45: Hyaluronic Acid Fillers

Hyaluronic Acid Fillers

Mark S. Nestor1,2,3, and Daniel Fischer1

1 Center for Clinical and Cosmetic Research, Aventura, FL, USA

2 Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

3 Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Miami Miller School of Medicine, Miami, FL, USA


The appearance of the aging face is a compilation of intrinsic aging as well as genetics which causes the pre‐programmed loss of fat, muscle, and bone and finally photodamage that affects the integrity of collagen and elastin and accelerates the aging process [1]. One of the hallmarks of the aging face is the loss of tissue volume and as well as the accentuation of lines and folds [2]. While many procedures can be used to improve the appearance of the aging face, the use of soft tissue dermal fillers has become one of the most popular ways of filling lines and wrinkles as well as replacing volume in the aging face [3].

According to recent statistics of the American Society of Aesthetic Plastic Surgeons, the use of dermal fillers is only second to Botox as one of the most popular non‐surgical cosmetic procedures performed in 2018. That same year, there were 2.6 million soft tissue filler procedures performed in the United States, an increase of 2% from the prior year. Of all the dermal fillers used in the United States, hyaluronic acid fillers accounted for at least 84% in 2018 with a 2% increase in their use since 2017 [4]. While hyaluronic acid fillers may not be “the perfect” filler in all aspects, they come very close to what most patients and physicians look for in the ideal filler, namely non‐permanent but long‐lasting, have few if any allergic aspects, minimal side effects, are relatively painless to inject, and safe because of the reversible nature of hyaluronic acid fillers. This chapter will outline the science and use of hyaluronic acid fillers including:

  1. The chemical composition and physical properties of hyaluronic acid fillers.
  2. The indications for the variety of FDA approved fillers.
  3. Injection techniques, both beginner and advanced.
  4. Complications of filler injections and their solutions.
  5. Future uses and indications for hyaluronic acid fillers.

Chemical composition and properties of hyaluronic acid fillers

At this time, there are twelve marketed FDA approved hyaluronic acid fillers used in the United States. These are listed in Table 45.1 [59]. All hyaluronic acid fillers are formed from either bacterial based or animal‐based hyaluronic acid. Hyaluronic acid is a polysaccharide, specifically a glycosaminoglycan that is formed from repeating D‐glucuronic acid and DN‐acetylglucosamine disaccharide units. The disaccharide units are linked together in a linear chain forming a large polymer with a total molecular weight of greater than 10 MDa. While both animal‐based and bacterial‐based hyaluronic acid fillers are on the market, the vast majority of utilized fillers are based on bacterial production. Native hyaluronic acid would break down very quickly if injected into the skin and needs to be altered and stabilized primarily by cross‐linking to have a long resident life in the skin. Since the basis of all bacterial‐based dermal fillers is the same, the difference between fillers and their properties depends upon the type and degree of cross‐linking as well as the manufacturing process that forms the ultimate filler [10].

Table 45.1 Food and Drug Administration (FDA) approved hyaluronic acid (HA) fillers [59].


  • Juvéderm ™ Ultra/Juvéderm ™ Ultra Plus
  • Juvéderm Voluma™ XC
  • Juvéderm Volbella™ XC
  • Juvéderm Vollure™ XC

  • Restylane®
  • Perlane®
  • Restylane Silk®
  • Restylane Lyft®
  • Restylane Refyne®
  • Restylane Defyne®
  • Restylane Kysse®

  • Hylaform® (taken off market)
  • Hylaform Plus® (taken off market)

  • Prevelle™ Silk (taken off market)

  • Belotero Balance®

  • Versa®

  • Teosyal RHA®

The important chemical and physical properties of the different filler substances include as noted, the type and degree of cross‐linking, the total hyaluronic acid concentration, the size of the particle and/or the consistency of the gel, and the degree of gel hardness also known as G prime.

