7. Soft Tissue Fillers
7.1 Introduction
Nonsurgical facial rejuvenation has become an increasingly important facet of an aesthetic surgeon’s armamentarium as the demand for less invasive procedures with minimal morbidity becomes the focus for many patients. Whereas traditional treatment of the aging face targets excess skin and components of facial descent, the nonsurgical approach with soft tissue fillers offers a bridge between skin care and surgical treatments such as facelifts and neck lifts. 1 These nonsurgical procedures, including the use of neuromodulators (botulinum toxin) and soft tissue fillers, are now the most common aesthetic treatments performed worldwide. It therefore behooves the aesthetic surgeon to have a thorough working knowledge of the various products, techniques, and advancements that largely constitute this ever-growing niche in facial rejuvenation.
The goal of this chapter is to provide an overview of the different classes of fillers and their indications for use, as well as to review the techniques for proper application. Furthermore, we endeavor to provide the reader with the uses of soft tissue fillers, giving particular attention to the facial skeleton. Lastly, we equip the reader with an overview of the common complications that are inherent in the use of soft tissue fillers and review their respective treatments. Patients often seek treatment with soft tissue fillers for soft tissue augmentation as the consequences of aging become more evident; therefore, an important aspect of treatment is to understand the stigmata of facial aging, as well as the physiologic al principles of rhytid development.
7.2 History
The practice of soft tissue augmentation began at the end of the 19th century, when Neuber harvested blocks of free fat from the upper arms and transferred them to concave defects in the face. 2 At the turn of the century, Gersvny used paraffin as an injectable filler for cosmetic enhancement. 3 Paraffin was initially embraced as a safe, inexpensive, and effective way to rejuvenate the face. As experience increased, significant complications such as paraffinomas and product migration were encountered, and the use of paraffin dwindled quickly. 4 In 1911, Bruning first reported the use of autologous fat injections to fill a postrhinoplasty deformity. 5 With the introduction of liposuction in 1975, several authors reported their experience using aspirated fat as a filler for soft tissue augmentation with promising results. 6 Although autologous fat transfer has been widely accepted as a viable method of augmentation in aesthetic medicine, disadvantages include the need for harvesting, operator dependence on graft survival, and the significant downtime associated with the use of blunt cannulas for injection of small parcels of fat throughout the face. The early development of a bovine collagen gel in the 1960s by Gross and Kirk led, in 1981, to the Food and Drug Administration (FDA) approval of an injectable bovine collagen filler, Zyderm I (INAMED Aesthetics). About 20 years after approval of bovine collagen in the United States, a bioengineered human collagen was developed to obviate the need for skin testing and reduce the incidence of hypersensitivity reactions. CosmoDerm and CosmoPlast received FDA approval in 2003. Hyaluronic acid, a naturally occurring biopolymer, was first identified as a viable dermal filler in 1989 by Balazs, who noted its biocompatibility and lack of immunogenicity. 7 In 1998, the first efficacy studies of nonanimal stabilized hyaluronic acid (Restylane, Q-Med) were performed. In 1999, the product was purified further to reduce immunogenicity and hypersensitivity reactions. In 2003, after 4 years of use in Europe, Restylane was approved in the United States by the FDA, and it has maintained a large share of the hyaluronic acid filler market since. Other FDA-approved hyaluronic acid fillers include Restylane Perlane, Juvederm, Elevess, and Prevelle Silk. In Europe, many more hyaluronic acid and other fillers are available for soft tissue augmentation. 8 Although testing of fillers by the FDA delays approval in the United States, it is likely that many of the fillers currently available in Europe will become available for use in the United States in the near future. 9
7.3 Skin Aging and the Development of Rhytids
Notable changes with skin aging initiate between the third and fourth decade of life, and this process is the result of both intrinsic and extrinsic factors. The process of skin aging is both dynamic and multifactorial insofar as it is caused by numerous elements that are either uncontrollable by the patient, that is, intrinsically related aging factors, or largely avoidable, as in extrinsic factors. 10
Intrinsic aging refers to the time-dependent process of aging that is largely predetermined by genetics and the effects of which cannot be overcome or manipulated through behavioral change. At the histological level, intrinsic aging shows a characteristic pattern of epidermal and dermal atrophy, reduced thickness of the epidermal rete ridges, and an overall reduction in the number of fibroblasts and mast cells. 11 Intrinsic aging also results in subcutaneous tissue atrophy. The combined loss of collagen fibers, elastin, and other components of the extracellular matrix decreases the turgor and thickness of the dermis. 12 , 13 Chronological aging also negatively affects the barrier function of skin due to the integrity loss at the stratum corneum layer of the epidermis, resulting in increased water loss. Combining these untoward effects of intrinsic aging clinically yields skin that is drier, less elastic, and coarser, heralded by the onset of facial wrinkling and exaggeration of expression lines.
