CHAPTER 42 DERMAL AND SOFT-TISSUE FILLERS: PRINCIPLES, MATERIALS, AND TECHNIQUES
Z. PAUL LORENC
As Baby Boomer and Gen X populations transition to mid- and later life, numerous nonsurgical cosmetic procedures and materials have been developed for this demographic. The American Society for Aesthetic Plastic Surgery reported a 155% increase in cosmetic procedures from 1997 to 2010. Nine and a half million of these procedures were performed in the United States. Second only to injections of neuromodulators (Chapter 43), such as OnabotulinumtoxinA (Botox), AbobotulinumtoxinA (Dysport), and IncobotulinumtoxinA (Xeomin), the use of dermal filler/volumizing agents topped the list for nonsurgical rejuvenation.1
Dermal fillers have been used for decades. Early applications involved autologous fat grafting with only short-term benefits.2 The popularity (and profit) of bovine collagen as a filler material in the 1980s generated an explosion in the development of injectable soft-tissue fillers, with varying properties, longevity, and ease of use that have significantly altered the landscape of minimally invasive cosmetic correction.2
In the past decade alone, the vast array of dermal fillers/volumizing agents on the market, coupled with their efficacy, versatility, biocompatibility, resorbability, cost-effectiveness, and relative ease of administration, has created both opportunities and challenges for patients and practitioners. Involving little downtime for the patient, minimal adverse events, and generally less than an hour to administer in a practitioner’s office, injectable agents help restore youthful vitality by effacement of wrinkles, repleting volume, and recontouring in the face, hands, and less visible parts of the body.3
The field of facial rejuvenation has evolved along with the growth in noninvasive applications. Once focused on filling wrinkles, lines, and depressions, practitioners now attempt to recontour by volume replacement. The face does not age uniformly, and corrective modalities and materials are selected based on the relationship of the whole to its parts.4,5 The ideal filler/volumizing agent would be safe, biocompatible, noninflammatory, nonallergenic, stable, easily deliverable, pliable, nonmigratory, and durable.6,7 The clinical performance of any agent depends upon its physiochemical characteristics and interaction with the recipient.
The in vivo and in vitro characteristics of soft-tissue fillers are outlined in Table 42.1. An understanding of physiochemical characteristics enables the practitioner to assess their deliverability, performance, immunogenicity, applications, aesthetic effectiveness, and longevity.2,8
The ultimate behavior of soft-tissue fillers is a function of a number of scientific variables. These include biocompatibility/ biofilm formation, viscosity, gel/fluid ratio, Hyaluronic Acid (HA) concentration, percentage of cross-linking with degree of pendant cross-linker, particulate versus liquid versus fibrillar constituency, particle size, elastic modulus (G′), complex viscosity (h*), and extrusion characteristics. Especially critical to the mechanism of action are lifting ability/elasticity and viscosity. Recent assessments of HA-based and calcium hydroxylapatite (CaHA) soft-tissue fillers have explored the relationship of their physiochemical properties to performance on rheologic tests, which measure the flow of fluids and physical changes of solids under applied stresses and strains.9-11
A soft-tissue filler’s utility is determined in part by its viscosity (h*), elasticity (G′), and plasticity, all of which constitute a product’s rheology.9,11 Rheologic testing replicates the movement and action of gravity on facial tissues, by applying shearing force to popular HAs and CaHA.9-11 In one study, investigators found that, largely due to the products’ high G′ value, CaHA (Radiesse, Merz Aesthetics, San Mateo, CA) retained structural integrity, viscosity, and elasticity.10,11 In clinical applications, injecting stiffer (high G′, more lifting capacity) products into the skin could prove more challenging for the practitioner. Agents with low G′ may be more effective for filling superficial wrinkles, areas around the lips, and lips themselves, while gels resistant to dynamic force (high G′) may be more suitable for deeper fold correction, to volumize the malar eminence, augment the mentum, or volumize the temporal hollow9 (Figure 42.1).
Molecular cross-linking confers strength and structural integrity to HA-based gels, allowing the filler to retain its shape until it is degraded and metabolized by the body.9 Cross-linking entails a delicate balance to simultaneously provide effective biomechanical properties while maintaining biocompatibility and tissue interactivity.9 The amount and the degree of cross-linking—not the HA concentration alone—determines filler duration.12,19 When gels undergo similar modifications with like concentration, the higher cross-link to pendant (partially bound cross-linker) ratio will assure a less degradable, more stable, and longer lasting effect.9
FIGURE 42.1. Elasticity characteristics of dermal fillers. From Sundaram H, et al. Comparison of the rheological properties of viscosity and elasticity in two categories of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol Surg. 2010;36:1859-1865.
