Soft Tissue Augmentation

Samantha L. Schneider, MD

Hema Sundaram, MD

M. Laurin Council, MD

Chapter Highlights

Soft tissue augmentation is currently the second most common minimally invasive aesthetic procedure in the United States.
Numerous soft tissue fillers are commercially available, but the most commonly used products are made of hyaluronic acid.
Soft tissue augmentation is most commonly performed on the face; other anatomic locations include the dorsal hands and genitalia.
Common adverse events include edema and ecchymosis. Serious adverse events include vascular occlusion, resulting in tissue necrosis, blindness, and central nervous system sequelae.
Strong understanding of anatomy and appropriate training of the injector are paramount to prevent complications and maximize aesthetic results.

Aesthetic medicine has continued to grow in the United States and worldwide. Patients are increasingly interested in minimally invasive procedures such as soft tissue augmentation with fillers, which has been shown to improve patients’ psychosocial states.¹ In 2011, Americans spent $10.4 billion on elective surgical and nonsurgical procedures,¹ with soft tissue fillers representing the second most common minimally invasive procedure after botulinum toxin.² Physician administrations of soft tissue fillers have more than doubled from 1.3 million in 2007 to 2.7 million in 2017,³ and the number of treatments performed annually has grown by over 300% from 2000 to 2017.⁴ All of these statistics demonstrate the importance of fillers in the practice of dermatology.

HISTORY

For almost a century, patients have been interested in soft tissue augmentation. As early as the early 20th century, clinicians were offering fat transplantation for augmentation; however, it was limited in its longevity and was a more invasive procedure compared to the soft tissue fillers that we have today. These limitations encouraged research into other options for tissue augmentation, which led to the utilization of liquid injectable silicone products in the 1950s.⁵ With the early liquid injectable silicone products, there were issues with purity and the formation of granulomas, foreign body reactions, and extrusion of the product through the skin.⁶ Due to these adverse events, the Food and Drug Administration (FDA) banned the sale of injectable liquid silicone for aesthetic purposes in the 1960s.⁵ These issues prompted the search for other injectable products and ultimately the creation of collagen products in the 1970s.⁶ The first collagen injectable was bovine collagen; however, it only had short-lived results. Additionally, skin testing was required prior to use of bovine collagen fillers to identify those at risk for allergic reactions. These concerns led to the development of additional soft tissue fillers, including some hyaluronic fillers, in the 1990s and early 2000s.⁶

RHEOLOGY AND BIOPHYSICAL PROPERTIES

In order to choose the appropriate soft tissue filler products to address a particular patient’s needs, it is important to understand the products’ physical properties. Rheology is the study of how materials react and deform under mechanical stress, which ultimately helps physicians understand the rationale for the behavior of certain soft tissue fillers.⁷ These include many of the fillers available for aesthetic use today, particularly hyaluronic acid (HA) and calcium hydroxylapatite (CaHA). There are four main parameters to consider—G′, Viscosity, G*, and tanδ, as well as a product’s cohesivity.

G′ (elastic modulus) is a measurement of the product’s elastic properties, which quantifies the ability of the filler to recover its initial shape when faced with applied force.⁷ Another way to explain G′ is that it represents the fillers’ ability to resist deformation once placed within the skin.⁸ G′ is typically related to the amount of hyaluronic acid cross-linking present in a product, with more cross-linking leading to a higher G′ value.⁹ Higher G′ products aid in lifting and volumizing and are particularly useful for subcutaneous implantation in areas with higher levels of muscular activity as they are more effective at resisting deformation.¹⁰^,¹¹ Higher G′ products can be of value in areas such as the nasolabial folds, upper cheeks, nasal dorsum, and chin where these products provide outward projection.¹² Soft fillers, with lower G′, are less resistant to deformation and may provide a softer feel in thinner-skinned, mobile areas such as tear troughs and lips.¹² G″ (viscous modulus) is a measurement of a filler’s viscosity.¹⁰ Viscosity, which can also be measured as complex viscosity, determines how spreadable the product will be in the tissue, as well as its resistance to flow (extrusion force) during the injection. Higher viscosity products stay localized to the site of injection, whereas lower viscosity products are more likely to spread.⁹^,¹⁰ G* (complex modulus) measures viscoelasticity of the filler product. It is a measure of how much applied energy is stored versus how much is dissipated.¹³ Fillers with higher G* represent harder fillers, which should be injected more deeply.¹³ Tanδ is the ratio of a product’s viscosity to its elasticity, which describes the filler’s balance between fluidity (related to viscosity) and elasticity.¹³ Finally, cohesivity describes the ability of the solid and fluid phases of the filler gel to remain together.¹⁴^,¹⁵ For hyaluronic acid fillers, the affinity between the solid and fluid phases may contribute to three-dimensional tissue expansion rather than outward tissue projection alone.¹² Keeping these concepts in mind can allow the physician to select the most appropriate product for a given injection location and patient goal.

