Key points

Introduction

The use of cosmetic injectables, including collagen, hyaluronic acid (HA), fat, synthetic polymers (polylactic acid, polymethylmethacrylate), and calcium hydroxyapatite, has significantly increased in popularity over the past 2 decades. The American Society of Plastic Surgeons reports an increase from 652,888 soft tissue filler procedures in 2000 to 2.3 million in 2014, whereas more invasive surgical procedures have become slightly less popular (the number of facelifts have decreased by 4% from 2000 to 2014). HA has become the top injected soft filler agent around the world (1.8 million procedures reported in 2014 ). The goal of this report is to investigate the rapid transition from other soft tissue fillers to HA following US Food and Drug Administration (FDA) approval and the interesting biomechanical and biochemical advantages behind this immensely popular biomaterial.

Early biomedical applications of HA were quite diverse, including joint synovial fluid replacement to treat osteoarthritis and in ophthalmologic surgery as a vitreous replacement and for retinal detachment surgeries. In 1994, Ghersetich and colleagues reported decreased skin HA content with aging. HA-based dermal fillers were first available in 1996 in Europe, but the first HA cosmetic injectable was not approved by the FDA in the United States until 2003 with the approval of Restylane (Q-Med, Uppsala, Sweden) followed by Hylaform in 2004 (Genzyme [now Allergan], Santa Barbara, CA, USA). HA injectable fillers have been used as dermal fillers to restore soft tissue loss from aging in a variety of sites from the nasolabial folds, temporal fossa, malar fat pads, marionette lines, lip augmentation, and glabellar lines. They have also been used to correct the lipoatrophy associated with human immunodeficiency virus and for vocal fold augmentation. HA has also been studied as a skin-rejuvenating agent in mesotherapy, which involves multiple microinjections into the skin dermis for skin rejuvenation.

Significantly, HA fillers were approved by the FDA as a device rather than a drug, which helped hasten its approval in the United States. One of the criteria by which the FDA defines a medical device is “the intent to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.” Indeed, the biomechanical effects of HA on the local microenvironment of the injected site are key to its success as a soft tissue filler. HA fillers have additional interesting properties beyond simple volumizing agents; they have been shown to increase collagen production in the local environment as well as change the fibroblast morphology.

An ideal soft tissue implant for cosmetic purposes has the following characteristics: (1) biocompatibility or low tissue reactivity; (2) minimal migration; (3) ease of applicability; (4) bioresorbability; and (5) nonteratogenicity and noncarcinogenicity. HA fillers fulfill all of these requirements in that they have not been shown to bind the surrounding cells on injection, produce very little inflammatory reaction because HA is structurally identical across species, possess viscoelastic properties that allow for easy injection as well as maintenance of shape over time, and are ultimately temporary. The minimal tissue reactivity and migration properties of injected HA support the perception of HA fillers as implants and were key to FDA approval as a device. A thorough knowledge of HA biomechanics, biochemistry, manufacturing processes, and materials science properties will help guide the clinical practitioner and lead to optimal outcomes for patients.

Introduction

The use of cosmetic injectables, including collagen, hyaluronic acid (HA), fat, synthetic polymers (polylactic acid, polymethylmethacrylate), and calcium hydroxyapatite, has significantly increased in popularity over the past 2 decades. The American Society of Plastic Surgeons reports an increase from 652,888 soft tissue filler procedures in 2000 to 2.3 million in 2014, whereas more invasive surgical procedures have become slightly less popular (the number of facelifts have decreased by 4% from 2000 to 2014). HA has become the top injected soft filler agent around the world (1.8 million procedures reported in 2014 ). The goal of this report is to investigate the rapid transition from other soft tissue fillers to HA following US Food and Drug Administration (FDA) approval and the interesting biomechanical and biochemical advantages behind this immensely popular biomaterial.

Early biomedical applications of HA were quite diverse, including joint synovial fluid replacement to treat osteoarthritis and in ophthalmologic surgery as a vitreous replacement and for retinal detachment surgeries. In 1994, Ghersetich and colleagues reported decreased skin HA content with aging. HA-based dermal fillers were first available in 1996 in Europe, but the first HA cosmetic injectable was not approved by the FDA in the United States until 2003 with the approval of Restylane (Q-Med, Uppsala, Sweden) followed by Hylaform in 2004 (Genzyme [now Allergan], Santa Barbara, CA, USA). HA injectable fillers have been used as dermal fillers to restore soft tissue loss from aging in a variety of sites from the nasolabial folds, temporal fossa, malar fat pads, marionette lines, lip augmentation, and glabellar lines. They have also been used to correct the lipoatrophy associated with human immunodeficiency virus and for vocal fold augmentation. HA has also been studied as a skin-rejuvenating agent in mesotherapy, which involves multiple microinjections into the skin dermis for skin rejuvenation.