Particle size, shape, and distribution (G*) have an influence on extrudability and potential bruising. If the particles are dispersed too loosely or closely and still remain large, they may prevent a smooth flow of filler and result in subsequent bruising from sporadic delivery. These inherent physiochemical characteristics affect the forces necessary to inject an agent.8 In general, higher G′ helps assure stability for optimum sculpting/ lifting, while higher h* enables materials to withstand applied forces once injected.11
Particle size is another consideration. An evaluation of the impact of particle size on phagocytosis was performed. Polymethylmethacrylate (PMMA) microspheres of <20 µm in diameter promoted phagocytosis, potentially inducing adverse skin reactions and rendering the particles nonviable.7 In another study, PMMA particles of different sizes demonstrated that larger sized microspheres >40.2 µm were not phagocytized.7,13 In addition to particle size, inflammatory response is affected by particle shape, contact angles, collision factors, surface tension, and surface charge. In one study, an in vivo implantation of irregularly shaped polymer implants initiated host inflammatory response in contrast to smooth-surfaced PMMA microspheres.7 For now, particle size >20 µm appears less likely to induce an inflammatory response than smaller sized microspheres.
CLASSIFICATION OF AGENTS BY FUNCTION
In spring 2011, a panel of physicians recommended categorization of injectable fillers by their function and clinical outcomes.14 The categories include neuromodulators, collagen-based agents, replacement agents, biostimulatory agents, long-lasting agents, and autologous fat (Table 42.2). (Neuromodulators are covered in Chapter 43.)
Derived from bovine, porcine, and live or cadaveric human dermal tissue, collagen provides support and strength to the skin. Skin testing is required for agents containing bovine collagen.
Cymetra (LifeCell Corporation, Branchburg, NJ), an aseptic particulate, injectable form of AlloDerm prepared for delivery in 0.5% lidocaine with 1:200,000 epinephrine, is derived from isogenic human tissue. Indicated for augmenting lip volume, nasolabial fold injection (NLF) correction, and burn and scar treatment, Cymetra is obtained from tissue banks or cadavers, which have been tested and screened for immunologically threatening risk factors.15
Fascian (Fascia Biosystems, Beverly Hills, CA), a particulate replacement agent indicated for upper and lower lip augmentation, correction of facial rhytides, and volume restoration of the face, is obtained from human cadaver fascia lata and prepared for delivery in a sterile normal saline solution and 0.5% lidocaine.15,16
Artefill (Artes Medical, Inc., San Diego, CA) is a long-lasting biostimulatory agent, comprised of round, smooth PMMA microspheres of 30 to 50 µm in diameter, suspended in an 80% gel matrix of denatured bovine collagen with 0.3% lidocaine hydrochloride.17,18 As the collagen degrades, the body produces a collagenous matrix around the implanted spheres. Artefill, indicated for NLF volumizing, is considered permanent. Skin test is required 2 weeks before application.17
This category includes HAs, which occupy deep dermal or subcutaneous space before dissipation.5 Drawn from animal or nonanimal sources (nonanimal-stabilized hyaluronic acid [NASHA]), HA is water soluble and cross-linked to create a gelatinous substance that does not break down rapidly in the system20 (Figure 42.2).
The concentration of HA and amount of cross-linkage play large roles in the agent’s performance and persistence.9 These NASHA fillers are approved as soft-tissue injectable agents for NLFs of moderate to severe facial rhytides but are used off-label for diverse applications such as tear trough correction and soft-tissue augmentation of the dorsum of the hands.10 In 2011, Restylane (Medicis, Scottsdale, AZ) received an expansion of its label from the Food and Drug Administration (FDA) to include lip augmentation.