Extrinsic aging is preventable and is the result of exposure to exogenous factors such as air pollution, nicotine use, microorganisms, and gravity; sun exposure is the extrinsic factor that is considered to be the most deleterious to the skin. 14 Histological confirmation of extrinsic aging is made quite easily, with the pathognomonic feature being solar elastosis. 15 The collagen bundles of photoaged skin are marked by being fragmented, more soluble, and thickened, leading to both epidermal and dermal thickening. 16 Clinically, extrinsic aging is demonstrated by thick skin with irregular pigmentary changes (such as ephelides or lentigines), areas of purpura, telangiectasia, benign lesions, and the onset of both wrinkles and deep folds.
It is the onset of wrinkles, folds, and volume loss, though, that drives patients to seek out soft tissue fillers. Without an understanding of the developmental process involved in their formation, their correction becomes that much more nebulous. Wrinkles, creases, furrows, and folds are all terms often applied to aged skin that is actinically damaged, despite the fact that they imply different meanings. Wrinkles are superficial dermal creases that are thought to be caused by a combination of epidermal thinning, flattening of the dermoepidermal junction, and the reduction in collagen abundance. 17 Mimetic wrinkles are those skin creases and folds that are caused by repeated folding of the skin as a result of underlying cutaneous muscle contraction, the formation of which can be largely minimized through the use of neuromodulators (Botox). 18 , 19 Mimetic wrinkles, referred to frequently as lines and furrows, form perpendicular to the direction of their associated muscles and occur in numerous areas within the face, including the perioral area, periocular area, glabella, and forehead. These wrinkles, although they initially appear only in dynamic form, eventually transform into static wrinkles, which remain visible despite underlying cutaneous muscle inactivity. 20 Folds are larger grooves with skin overlap and are generally the result of soft tissue descent that occurs with age due to loss of elasticity, bony atrophy, gravity, and intrinsic aging, examples of which include the nasolabial fold (NLF), jowls, and marionette lines. 21
Classification schemes are often created and rigorously applied to guide treatment, and there is no difference with regard to wrinkle formation. The Lemperle wrinkle scale classification is based on wrinkle depth and can be useful in guiding treatment decisions (Table 7-1). 21 Superficial wrinkles, or class 1 and 2 wrinkles, are often amenable to dermabrasion, chemical peels, and laser treatment. As the wrinkle progresses further in class, alternative treatment modalities must be used, such as soft tissue fillers, neuromodulators, and invasive surgical techniques.
