Introduction to soft tissue fillers

Soft tissue fillers have evolved since the days of bovine collagen. Currently, there are at least 20 different biodegradable soft tissue fillers in the market. The rapidly evolving technology behind these products changed the practice of esthetic medicine and expanded the cosmetic marketplace by attracting patients interested in affordable, minimally invasive procedures. In this series, we aim to review the most pertinent advances in soft tissue filler technology and their implications for clinical practice. The first commercial fillers to gain Food and Drug Administration (FDA) approval were implantable purified bovine collagen products developed by Allergan in the early 1980s (Zyderm™, Zyplast™). These products required an intradermal skin test before injection due to the risk of hypersensitivity reactions to the bovine-derived peptides.1 They also suffered from high manufacturing costs and short-lived clinical results.2 The first-generation bovine collagen fillers are no longer available in the market, but several products were subsequently developed and remain in the market today in solution with polymethylmethacrylate (PMMA) such as Bellafill™ (Suneva Medical). The advent of Restylane™ (Galderma) in 2003 heralded a new era for soft tissue augmentation. Restylane™ was the first filler based on cross-linking of hyaluronic acid (HA), a naturally occurring, protein-free glycosaminoglycan present in the dermis. HA retains water in the extracellular matrix of the dermis by forming a backbone for the binding of large polymer complexes with negative charges.3 Cross-linking inhibits the enzymatic breakdown of HA products in fillers and allows for much longer duration of clinical efficacy.4 Since Restylane was approved, many other HA fillers have been introduced to the market with a variety of different properties aimed at specific indications from nasolabial fold volumization to jawline contouring. The unique cross-linking of each HA filler confers specific physical properties, which dictate the indicated uses for the product. In physics, rheology is the study of the deformation and flow of liquids. In the context of esthetic medicine, rheology refers to the study of soft tissue filler properties affecting their clinical performance. To choose the best filler for a case, the esthetic physician should consider the local physical forces including lateral sheering forces and vertical compression that will be applied to the filler. The elasticity (G′) of a filler describes its ability to resist lateral sheering forces and restore its original shape after forces are applied. The viscosity (G″) of a filler measures its inability to restore its original shape after forces are applied. The hardness (G*) describes the total energy needed to deform the filler.5 The cohesivity of a filler reflects its ability to resist dissociation from other HA molecules.6 Experimental adjustment of these rheological properties in the laboratory setting has yielded a plethora of new HA products. In turn, new techniques and applications of these novel products have developed, which have expanded and complicated the decision-making process for clinicians. HA fillers were not the only soft tissue augmentation products to benefit from technological advancements. A variety of non-HA fillers have emerged with FDA approval. In 2006, Radiesse™ (Merz) gained FDA approval for facial lipoatrophy and deep rhytid treatment. This product consists of microspheres of implantable synthetic calcium hydroxylapetite (CaHA).7 In 2021, Radiesse™ became the first soft tissue filler to gain FDA approval for jawline contouring. In practice, Radiesse™ is a firmer product than HA fillers and can be used for the correction of deep rhytids, nasolabial folds, or hands, along with volumization of deep anatomic planes such as supraperiosteal contouring of jawlines. Bellafill™ (Suneva) is a solution of PMMA microspheres intended to stimulate collage production and bovine collagen for immediate volumization. Since this product contains bovine collagen, a skin test is indicated before use. Bellafill™ benefits from the long-lasting effects of its PMMA microspheres, which lasts up to 5 years and is the only soft tissue augmentation product FDA approved for acne scarring treatment.8 Sculptra™ (Galderma) is a poly-l-lactic acid (PLLA) solution designed to stimulate in situ collagen synthesis and fibroplasia. This stimulation occurs through the activation of a subclinical inflammatory response by hydrolyzed PLLA microparticles that are ultimately encapsulated by newly deposited collagen leading to an increase in overall dermal thickness.9 In contrast to the instant, in-office volumizing effects of more traditional fillers, Sculptra volumizes skin gradually as de novo collagen synthesis occurs. Traditional classification schemes for soft tissue fillers have grouped fillers as HA versus non-HA materials. The biostimulatory effects of dermal fillers will be a key future property for classifying soft tissue fillers and considering