HAs are sometimes referred to as either heavy HAs or light HAs, based on the length of their chains of repeating disaccharides, degree of cross-linking, and content of free HA and HA concentration among many other factors. Heavy HAs include Restylane-L, Perlane-L (Medicis, Scottsdale, AZ), and Juvederm Ultra XC/Ultra Plus XC (Allergan, Irvine, CA).9
Light HAs include Prevelle Silk (Mentor Corp., Santa Barbara, CA) and Belotero (Merz Aesthetics, San Mateo, CA). Prevelle Silk, with an HA concentration of 5.5 mg/mL is prepared with lidocaine for comfortable injection and indicated for moderate to severe facial lines, folds, and wrinkles, such as NLF. This particular HA formulation behaves in an “isotonic” manner once injected, with no appreciable edema post injection. Belotero, FDA cleared in 2011, is produced with cohesive polydensified matrix technology, a homogenous gel matrix that permits the material to integrate uniformly into the skin without volume loss or dispersal.20 Belotero’s indication in the United States is for injection into the mid- to deep dermis for correction of moderate to severe facial wrinkles and folds, such as NLFs. This agent’s particular physiochemical characteristics are ideal for superficial dermal injections with long duration and avoidance of the Tyndall effect.
FIGURE 42.2. Photomicrograph of restylane. Each scale bar = 100 µM. From Stcoks D, et al. Rheological evaluation of the physical properties of hyaluronic acid dermal fillers. J Drugs Dermatol. September 2011;10(9):974–980.
These agents stimulate new collagen growth.
CaHA (Radiesse; Merz Aesthetics, Inc., San Mateo, CA), suspended in an aqueous carboxymethylcellulose carrier, immediately volumizes the area of implantation and is a durable corrective agent indicated for moderate to severe facial folds and wrinkles but effective as an off-label volumizing agent for the malar area, temporal hollow, and the dorsum of the hands.21 Over time, macrophages begin to dissolve the gel carrier, while CaHA microspheres become surrounded by fibroblasts, forming a matrix to support neocollagenesis. In 12 to 18 months, the microspheres are degraded by macrophages and disappear2 (Figure 42.3).
Poly-L-lactic acid (PLLA) (Sculptra Aesthetic; Sanofi-Aventis; Bridgewater, NJ) comprises microparticles of PLLA suspended in carboxymethylcellulose, non-pyrogenic mannitol, and sterile water for injection. The vial contains 367.5 mg of lyophilized PLLA microparticles requiring dilution with sterile water. Depending on the area of the body to be treated, the vial may be reconstituted using a range of sterile water volumes (5 to 24 cc) in an off-label manner.22 The injectable implant stimulates fibroblasts to produce collagen, enabling correction for up to 2 years and is especially effective for restoring volume to enable facial contouring after atrophy23 (Figure 42.4).
Polyacrylamide hydrogel (Aquamid; Contura SA, Montreux, SW) is a soft volume filler, which integrates naturally into the body’s own tissue. Consisting of approximately 97.5% water and 2.5% cross-linked polyacrylamide gel, the highly elastic filler allows continuous water exchange with the surrounding tissue, reducing the risk of biofilm formation. Aquamid is at present awaiting FDA clearance.24
FIGURE 42.3. Thick-section light microscopy at 9 months showing microspherules surrounded by thick collagen and histiocytes. Courtesy of David J. Goldberg, M.D., J.D.
LAVIV (Fibrocell Science, Exton, PA), approved for the treatment of moderate to severe NLFs, is derived from a patient’s own fibroblasts after obtaining via a skin punch biopsy. LAVIV is being investigated for the treatment of rolling, depressed acne scars, but is not currently approved for this indication.25
Platelet-rich plasma (PRP), drawn from the patient’s blood, is processed to contain a high concentration of platelets and growth factors to promote soft-tissue healing.26 Widely applied in orthopedics, PRP has been also used off-label for fine lines and wrinkles using superficial intradermal injection techniques.
Silicone (Si) (Silikon 1000; Alcon, Fort Worth, TX) is injected in microdroplets. Over 3 months, collagen capsules surround and support the liquid silicone microdroplets.27 Si is used for off-label augmentation of NLFs, labiomental folds, mid-malar depressions, lip atrophy, and correction of acne and scar tissue28,29 (Chapter 7).
PMMA (ArteFill; Suneva Medical, Inc.; San Diego, CA).
See Collagen Based Agents section.
The body’s own subcutaneous fat is harvested, processed, and injected to volumize or augment areas of the body that have undergone atrophy (Chapter 44).