Class | Description |
0 | No wrinkle |
1 | Just perceptible wrinkle |
2 | Shallow wrinkle |
3 | Moderately deep wrinkle |
4 | Deep wrinkle, well-defined edges |
5 | Very deep wrinkle, redundant fold |
Loss of appropriate facial fullness and youthful appearance occurs in most areas of the face to varying degrees, including the periorbital, malar, forehead, temporal, glabellar, mandibular, mental, and perioral zones. 22 A recent study determined that facial subcutaneous fat is partitioned into multiple independent anatomical compartments, which may age independently, resulting in abrupt contour changes between them. 23
Reestablishing the integrity of these foundation structures through appropriate volume restoration and contouring has proven to be a highly effective means of harmonizing features, contours, proportions, and balance associated with the youthful face. 23
The incorporation of volumizing techniques into the nonsurgical armamentarium represents a significant advancement in the approach to rejuvenation. Previously, emphasis had been placed primarily on lines and wrinkles. This initial focus of rejuvenation was two-dimensional, being confined to line effacement and improvement of the tone and texture of the skin. However, because they have transitioned to a three-dimensional approach that also addresses volume loss in soft and bony tissues, aesthetic physicians are now better equipped to treat both cause and effect. 24 The aesthetic physician has concurrently evolved into a global rejuvenator and beauty maximizer. 25
7.4 Classification of Fillers
Volume restoration and soft tissue enhancement date back to nearly a century ago, when autologous fat was first used and described. 26 A variety of products since that time have been introduced and used and have yielded results that have largely prohibited their continued use. Products such as paraffin, Vaseline, and impure silicone have all been used and have caused a variety of complications, such as granulomas, fistulas, abscesses, and disastrous swelling. 27 Given the paucity of rigorous scientific study, these products have largely been discontinued; the first FDA-approved filler for soft tissue augmentation was bovine collagen in 1981, and it soon became the gold standard to which other fillers were compared. 9 Because of its rapid resorption and limited duration of effect, as well as its allergenic potential, numerous other filler products have since been developed. Despite the vast array of soft tissue fillers available, the ideal filler has not been found, and certainly opinion varies with regard to what constitutes the “ideal” filler. Despite the disagreement, numerous characteristics of a perfect filler have been identified (Table 7-2).
Today, there is an impressive selection of products available for physicians and patients to choose from that can yield astounding results in a safe forum with low morbidity, provided the physicians are well versed and educated in the various products and their applications. Although rigorous scientific study of current filler options is ongoing, a balance must be struck between embracing new products and ensuring the safety of patients. Fillers can be classified according to duration of effect, stimulatory effect, or permanency 28 ; however, for the purposes of this chapter, fillers will be classified in the following categories: autologous, biological, and synthetic products.
7.4.1 Autologous Fillers
Autologous materials used as fillers are derived from the patient’s native tissue and come closest to being the ideal filler in terms of composition, although the inconvenience involved in harvesting them and the morbidity associated with the harvesting largely precludes their everyday use. 28 , 29 The process of harvesting the material and implanting it is a two-step procedure that can lead to complications, particularly the harvesting step. The upside, though, is that factors such as toxicity, allergenicity, teratogenicity, carcinogenicity, and immunogenicity are not significant whatsoever. Issues such as migration, inflammatory reactions, and loss of persistence do arise, however. Autologous fillers include dermis, fascia, cartilage, platelet-rich fibrin matrix (PRFM), and fat grafts.
Dermal grafts have a long and reputable history of use in correcting contour deformities in the reconstructive forum, spanning more than 70 years. 30 With appropriate handling and careful placement, these grafts can provide reasonable long-lasting results. As the fat content of the dermal grafts increases, there is a corresponding decrease in the survivability, as dermal–fat grafts rely on revascularization through the dermal component; however, if the surface area of the dermis is large compared with that of the adipose element, survival is enhanced. 30 , 31 , 32 Fascial grafts, harvested from the temporalis or the fascia lata of the thigh, can be readily used. In a well-vascularized bed, fascial grafts can offer a permanent solution through creeping substitution by host fibroblasts while the viability of the fascial fibroblasts remains; it is known, however, that fascial grafts tend to shrink and thicken during the first 5 days of healing and that the temporal fascia shrinks in greater proportion compared to fascia lata. 33
7.4.2 Platelet-Rich Plasma
