nel prossimo paragrafo. ...
Adverse reactions to systemic drugs rarely may be due to vehicle components, such as preservatives, colorants and antioxidants. We report the case of a 44-year-old woman affected by localized pustulosis of the chin, neck and V of the chest, appeared after 2 days of intramuscular therapy with diclofenac. The patch test showed positive reaction to the drug as it and to sodium metabisulphite (5% pet). Sodium metabisulphite is an antioxidant mainly used in the food industry. However, it is present in some parenteral drugs, such as local anesthetics with adrenaline, diclofenac, and corticosteroids.
... HA is not only a biologic and naturally occurring filler, but it also has a variety of different biological effects that depend on its molecular size. 26 Small fragments are proinflammatory whereas long chains inhibit inflammation. [27][28][29] For its use as a filler, it has to be stabilized and the way and degree of stabilization are also important for the tolerability of HA. 30 The more HA is cross-linked and thus stable the more its tolerability is reduced. ...
Injectable fillers nowadays represent a pillar in facial rejuvenation and make a significant contribution to the success of the treatment. Despite their obvious benefits, a wide range of possible complications such as immediate, late, delayed, temporary, or irreversible adverse effects have to be respected. Differentiating the various filler materials, these effects are assigned to histopathology findings and currently available treatment options.
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... It is claimed to be a biologic substance without species specificity; however, the natural glycosaminoglycan moiety is linked to species-specific proteins and also the production process is critical. In addition to being a biologic and naturally occurring filler it also has a variety of different biologic effects that depend on its molecular size (Clifford & Clark, 2007). Small fragments are proinflammatory whereas long chains inhibit inflammation (Mummert, 2005;Wright & Day, 2005;Stern, Asari, & Sugahara, 2006). ...
Artecoll was developed about 20 years ago and underwent a number of production changes until it recently became FDA approved under the new name of Artefill. This product contains 20% polymethyl methacrylate (PMMA) microspheres with a diameter of 30 to 40 microm, which are suspended in a 3.5% atelo-collagen solution. The PMMA microspheres are now purified and no longer have an electrostatic charge, which in part was the cause for the early granulomatous reactions. Further, PMMA has long been known as bone cement and has been used in cosmetic surgery with a very good safety record. PMMA microspheres are biologically inert and nondegradable. The treatment results are therefore permanent and technical errors as well as incorrect injections will last. Due to the early record of granuloma formation, there is still a debate as to whether this product-as well as all other permanent fillers-should be injected for cosmetic reasons or not. With proper indications, excellent injection techniques, and realistic expectations as to what can be expected, this product has now proved to be one of the superior permanent filler substances.
India is primarily an agricultural country where roughly 60% of the population depends on agriculture and related industries like animal husbandry for a living. Livestock, poultry, and other related industries like apiculture (beekeeping), pisciculture (Fish farming), etc., are all examples of animal husbandry activities. Due to artificial breeding, cattle now serve a variety of tasks and purposes. Several breeds have evolved to suit the diverse situations in human households. However, the waste produced by the rearing of these livestock is substantial. Our nation produces many lakh tons of agricultural waste annually, including leftovers from harvesting plants and crops and dung and urine of cattle and fowl. The demand for animal products also expanded due to fast population expansion, urbanization, rising per capita income, and shifting lifestyles, making it necessary to regulate animal waste. Effective use of this underutilized waste can generate significant cash for farmers, doubling their income and the national economy's wealth. Different methods to exploit animal waste are: using manure are fertilizers, production of biogas, bio-oil generation, fabrication of panchagavya, algal cultivation, manufacturing of value-added products like dried manure solid (DMS) for cattle bedding, cosmetic products from bee wastes, snail derivatives and land animal derivatives.
Clinical, observational and descriptive, longitudinal and prospective study lasting 22 months conducted on 40 patients treated at the School of Dentistry, Universidad de la República. Objective: To assess the efficacy, duration and adverse effects of hyaluronic acid (HA) implants for nasolabial grooves (NLG). Methodology: Clinical study of HA implantation in the mid-dermis in cases of deep NLG, grades 2 to 5 in the Wrinkle Severity Rating Scale (WSRS). Clinical and photographic records of each case were obtained and classified pre and post-application for 12 months using the WSRS, GAIS and PSSS scales. Results: expressed in times, percentages and graphs. Efficacy: very good = 100% cases. Mean effective clinical duration: 10.5 months. Adverse effects to the product: none. Patient rating: Good to very good. Conclusion: dermal injectable HA (TEOSYAL Deep Lines®) is effective to correct deep NLG. Average duration of 10.5 months with a “slow fall”. Adverse reactions: none.
For volumizing the aging face, few fillers display the versatility, endurance, and safety profile as autologous fat. Fat is the perfect choice for those patients wishing to add contour and projection to an otherwise flat visage. Understanding the concepts of facial volumetric aging is paramount to success with any filler but especially one as long lasting as autologous fat. In youth, facial contours are "balanced" with fat resplendent and diffuse. As the face ages, the fat becomes "unbalanced" and dependent on its overall body content. Recent anatomical research suggests that the face is made up of discrete separate fat compartments and that these compartments age individually. This is perfectly illustrated by comparing the atrophic aging seen all over in a patient of ascetic body type with the combination of hypertrophic and atrophic aging seen in a more corpulent individual. It appears that increasing body fat leads to deposits or hypertrophy of fat in certain fat compartments, while others remain atrophic (Figure 11.1A, B). It is unknown as to why the face ages compartmentally, but luckily, the transfer of autologous fat back into the atrophic areas can restore a sense of balance and youth to the face. PLANNING During the initial consult, it is helpful for patients to bring in a photograph of what they looked like ten years ago. It is important to ask the weight of the patient currently as compared with the time of the old photograph.
