Restylane Filler Product Family

Introduction

The use of an exogenous material to augment soft tissue can be traced back to Neuber in 1893, who used fat transplanted from the arms to correct facial defects. Since that time, substances used to volumize the face have changed rapidly and include both biodegradable and nonbiodegradable products. The Restylane family is a class of nonpermanent, biodegradable fillers with an average duration of action of 6 to 12 months, with demonstrated effect up to 18 months or longer at certain sites. This chapter will review the current Restylane products available in the US marketplace and provide injection tips for the most common facial areas injected. Patient preparation, potential complications, as well as advice on how to manage patient expectations will be discussed.

Background

Restylane injectable fillers are commonly used to correct moderate to severe facial lines, restore volume loss that occurs during the natural course of aging, and augment natural volume to achieve desired cosmesis. Since the US Food and Drug Administration (FDA) approval of Restylane in December 2003, the Restylane injectable market has continued to expand, along with the hyaluronic acid (HA) filler market in general. According to the American Society for Dermatologic Surgery (ASDS), there were approximately 1.6 million soft tissue filler injections performed in 2019 alone by ASDS members, which represents an increase in 78% over the last 8 years. This does not include procedures performed by plastic surgeons or other aesthetic practitioners. Moreover, the recent COVID-19 pandemic has led to an even larger boom in injectables, in light of increased work from home and video conferencing. When it comes to filler selection, knowing where to place these fillers is as important as understanding the subtle differences between their rheologic and physicochemical properties. In general, Restylane injectables are safe, confer a soft look, are predictable in their volumizing capacity, and, crucially, are easily reversible with hyaluronidase.

Basic science

HA, or hyaluronan, is an anionic, hydrophilic, nonsulfated glycosaminoglycan that is abundant in human connective tissue. As one of the chief components of the extracellular matrix, HA stabilizes intercellular structures and forms part of the fluid matrix in which collagen and elastic fibers become embedded. With age, HA concentration in the skin decreases, resulting in reduced dermal hydration, which manifests as an increase in lines and folds. In addition, excessive exposure to ultraviolet B rays causes cells in the dermis to stop producing HA. In its natural form, HA has a half-life of 1 to 2 days and is metabolized by the liver to carbon dioxide and water. As a compound, it can absorb up to 1000 times its molecular weight in water; its mechanism of action as a filler is mainly through hydration. In a large immunogenicity study, nonanimal stabilized HA (NASHA) products did not elicit cellular or humoral responses in 98% of participants, suggesting that these products are not commonly allergenic or immunogenic. However, hypersensitivity reactions have rarely been reported, such as acute angioedema within minutes after injection of HA filler in the lips.

There are several important factors, known as the rheologic and physicochemical properties, in the formulation of HA filler products that determine how the product will function ( Table 5.1 ). The HA molecule is stabilized with cross-linked hydroxyl groups. It is this cross-linking that confers longevity and mechanical strength to the product in the skin. Cross-linking and concentration of HA are key in determining the filler’s rheologic properties—elastic modulus (G′), viscous modulus (G′′), tan δ (G′′/G′), and complex modulus (G*)—and physicochemical properties—gel fluid uptake (or swelling factor [SwF]) and gel cohesion. Briefly, G′ represents the ability of the filler to rebound to its original shape when acted on by dynamic forces, with a higher G′ typically signifying a firmer product. G′′ represents the filler’s viscosity or resistance to dynamic forces, whereby a higher G′′ gel is often thicker and requires more force to eject. Tan δ (G′′/G′) is the proportion of viscosity to elasticity. G* represents the ability of the filler to resist deformation, which for most HA fillers is comparable to G′. SwF is a marker of gel hydration status, or how much the gel will expand when binding water, whereby a gel with higher SwF is further from equilibrium and will take up more fluid after injection. SwF is not to be confused with tissue swelling. Lastly, gel cohesion represents the filler’s dissociation rate, such that a highly cohesive gel dissociates less readily and has greater ability to lift. Table 5.1 delineates the rheologic and physicochemical properties of all of the Restylane products available in the US marketplace. An understanding of these properties, discussed in greater depth in Chapter 4 , is crucial for the injector in product selection, as certain products are better suited than others when it comes to anatomic site and depth of placement.

Owing to the structural matrix of HA filler products, the degradation curve of implanted HA is not linear. Rather, the product retains its effect until the structural complex around the HA molecule is broken down. Once the unbound HA is exposed, efficacy is then lost ( Fig. 5.1 ). As a result, patients will often suddenly notice a change in their appearance rather than experience a gradual loss over time. In addition, patients sometimes feel they look worse after HA injection than they did prior to it; however, this is more of a function of selective memory. For this reason, taking preinjection photographs is important. As with natural hyaluronan, HA fillers can be quickly dissolved with the enzyme hyaluronidase in the case of adverse events or unwanted filler. It has been demonstrated that filler products with greater number of HA cross-linking bonds and greater concentration of HA take longer to dissolve with hyaluronidase.

Choosing the right Restylane filler product

The Restylane filler family is divided into two classes based on HA cross-linking technology, NASHAs and XpresHAn. The NASHAs include Restylane, Restylane-L, Restylane Lyft, and Restylane Silk. The XpresHAn products on the US market include Restylane Refyne and Restylane Defyne. The main difference between commercially available Restylane products on the current US market is the firmness, or G′, of the product, and SwF. The NASHAs have a higher G′ and lower SwF compared with the XpresHAn products, which have relatively lower G′ and higher SwF. The higher the G′, the more firm, less elastic, stiffer the product and the longer it lasts in tissue ( Table 5.1 ). The NASHAs’ higher G′ enables greater lift and they are therefore often injected at deeper planes (subcutaneous and supraperiosteal), whereas the XpresHAn products, with their lower G′, have greater SwF and greater cohesivity. It is postulated that higher cohesivity gels have greater intradermal integration. Lower G′ products, as they are softer, are more often indicated for more superficial injection planes and can be layered on top of higher G′ products. Lower G′ fillers can also be placed in deeper planes, although greater quantity is required to achieve the desired effect.