Selphyl (Aesthetic Factors) is a patented extraction system that removes PRFM from the patient’s own blood that can subsequently be used as a soft tissue filler. 34 , 35 The collection of a 9-mL blood sample allows for the collection of 4 mL of PRFM, which can be subsequently injected in an office-based setting or in the operating room. The development of collagen and dermal matrix increases over a period of 3 weeks, and the results are purported to be sustainable much beyond this time frame as a result of the growth factors inherent in the PRFM stimulating and sustaining collagen production, such as platelet-derived growth factor, vascular endothelial growth factor, transforming growth factor-β, and insulin-like growth factor. 34 Applications of Selphyl system include correction of NLFs and glabellar lines, as well as treatment of acne and other scars. 35
There are multiple preparation systems for platelet-rich plasma (PRP) available on the market, including Harvest SmartPrep Platelet Concentrate System (Harvest Technologies), the 3i Platelet Concentrate Collection System (3i Implant Innovations; BTI (Biotechnology Institute, Vitoria), the Vivostat System (Vivolution), the Cascade-Esforax System (Cascade Medical Enterprises), the RegenPRPKit (RegenLab, Mollens-VD), and Plateltex (Bratislava). The preparation and processing of PRP is quite similar in most of the platelet-concentrating systems, although the anticoagulant used and the speed and duration of centrifugation may differ with different systems. 36 , 37 Contraindications to the use of PRP can be divided into systemic and local. 36 , 38 , 39 The systemic contraindications include platelet disorders, thrombocytopenia, antiaggregating therapy, bone marrow aplasia, uncompensated diabetes, sepsis, and cancer. However, the local contraindications include osteomyelitis and loss of substance of more than 50% of the segments treated in the case of chronic or posttraumatic wounds. Tobacco use and genetic disorders were not considered contraindications by Cervelli et al. 36 , 38 , 39 The preparation of PRP involves the isolation of PRP, after which gel formation is accelerated using calcium chloride and bovine thrombin. It has been discovered that the use of bovine thrombin may be associated with the development of antibodies to the factors V and XI and thrombin, resulting in the risk of life-threatening coagulopathies. Bovine thrombin preparations have been shown to contain factor V, which could result in stimulation of the immune system when it is challenged with a foreign protein. Other methods for safer preparation of PRP include the use of recombinant human thrombin, autologous thrombin, or perhaps extrapurified thrombin. Alternative methods of activating PRP need to be studied and made available. 40 , 41
Lipotransfer was initially documented in 1893, when Neuber performed the first autologous free fat transfer to treat scars of the arm. 42 En bloc transfers of fat have the disadvantage of losing nearly half their volume after transplantation and can result in the development of cysts, calcifications, and areas of fat necrosis. These untoward effects of fat transfer can be attenuated by injectable fat grafting in which small intact parcels of fatty tissue are harvested atraumatically and injected in small aliquots in the area of need. 43 , 44 If the fat survives, the effects are permanent; however, unpredictability of the survival, the need for a donor site, and the time required to both harvest and inject the fat, as well as the possible need for repeat injections, are the main disadvantages. 44
With the advent of Illouz’s liposuction technique in the 1980s, plastic surgeons obtained access to large volumes of adipose tissue that was routinely discarded. Innovation led to its use for soft tissue augmentation. 45 Miller is credited with introducing the idea of body contour correction by injecting fat parcels through metal cannulas. 46 Coleman 47 offered significant insights into a fat tissue refinement and implantation technique to improve viability and sustainability of clinical results. Although contour restoration remains the primary objective of fat grafting, plastic surgeons have identified additional attributes that grafted fat provides. The quality of skin overlying grafted fat anecdotally demonstrates softened wrinkles, reduced pore size, and improved pigmentation. 31 Others have stated that the skin appears more hydrated and elastic. 45
A pluripotential cell line exists within the stromal vascular fraction of adipose tissue known as preadipocytes, or adipose-derived stem cells (ADSCs). 45 , 48 Ease of ADSC harvest through liposuction has facilitated acquisition of stem cell–rich tissue for use in tissue regenerative research. 49 , 50 Mechanisms to explain the therapeutic effect of ADSC vary. Aged skin models, basic science study, and clinical reviews of fat injection therapy for radiation dermatitis or necrosis have demonstrated that ADSCs increase dermal collagen synthesis and vascularity through production of growth factors after implantation. 45 , 51 , 52 , 53 Others suggest that ADSCs possess the ability to differentiate into epithelial cells by expressing markers (e.g., p.63). This may provide greater insight into the mechanism of the lasting skin improvements previously reported after fat grafting and spur investigation into the use of ADSC for aesthetic and reconstructive tissue engineering applications. 54
P.63 is a well-documented epithelial stem cell marker that maintains epithelial stem cell proliferative capacity, serves as a significant player in epithelial cell layering, and demonstrates high levels of expression in the progenitor cell layers of skin, breast, and prostate. 55 Numerous stem cell isolation systems are available on the market worldwide (Celution by Cytori Therapeutics Inc.). Their use is restricted to clinical trials in the United States and Canada.