INTRODUCTION A wide variety of synthetic fillers are now available. Such fillers can be divided into a variety of categories. One descriptive category relates to filler duration. Fillers can last in the human body for short periods of time or they can be permanent. BioAlcamid® is a permanent prosthesis-type filler. It is used in many parts of the world but is not yet available in the United States. An ideal biomaterial must be nonallergic, inert, sterile nonpyogenic, noncancer producing, stable, incapable of migrating, and most importantly biologically compatible with the host tissue. The latter factor is required because it impacts on the ability of the filler to coexist with surrounding tissues without either stimulating the immune system or causing persistent inflammatory reactions. BIOALCAMID® BioAlcamid®, a synthetic polyalkylamide manufactured by Polymekon in Italy, is a permanent implant that fulfills some, but certainly not all, of the aforementioned requirements. CLINICAL STUDIES There are only a few studies that have evaluated the safety and efficacy of BioAlcamid® implants. In a clinical study performed by Protopapa et al., eighty BioAlcamid® implants were injected into seventy-three subjects aged sixteen to forty-eight years (forty females and thirty-three males). All patients were HIV+ and suffered from lipodystrophy syndrome to varying degrees. Individuals with uncompromised diabetes mellitus and psychiatric disorders and pregnant women were excluded from the study. No prior skin tests were done. Initial implants were placed in the face. Ultimately, three patients requested further corrections to their buttocks; four patients requested corrections to their limbs.
INTRODUCTION Dermal fillers have been available for more than 100 years, originally as injectable fat and more recently as biocompatible soft tissue fillers. The use of fillers has continued to increase in cosmetic surgery practices with the greater demands from patients for aesthetic improvement without surgery. This increase is secondary to not only the growing indications and availability of dermal fillers but also the desire for rejuvenation from a wider patient population among varying age groups and ethnicities. Currently available dermal fillers include porcine, bovine, and human collagens, hyaluronic acid (HA) preparations of animal or biosynthetic origin, poly-l-lactic acid products, polymethacrylate, and calcium hydroxyapatite. The use of soft tissue fillers is an attractive office procedure for providers because of the associated ease, cost, and minimal discomfort involved in treatment. Although the use of injectable soft tissue fillers is relatively safe, it is important to select patients carefully and counsel them appropriately to avoid complications. The process of informed consent is a crucial component of the relationship that must develop between the provider and the patient to minimize the already rare occurrence of legal complications. PATIENT SELECTION The media and manufacturer marketing has instilled views and expectations of complete rejuvenation of facial aging in patients by the use of fillers. Patient selection is important to have satisfied patients and reduce undesired outcomes. A thorough review of the history is the first step in this process.
INTRODUCTION There has been a paradigm shift in cosmetic surgery. We are now replenishing volume that has been depleted in the facial region as opposed to removing excess skin that remains. Facial lipoatrophy is a facet of a more general condition, lipodystrophy. It is a symptom of various conditions that include congenital disorders, HIV-related therapies, and aging. Because facial lipoatrophy, regardless of cause, is a disfiguring condition that affects many people, several devices have been used in an attempt to provide aesthetic correction for this condition. Some of these injectable devices include fat, collagen, hyaluronic acids, calcium hydroxylapatite, silicones, poly-L-lactic acid (PLLA), and polymers such as polymethyl methacrylate and polyacrylamide. Sculptra is a synthetic, biodegradable, and biocompatible injectable composed of PLLA. This is one of the few substances approved in Europe and in the United States for correction of lipoatrophy that has pending cosmetic uses. Injectable PLLA is a new class of devices that provides a semipermanent option to correct the visible signs of facial lipoatrophy. Sculptra was approved with CE Mark certification under the trade name New-Fill in Europe. It has been estimated that 150,000 patients in over thirty countries have been treated with New-Fill since 1999. Sculptra has been used to increase the volume of depressed areas, such as skin creases, wrinkles, folds, and scars. In 2004, PLLA’s approval was extended in Europe to include the large volume corrections of facial lipoatrophy.
INTRODUCTION As the armamentarium of fillers for soft tissue augmentation expands, physicians and patients continue to seek those that approach criteria for the "ideal filler." Regardless of treatment area, the ideal filler would demonstrate versatility, biocompatibility, consistency of results, a natural feel, an excellent safety profile, and a superb cost-to-benefit ratio. Furthermore, it would be easy to inject, have minimal side effects, and not require allergy testing. The ideal filler would also achieve some degree of longevity and, arguably, permanence. Liquid injectable silicone (LIS) is the original permanent, synthetic soft tissue-augmenting filler that may be employed for a variety of cutaneous and subcutaneous atrophies. Used worldwide for at least forty years, it distinctively meets a majority of the criteria that would define the ideal filler, including versatility, reliability of results, a natural feel, and an excellent cost-to-benefit ratio. When LIS is appropriately administered with the microdroplet serial puncture technique, patients may obtain enduring correction of scars, rhytids, and depressions, as well as lasting augmentation of lips and other facial contour atrophies and deformities. However, the "permanence" of LIS refers to the enduring nature of the product in vivo rather than a "permanent" cosmetic result. Although the progressive tissue volume loss of aging will continue to occur, the degree of correction due to placement of LIS will persist. For this reason, silicone and other permanent fillers are much less forgiving than temporary fillers, in that overcorrection or undesired augmentation will also persist. Hence, experience and precise technique are prerequisites to favorable patient outcomes.
INTRODUCTION The demand for safe, effective, long-lasting, and biocompatible dermal filler materials is increasing as a growing number of patients seek minimally invasive options for aesthetic improvement. For a substance or device to be amenable for soft tissue augmentation, in addition to producing the desired cosmetic results, the product must be well tolerated, exhibit a minimum of undesirable reactions, and be nonteratogenic, noncarcinogenic, and nonmigratory. In addition, the material or device must be easy to use and provide predictable, persistent correction through reproducible implantation techniques. Finally, in the United States, the Food and Drug Administration (FDA) review and approval of such products not only substantiates they meet safety and efficacy requirements but also assures adherence to important manufacturing and product labeling requirements postapproval. Numerous attempts have been made to develop safe biological (e.g., collagen, hyaluronic acid) or synthetic (man-made) materials to fill unwanted wrinkles and scars. Currently, in the United States, there are about twelve or more different soft tissue fillers approved for cosmetic use; in Europe, there are approximately eighty CE marked approved cosmetic fillers with many more available worldwide. Historically, biologic filler materials that use "natural-based" core substances such as collagen and hyaluronic acid materials have predominated the marketplace. These materials, whether they are derived from a bioengineered or extracted from a natural source, typically have been modified to improve tolerability (e.g., removal of impurities) and modified to improve durability (e.g., cross-linked).