Significantly, HA fillers were approved by the FDA as a device rather than a drug, which helped hasten its approval in the United States. One of the criteria by which the FDA defines a medical device is “the intent to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.” Indeed, the biomechanical effects of HA on the local microenvironment of the injected site are key to its success as a soft tissue filler. HA fillers have additional interesting properties beyond simple volumizing agents; they have been shown to increase collagen production in the local environment as well as change the fibroblast morphology.

An ideal soft tissue implant for cosmetic purposes has the following characteristics: (1) biocompatibility or low tissue reactivity; (2) minimal migration; (3) ease of applicability; (4) bioresorbability; and (5) nonteratogenicity and noncarcinogenicity. HA fillers fulfill all of these requirements in that they have not been shown to bind the surrounding cells on injection, produce very little inflammatory reaction because HA is structurally identical across species, possess viscoelastic properties that allow for easy injection as well as maintenance of shape over time, and are ultimately temporary. The minimal tissue reactivity and migration properties of injected HA support the perception of HA fillers as implants and were key to FDA approval as a device. A thorough knowledge of HA biomechanics, biochemistry, manufacturing processes, and materials science properties will help guide the clinical practitioner and lead to optimal outcomes for patients.

Hyaluronic acid structure and biochemistry

HA is a naturally occurring polymer found in the extracellular matrix of many tissues, including human hyaline cartilage, synovial joint fluid, skin dermis, brain, vitreous fluid, and soft connective tissues. It is a nonsulfated glycosaminoglycan polymer consisting of alternating d -glucuronic acid and N -acetyl- d -glucosamine monosaccharide that are cross-linked into long chains. Up to 30,000 of these disaccharides can be linked to form a long chain of molecular weight ranging from 10 ⁵ to 10 ⁷ Da that will arrange itself into a coil in aqueous solution, binding up to 1000 times its weight in water. Although much of the HA found in the body residents within the extracellular matrix, some of the HA forms pericellular coats or is localized within the cell. The intracellular function of HA is not yet completely understood. HA has also demonstrated antiviral activity for Herpes simplex virus-1 and Coxsackievirus B5 in vitro . Absence of HA has been described in mucopolysaccharidosis IX, whereas elevated serum HA has been noted in the skin of patients with Marfan, Ehlers-Danhlos syndromes, as well as several autoimmune diseases, including scleroderma, dermatomyositis, and lupus. Melanoma and basal cell carcinoma cells have been found to promote HA synthesis and deposition.

The distribution of HA varies with aging; for example, newborn mice epidermis contains 80 to 90 ng/mg of dry weight HA, but adult mice epidermis contains just 20 to 30 ng/mg of dry weight HA. In addition, different anatomic sites contain different amounts of HA; for example, forearm skin contains twice the amount of HA as back skin. HA metabolism also varies by location; within the epidermis, HA is degraded by hyaluronidase enzymes following endocytosis, whereas in the dermis, degraded HA is drained by afferent lymphatics.

Role in wound healing

HA may play a key role in wound healing and skin regeneration. It is theorized that scarless wound healing found in fetal skin may be due to the higher HA content compared to children or adults. HA may also play different roles depending on the size of the macromolecule; in early wounds, HA is broken down into low-molecular-weight HA that promotes cytokine secretion and stimulates angiogenesis, whereas during tissue remodeling, high-molecular-weight HA promotes fibroblast and keratinocyte migration and proliferation. It is not quite understood why HA cosmetic injectable fillers are so well tolerated given their known effect on wound healing, but local inflammatory reactions seem to be rare. Glucocorticoids decrease the amount of HA in the epidermis, which leads to steroid-induced atrophy.