The most commonly used hyaluronic acid products in the United States use BDDE (1,4‐butanediol diglycidyl ether) as cross‐linking agents. This includes Juvéderm Ultra and Ultra Plus, Juvéderm Voluma, Juvéderm Volbella, Juvéderm Vollure, Perlane, Restylane, and Belotero which are the most commonly used hyaluronic acid products in the United States. Juvéderm Ultra and Ultra Plus, Perlane, and Restylane all utilize a hylacross network of high‐molecular weight HA while Juvéderm Voluma, Volbella, and Vollure are composed of both low‐ and high‐molecular weight HA that are more tightly cross‐linked [11]. The advantage of this type of molecular architecture is that it minimizes water uptake and therefore the amount of swelling that otherwise would occur post‐treatment [6, 12]. Belotero has a unique cohesive polydensified matrix which has a high concentration of non‐cross‐linked molecules and the degree to which the filler is cross‐linked is not uniform, creating areas of greater and lesser density, thus polydensified [13]. Restylane Defyne and Refyne are HA fillers that utilize XpresHAn crosslinking technology and have been shown to be effective in treating the nasolabial fold and marionette line regions by adding volume and producing a dermal tightening effect [14]. The degree of cross‐linking indicates the percentage of hyaluronic acid disaccharide monomer units that are bound to a cross‐linking molecule. For hyaluronic acid fillers, some feel that when all factors are equal, a higher degree of a cross‐linking agent may translate into a longer persistence of the filler. There are questions, however, about the effect that cross‐linking has on biocompatibility, namely setting the filler as a foreign substance. Therefore, there may be an optimal degree of cross‐linking that may give the longest duration of residence in the skin without causing biocompatibility issues.

Total HA concentration refers to the amount of hyaluronic acid per milliliter in a product. It generally measures both cross‐linked hyaluronic acid and free hyaluronic acid in a product. Free hyaluronic acid or non‐cross‐linked hyaluronic acid is generally added in varying amounts to some products to improve lubrication or product flow. The most widely used hyaluronic acid products are of similar concentration but may vary as to the degree of free or non‐cross‐linked hyaluronic acid, gel hardness, and hyaluronic acid gel consistency. The two most popular hyaluronic acid product lines, namely the Restylane product line and the Juvéderm product line, are produced by different mechanical means. The Restylane product line is sieved, thus it is pressed through screens to split the molecules into different size particles; the smallest in Restylane Silk and the largest in Restylane Lyft. The Juvéderm line is manufactured in a way that homogenizes the particles in a blender‐type apparatus. Juvéderm Voluma is created with a combination of low‐ and high‐molecular weight hyaluronic acid, creating a more mobile fiber network which facilitates cross‐linking to 1,4‐butanediol.

Belotero Balance is non‐sieved, meaning no particle sizing occurs and the product consists of homogeneous masses of both cross‐linked and non‐cross‐linked hyaluronic acid molecules with variable shapes and sizes [15]. Belotero Balance begins with longer strands that are not cross‐linked creating softer areas with less cross‐linking and firmer areas with more cross‐linking.

The different formulations and production strategies yield different gel hardness or G prime to the variety of different products. Clinically, G prime can be thought of both as the amount of force that is necessary to inject a product through a specific‐sized needle, as well as the lifting capacity of the filler. In general, fillers that are thicker are more difficult to inject through smaller needles, but based on their properties can act to bring in more water and thus cause more tissue lifting in a given area. This is critical to the product’s in vivo behavior and clinical indication and the reason that products are not easily interchangeable.


Most HA fillers are FDA approved to fill “moderate to severe lines and folds” such as the nasolabial fold. Juvéderm Voluma and Restylane Lyft are approved for midface volumization (Restylane Lyft is also known as Perlane so that it is also approved for moderate to severe lines and folds such as the nasolabial fold). Restylane is also approved for lip augmentation and Restylane Silk is approved for lip augmentation as well as perioral lines.

