Many types of cosmetic injectables, such as dermal fillers, have become more and more popular in recent years. Hyaluronic acid is the most commonly used dermal filler ingredient, accounting for more than 92% of all dermal fillers sales in the United States. In this article, we will discuss various aspects of hyaluronic acid dermal fillers, including how they are regulated, how they are used, and their general physical characteristics.  We’ll also take a look at some other commonly used, FDA-approved classes of dermal fillers.

Regulation

The regulatory landscape for dermal fillers is quite diverse and interesting (and complicated). In 2013, a report by the U.S. Department of Health termed this as a “crisis waiting to happen.” In the United Kingdom, dermal fillers have been classified as a medical device, rather than as a drug, meaning that dermal fillers can be used cosmetically without being subject to the EU General Product Safety Directive, Care Quality Commission, or CE standards.

Given this, medical practitioners typically turn to guidelines established by the USA’s FDA. This approach is not without its drawbacks, however, including that only a limited number of hyaluronic acid dermal fillers are FDA-approved for specific treatments, so this approach of turning to the FDA for guidance is has limited applicability. Due in part to this limitation, it is commonly held that practitioners work on the basis of clinical judgement, rather than following FDA guidelines to the letter.

Hyaluronic Acid Present in the Human Body

Hyaluronic acid is a naturally-occurring chemical, already present throughout the human body. It consists of a long, linear polysaccharide that consists of repetitive disaccharide units of glucuronic acid and N-acetylglucosamine. Importantly, hyaluronic acid polymers vary in length, which in turn influences their weight. The weight of the hyaluronic acid chain impacts their behavior and properties within human tissue; high-molecular weight (HMW) hyaluronic acid chains are involved in inflammation reduction and angiogenesis, whereas polymers with low molecular mass will act to increase inflammation and angiogenesis.

Approximately 50% of the total hyaluronic acid in the human body is found in the skin. In the skin, the hyaluronic acid acts as a scaffold or structure for the extracellular matrix, providing hydration, turgor, and rigidity while also allowing for cellular movement and regeneration. Hyaluronic acid also protects the skin from free-radical damage, particularly against UVA and UVB rays. In the tissue, hyaluronic acid is quickly metabolized, with a fast turnover rate, whereby a third of the body’s total volume of hyaluronic acid is recycled daily.

Hyaluronic acid levels in the body are regulated by a balance between hyaluronan synthases, including HAS1, HAS2, and HAS3, and hyaluronidases, including HYAL1, HYAL2, and HYAL3. Due to their ability to degrade hyaluronic acid, hyaluronidases are used to successfully reverse the effects of hyaluronic acid filler treatments. Hyaluronidases are categorized based on their mode of action: mammalian (endo-Beta-N-acetylhexosaminidase), leech/hookworm (endo-Beta-D-glucuronidase), and finally, microbial (Hyaluronate lyase).

Hyaluronic Acid-Based Dermal Fillers

Hyaluronic acid dermal fillers are composed of long hyaluronic acid chains, typically crossed-linked with chemicals such as 1,4-butanedioldiglycidyl ether (BDDE) for Restylane, Belotero, and Juvederm; 1,2,7,8-diepoxyoctane (DEO) for Puragen; or divinyl sulfone (DVX) for Hylaform, and are suspended in a physiological or phosphate-buffered solution. The product is then processed as either a homogeneous gel or a suspension of particles contained within a gel carrier.

As different manufacturers have various methods to produce their dermal filler gels, there becomes a remarkable selection of fillers available, each with unique properties in terms of particle size, degree of cross-linkage, and concentration. These physical characteristics determine the clinical performance of the different dermal filler.

Hyaluronic acid fillers can be grouped according their different particulate forms. Monophasic gels consist of a single phase of hyaluronic acid. Monophasic gels can be subdivided into monodensified gels, such as Juvederm and Teosyal, in which hyaluronic acid is mixed and cross-linked in a single step. In addition, there are polydensified gels, such as Belotero dermal fillers, in which hyaluronic acid goes through two stages of cross-linking. Biphasic gels have two phases of hyaluronic acid, which is usually cross-linked hyaluronic acid that is then suspended together with non-crosslinked hyaluronic acid, which serves as a carrier.