When selecting a Restylane product based on anatomic location, the authors have several recommendations ( Table 5.2 ). For areas necessitating greater correction or lift, such as along zygomatic and malar cheeks, jawline, and temples, the authors prefer higher G′ products, such as Restylane Lyft or Restylane-L. Restylane-L may also be used with great results for lip augmentation, and in a patient desiring a cost effective, one-syringe treatment of multiple sites, Restylane-L is a great option. For lip augmentation where greater support is desired, Restylane-L is the authors’ preferred filler. However, for a softer, generally plumper lip, Restylane Kysse is a wonderful option. The authors rarely use Restylane Silk with Restylane Kysse now on the market.

For the infraorbital hollows that necessitate greater correction, the authors often choose Restylane-L, with optimal placement in the supraperiosteal plane. The greater G′ of Restylane-L enables more lift here. For patients with infraorbital hollows that are less deep, or when the superficial skin has a thin appearance, a lower G′ product, such as Restylane Refyne, is a nice choice due to better dermal integration. However, this product has greater swell factor; therefore, caution in not overcorrecting should be taken. Incorrect product selection, incorrect technique of filler placement, filler migration, and blockage of lymphatic drainage, among other reasons can all lead to unwanted effects in this sensitive area, which, to the less advanced injector’s eye, may be difficult to recognize as filler complications. With Restylane-L in this region, the injector should be aware that because this is a particle filler, when the product metabolizes several years after placement, the product imbibes a lot of water and some patients may experience superficial edema. If this occurs, the product should be dissolved with hyaluronidase and, if the patient desires, new filler may be placed in the appropriate plane.

For correction of moderate to deep wrinkles and folds, such as nasolabial folds and marionette lines, the authors like Restylane Defyne, as this intermediate G′ product integrates well into the dermis and is not evident upon facial animation. Restylane-L, although not the ideal choice here, may be used in the patient who desires cost effectiveness and minimal syringe number. Restylane Defyne was recently FDA approved for chin augmentation, and the authors like this product, as well as the higher G′ products, Restylane Lyft and Restylane-L, for the chin. For correction of mild to moderate degree nasolabial folds and marionette lines, or other fine lines, Restylane Refyne works quite well due to the lower G′ and dermal integration.

Additionally, it should be noted that not all of the HA in a given filler is cross-linked. Some is free, fragmented, or only lightly cross-linked so that the gel can actually flow out of the syringe with ease. As discussed previously, the cross-linking is what confers longevity to the product, and this does vary within and between brands. In addition to cross-linking, it is worth mentioning that not all HA products are packaged in the fully hydrated state. Due to SwF, volume is created via hydration, and for this reason, patients will often look better or more filled 24 hours after treatment with products like Restylane, which are not completely saturated in the syringe. With that in mind, it is prudent not to overcorrect when using Restylane products.

Patient evaluation

Prior to injection with any filler, a careful patient history should be obtained. Pertinent items to note in this history include a history of herpes simplex virus, pregnancy or breastfeeding, history of keloid formation, presence of any autoimmune disease, and allergy to lidocaine because most of the fillers now come premixed with lidocaine. A medication history should include use of multivitamins, fish oil, vitamin E, blood thinners, aspirin, ibuprofen, and Gingko biloba because all of these can predispose the patient to bruising. Unless medically necessary, the patient should be advised to discontinue these medications 14 days prior to treatment. In addition, alcohol use within 48 hours of injection can cause an increase in bruising tendency. The authors recommended that patients avoid dental procedures 2 weeks prior to and after obtaining filler.

With the recent COVID-19 pandemic and advent of novel vaccines, new data have come to light concerning vaccine side effects as related to injectable filler. In the Moderna mRNA-1273 vaccine trial, 3 subjects out of 15,184 who received at least one dose of the vaccine developed facial or lip swelling in areas of injectable filler placement, while this did not occur for any subjects in the placebo group. The ASDS has released guidance on SARS-CoV-2 mRNA vaccine side effects in injectable filler patients and recommend that patients already treated with fillers should not be discouraged or precluded from receiving vaccines of any kind. Similarly, patients who have had vaccines should not be precluded from receiving injectable fillers in the future. These injectable filler vaccine-related adverse events are rare, temporary, and often responsive to oral corticosteroids and intralesional hyaluronidase and have seen a success in case reports with oral angiotensin-converting enzyme (ACE) inhibitors such as lisinopril. The authors recommend similar timing with regard to getting the SARS-CoV-2 mRNA vaccine as with dental procedures, waiting 2 weeks on either end of filler placement to obtain the vaccine, and most importantly, counseling the patient on this possible side effect so they know to return promptly to the office if this occurs.

If the patient has had fillers in the past, it is recommended that the physician document how long ago, where the fillers were placed, and if the patient was satisfied with the results. Additionally, the prior filler administered should be noted. Adverse reactions have been described in case reports of patients and in murine models where different consecutive fillers were injected at the same site. In addition to history, preinjection photography is a must. These authors prefer at least three views: frontal and left and right side at an oblique angle. If a patient is having a specific area corrected, a close-up picture of that area is also advisable. Informed consent must be obtained, and the patient should be aware of the financial cost of the procedure prior to opening the first syringe. We also advise that baseline facial asymmetry be discussed with the patient and noted in the chart. From a physician standpoint, it is important to inform your malpractice coverage carrier of your intention to use fillers because many uses are considered off-label.