Historically, fillers such as collagen were used to fill fine lines and wrinkles including those in the perioral and periorbital regions. Collagen fillers were injected in the mid‐dermis and usually had a clinical life in the skin of approximately 3 to 6 months. Hyaluronic acid fillers are generally injected deeper in the skin, most often below the dermis in the superficial subcutaneous layer and traditionally have primarily been indicated for deeper lines and folds [16, 17]. Prior to the availability of Belotero Balance, and to a lesser extent Restylane Silk, hyaluronic acid fillers could not be injected superficially because of the risk of the Tyndall effect; whereby the filler appears as a blue hue directly under the skin [18]. This occurs because the hyaluronic acid implanted into the superficial dermis scatters the light, striking it so that blue light, which has a shorter wavelength, is reflected back to an observer’s eye. Belotero Balance has been used to inject superficial lines in the perioral, periorbital, and cheek areas and has not been shown to exhibit Tyndall effect even when it is injected very superficially in the dermis [19]. The majority of hyaluronic acid fillers used to date were initially used in the nasolabial fold, mesolabial fold as well as other similar lines and folds in the face. Revanesse Versa, approved in 2017, has been shown to be particularly effective in treating facial rhytides of the nasolabial folds. The effects of this product have been shown to last for up to 12 months [20].

Hyaluronic acid fillers have also eclipsed into volume replacement. Thicker hyaluronic acid fillers such as Juvéderm Voluma and Restylane Lyft are FDA‐approved for volume deficit replacement in the midface, with reports of durability of Juvéderm Voluma of up to 2 years after initial volume replacement [21]. Since the release of Juvéderm Voluma to the market, Juvéderm Vollure and Juvéderm Volbella have brought additional advantages to volume replacement, as illustrated in Table 45.2. Another relatively new product line includes the Teosyal RHA (Resilient Hyaluronic Acid) family which has been approved for a variety of uses from superficial to deep wrinkles as well as volume replacement. Indication depends on the specific product and results have been shown to last from 6 to 9 months [24].

Table 45.2 Comparison of Juvéderm Vycross products [12, 22, 23].

Product Advantages Indicated locations
Voluma (2013) Adds volume and structure and lifts tissue, eyebrow shaping Temples, forehead, acne scars, all areas of cheek, jaw angle and line
Vollure (2017) Fills and contours lines, eyebrow projection Forehead, mid‐cheek accordion lines, marionettes, perioral cutaneous and vermilion
Volbella (2016) Smooths superficial fine lines and adds volume to perioral region Periorbital, tear trough, glabella, forehead lines, fine cheek lines, vermilion and perioral areas, upper lip lines, ear lobes

Hyaluronic acid fillers may be used to augment areas such as the lips by replacing lost volume due to aging and by enhancing lip volume. Restylane Silk has also been shown to significantly improve perioral lines. The most recently approved HA filler, Restylane Kysse, was approved in May of 2020 to add fullness to the upper lip and surrounding lines. Unlike other filler used for this purpose that last 3–6 months, Restylane Kysse has been shown to last up to 12 months [25]. Additionally, fillers are used to replace volume in areas such as the hands and resculpt and act as reshaping agents in areas such as the nose and the chin [26, 27]. Hyaluronic acid fillers have significant advantage over other fillers for these indications because of their longevity and overall low incidence of inflammation and significant swelling. Comparisons between HA fillers are illustrated in Table 45.3 [28].

Injection techniques

Fillers in general are injected using four basic techniques:

  1. Droplet injection.
  2. Linear threading either antegrade or retrograde.
  3. Fanning.
  4. Volumizing.

As noted, the majority of hyaluronic acids are injected either in the deep dermis or superficial subcutaneous layer and studies have shown that the vast majority of injections are in the subcutaneous layer [17]. Most administrators use a combination of injection techniques depending upon the specific area that is being injected. Studies have shown that slower injection techniques tend to decrease side effects and swelling as well as decrease patient discomfort [33].

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Nov 13, 2022 | Posted by in Dermatology | Comments Off on 45: Hyaluronic Acid Fillers
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