INTRODUCTION In the last five years, there has been an increased demand in the number of fillers available in the market. This corresponds with the increased demand for less-invasive procedures among consumers. The result is a wide array of choices for the patient and injector to address almost any type of problem. In this chapter, we outline the various applications of fillers throughout the body. BACKGROUND The ideal injectable filler remains elusive to this day. The properties we look for in an ideal injectable filler include safety, ease of use, consistency of results, and longevity of results. Liquid silicone was the first filler available to treat contour defects, scars, and rhytids of the face. It was widely used for two decades until concerns about long-term safety caused it to fall out of favor. Several years ago, a new liquid silicone product was cleared by the FDA and has been used in an "off-label" fashion for cosmetic enhancement of the face. Liquid silicone is a permanent filler. Bovine collagen was the second available injectable filler and was widely used with a very low incidence of complications. Allergy testing of the skin was necessary with Zyderm and Zyplast. These products lasted for a few months after injection, requiring frequent administration. Over the years, collagen-based products have evolved. Cosmoderm and Cosmoplast (human collagen) eliminated the need for skin testing. Evolence (porcine collagen) is cross-linked, giving it a longer-lasting quality, and it does not require skin testing. Autologous fat transfer techniques were introduced around the same time as bovine collagen.
INTRODUCTION The skin’s natural aging process manifests itself in the form of contour changes, wrinkles, the depletion of subcutaneous fat, and the loss of dermal collagen and elastin. Today’s patients are seeking skin rejuvenation to achieve a natural and youthful appearance through minimally invasive procedures with no downtime. Thinning of the lips and deepening of the nasolabial folds and marionette lines are common manifestations of the aging process. Despite multiple treatment modalities and advances in cosmetic surgery, long-lasting, natural-looking augmentation in these areas continues to present a challenge. Available since January 1, 2001, Advanta expanded polytetrafluoroethylene (ePTFE) implants (Ocean Breeze Surgical, Amherst, NH) have been used successfully for augmentation of thinning lips, deep nasolabial folds, and marionette lines without the risk, recovery time, and expense of major surgery. DESCRIPTION OF THE ADVANTA ePTFE IMPLANT Advanta ePTFE implants are an expanded porous polytetrafluoroethylene material with a unique dual- porosity structure. ePTFE is a stable polymer of carbon atoms with a coating of fluorine atoms. The unique dual-porosity structure has a soft high-porosity 100-µm central core surrounded by a smooth, medium-porosity 40-µm outer core. This unique dual-porosity concept promotes tissue integration, vascular ingrowth, and stability. This is critical in preventing migration and reducing shrinkage. The dual-porosity structure is also responsible for a soft feel giving it natural-looking results. Advanta ePTFE implants are available in sheets and geometrical shapes with and without reinforcement. The implants are either round or oval (Figure 9.1).
INTRODUCTION With the unprecedented rise in the use of injectable fillers, an increasing number of patients are approaching their physicians to undergo soft tissue augmentation. It is absolutely essential to educate patients about the procedure, its potential benefits, and its potential complications. As always, this should be done prior to the procedure to be most effective. Detailed pre- and postprocedure instructions are an essential part of this education process. It is this education that ultimately empowers patients and helps them to achieve their ideal cosmetic outcome. Effectively written pre- and postprocedure instructions serve multiple important functions in educating patients regarding their cosmetic procedures. First and foremost, the instructions help patients to understand what to expect from the procedure. Second, they educate patients regarding potential adverse events and possible complications from procedures. Third, they educate patients regarding potential medications and activities that may compromise the postprocedure period or even the cosmetic outcome of the procedure. Finally, they allow the physician to instruct the patient in the management of simple and common postprocedure issues and events that may occur. In order for these instructions to be of the most benefit, it is essential that they be written in layman’s terms. Instructions with complex medical terminology will only serve to confuse the patient, increase their anxiety regarding the procedure, and decrease their likelihood of achieving their desired outcome. The instructions should always be reviewed prior to the procedure with the patient.
INTRODUCTION Slowing down the inevitable course of skin aging has been a popular notion for hundreds of years. Ancient Egyptians compounded early chemical peels using the lactic acid in milk and performed an early form of microdermabrasion with salt, alabaster, and animal oils. More sophisticated methods including soft tissue augmentation with autologous fat were first reported in the German literature by Neuber in 1893. The first U.S. Food and Drug Administration (FDA)-approved filler was bovine collagen (Zyderm I) in 1981. Since then, a myriad of soft tissue fillers have been introduced. These include both bovine and human collagens (Zyderm, Zyplast, CosmoDerm, and CosmoPlast), hyaluronic acids (Restylane, Perlane, Juvederm, and Hylaform), calcium hydroxyapatite (Radiesse), poly-l-lactic acid (Sculptra), and synthetic polymers such as liquid silicone and Artecoll or Artefill. These procedures have gained popularity as they are generally safe in experienced hands, and many show rapid improvement yielding high levels of clinical satisfaction. All cosmetic procedures have associated risks. As the incidence of soft tissue augmentation has increased, as would be expected, adverse effects have been reported more commonly. In a survey of 286 patients, McCraken et al. recently reported a 5 percent complication rate among ophthalmologists performing soft tissue augmentation procedures. This article will emphasize the prevention, identification, and treatment complications with a focus on temporary fillers. Permanent fillers (such as Artecoll) permit greater longevity with which comes the greater risk of adverse sequelae. These permanent substances present a greater risk of causing late-onset (>one year) granulomas.
INTRODUCTION Presently, there is no one ideal filler for all patients, for all indications, and in all situations. It is unlikely that this will ever occur, given the extreme variables in patients and in the goals of aesthetic filler injections. The type of product best for lip injection may not be the best for volumetric cheek filling or for dorsal hand augmentation. The injectable filler best for a young woman with fine skin texture is different than that for an older man with redundant folds or for acne scars. The cost of material, duration of effect, and the social downtime issue all play a role in making the final decision of product choice. In the end, it is the technical skill of the physician and the familiarity with the product that are the most important factors in the clinical result. This discussion will review the key issues to help the practicing aesthetic physician choose the ideal FDA (Federal Drug Association) approved filler for each patient. Fillers that have not been FDA approved in the United States, autologous fat (an excellent global restorative filler), and silicone (an excellent permanent filler for HIV lipotrophy) will not be discussed here. CHARACTERISTICS OF THE IDEAL FILLER The ideal filler is nonallergenic, durable yet reversible, has a natural look and feel after injection, is able to be injected in off-face areas, and is very safe. It should be easy to inject and should cause only little pain, swelling, or bruising.