FILLERS

There are many options available on the market today for soft tissue augmentation including hyaluronic acid, poly-L-lactic acid (PLLA), CaHA, and permanent fillers including poly-methymethacrylate (PMMA). Table 3.1 provides a comprehensive overview of products available on the US market and their FDA indications.¹⁶^,¹⁷^,¹⁸^,¹⁹

TABLE 3.1 Commercially Available Fillers in the United States

Trade Name	Company	Year of FDA Approval	Composition	Anesthetic	Cross-Linking	US FDA Aesthetic Indications
Bellafill^® (previously known as Artefill)	Suneva Medical, Inc.	2015 (2006)	20% PMMA microspheres, 3.5% bovine collagen	0.3% Lidocaine	N/A	^aCorrection of nasolabial folds and moderate to severe, atrophic, distensible facial acne scars on the cheek
Belotero Balance^®	Merz Pharmaceuticals	2011	22.5 mg/mL HA	None	BDDE-crosslinked cohesive polydensified HA	^aInjection into facial tissue to smooth wrinkles and folds, especially around nose and mouth (e.g., nasolabial folds)
Juvéderm^® Ultra^TM	Allergan	2006	24 mg/mL HA	None	BDDE-crosslinked Hylacross HA	^aModerate to severe facial wrinkles and folds
Juvéderm^® Ultra Plus^TM	Allergan	2006	24 mg/mL HA	None	BDDE-crosslinked Hylacross HA	^aModerate to severe facial wrinkles and folds
Juvéderm^® Ultra Plus XC^TM	Allergan	2010	24 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked Hylacross HA	^aModerate to severe facial wrinkles and folds
Juvéderm^® Ultra XC^TM	Allergan	2010	24 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked Hylacross HA	^aModerate to severe facial wrinkles and folds
Juvéderm^® Volbella XC^TM	Allergan	2016	15 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked Vycross HA	^aLip augmentation ^aPerioral rhytids
Juvéderm^® Vollure XC^TM	Allergan	2017	17.5 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked Vycross HA	^aInjection into mid to deep dermis for moderate to severe facial wrinkles and folds (i.e., NLF)
Juvéderm^® Voluma^TM XC	Allergan	2013	20 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked Vycross HA	^aDeep (subcutaneous and/or supraperiosteal) injection for cheek augmentation for age-related volume deficit in the midface
Radiesse^®	Merz Pharmaceuticals	2006 (Approval in 2015 for hands)	Calcium hydroxylapatite	None	N/A	^aSubdermal injection for moderate to severe facial wrinkles and folds (e.g., NLF) ^aLipoatrophy in HIV-positive patients ^aDorsal hands
Radiesse^® (+)	Merz Pharmaceuticals	2015	Calcium hydroxylapatite	0.3% lidocaine	N/A
Restylane^®	Galderma Laboratories, L.P.	2011 (2003)	20 mg/mL HA	None	BDDE-crosslinked NASHA	^aLip augmentation
Restylane-L^®	Galderma Laboratories, L.P.	2012	20 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked NASHA	^aInjection into mid to deep dermis for moderate to severe facial wrinkles/folds (i.e., NLF) ^aLip augmentation
Restylane^® Defyne	Galderma Laboratories, L.P.	2016	20 mg/mL HA	3mg/mL lidocaine	BDDE-crosslinked XpresHAn HA	^aInjection into mid to deep dermis for moderate to severe deep facial wrinkles and folds (e.g., NLF)
Restylane^® Lyft with lidocaine (previously known as Perlane)	Galderma Laboratories, L.P.	2018	20 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked NASHA	^aInjection into deep dermis to superficial subcutis for moderate to severe facial folds and wrinkles (i.e., NLF), subcutaneous to supraperiosteal implantation for cheek augmentation and correction of age-related midface contour deficiencies in patients ^aInjection into subcutaneous plane of dorsal hand to correct volume deficit
Restylane^® Refyne	Galderma Laboratories, L.P.	2016	20 mg/mL HA	3mg/mL lidocaine	BDDE-crosslinked XpresHAn HA	^aInjection into mid to deep dermis for moderate to severe facial wrinkles and folds (e.g., NLF)
Restylane^® Silk	Galderma Laboratories, L.P.	2014	20 mg/mL HA	0.3% Lidocaine	BDDE-crosslinked NASHA	^aLip augmentation ^aDermal implantation for perioral rhytids
Restylane^® Kysse	Galderma Laboratories, L.P.	2020	20 mg/mL HA	3mg/mL lidocaine	BDDE-crosslinked XpresHAn HA	^aLips and perioral rhytids in adults over 21 years of age
RHA2^®	Teoxane SA/Revance Therapeutics	2017	23 mg/g	0.3% Lidocaine	BDDE-crosslinked Resilient HA	^aMid to deep dermis or correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds
RHA3^®	Teoxane SA/Revance Therapeutics	2017	23 mg/g	0.3% Lidocaine	BDDE-crosslinked Resilient HA	^aMid to deep dermis for correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds
RHA4^®	Teoxane SA/Revance Therapeutics	2017	23 mg/g	0.3% Lidocaine	BDDE-crosslinked Resilient HA	^aDeep dermis to superficial tissue for correction of moderate to severe dynamic facial wrinkles and folds, such as nasolabial folds
Revanesse Versa	Prollenium Medical Techologies	2017	22-28 mg/mL	None	BDDE-crosslinked	^aInjection into the mid to deep dermis for correction of moderate to severe facial wrinkles and folds, such as nasolabial folds
Revanesse Versa (+)	Prollenium Medical Techologies	2018	22-28 mg/mL	0.3% Lidocaine	BDDE-crosslinked
Sculptra^® Aesthetic	Galderma Laboratories, L.P.	2009 (2004 approval as Sculptra for HIV lipoatrophy)	367.5 mg PLLA (per vial)	None	N/A	^aShallow to deep contour modification for facial wrinkles aLipoatrophy in HIV-positive patients
BDDE, 1,4-butanediol diglycidyl ether; HA, hyaluronic acid; NASHA, Nonanimal stabilized hyaluronic acid; NLF, nasolabial fold; PLLA, poly-l-lactic acid.
^aAll are US FDA-approved for patients> 21years of age.