7.4.3 Biological Fillers
The quest for the ideal soft tissue filler has led to the development of numerous biologic fillers, including bovine collagen, human collagen, collagen matrices, preserved fascia, decellularized human dermis, and hyaluronic acids. 56 Despite the biocompatibility of these implants, reabsorption, lack of longevity, and issues of sensitization to foreign animal or human proteins still plague their use. Numerous FDA-approved biological fillers are available (Table 7-3).
AlloDerm (Lifecell Corp.) is an allogenic, structurally intact acellular dermal matrix graft that is processed from tissue-banked human skin, which is nonimmunogenic given its acellularity. 57 Once processed, rehydrated, and in contact with viable tissue, it becomes a biological scaffold for tissue remodeling as it eventually becomes repopulated into necessary cellular subtypes from circulating stem cells resulting in soft tissue regeneration. 58 Some of the known cosmetic applications of AlloDerm include lip augmentation, NLF correction, rhinoplasty, septal perforations, and blunting of glabellar wrinkles; common uses for reconstructive purposes include breast reconstruction, Frey’s syndrome, and eyelid reconstruction. 59 , 60 , 61 , 62 , 63 Complications with AlloDerm use include infection, graft take, and palpability of the grafted material.
Cymetra (Lifecell Corp, Branchburg, NJ) is a lyophilized acellular collagen matrix that is essentially a micronized form of the company’s product AlloDerm and can be used as an injectable filler. 59 Cymetra must be reconstituted with either lidocaine or saline, and as with AlloDerm, after injection, host fibroblasts infiltrate the implanted material. The longevity of Cymetra’s effects is reportedly between 4 and 6 months, and it has sustained longevity greater than that of bovine collagen at 1 and 3 months. Cymetra is FDA approved for subcutaneous injection and can be used for lips, NLF correction, and deep wrinkles. 59
Fascian (Fascia Biosystems) is preserved particulate fascia lata that can be used for soft tissue augmentation. Fascian is prepared from prescreened human cadaver fascia lata that has been freeze-dried and irradiated. It is packaged in three particle sizes. Once injected, it initiates a process of collagen repopulation of the injected graft material. 33 , 64 , 65 The material can be injected intradermally, subdermally, or into deep tissue and has been used to correct wrinkles, scars, and fat atrophy, as well NLFs.
Zyplast (Allergan) has been approved by the FDA for use as a soft tissue filler since 1981 and has become the gold standard to which all other soft tissue fillers are now compared. Bovine collagen is indicated for the correction of facial rhytids and lip augmentation, as well as for treatment of scars (e.g., acne, postoperative, and posttraumatic). Bovine collagens are xenogeneic implants, and therefore they can potentially elicit allergic reactions in approximately 3% of the population; to mitigate this risk, two skin tests should be performed before injecting any bovine collagen product. 66 Bovine collagen is readily resorbed, which limits its usefulness because frequent injections are often required, with the overall duration of effect being less than 6 months. 67 In an effort to eliminate the need for repeated allergy testing, human fibroblastic collagen was developed and marketed as CosmoDerm and CosmoPlast (Allergan); these products contain purified collagen (types 1 and 3) from human fibroblast cell culture lines screened for viral and bacterial pathogens. 68 Approved by the FDA in March 2003, these products have a limited and waning role in the filler market. Both these injectable products are packaged with lidocaine (to provide anesthesia), making regional nerve blocks generally unnecessary. Although rare, complications with collagen injections have been reported, including vascular necrosis after glabellar collagen injections. 67 However, the most significant issues with collagen products have been their lack of longevity and their potential for a bumpy, irregular outcome. 69 A new porcine-based collagen product called Evolence (ColBar Life Sciences) helped to restore collagen’s reputation in the filler market, with results lasting up to 18 months in 66% of treated patients. 69 Evolence has been approved by the FDA since June 2008 for moderate to severe facial wrinkles and folds. However, Evolence is no longer available. The technology was bought by Johnson & Johnson, which stopped marketing it little more than a year after it was launched 67 , 69 .