ANATOMICAL CONSIDERATIONS FOR AGENT SELECTION
While the youthful face presents with smooth transitions among fat compartments, the face does not age uniformly.4 Investigators have demonstrated that subcutaneous facial fat resides in discrete compartments that respond independently to the aging process. For example, patients with midface hollows and facial volume loss display intact NLF and jowl fat.4 In studies, dyes were injected into the hemi-faces of cadaver dissections of men and women from 47 to 92 years old to examine fat compartments in the areas near the NLFs, cheeks, forehead and temporal space, orbital muscles, and jowls.4The dye revealed distinct boundaries, suggesting highly compartmentalized subcutaneous fat tissue as well as vascular connectivity between these zones. The studies also revealed the presence of multiple layers of deep fat residing above and beneath the facial muscles.
FIGURE 42.4. B/A of patient, 54 years old, with PLLA injections, 12 months after PLLA injections to temporal fossa/cheeks, two vials/session × 2 sessions, 9 cc sterile water dilution per vial.
These pivotal anatomical observations have contributed to the way in which practitioners approach restoration of facial volume. Adding volume to the midface, deep medial fat compartment, indirectly affects the NLFs, the hollow tear trough, and even the oral commissure, as the middle third of the face supports the upper and lower third.30 Augmenting the pyriform region with PLLA, CaHA, or HA can enhance the entire NLF and midface.
Studies have assessed the qualities constituting attractiveness: youthfulness, sexual dimorphism, averageness, and side-to-side symmetry.31 Further assessment of the perioral and periorbital areas and midface volumization provides a framework for restorative intervention.5 In addition, the face has been analyzed and mapped three-dimensionally by regions that may dictate technique, treatment, and agent selection.30
Evaluating the face in thirds affords a reliable guide to sculptural treatment. Horizontally dividing the face into thirds offers an evaluative tool for the clinician in determining both approaches and agent selection. Left-to-right symmetrical evaluation assists both the practitioner and the patient in evaluating which areas of the face may require more correction than others.
Implantation of volumizing agents may also be used to compensate for diminished skeletal support. Ultimately, however, the choice of injectable agent is anatomically based, i.e., the corrective needs of the patient’s face drive filler selection. It is of critical importance to be familiar with each agent’s physiochemical properties in order to match a particular anatomical area with the proper agent.
OTHER CONSIDERATIONS IN FILLER SELECTION
A candid conversation between the practitioner and the patient regarding available, recommended correction options and protocols, expectations and realistic outcomes, and potential posttreatment complications may help reduce anxiety and discomfort and manage patient expectations. Informed consent is recommended for all procedures, as are pre- and posttreatment photographs of the affected areas.
Durability of Effect
Injectable agents and devices may remain in the body for varying lengths of time, depending upon the physiochemical composition of the agent, the extent of perceived correction, and movement of the treatment area. The durability differentiates each agent in terms of cost and recovery time. The collagens, generally shorter term agents that correct for 3 to 6 months, entail frequent treatments, while HAs may persist for 12 months. Synthetic fillers and compounds tend to persist for 12+ months (CaHA and PLLA, from 6 to 18 months; PMMA, 5+ years; and Si, permanent).
Combining and Layering Agents
Given the interrelationships and interactivity of structural facial anatomy, a clinician may combine technique, modalities, and agent selection to the overall corrective protocol to achieve a comprehensive goal. Off-label combination approaches to aesthetic rejuvenation may include layering dermal fillers/volumizing agents at different depths or combining neuromodulators to relax the muscles and increase the agent’s persistence.2 In clinical practice, determining which fillers most effectively rejuvenate in tandem depends on the interaction of agent physiochemical properties; the mechanical and aesthetic interrelationship among the areas of the face; desired corrective intervention; and patient/physician experience with each material. These variables will guide the practitioner’s choice, application, technique, and delivery of the injectable filler/volumizing agent.
Efforts to enhance and optimize the patient’s experience upon injection of dermal fillers/volumizing agents have led practitioners to study the salutary effects of premixing lidocaine with agents such as CaHA and HA. The amount of injectable anesthetic may be calibrated based upon the anatomical area targeted for treatment. For example, when employed with a tiered approach, CaHA retains its integrity when combined with lidocaine. The three-tiered approach of lidocaine dilution with CaHA permits varying degrees of dermal and subcutaneous injection with no compromise to G′ lifting ability. Depending upon the anatomical injection site the diluent volume varies. The recommended initial diluent is 1% lidocaine.32 In addition, Restylane-L, suitable for correction of severe to moderate wrinkles and folds, also works to improve the tear trough deformity.15,32 Combining Restylane-L 1.0 cc with 1% lidocaine in a 1:1 ratio disperses the filler to lower its viscosity and concentration upon injection, allowing for smooth and uniform deposition as well as minimizing the possibility of the Tyndall effect.32
Injection technique and the plane of injection for filler/ volumizing agent implantation is a function of the agent’s characteristics and the patient’s anatomy. Physiochemical properties of the agent, facial zone, treatment area, and extent of indicated correction determine several variables: needle size, cannula gauge, angle and injection pattern; filler volume, quantity and dilution; plane of injection; and pre- and post-procedure protocols.