INTRODUCTION Synthetic particulate-based materials are notable for their ability to provide a robust and durable implant and have long been used as bulking agents in a variety of surgical and nonsurgical settings. Radiesse® (BioForm Medical, Inc., San Mateo, CA) is an injectable filler material composed of synthetic calcium hydroxylapatite (CaHA) microspheres suspended in an aqueous carrier gel. Seventy percent of the composition of Radiesse is sodium carboxymethylcellulose carrier gel; the remaining 30 percent of the composition is CaHA microspheres. These uniform microspheres (25-45 microns) are identical in composition to the mineral portion of human bone and teeth. CaHA has been used for over twenty years in various forms in plastic and reconstructive surgery, otology, otolaryngology, neurosurgery, orthopedic surgery, maxillofacial surgery, and dentistry. The excipients that comprise the aqueous gel carrier (i.e., cellulose, glycerin, and sterile water) are classified as "Generally Recognized as Safe" (21 CFR 182) by the Food and Drug Administration and have an extensive record of use in intramuscular injectable products such as Cortone®, Decadron®, and Dalalone®. The components of CaHA occur naturally in the body and therefore are inherently biocompatible. Results from extensive in vitro and in vivo safety studies, including toxicology assessments, standardized biocompatibility testing, and a three-year animal study, demonstrate that injectable CaHA is biocompatible, nontoxic, nonirritating, and nonantigenic. Because CaHA contains no animal or human tissue derivatives, patient sensitivity testing is not required before use.
The present treatise has outlined the major advances in the development and utilization of fillers in the United States. Fillers are playing an ever-expanding role within this clinical setting. Combination programs employing toxins, fillers, light source, and radiofrequency technologies make up the backbone of noninvasive photorejuvenation programs. The therapeutic armentarium of fillers available in this country continues to evolve annually. There are six major trends in next-generation fillers that have evolved in this regard. A well-accepted and standardized classification schema of these agents has yet to be evolved. LONGER ACTING FILLING AGENTS There is definitely a trend toward longer acting fillers. In our busy world and for economic reasons, individuals would like to minimize the number of filler treatments that are necessary while still maintaining effect. The major question that is not universally accepted is what is that optimal duration of effect? Most physicians feel that an intermediate-acting filler with duration of twelve to eighteen months is optimal. This allows for longevity greater than older generation collagens and traditional hyaluronic acid derivatives; however, if there are adverse sequelae, it will resolve within a reasonable period of time, although one may expect as we move down the road that this timeline may continue to expand. SITE-SPECIFIC FILLERS Another major trend in fillers is specific capabilities. This means that they have clinical and physical characteristics that are uniquely beneficial for given anatomic areas. Examples of such site-specific areas are the lips and tear troughs, where lighter fillers with greater laminar flow characteristics would be more beneficial.
INTRODUCTION Dermal filling agents and botulinum neurotoxin are currently widely utilized for facial augmentation and global restoration of the aging face. For years, the conventional wisdom regarding dermal injectables for facial rejuvenation was "Botox for the upper face; Fillers for the lower face." However, cosmetic dermatologists have advanced from the practice of treating single lines and wrinkles toward filling large facial areas to globally restoring natural facial contours (Ditre, 2008). Cosmetic dermatologists now have a better understanding of the facial aging process, and as new fillers become available, there is an increased recognition that when treating the aging face, the combination of soft tissue augmentation and botulinum toxin takes part in principal roles to fill, lift, tighten, and relax rhytids. OVERVIEW OF INJECTABLE DERMAL FILLERS Over the last four years, the US Food and Drug Administration (FDA) has approved many dermal filling agents. European countries and South America have had numerous dermal filling agents available for several years. Therefore, it can be quite difficult to decide what filler to use and where the filler should be injected. Injectable dermal fillers can be grouped according to their degree of degradability. In general, fillers may be classified into biodegradable and nonbiodegradable products. The degradable material may be further classified into xenografts (derived from another species such as bovine collagen or hyaluronic acid of bacterial or avian origin), autografts (from the same person, such as autologous fat), and synthetic products (PLLA and CaHA) (Jones, 2007, p. 106).
EMERGENCE OF HYALURONIC ACIDS As we age, the underlying connective tissue responsible for the skin’s youthful elasticity and fullness degenerates. This degeneration is exacerbated by several factors, especially sun exposure and repeated use of underlying muscles. These factors are particularly evident in facial skin. Crow’s feet, laugh lines, and smile lines are among the most common cosmetic complaints. Consequently, a fervent desire exists to employ effective and safe cosmetic treatments to bolster the underlying tissue and mitigate these changes. Injectable fillers have proven to be an effective method of achieving this goal. The first FDA-approved cosmetic filler that generated substantial enthusiasm was collagen. These products, though effective, had substantial drawbacks, including limited longevity and concerns for allergic reaction. The demand for a filler that not only bypassed the need for allergy testing but also offered greater longevity inspired the development of additional fillers, notably hyaluronic acid agents. In December 2003, Restylane became the first FDA-approved hyaluronic acid product offered in the United States, and several others have since followed or are pending approval. Aside from longevity and low allergenicity, these newer fillers offer other advantages. Particularly valuable are their inherent ability to bind large amounts of water to further bolster rhytids and cosmetic effect. EXAMPLES OF HYALURONIC ACIDS Clinicians use several varieties of hyaluronic acids, including FDA-approved agents such as Restylane, Perlane, Juvederm, Hylaform, Hylaform Plus, Captique, Elevess, and Prevelle Silk. Other hyaluronic acid products, many of which are already used internationally, are expected to be approved by the FDA in the near future.
Despite a constant improvement in manufacturing and purification technologies, hyaluronic acid dermal fillers continue to be the cause of adverse effects. The injection site reactions are the most frequent not immune-mediated side effect. They are often related to technical mistakes during the treatment. Although there are not differences in hyaluronic acid chemical composition among various tissues or species, some cases of immune-mediated adverse reactions have been reported. The most common is the appearance of foreign body granulomas. It is still unclear if these reactions are due to the hyaluronic acid molecule itself, to the presence of impurities resulting from production processes, or to degradation products of the hyaluronic acid molecule. Viscoderm® is a hyaluronic acid produced by fermentation from streptococcus. In the years 2006-2011 it was created a monitoring system designed to detect any adverse reaction due to the treatment with Viscoderm® that was not reported in the product data sheet. It was performed in 4 european countries (Italy, Great Britain, Germany, France), submitting patients to a 6-years follow up. There have been not reported side effects not listed in the data sheet.