Hyaluronic Acid

Hyaluronic acid (HA) products were first approved for use in the United States in 2003.⁶ Glycosaminoglycans occur naturally in the body to provide scaffolding and volume. With age and increasing exposure to ultraviolet radiation, a patient’s natural HA decreases. There is also loss of all hard and soft tissues, including fat, prompting clinicians to supplement with soft tissue facial fillers.²⁰ A patient’s decreasing facial volume due to loss of bone, fat, and other subcutaneous and cutaneous components results in the accentuation of facial lines and hollows.

HA fillers restore volume themselves and can potentially upregulate synthesis of new collagen and elastin. Volumizing with HA fillers predominantly relies upon their intrinsic ability for hygroscopic uptake of up to 1000 times their molecular weight in water, allowing hydration to augment tissue volume.²⁰ They are polysaccharides composed of alternating residues of monosaccharides D–glucuronic acid and N-acetyl-D–glucosamine.⁶^,⁷ Streptococcal bacteria fermentation processes are used to develop most HA fillers.⁶ Because HA fillers do not have any protein components, typically there is little or no immunologic reaction when they are injected into patients.²⁰^,²¹

Non-crosslinked HA has a short half-life of in the skin approximately 1 to 2 days.²⁰ HA fillers have varying levels of crosslinking to slow their degradation.²⁰ Several commercially available products use a 1,4-butanediol diglycidyl ether (BDDE) cross-linking agent.²⁰

Understanding of the properties of various HA fillers allows the provider to select the most appropriate product for each patient. In order to create the scaffolding network that leads to volume, many products have a combination of low molecular weight and high molecular weight HA. Products with a higher concentration of HA have a stiffer consistency and have been associated with increased duration in the tissue. Higher molecular weight HA allows for greater lift. Less cross-linked products are easier to inject into the patient but may be more quickly degraded, although newer methods of HA manufacture allow a decrease in cross-linking while preserving durability. As previously discussed, HA fillers rely upon hygroscopic water update to create maximal volume. Patient can therefore develop increased volume over the days and weeks following filler injection.²⁰ This is important to consider during the in-office procedure so as not to overvolumize patients.

HA products are highly versatile and can be used in most anatomic locations. They are highly malleable, and clinicians sometimes mold filler immediately after injection to optimize the appearance and minimize nodules.²⁰ Softer, less viscous HA products are useful in the lips, tear troughs, and superficial wrinkles, whereas harder, more viscous HA products are injected into areas of deep volume loss such as the cheeks and temples.⁷^,¹³ Most HA products are FDA-approved for correction of nasolabial folds. Because of the large variety of products, many providers develop a multifaceted, patient-centric approach where various products are used in layers to provide the best cosmetic outcomes. Using this technique, higher G′, more viscous products are placed deeper for maximal volume achievement, whereas fine lines are addressed with lower G′, less viscous products more superficially.¹² HA lasts anywhere from 6 to 18 months, or longer, depending on the product and the location of implantation.⁶^,⁷^,²² HA products also have the advantage of being reversible with varying doses of hyaluronidase.²³^,²⁴^,²⁵^,²⁶