Although needle sizes relate primarily to filler viscosity and its impact upon extrusion, G′ and h* help enable a filler to resist movement imposed by an external force.9 Lower h* fillers (e.g., Prevelle and Belotero) that are easily extruded can be administered with smaller bore 30G needles, while larger bore needles (27G) afford less resistance to the flow of highly viscous products (e.g., Juvederm Ultra Plus and Perlane).33
Manufacturers are keenly aware of the ergonomics of injection and are addressing the subject with new designs and adaptive strategies. For example, the growing trend in blunt cannula and automated injection assist devices (Artiste) requires fewer punctures and allows continuous, predictable filler placement with less pain for the patient and less fatigue for the physician. Advocates of cannula point to a theoretically decreased chance of intravascular injection.
Prior to treatment, a patient should be administered topical anesthetics, nerve blocks, ice packs, and dermal or filler-diluted (i.e., Radiesse, Restylane, and Sculptra) lidocaine injections. During treatment, one must always strive to avoid the vascular network during product delivery. Utilizing lidocaine-containing epinephrine may decrease the chance of intravascular injection. A slow, uniform injection in the correct plane minimizes the likelihood. Post injection, massaging the injected area helps attain even filler distribution.2
Threading, Crosshatching, and Fanning
Filler/volumizing agents may be delivered slowly through an antegrade (i.e., forward) or retrograde (i.e., backward) linear threading technique, which delivers the filler in a continuous, uninterrupted flow along the depression. Threading, crosshatching, and fanning allow for horizontal, vertical, crosshatch (gridding), fanning, or diagonal, parallel layering.34
Depending upon the desired augmentation, a quantity of filler is deposited as a bolus. The bolus is then molded and massaged into the desired shape and contour. Depot injections are often used in the hand or in augmenting the temporal hollow via a supraperiosteal placement.
Small quantities of filler are injected in close proximity along the same wrinkle or crease to form a continuous line of volumization. This particular technique allows for predictable agent placement and is easily mastered.
ADVERSE EVENTS AND TREATMENT
Every injectable filler has the potential to cause adverse events. The degree of possible complication, time of onset from injection, and the type of reaction (i.e., immunologic versus technical error) dictate treatment.35 Even though FDA-cleared dermal filler/volumizing agents undergo rigorous testing before approvals are issued, patients and practitioners should be well informed about the possibility of postinjection adverse events. As the popularity and development of dermal filling/volumizing agents grow worldwide, patients and physicians should resist using potentially contaminated, unregulated agents that have not been approved by the appropriate governing agencies.
The physician should conduct a thorough patient evaluation, eliciting a comprehensive clinical history to determine individual immunological contraindications, bleeding disorders, or hypersensitivity to the physiochemical properties of a given agent.36 Thoughtful consideration of the agent’s compatibility, injection technique, needle size, patient anatomy, and duration of the filler in the body may prevent serious reactions.34 Prior to treatment candidates should be counseled to discontinue the intake of anticoagulants, anti-inflammatory medications, vitamin E or other medicines, or nutritional supplements that may inhibit clotting or platelet adhesions. Antiviral prophylaxis is appropriate for patients with a history of “cold sores.” Application of a topical anesthetic or nerve block, mixing filler with lidocaine, and/or applying icepacks may reduce the discomfort of injection.