Finally aesthetic medicine got through to men. In western civilization, the number of treatments with dermal fillers and botulinum toxin type A is continuously increasing in men. However, the treatment of men is different from the treatment of women. To have good results and satisfied patients the treatment of men you should not only consider the anatomic differences between men and women but also the different aesthetic expectations as well. Because the goal is not to feminize men but to achieve an improvement in appearance: men want to look relaxed, well-rested, and handsome. Injectable dermal fillers, like hyaluronic acid, reduce wrinkles and folds and help to compensate loss of volume as in the cheek area. However, some rules should be kept in mind while using hyaluronic acid products: (1) the used product has to be injected for the indication it was designed for, e.g. for cheek augmentation a more solid dermal filler should be used and injected deeply while, on the other hand, the treatment of fine wrinkles should be done with a more fluid dermal filler, (2) saving money by injecting insufficient amounts of a biodegradable dermal fillers will result in dissatisfied patients. An adequate quantity should be injected from the start to make sure that the patients are satisfied for a longer time.
Background:
Cohesion is described as the force between particles of the same substance that acts to unite them. Contrary to rheology, there are currently no ready-made instruments designed to measure cohesion, or methods which could be easily adapted to gels. To study and compare the possible clinical effects from the cohesive properties of a gel, it is necessary to standardize the definition and measurement of cohesion.
Objective:
The purpose of this study was to develop and evaluate methods for measuring cohesion.
Methods and materials:
Three different methods were evaluated and compared with measures of perceived cohesion; compression force, dispersion in water and drop weight. Two different families of fillers (Emervel and Restylane) were used for evaluating the different methods.
Results:
The compression force did not reflect the measures of perceived cohesion. The dispersion method showed variable results over time, had some practical issues, and is evaluated by subjective assessment. The best correlation to the perceived cohesion was found with the drop weight method.
Conclusion:
The drop weight method which closely resembles the definition of cohesion (IUPAC) was considered to be the best method for measuring cohesion.
There is a tremendous clinical need for long-lasting, injectable materials for soft tissue reconstruction. Methylcellulose is an FDA-approved polysaccharide derivative of cellulose that is inexpensive, renewable and biocompatible, and may serve as an alternative to existing synthetic and natural fillers. In this study, methylcellulose was modified with functional methacrylate groups and polymerized using a redox-initiation system to produce hydrogels with tunable properties. By varying the percent methacrylation and macromer concentration, the equilibrium moduli of the hydrogels were found to range between 1.29± 0.46 and 12.8± 2.94 kPa, on par with human adipose tissue, and also displayed an inverse relationship to the swelling properties. Rheological analyses determined gelation onset and completion to be in accordance with the ISO standard for injectable materials. Cellulase enzymatic treatment resulted in complete degradation of the hydrogels by 48 hours, presenting the possibility of minimally-invasive removal of the materials in the event of malposition or host reaction. In addition, co-culture experiments with human dermal fibroblasts showed the gels to be cytocompatible based on DNA measurements and live/dead staining. Taken together, these redox-polymerized methylcellulose hydrogels may be of use for a wide range of clinical indications requiring soft tissue augmentation.
There are many types of dermal fillers currently used for cosmetic and medical indications in routine clinical practice. Fillers can be classified as temporary, semipermanent, or permanent depending on the length of time the substance remains in tissue. They can also be classified by the composition of the product. Materials can be based on collagen (bovine, porcine, and human), hyaluronic acid, poly-L-lactic acid, calcium hydroxylapatite, polymethal methacrylates, and polyacrylamide gels, among others. Temporary fillers are the products most often used for cosmetic purposes, in particular hyaluronic acid. This is due to the ease of application of fillers based on this substance, the good results obtained, and their safety profile. This review presents an overview of the techniques used for the correct placement of dermal fillers and the most common clinical indications for these procedures. It also covers the nature, properties, and mechanisms of action of the principal temporary, semipermanent, and permanent dermal fillers as well as the indications for each type of material. Finally, we describe the most common complications encountered and their treatment.
Purpose:
To enhance lips ageing rejuvenation with specific microcannula and hyaluronic acid.
Method:
Clinical review was conducted from December 2010 to December 2011 among 46 patients complaining of predictable changes on lips and perioral region such as deficiency in contour definition, volume and projection. Lips rejuvenation injections were made using the hyalurostructure technique.
Results:
Forty-two patients (92%) with a 6-month follow-up were satisfied or very satisfied with the aesthetic results after the hyalurostructure of the lips and the perioral region rejuvenation. The use of the specially designed cannula led to fewer complications. We noticed 40 oedemas (87%) that appeared 24-48 h after the injection and seven patients (15.2%) with haematomas. We noted fewer surface irregularities and a better distribution of the product. Patients' records showed the procedure was painless.
Conclusion:
The hyalurostructure technique reduces the number of punctures compared to that of the conventional method. The microcannula's blunt tip reduces the risks of intravascular injection of the substance and of reach and disruption of the key structures like vessels and nerves. Results revealed that the hyalurostructure used for lips rejuvenation and helps to maintain a natural effect and avoids pain.
Several soft-tissue dermal fillers have been reported to provoke immunogenicity and may cause adverse reactions despite claims regarding their safety. This study aimed to assess biomaterial-induced macrophage activation, cell-mediated immune response and oxidative stress in 169 patients with dermal bioimplants. To this end, we analysed plasma concentrations of myeloperoxidase (MPO), the chitinase-like proteins chitotriosidase and YKL-40 and molecular oxidative damage. The present study shows, for the first time, that the components of innate immunity: chitotriosidase and YKL-40, are significantly higher in patients with certain bioimplants and these markers of monocyte/macrophage activation rose progressively as adverse reactions (AR) evolved. Plasma MPO levels increased 4-fold in filler users with AR and 3-fold in those without. Analysis by filler type showed subjects injected with calcium hydroxylapatite, methacrylate, acrylamides and silicone to have values significantly above those of non-filler subjects for at least two plasma biomarkers, probably because the afore-mentioned biomaterials are permanent and prone to trigger AR in the long term. By contrast, hyaluronic acid alone elicited little immune response. Plasma concentrations of markers of oxidative damage to lipids and proteins were found to be significantly higher in users of four of the nine dermal fillers studied. These diffusible products of molecular peroxidation would stem from the reaction catalysed by MPO that generates potent oxidants, leading to cell oxidative damage which, in turn, may exert deleterious effects on the organism. Overall, the results of this study on the effects of a range of dermal fillers point to chronic activation of the immune response mediated by macrophages and PMNs. The increases in plasma of MPO, chitotriosidase and YKL-40 proteins and products of macromolecular peroxidation suggests that these molecules could serve as blood-based biochemical markers and alert to the risk of chronic immune system activation and development of adverse events that may arise from the use of certain bioimplants.