Poly-L-Lactic Acid

PLLA was first developed by French chemists in the 1950s⁵ and ultimately approved by the FDA in 2004.⁶^,²⁷ It is a synthetic polymer that comes in powder form and is reconstituted using sterile water 48 to 72 hours before injection. Once injected, the particles settle into the subcutaneous tissue and the water is absorbed by the body.⁷^,²⁸ The particles in the subcutis are treated as small foreign bodies similar to PMMA, which induces fibrosis and collagenesis.⁵^,⁶^,⁷^,²⁸ It is important to keep this in mind as the injections are being performed because the patient will lose some volume initially as the water is resorbed and then will gain more volume over the following several months with collagenesis.⁷^,²⁸ Techniques to avoid clogging the needle while injecting the PLLA suspension include using a 25-gauge needle or a wider cannula for injection, reconstituting the particles with larger volumes than recommended by the package insert, storage of the reconstituted product for 48 to 72 hours before injection, and thorough remixing of the product suspension just prior to injection.⁷^,²⁸

PLLA is injected into the subcutaneous tissue.⁷ It was first approved by the FDA for HIV lipoatrophy where it has shown improvement in skin thickness, confidence, self-perception and quality of life, and decreased anxiety and depression.⁵^,⁶^,²⁹ For the cosmetic patient, PLLA is most frequently used in the cheeks but can be used in other facial areas.⁶ After FDA approval for HIV lipoatrophy, the FDA indications of PLLA were expanded to include shallow to deep nasolabial fold rhytids and other facial wrinkles that are amenable to a deep dermal grid pattern of injection.²⁷ Patients typically require three injections spaced 4 to 8 weeks apart.⁵^,⁷^,²⁸ The durability of results from PLLA is, on average, 18 to 24 months,⁵^,⁶^,²⁸^,²⁹ though some report durability up to 3 years.²⁹

PLLA has the potential side effect of delayed-onset nodules, which is why many clinicians consider this product to be contraindicated in the lips and tear troughs.⁵^,⁶ The incidence of nodules has decreased significantly with the use of larger reconstitution volumes, reconstitution 48 to 72 hours ahead of injection, and mixing well prior to injection.²⁹ In addition, some clinicians recommend that patients massage the injected areas five times daily for 5 days to prevent nodule formation.⁵^,⁷^,²⁸^,³⁰ Other clinicians recommend massage only on the day of injection.²⁸ No objective evidence exists to support massage as an effective method of preventing nodules.³⁰

Calcium Hydroxylapatite

CaHA, a natural component of bone, is now also used as a commercial filler.⁵^,⁷ Similar to PMMA and PLLA, CaHA is a 30% concentration of small spherules (approximately 25-45 µm diameter) of synthetic CaHA in a neutral gel matrix composed of sodium carboxymethylcellulose which is resorbed after injection.⁶^,⁷ After the gel is resorbed, the microspherules remain in the tissue and stimulate collagen formation.⁵^,⁶ Over time, the body breaks down the microspherules into calcium and phosphate, which are excreted by the body.⁵^,⁶

CaHA is injected into the deep subcutaneous tissue,⁷ typically with a 27-gauge needle or blunt cannula.⁶^,³¹ CaHA is now FDA-approved with and without 0.3% lidocaine for use in patients with HIV lipoatrophy⁶^,³²^,³³^,³⁴ as well as for moderate to several facial wrinkles and folds (such as the nasolabial folds) that would permit subdermal injection.³³ In 2015, CaHA became the first FDA-approved filler for the dorsal hands.⁵^,⁶^,³³^,³⁵ For the cosmetic patient, it can be used for the chin, mandibular line, nasolabial folds, marionette lines and midface as well as for atrophic scars. Mixing CaHA with lidocaine suspension and/or saline, to reduce its G’ and viscosity and make it softer and more spreadable, is preferred by some when injecting the hands, face or other areas. CaHA can form subcutaneous nodules and is thus avoided in the lips and tear troughs. Since there has been no reversal agent, nodules have been addressed by saline or lidocaine dispersion or by excision.⁵^,⁶^,⁷^,¹⁰ Robinson reported in a proof-of-concept study that intralesional sodium thiosulfate, topical sodium metabisulfite under occlusion, or a combination of the two could potentially dissolve CaHA filler in cadaveric porcine skin samples.³⁶ Rullan et al. applied these concepts to two patient cases and illustrated the utility of intralesional sodium thiosulfate to dissolve CaHA nodules in vivo.³⁷ The durability of results from CaHA is typically 1 to 2 years depending on the site injected.⁵^,⁶^,⁷^,³² CaHA has a radio-opaque appearance on x-ray and CT images because it is composed of a constituent of the bone.⁷

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