Immediate complications include redness, swelling, and vascular compromise, requiring aggressive, early intervention and treatment. In the rare instance of impending necrosis, after the injection is stopped, aggressive therapy employing gentle massage, warm compresses, use of acetyl salicylic acid, and topical application of nitroglycerin 2% should be started. If HA fillers have been injected, hyaluronidase injection will remove some of the product and reduce pressure on the blood vessel limiting the area of possible necrosis. Low molecular weight heparin injections into the area may limit the progression of the necrosis as well.37-39
Up to 6 months posttreatment, adverse events may include nodule development due to excessively superficial placement, use of an agent in an inappropriate anatomical area, or inappropriate dilution of the agent. Clinicians must be able to differentiate between nodules and granulomas, the latter of which represents a delayed immunological response. This is critical since the treatment varies significantly. Nodules are secondary to the material placed; treatment may involve massage, hyaluronidase injection, I/D, or excision. Granulomas may respond to steroid injections combined with antimetabolites such as 5-fluorouracil. For HA-induced granulomas, hyaluronidase may be indicated as the initial treatment.40
Attention to sterile technique during injecting will likely reduce the introduction of pathogens into the area. However, biofilms, rare but possible with any injectable implant, may present after more than a year postinjection and require aggressive antibiotic treatment. The concern about the possibility of biofilm supports earlier cautions against importation or use of unapproved products27 (Table 42.3).
Although the practice of filler/volumizing agent injection is aesthetically driven, the practice of aesthetic medicine is based upon science. To meet patient’s expectations, practitioners consider a range of products and protocols to recontour, revolumize, and restore vitality and elasticity to the face. The physiochemical properties of these fillers determine their clinical performance, longevity, ease of delivery, safety, efficacy, and cost. Thoughtful assessment of the patient’s needs combined with a thorough knowledge of available options will benefit the physician, patient, and industry as it continues to mature.
Growing exponentially in popularity, minimally invasive aesthetic correction has become a dynamic field. Development of new soft-tissue filler/volumizing agents with more versatility, efficacy, and biocompatibility has generated an international market for affordable, durable, safe, and effective agents that can offer a refreshing, youthful appearance to a generation reluctant to succumb to the external aging process.
1. American Society of Plastic Surgeons. Cosmetic Surgery National Data Bank: Statistics 2010. http://www.surgery.org/sites/default/files/Stats2010_1.pdf. Accessed November 2, 2011.
2. Alam M, Gladstone H, Keamer EM, et al. ASDS guidelines of care: injectable fillers. Dermatol Surg. 2008:34:S115-S148.
3. Lemperle G, Holmes RE, Cohen S, et al. A classification of facial wrinkles. Plast Reconstr Surg. 2001;108:1735-1750.
4. Rohrich RJ, Pessa JE. The fat compartments of the face: anatomy and clinical implications for cosmetic surgery. Plast Reconstr Surg. June 2007;119(7):2219-2227; discussion 2228-31.
5. Lorenc ZP. New consensus recommendations for injectable shaping agents: an expert interview with Z. Paul Lorenc, MD. Medscape Educ Dermatol. http://www.medscape.org/viewarticle/732944. Accessed November 5, 2011.
6. Lemperle G, Morehenn V, Charrier U. Human histology and persistence of various injectable filler substances for soft tissue augmentation. Aesthetic Plast Surg. September-October 2003;27(5):354-366; discussion 367. Epub 2003 December 4.
7. Morhenn VB, Lemperle, G, Gallo RL. Phagocytosis of different particulate dermal filler substances by human macrophages and skin cells. Dermatol Surg. June 2002;28(6):484-490.
8. Lorenc ZP, Nir E, Azachi M. Characterization of physical properties and histologic evaluation of injectable dermicol-P35 porcine-collagen dermal filler. Plast Reconstr Surg. June 2010;125(6):1805-1813.
9. Kablik J, Monheit GD, Yu L, Chang J, Gershkovich J. Comparative physical properties of hyaluronic acid dermal fillers. Dermatol Surg. 2009;35:302-312.
10. Stocks D, Sundaram H, Michaels J, Durrani MJ, Wortzman MS, Nelson DB. Rheological Evaluation of the Physical Properties of Hyaluronic Acid Dermal Fillers J Drugs Dermatol. 2011;10(9):974-980.
11. Sundaram H, Voigts MS, Beer K, Meland M. Comparison of the rheological properties of viscosity and elasticity in two categories of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid. Dermatol Surg. 2010;36:1859-1865.
12. Laurent UBG, Reed RK. Turnover of hyaluron in the tissues. Adv Drug Deliv Rev. 1991;7:237-255.
13. Laeshke K. Biocompatibility of microparticles into soft tissue fillers. Semin Cutan Med Surg. 2004;23:214-217.
14. Rohrich RJ, Hanke CW, Busso M, et al. Facial soft-tissue fillers: assessing the state of the science conference—proceedings report. Plast Reconstr Surg. April 2011;127(4 Suppl):22S.