The authors have indicated no significant interest with commercial supporters.
There are many types of dermal fillers currently used for cosmetic and medical indications in routine clinical practice. Fillers can be classified as temporary, semipermanent, or permanent depending on the length of time the substance remains in tissue. They can also be classified by the composition of the product. Materials can be based on collagen (bovine, porcine, and human), hyaluronic acid, poly-L-lactic acid, calcium hydroxylapatite, polymethal methacrylates, and polyacrylamide gels, among others. Temporary fillers are the products most often used for cosmetic purposes, in particular hyaluronic acid. This is due to the ease of application of fillers based on this substance, the good results obtained, and their safety profile. This review presents an overview of the techniques used for the correct placement of dermal fillers and the most common clinical indications for these procedures. It also covers the nature, properties, and mechanisms of action of the principal temporary, semipermanent, and permanent dermal fillers as well as the indications for each type of material. Finally, we describe the most common complications encountered and their treatment.
The types and number of dermal fillers have evolved, allowing clinicians to select the most appropriate agent for each specific use. Filler properties differ both between and among classes, so clinicians must have a thorough understanding of these properties and the best techniques to use to provide the most satisfactory outcomes. This article reviews and highlights the key properties of different types of fillers, technical aspects of their use, safety considerations and the importance of patient factors in treatment selection. Making the right treatment choices must involve all of these issues to optimize aesthetic outcomes and patient satisfaction. The authors illustrate how to make the best choices through a series of case examples using a variety of filler types. Although most fillers can provide acceptable outcomes when used appropriately, the hyaluronic acids have become the most frequently used products because of their physicochemical properties and clinical benefits.
While bone marrow-derived mesenchymal stem cells are known and have been investigated for a long time, mesenchymal stem cells derived from the adipose tissue were identified as such by Zuk et al. in 2001. However, as subcutaneous fat tissue is a rich source which is much more easily accessible than bone marrow and thus can be reached by less invasive procedures, adipose-derived stem cells have moved into the research spotlight over the last 8 years.
Isolation of stromal cell fractions involves centrifugation, digestion, and filtration, resulting in an adherent cell population containing mesenchymal stem cells; these can be subdivided by cell sorting and cultured under common conditions.
They seem to have comparable properties to bone marrow-derived mesenchymal stem cells in their differentiation abilities as well as a favorable angiogenic and anti-inflammatory cytokine secretion profile and therefore have become widely used in tissue engineering and clinical regenerative medicine.
The number of dermal fillers has expanded dramatically; clinicians can benefit from practical information on their optimal use.
To review key determinants of dermal filler performance, to discuss technical considerations, and to illustrate these factors based on the author's clinical experience.
Current literature pertaining to the physicochemical properties of hyaluronic acid (HA) dermal fillers and implications for clinical use was reviewed. The author provides clinical guidelines for optimizing outcomes, illustrated with three case examples.
Hyaluronic acids are nonimmunogenic, versatile, reversible, and have excellent benefit-risk profiles, making them near-ideal filling agents. They differ in their manufacturing processes, viscosity, hardness, cohesivity, ease of injection, and ideal uses. Patient counseling and education with individualized selection of the appropriate agent is critical to provide satisfactory outcomes.
Clinicians must be technically proficient, balance esthetic need with facial anatomy, and consider HA properties to provide optimal outcomes.
Over the last 20 years, developments in injectable dermal fillers have led to a revolution in facial soft-tissue augmentation. The demand for dermal fillers for facial soft-tissue augmentation procedures has increased due in part to the less invasive nature of these products compared with surgical procedures. Available options in the United States have expanded from autologous tissues and animal-derived collagens to bacterially fermented biopolymers and synthetic implants. Beyond their physical composition, currently available products are further differentiated by their recommended depth of injection, suitability for different facial areas, and duration of aesthetic improvement. While older dermal fillers rely on the integrity of the injected material to achieve their clinical effects, some newer products are postulated to act by stimulating the patient's own biological and cellular processes. This article examines breakthroughs in facial soft-tissue augmentation that have expanded the palette of options available to physicians.
To assess the safety and effectiveness of hyaluronic acid (HA) fillers in skin of color.
Two prospective studies followed up subjects with Fitzpatrick skin phototypes of IV, V, or VI for 24 weeks after dermal filler injections. In a double-blind, randomized study, subjects were injected with one of three high concentration (24 mg/mL) HA fillers (Juvéderm Ultra, Ultra Plus, and 30) in one nasolabial fold and Zyplast collagen in the other. In an open-label, randomized study, subjects received one of three low concentration (5.5 mg/mL) HA fillers (Hylaform, Hylaform Plus, and Captique) in both nasolabial folds.
A total of 160 subjects (a subset of 439 study subjects) were randomized and treated with one of the three high concentration fillers, and 119 subjects were randomized and treated with one of the three low concentration fillers. For subjects treated with the high concentration fillers there were no occurrences of hypersensitivity or hypertrophic scarring, and no increased incidence of hyperpigmentation or hypopigmentation in non-Caucasian vs. Caucasian subjects. For subjects treated with the low concentration fillers there were no occurrences of keloid formation, hypertrophic scarring, hypopigmentation, hypersensitivity, and three instances of mild hyperpigmentation. For all of the fillers the majority of subjects maintained >/=1 point improvement in nasolabial fold severity scores through 24 weeks.
All of the HA fillers were well tolerated in individuals with skin of color and demonstrated effectiveness throughout the 24 week period. Furthermore, the fillers provided smooth, natural-looking wrinkle correction in darker skin types.