Hyaluronic acid (HA) is a naturally occurring linear polysaccharide found in the extracellular matrix of connective tissue, synovial fluid, cartilage, and bone, and it forms the elastoviscous fluid matrix or lattice in which collagen and elastic fibers may form. 70 The chemical nature of HA, unlike that of collagen, is quite uniform from species to species; therefore, the propensity for immunogenic or allergenic reactions is minimal. HA, although seemingly ideal for use as a tissue filler, lasts only approximately 1 to 2 days in its natural form; it is locally degraded rapidly and metabolized by the liver. 71 To overcome this rapid effect, HAs have been crosslinked into larger, more stable compounds with similar biocompatibility yet significantly longer residue time, as enzymes such as hyaluronidase (HYAL) cannot penetrate the gel matrix and initiate the degradation process. 70 The hydrophilic nature of HA allows it to maintain its shape using the body’s own moisture. One gram of HA can bind up to 6 L of water. 71 Therefore, HAs as a soft tissue filler have the property of maintaining bulk postinjection. 71 Over time, the injected hyaluronic gel is slowly absorbed by the surrounding tissues and disappears by a process called isovolumetric degradation. As the HA gradually degrades, each molecule binds more water, and eventually, the same volume can be maintained with less HA. This provides a natural-appearing volume correction and cosmetic persistence until the product is almost completely degraded. 72 The important differences between currently available HA fillers include the source of HA, concentration of HA in each syringe, agent used for crosslinking HA polymers, degree of modification and crosslinking, amount of free unmodified HA present, and whether the product is monophasic (cohesive gel) or biphasic (particulate). In addition, the elastic modulus (G’) of a gel is a measure of its firmness and resistance to deformation when a force is applied. 73 A comparison of HA fillers is shown in Table 7-4.
At the time of writing this chapter, nine FDA-approved HA fillers are available commercially for use. Restylane (QMed/Galderma; Medicis/Valeant) was the first HA soft tissue filler to receive FDA approval, in December 2003, for correction of soft tissue wrinkles of the face and is manufactured via recombinant technology in bacteria. 74 Restylane has been marketed as three products that vary in the size of their constituent particles to maximize aesthetic benefits according to application: Perlane, Restylane, and Restylane Touch (fine lines), in order of decreasing particle size. The family of Restylane products have a shelf life of 1.5 years with a longevity of action of between 6 and 12 months. 75 Restylane is an HA concentration of 20 mg/mL with a particle size of 400 µm. 74 It had originally been postulated that Restylane’s physical volume was the sole cause for the volumetric improvement; however, a recent study revealed that Restylane operates as an effective dermal filler by physically stretching dermal fibroblasts, which induces de novo collagen formation while inhibiting the breakdown of existing collagen. 76 Perlane (QMed/Galderma; Medicis/Valeant), approved by the FDA in 2007, contains 8,000 gel particles per milliliter and is indicated for deeper injections. In February 2010, Restylane-L and Perlane-L were approved by the FDA. These are lidocaine-containing products of Restylane and Perlane.