15. Bergeret-Galley C. Comparison of resorbable soft tissue fillers. Aesthet Surg J. January-February 2004;24(1):33-46.
16. Dermal filler product comparison. Aesthetic Buyers Guide. May/June 2007. www.miinews.com. Accessed November 3, 2011.
17. Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg. 2007;33:S222-S230.
18. Lemperle G, Knapp TR, Sadick NS, Lemperle SM. ArteFill permanent injectable for soft tissue augmentation: I. Mechanism of action and injection techniques. Aesthetic Plast Surg. June 2010;34(3):264-272. Epub 2009 September 29. Presented in part at the First World Congress on PMMA Fillers, Guadalajara, Mex, 5-6 December 2008. http://www.escholarship.org/uc/item/45b4s0jb?display=all. Accessed November 5, 2011.
19. Tezel A. Frederickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther. 21 December 2007; 1-8.
20. Lorenc, ZP. HA-cohesive polydensified matrix technology – clinical implications. Presented at aesthetic plastic surgery and anti-aging medicine: the next generation. June 12, 2011.
21. Busso M, Applebaum D. Hand augmentation with Radiesse (calcium hydroxylapatite). Dermatol Ther. November-December 2007;20(6): 385-387.
22. Lorenc ZP. Techniques for the optimization of facial and non-facial volumization with injectable poly-L-lactic acid. Aesthetic Plast Surg. 2012;36:1222-1229.
23. Vleggaar D. Soft-tissue augmentation and the role of poly-L-lactic acid. Plast Reconstr Surg. September 2006;118(3 Suppl):46S-54S.
24. Wolters M, Lampe H. Prospective multicenter study for evaluation of safety, efficacy and esthetic results of cross-linked polyacrylamide hydrogel in 81 patients. Dermatol Surg. 2009;35(Suppl):338-343.
25. Fibrocell Technologies, Inc. Highlights of prescribing information. http://www.mylaviv.com/pdf/LAVIV-prescribing-info.pdf (2011). Accessed November 9, 2011.
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27. Jones D. Semipermanent and permanent injectable fillers. Dermatol Clin. 2009;27:433-444.
28. Fulton JE Jr, Porumb S, Caruso JC, Shitabata PK. Lip augmentation with liquid silicone. Dermatol Surg. November 2005;31(11 Pt 2):1577-1586.
29. Barnett JG, Barnett CR. Treatment of acne scars with liquid silicons injections: 30-year-perspective. Dermatol Surg. 2005;31(11 pt 20):1542-1549.
30. Fitzgerald R, Gravier MH, Kane M, et al. Facial aesthetic analysis. Aesthet Surg J. July-August 2010; 30 (Suppl):25S-27S.
31. Bashour M. History and current concepts in the analysis of facial attractiveness. Plast Reconstr Surg. 2006;118:741-756.
32. Lorenc ZP. A three-tiered approach to the use of premixed lidocaine with calcium hydroxylapatite for treatment areas of the face. Cosmetic Dermatol. 2012;25(6):266-270.
33. Sherman R. Avoiding dermal filler complications. Clin Dermatol. 2009;27:523-532.
34. Jones D, Flynn TC, Hyaluronic acids: clinical applications. Injectable Fillers. http://www.medscape.org/viewarticle/709469_2. Accessed November 8, 2011.
35. Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding and treating dermal filler complications. Plast Reconstr Surg. 2006;118(3 Suppl):92S-107S.
36. Grimes PE. Aesthetics and Cosmetic Surgery for Darker Skin Types. Chicago, IL: Lippincott Williams and Wilkins (Wolters Kluwer Health); 2007.
37. Schanz S, Schippert W., Ulmer A, et al. Arterial embolization caused by injection of hyaluronic acid (Restylane). Br J Dermatol. 2002:146:928-929.
38. Hirsch RJ, Cohen JL, Carruthers JD. Successful management of an unusual presentation of impending necrosis following a hyaluronic injection embolus and a proposed algorithm for management with hyaluronidase. Dermatol Surg. 2007:33:357-360.
39. Hirsch RJ, Lupo M, Cohen JL, Duffy D. Delayed presentation of impending necrosis following soft tissue augmentation with hyaluronic acid and successful management with hyaluronidase. J Drugs Dermatol. 2007;6: 325-328.
40. Brody HJ. Use of hyaluronidase in the treatment of granulomatous hyaluronic acid reactions or unwanted hyaluronic acid misplacement. Dermatol Surg. 2005;31:893-897.