The European market offers a great variety of mono and biphasic hyaluronic acid products. These products continue being mainly applied for facial treatments, viz. for the augmentation of wrinkles and volume defects. This supplement summarizes the author's fifteen years experience in the aesthetic clinical and private office daily routine. Innovative minimal invasive techniques and indications at exceptional localizations, while using the non-animal, stabilized hyaluronic acid of the NASHA gel technology, constitute the focus. For the first time ever, defects in the face, hand and foot area can be reversibly treated without scalpel and as an alternative to surgery--with the NASHA product portfolio.These non-invasive interventions constitute a gentle and safe method to reduce stigmatizing skin changes, with no downtime. The gracefully shaped aesthetic outcomes as well as the effective therapeutic results are highly appreciated by the patients.
Learning Objectives: The reader is presumed to have a broad understanding of plastic surgical procedures and concepts. After studying this article, the participant should be able to:
Describe the current clinical applications and limitations of autologous fat grafting.Identify the important physiological steps and molecular pathways of neoadipogenesis.Cite current in vitro and in vivo models for the analysis of fat grafting techniques.
Physicians may earn 1 AMA PRA Category 1 credit by successfully completing the examination based on material covered in this article. The examination begins on page 322. ASAPS members can also complete this CME examination online by logging on to the ASAPS Members-Only website (http://www.surgery.org/members) and clicking on “Clinical Education” in the menu bar.
Autologous fat transplantation has become a well established and frequently applied method of soft tissue augmentation for both cosmetic and reconstructive indications. There is no consensus, however, about the best fat grafting technique, nor is there reproducible data regarding its durability. The most significant drawback to autologous fat grafting remains its largely unpredictable rate of resorption. A thorough understanding of the developmental biology and molecular regulation of adipogenesis and adipocyte survival is critical to optimizing the fat grafting technique. Consequently, numerous in vitro and in vivo studies on fat graft viability have recently been undertaken. Here, we discuss the latest advances in the basic science of adipogenesis, adipocyte viability, and its clinical application to fat grafting, arguing that the data produced by in vitro and in vivo studies still fail to produce a clear picture of the required components for successful, consistent, and durable fat transplantation; however, it is undetermined if this lack of clarity may simply be a lack of systematic scientific data acquisition or if these findings truly reflect the biology of neoadipogenesis. As a first step in strengthening autologous fat grafting scientific data collection, we recommend that a collective, multidisciplinary, multicenter effort be undertaken to establish in vitro and in vivo models of neoadipogenesis that are clearly reproducible from one investigator to another. With the implementation of systematic scientific approaches to the study of neoadipogenesis, we anticipate the future of autologous fat transplantation for correction of soft tissue volume loss to be extremely promising.
This chapter describes the molecular pathways as well as the cellular mechanisms of hyaluronan (HA) catabolism. Biodegradation of HA is a step-wise process. In the extracellular matrix (ECM) of most mature tissues, HA is of high molecular weight. The metabolism of HA is very dynamic. Some cells, such as chondrocytes in cartilage, actively synthesize and catabolize HA in a balanced fashion throughout life, thereby maintaining a constant concentration in the tissue. Other cells, for example dermal cells, synthesize more HA than they catabolize. HA can only leave the tissue of origin when the ECM is at least partially disintegrated. Extracellular hyaluronidases or ROS can render HA short enough to be released from the matrix. Then, it is either immediately internalized by cells and degraded in lysosomes, or transferred to the circulation from where it is cleared at special sites in the liver, lymph nodes or the kidneys. The end products of degradation, glucuronic acid and N-acetylglucosamine, can thus be reused for polysaccharide biosynthesis. In the kidneys, only trace amounts are lost into the urinary system. In this manner, about one-third of the total HA in the human body can be metabolically removed and replaced daily.
Hyaluronans are used widely in the treatment of osteoarthritis of the knee. Three commercial hyaluronan preparations currently are available in the United States: sodium hyaluronate (Hyalgan), sodium hyaluronate (Supartz), and hylan G-F 20 (Synvisc). Although the sodium hyaluronates are derived naturally, hylan is chemically modified to increase its molecular weight. All three products have been shown to be well tolerated in clinical trials, however, there have been reports in the literature of pseudoseptic reactions, or severe acute inflammatory reactions, after injections with hylan. Our study reviewed the reported incidence of pseudosepsis. The pathogenic mechanisms and clinical treatment of this reaction are presented.
The glycosaminoglycans metabolism is disturbed in progressive systemic sclerosis (PSS). Serum hyaluronic acid (HA) is elevated in this disease.
This study was conducted to determine the HA plasma concentrations of patients with PSS according to the different stages of the disease.
We studied 48 patients divided into three subgroups: subgroup 1 (n = 10), with skin compromise without evidence of other organ involvement; subgroup 2 (n = 21), with skin and esophagus involvement; subgroup 3 (n = 17), with skin, lung and other internal organ involvement. A radiometric assay was performed for quantification of HA.
Our results confirm the increase in plasma HA in patients with PSS. They also suggest that lung involvement is the main feature responsible for high plasma concentrations of HA. The plasma HA levels were elevated in patients compared to normals (p <0.001). Significant differences were observed between subgroups 1 and 3 (p <0.01) and between subgroups 2 and 3 (p <0.01). A positive correlation between disease severity scores and plasma HA values was observed (p <0.01).
An important elevation of HA plasma levels could be a serologic marker of disease severity, progression and degree of visceral involvement.
The ideal soft tissue augmentation material should be an inert, safe, volume-filling material that is easy to use and remains in place over time. Hylan b gel, a cross-linked hyaluronic acid, may have many of these characteristics.
We assessed the potential value of hylan b gel as a soft tissue augmentation material.
A 12-month guinea pig model was used to investigate the tissue effects of hylan b gel versus "collagen" controls.
Hylan b gel was found to be biologically compatible and stable in dermal tissues. At 1 year, only hylan b gel implants were evident (12 of 16 test sites).
In this model hylan b gel performed favorably when compared with the most commonly used soft-tissue augmentation products. The material possesses many desirable implant material characteristics.
Although hyaluronan has been acknowledged as being free of species and organ specificity, for 4 years I have encountered a variety of adverse reactions to injectable hyaluronic acid as used in aesthetic medicine.
I have tried to prove that some of those side effects may be allergic reactions to the commercial preparations of injectable hyaluronic acid.