In aesthetic literature and within practicing physicians, there is much debate about the superiority of one gel type over the other. However, it is more likely that no one method is truly better than the other, for all use cases. Rather, some fillers are better suited for different cases, as the desirability of the physical characteristics of a filler will vary by individual therapeutic indication.

Dermal Filler Rheology

The rheological properties of a dermal filler – that is, the characteristics that affect the way the material responds to external forces – are instrumental to determining the performance of the particular product. Once implanted, dermal fillers are subjected to external pressures, such as shearing, compression, gravity, and also vertical compression and stretching pressure from facial muscle movement. Practitioners should understand the way dermal fillers will respond when injected into a patients’ specific area or skin layer, to be able to then successfully tailor and select the most suitable filler for producing optimal results.

Very different dermal filler properties are desired for different facial areas. For example, a dermal filler with volumizing and projecting properties is most appropriate for the treatment of the very deep subdermal layers of the cheeks. On the other hand, if injecting the filler into superficial layers, spreadability of the filler is more highly valued, in order for the dermal filler to integrate seamlessly with the tight connective tissue found in the upper layers of the skin.

Many different factors are used to measure the various rheological aspects of a dermal filler. These include:

• Complex modulus (G*): Sometimes referred to as the filler’s hardness –  the complex modulus refers to how difficult it is to alter the shape of the filler.
• Elastic modulus (G’): A measure of a dermal filler’s stiffness and its ability to resist deformation under external pressure.
• Cohesivity: The relative lifting capacity of a filler. Cohesivity is generally determined by the concentration of hyaluronic acid and the degree of cross-linking.
• Viscous modulus (G”): The inability of a filler to recover its shape after the shear stress is removed.

Desirable Physical Characteristics of Dermal Fillers According to Treatment Areas:

• Mid-face – Fillers are placed deep – or sub-dermally in the cheeks with the goal of volume restoration. Therefore, the ideal dermal filler in this area is one that can withstand shear deformation and compression, with minimal displacement, and is able to maintain its shape. To achieve these goals, the dermal filler should be highly elastic and also have low viscosity in order to allow for ease of injection. Suitable dermal fillers therefore should have medium-to-high cohesivity. Examples of such dermal fillers include Juvederm Voluma, Belotero Volume, Restylane Lyft, Teosyal Ultra Deep and Teosyal Ultimate.
• Fine Lines and Lips – For these indications, the dermal filler used should be able to effectively restore volume in the intradermal and sub-dermal levels. It should be volumizing without adding too much bulk, and should be easily spreadable. Suitable dermal fillers in these areas will have low viscosity, elasticity, and cohesivity profiles. Some examples of dermal fillers meeting this criteria includes Juvederm Volbella, Teosyal RHA 2, Restylane Kysse, Restylane Refyne, and Belotero Balance.
• Lower Face – Dermal fillers used in the lower face are placed in the deep dermal or subdermal planes, for the purposes of restoring facial volume. The suitable dermal filler should confer minimal projection, be non-palpable, and should be highly mouldable/spreadable. The desirable rheological properties of a dermal filler for these purposes include moderate elasticity, low-medium cohesivity, and low viscosity. Dermal fillers that have such properties include Juvederm Volift, Restylane Refyne, Belotero Intense, and Teosyal RHA 3.
• Chin and Nose – Treatments in the nose and chin are usually for nasal and chin projection. Therefore, the dermal filler should have a minimal lateral spread while conferring maximum vertical projection. A filler suitable to treat the nose and/or chin should have low viscosity (for ease of injection), high elasticity, and high cohesivity. Such dermal fillers include Belotero Volume, Restylane Lyft, Juvederm Voluma, and Teosyal Ultimate.