The second group of HAs available in North America is known as Juvederm (Allergan). It is a similar non–animal-based HA with a slightly higher concentration of HA (24 mg/mL) and more extensive crosslinking (classified as Hylacross HA). It was approved by the FDA in 2006 and has been on the market in Canada and Europe since 2003 for correction of moderate to severe facial wrinkles. 77 The Juvederm family of products are marketed as Juvederm Ultra and Juvederm Ultra Plus (more viscous), as well as Juvederm XC, which contains lidocaine. 78 Juvederm Voluma (Allergan) was FDA approved in 2013. It is similar to the other Juvederm family products as a non–animal-based HA, but it has a concentration that is similar to that of Restylane (20 mg/mL). Its patented Vycross technology incorporates short-chain HA together with long-chain HA to provide more efficient crosslinking than with Juvederm Ultra, which has only long-chain HA. Inclusion of the short chains of HA allows more crosslinkers to attach to HA chains at both ends, which results in longer product duration than with fillers that include only long-chain HA. The more efficient crosslinking also produces a higher-viscosity gel, which, in turn, produces greater lift capacity, as the gel is better able to lift against the pressure of the skin. 79
Hydrelle, originally called Elevess (Anika Therapeutics Inc, Bedford, MA), is a HA filler that also contains lidocaine. Hydrelle contains the highest concentration of HA on the market, 28 mg/mL, and it also contains 0.3% lidocaine; it was the first of the U.S. products receiving FDA clearance for an HA with lidocaine. It received FDA approval for use in the correction of facial rhytids in 2006. It is crosslinked with p-phenylene bisethyl carbodiimide or biscarbodiimide, which is a novel HA crosslinker. 80
Prevelle Silk (Genzyme Corp., Mentor Corp.) is abacterially derived HA dermal filler that received FDA approval in 2008 for correction of moderate to severe wrinkles about the nasal and perioral area. Prevelle Silk is the second generation of an earlier HA filler known as Captique, which is no longer available. Captique contains 4.5 to 6 mg/mL of HA, is 20% crosslinked with divinyl sulfone, and has a gel particle size of 500 µm. Prevelle Silk contains Captique with 0.3% lidocaine to reduce pain on injection. 81
Belotero Balance (Merz Aesthetics) is the latest HA, approved by the FDA in 2011, and is available outside the United States under the brand name Belotero Basic (Merz). Although similar in some of its common properties to other approved HAs, Belotero has unique properties that make it particularly suitable for superficial injection. Belotero is an HA of high crosslink density, and it uses a cohesive polydensified matrix (CPM) technology that results in a cohesive gel with zones of greater and lesser density. 82 The CPM technology double-crosslinks monophasic HA strands with butanediol diglycidyl ether, which is the stabilizer. Linking the hyaluronic acid chains allows it to slow down degradation, making the product last longer. Belotero is softer (lower elastic modulus, G) than other HAs, making it highly suitable for injection into fine lines and other superficial injections. It also has a low viscosity, allowing the material to be spread evenly into surrounding tissues, thus allowing for a soft, smooth fill. 68
The tan delta is a measure of the presence and extent of elasticity. A gel with high tan delta will have a predominance of fluidity over elasticity, whereas low tan delta indicates a predominance of elasticity over fluidity. Sundaram and Cassuto compared the biophysical characteristics of HAs and found that the cohesive polydensified matrix HA (Belotero Balance) has the lowest elasticity and viscosity and the highest tan delta. This predicts its soft, flowing qualities and correlates with its homogeneous pattern of tissue integration after intradermal implantation. Non-animal-based stabilized HA (Perlane and Restylane) has the highest elasticity and viscosity and low tan delta. This predicts its firm, less flowing qualities and correlates with a bolus-like pattern of tissue integration. Hylacross HA (Juvederm) has intermediate elasticity, viscosity, and tan delta, correlating with its intermediate pattern of tissue integration. 83
The ninth and latest generation of HAs is Expression (Enhancement Medica). This is the first HA to be produced by fermentation of a bacterial strain, Bacillus subtilis, which is a well-established nonpathogenic host that is already being used to produce a series of products granted GRAS (generally recognized as safe) status in the United States. The Expression molecules are crosslinked with divinyl sulfone with a concentration of 20 mg/mL. Expression has the advantage of being packaged in a custom-made, larger-volume syringe (15mL). 84 It is currently marketed and sold for use as an intranasal splint in the United States. Its application for FDA approval as an aesthetic injectable filler is still pending.
Teosyal represents a product line of seven different HA-based dermal fillers produced by Teoxane Laboratories that are currently unavailable in the United States. The concentrations of HA range from 15 to 25 mg/g, and the line includes both crosslinked and non-crosslinked formulations. This line of fillers is designed to be injected anywhere from the superficial to the deep dermis, depending on the specific product used. Teoxane Laboratories estimates the longevity of their products to range from 2 to 18 months. 85 , 86
Finally, the Hylaform family, including Hylaform and Hylaform Plus (Allergan Inc.), unlike the other FDA-approved HA fillers, is animal derived (from rooster combs) and is approved for corrective use in facial wrinkles, folds, and grooves. 81 These two products are no longer used in the United States.
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