their clinical applications. Evidence suggests that HA fillers may induce neocollagenesis by mechanically stretching the extracellular matrix in the dermis and subsequently stimulating fibroblasts.10 This biostimulatory mechanisms contrast with non-HA fillers such as PLLA, which stimulates fibroblasts via an inflammatory cascade.11 As more downstream mechanisms are elucidated, the classification of soft tissue fullers may evolve. Regardless of product choice, injection of dermal fillers is considered an elective cosmetic procedure with costs covered by patients out-of-pocket in most cases. However, the use of dermal fillers for the treatment of medical conditions, such as volume replacement in facial nerve paralysis, is being actively researched.12 The Centers for Medicare and Medicaid Services has approved reimbursement for the use of dermal fillers in the treatment of facial lipodystrophy syndrome in human immunodeficiency virus (HIV) patients experiencing depression related to their HIV treatment.13 In the future, more indications for dermal fillers may be covered by patient insurance as possible medical benefits of these products are demonstrated. The advent of soft tissue filler injections has played a key role in the growth of the cosmetic procedure market. Overall, the number of minimally invasive cosmetic procedures has increased since the early 2000s as more patients elect for nonsurgical options like injectables or laser skin resurfacing. With this rise in nonsurgical cosmetic procedures, the placement of soft tissue fillers has been second only to the injection of neuromodulators (e.g., Botox™, Dysport™, Xeomin™, Jeuveau™) in total procedure number. The American Society of Plastic Surgeons (ASPS) estimates that their members performed 3.4 million soft tissue filler procedures in 2020.14 Of those 3.4 million procedures performed by ASPS members, the overwhelming majority occurred in Caucasian (78%) females (96%) in the age range of 40–54 years old (49%). The ASPS additionally estimates that these patients represent over $2.5 billon USD in expenditures on dermal filler injections in 2020 with nearly $1.8 billon USD devoted to HA fillers alone. This increase in filler injections over the last two decades has coincided with a shift in the interests of the general public. In particular, a survey of search engine trends from 2004 to 2017 demonstrated an increase in the use of the terms “Juvederm™” and “Radiesse™,” along with downward trends in the use of the terms “rhinoplasty,” and “liposuction.” There was also an observed significant increase in the search for a “dermatologist” with no significant change observed for “plastic surgeon.”15 These results suggest both an increase in the popularity of noninvasive procedures and an informed patient population aware of trends in cosmetic procedures such as the development of new HA fillers, and that this patient population is increasingly choosing dermatologists for these procedures. When searching for information related to filler injections and other cosmetic procedures, patients are relying on Internet sources and social media to inform their decisions. One survey of 500 plastic surgery patients reported 95% of patients considering a cosmetic procedure consulted an online source with 68% using the internet as their first source.16 Furthermore, 40% of patients reported they were strongly influenced by social media when choosing their providers. The novel influence of social media cannot be overstated as multiple studies have demonstrated the power of social media in motivating patients’ decisions related to cosmetic procedures, whether through influencers or advertising.15-17 Popular culture, including the actions of celebrities, is an additional significant influence shifting the preferences and decisions of patients interested in fillers. For example, media coverage of reality television star Kylie Jenner led to a dramatic increase in the usage of the search engine term “fillers” at the height of her media scrutiny with a sustained general increase in the following years.18 Techniques and technology surrounding soft tissue augmentation using dermal fillers have progressed significantly over the past few decades. The unique coevolution of Internet-based advertising and social media will continue to draw new patients with interest in these procedures. In the future, dermal fillers are likely to play an ever-increasing role in cosmetic dermatology and plastic surgery as the science of rheology advances. It is essential that clinicians offering these services remain up-to-date on novel products and techniques in a rapidly changing practice environment. The authors have nothing to report. Dr. Pearlman has received grant funding from the American Academy of Dermatology for research relating to DataDerm. He has served on advisory boards for Castle Biosciences. Dr. Schlesinger serves as an investigator and consultant for Abbvie, Galderma, Merz, and Suneva. The remaining author declares no conflict of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.