I began with intradermal tests to the reactive patients and to 2 witnesses; then lymphocyte transforming tests were performed at the University of Geneva (Switzerland). Histology was performed on the skin tests and on reactive treated areas of the face of different patients. A serum analysis was then done by Pr. Sainte Laudy of Laboratoire Pasteur--Cerba (France).
The skin tests were positive for one or the other or both of the injectable hyaluronic acid preparations used in aesthetic medicine. The different biopsies have shown for some a chronic inflammatory reaction, even 11 months after the treatment or a severe granulamatous reaction to foreign bodies. Serum analysis revealed positive antibodies against Restylane and/or Hylaform and even IgG and E anti-hyaluronic acid.
Since 1995, I have 8 patients with adverse reactions to injectable hyaluronic acid, which after several tests, may be allergic to those products. Isn't it time to introduce intradermal tests before any injection of this type, as done with injectable bovine collagen?
The antioxidative and/or free-radical-scavenging activities of R-(-)- and S-(+)-ibuprofen enantiomers, as well as of the drug racemate, were studied in vitro on measuring the kinetics of (uninhibited or drug-inhibited) degradation of high molecular weight hyaluronan by hydroxyl radicals. The continual flux of OH radicals at aerobic conditions was maintained by the H2O2 + Cu2+ system. The kinetics of hyaluronan degradation was monitored indirectly by capillary viscometry. Under experimental conditions, with no drug addition, the relative viscosity ([eta]rel) decreased continuously, reaching 13% of the initial [eta]rel. value in 4 h. Each drug tested exhibited a dose-dependent protective effect against hyaluronan degradation, however R-(-)-ibuprofen demonstrated a slightly greater activity than the drug S-(+)-enantiomer.
Hyaluronic acid (HA) fillers have been proposed as alternatives to other temporary skin fillers, such as bovine collagen, for treating facial skin lines and for providing lip augmentation. Several types of commercial HA fillers are now available in many countries. They include Restylane, which is produced by microbiologic engineering techniques, and Hylaform, which is HA extract derived from rooster combs. They have been approved for use in several countries, but not currently in the United States. There are no recommendations to perform pretreatment skin testing by the manufacturers.
Our purpose is to describe and comment on our experiences with Hylaform and Restylane fillers. Observation of any side effects and skin testing results were documented.
Between September 1996 and September 2000, 709 patients were treated with Hylaform and Restylane and were followed up clinically for at least 1 year. Three of these patients (0.42%) developed delayed skin reactions. Three other patients were referred for evaluation of their skin reactions from other practitioners. Five of these 6 patients agreed to skin testing of their forearms.
In the 5 patients tested, challenge intradermal skin testing was positive in 4 patients; the reactions started approximately 8 weeks after injection.
There was a slight incidence of delayed inflammatory skin reactions to two HA fillers. Both of these reactions occurred after the first and repeat injections. Challenge skin testing was positive in 4 of 5 tested patients.
BTX-A is the standard treatment for glabellar furrows. However, some individuals have resting glabellar rhytides that are sufficiently deep that they respond poorly to BTX-A alone.
To compare the efficacy of BTX-A combined with intradermal Hylan B with the efficacy of BTX-A alone in individuals with moderate to severe glabellar rhytides.
This was a retrospective study of 16 subjects with moderate to severe glabellar rhytides. Their response to Hylan B plus BTX-A was compared clinically and photographically to their response to BTX-A alone.
All subjects had moderate or severe glabellar rhytides at rest before treatment. After BTX-A alone, none (0%) had achieved no or mild rhytides. After BTX-A and Hylan B injection, only 1 of 16 (6%) had moderate glabellar rhytides, with the remainder (94%) being mild.
Moderate to severe glabellar rhytides were treated better by BTX-A combined with Hylan B injection than by BTX-A alone.
Hyaluronan is an extracellular and cell-surface-associated polysaccharide that is traditionally regarded as a biological 'goo' that participates in lubricating joints or holding together gel-like connective tissues. Although these are common physiological roles of hyaluronan in adult organisms, hyaluronan also functions as a microenvironmental cue that co-regulates cell behaviour during embryonic development, healing processes, inflammation and tumour development. Recent work highlights a key role for interactions between hyaluronan and tumour cells in several aspects of malignancy and indicates the possibility of new therapeutic strategies.
Sodium hyaluronate (HA) is widely distributed in extracellular matrixes and can play a role in orchestrating cell function. Consequently, many investigators have looked at the effect of exogenous HA on cell behavior in vitro. HA can be isolated from several sources (e.g., bacterial, rooster comb, umbilical cord) and therefore can possess diverse impurities. This current study compares the measured impurities and the differences in biological activity between HA preparations from these sources. It was demonstrated that nucleic acid and protein content was highest in human umbilical cord and bovine vitreous HA and was low in bacterial and rooster comb HA. Macrophages exposed to human umbilical cord HA produced significantly higher amounts of TNF-alpha relative to control or bacterial-derived HA. These results indicate that the source of HA should be considered due to differences in the amounts and types of contaminants that could lead to widely different behaviors in vitro and in vivo.
Since 1996, hyaluronic acid (HA) has been launched onto the market in Europe. Since then, different companies proposed their HAs. Biomatrix (NJ, USA) proposes an animal-derived HA (from rooster comb). Q-Med AB (Uppsala, Sweden) and LEA-DERM (Paris, France) are the main companies to have a nonanimal HA. HA is produced by bacterial fermentation from a specific strain of streptococci. HA has no species specificity and theoretically has no risk of allergy. No skin testing is necessary before injecting because HA is a biodegradable agent. To be utilized as a filler agent for improving wrinkles, scars, or increasing volumes, HA must be stabilized to obtain a sufficient half-life. Process of stabilization varies, according to each manufacturer. This explains the differences in longevity and in viscosity of the different products. Several HAs are suitable to fine lines, to deep wrinkles/folds, or to increase volume. A new indication for "rejuvenation" is injection into the superficial dermis and epidermis. The HA (stabilized or not) is not used to fill in but rather to hydrate and finally to rejuvenate the skin. This procedure must be repeated at intervals of a few weeks or months. If HA is the safest filler agent in cosmetic indications today, some rare side effects may appear and must be known to inform patients. Most of these complications are not severe and will disappear when the product is degraded.
- Meyer