Manufacturing

HA fillers are produced from both animal sources (rooster combs in the case of Hylaform; Biomatrix Inc, Ridgefield, NJ, USA) and nonanimal sources ( Streptococci equine Streptococcus equi bacteria such as Restylane; Q-Med). The nonanimal stabilized HA products are often referred to as nonanimal source hyaluronic acid (NASHA). Most HA injectable fillers are formed via particulate manufacturing; the exception is Juvéderm (Allergan), which is manufactured via a nonparticulate proprietary method. Processing via nonparticulate or particulate manufacturing is important in that particulate HA product longevity is strongly related to particle size, whereas nonparticulate HA duration is related to cross-linking density. Regarding technique, large particulate HA products will require larger-bore needles to inject (∼27 gauge) rather than the smaller-bore and less painful needles (∼30 gauge).

HA typically has to be cross-linked to avoid rapid degradation by hyaluronidase, temperature, or free radicals, and different HA fillers vary by the cross-linking density and resulting stiffness. Without cross-linking, exogenous HA is degraded by the liver and has a half-life of 1 to 2 days. HA fillers with a higher cross-linking density can be used for deep wrinkles, versus HA fillers with a lower cross-linking density are preferable for fine wrinkles. Cross-linking of HA may be monophasic (one treatment of cross-linking), such as Belotero (Merz Aesthetics Inc, San Mateo, CA, USA) and Juvéderm, or biphasic (cross-linked twice), such as for Restylane. Different chemicals are used to cross-link HA. HA can be cross-linked chemically by 1,4-butandiol diglycidylether (BDDE), such as for Restylane and Juvéderm, or divinyl sulfone (DVS), used in Hylaform (Genzyme now Allergan) and Captique (Genzyme Corp, Cambridge, MA, USA; no longer on the market). Biscarbodiimide (BCDI) is used to cross-link Elevess (renamed Hydrelle in 2010; Anika Therapeutics, Palo Alto, CA, USA), whereas 1,2,7,8-diepoxyoctane (DEO) is used to cross-link Puragen (Mentor Corp, FDA approval pending). Theoretically, oral antioxidants should reduce degradation of HA by free radicals, but that has not been proven.

Commercially available hyaluronic acid injectable fillers in the United States

Key differences among the HA injectable fillers include concentration, particle size, cross-linking density, and elastic modulus G′. Other factors to consider include cost, requisite needle size, duration, stiffness, hydration, presence of lidocaine, and type of cross-linking technology. Generally speaking, larger-particle, higher-density HA fillers are recommended for deep dermal injections, whereas smaller-particle, lower-density fillers are recommended for fine lines and wrinkles. Cross-linking may affect the longevity of the filler as well as diffusion through the skin. Cross-linking HA continuously as with Belotero has been shown to produce the most homogeneous integration as compared with a monophasic cross-linking (Juvéderm) or biphasic cross-linking (Restylane). The first HA filler approved by the FDA was Restylane in 2003. Since then, many HA fillers have entered the market and are summarized in Table 1 . One new HA filler called Dermal Gel Extra or Prevelle Lift has a much larger elastic modulus than pre-existing HA fillers and is similar to permanent filler materials such as hydroxyapatite; it is currently awaiting FDA approval.

Table 1

Summary of commercially available hyaluronic acid fillers

HA Filler	Subtype	HA Source	Cross-Linking Agent	HA Concentration (mg/mL)	% Cross-Linked HA	Particle Size (μm)	G′ (Pa)
Restylane		NASHA	BDDE	20	<1	250–300	864
	Fine Lines (Touch)	NASHA	BDDE	—	—	—	—
	Perlane (renamed Restylane Lyft June 2015)	NASHA	BDDE	20	<1	650	977
Juvéderm	Ultra	NASHA	BDDE	24	6	—	207
	Ultra Plus	NASHA	BDDE	24–30	8	—	105
	Voluma	NASHA	—	—	—	—	—
Belotero	—	NASHA	BDDE	22.5	—	—	128
Captique a	—	NASHA	DVS	5.5	20	500	—
Hylaform a	—	animal	DVS	5.5	12–20	500	100
	Plus	animal	DVS	5.5	12	700–750	140
Elevess	(renamed Hydrelle 2010)	NASHA	BCDI	28	—	200	—
Prevelle Silk	—	NASHA	DVS	5.5	12	350	230–260
Prevelle Lift	(also known as Dermal Gel Extra)	NASHA	—	22	7	—	1800
Puragen a	—	NASHA	DEO	20	—	—	—

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