Non-hyaluronic Acid Fillers

Dermal fillers consisting of materials other than hyaluronic acid are also available, and they have their own efficacy and safety profiles. Some of these fillers are discussed below.

Calcium Hydroxylapatite (CaHA)

Marketed under the brand name Radiesse, CaHA fillers were first approved for the correction of facial lipoatrophy in HIV patients, as well as for correcting moderate wrinkles and skin folds[3]. This dermal filler is made of 30% calcium hydroxylapatite microspheres, suspended in a 70% gel carrier. The calcium derivative in the filler is the same as the compound found in human bones and teeth. Due to this, Radiesse is non-immunogenic. This dermal filler offers results that last for approximately 12 months.

Poly-L-lactic Acid (PLLA)

PLLA stimulates fibroblasts’ synthesis of collagen, with results usually lasting for up to two years. This treatment necessitates multiple sessions in order to generate the best outcomes.  Previously, there have been concerns regarding this dermal filler’s propensity to cause delayed development of palpable nodules. However, many studies have created recommendations that reduce the risk of nodule formation, including a longer hydration time, adequate dilution, the addition of lidocaine, and the proper handling of the vials.

Sold as Sculptra, PLLA fillers were first FDA-approved in the United States in 2004 for the correction of facial lipoatrophy in HIV patients.

Collagen

The collagen used as material for fillers can be derived from porcine, bovine, or human sources. These may then be mixed with other materials such as PMMA or another gel carrier. Collagen-based dermal fillers are used for the correction of scars and wrinkles if injected superficially, and for the treatment of deep folds and facial contours if injected deeply.

Others

Other less commonly used dermal fillers include dextran particles, fat transfer, polyacrylamide gel, polycaprolactone, and agarose gel. These dermal fillers are all FDA-approved, but they are not as popular or widely used as the other fillers discussed above.

Considerations Before to Treatment

Certain patients are not suitable for hyaluronic acid based dermal filler injections. This includes patients with active infections or with known hypersensitivities to the dermal filler or to other components of the product, such as lidocaine.

In addition, patients with risk factors that could impact treatment and recovery should be identified and monitored more closely. Patients that fall under this category include those with certain physical issues, such as immunosuppression, dermatological problems, autoimmune disorders, or diabetes, and psychological issues, such as body dysmorphia, anxiety, or depression.

Complications

All fillers carry the risk of complications. Beyond the expected injection-related effects of redness, swelling, and bruising, patients should be informed of more serious potential risks. For instance, infections following dermal filler treatment, although rare, can be very dangerous if they occur. Infections can be caused by bacteria, fungi, or viruses.

Occasionally, nodule formation or granulomatous inflammation may occur as a result of an irregular tissue reaction to treatment. Treatment for these unwanted consequences entails injections of either cortisone, triamcinolone acetonide, or topical application of 5-florouracil. Surgical excision may also be suitable in certain circumstances. Another side effect to be aware of is anaphylactic reactions. These are typically rare, but they are very serious. Patients experiencing anaphylaxis can be saved by rapid treatment; is it vital, therefore that practitioners who offer injectable procedures are up-to date on anaphylaxis training and keep the proper safety equipment on hand at all times.

Administering injectable dermal fillers can cause vascular compromise, which is when inadvertent injection of filler into a blood vessel causes the disruption of blood flow through a tissue compartment. This leads to serious ramifications, such as blanching, pain, mottling, tissue ulceration, and necrosis. Embolization has also been reported, and this can lead to complications such as blindness, extensive necrosis, and stroke. Minimizing the risk of vascular compromise can be achieved by following these guidelines:

• Use of a cannula rather than a needle. The wider diameter of the blunt-tip cannula is far less likely to pierce through a blood vessel and is better to aspirate.
• Practicing needle aspiration prior to injection.
• Only administer small amounts of the dermal filler into a single area. Large amounts into a blood vessel can be lethal to the patient.
• Using retrograde rather than anterograde injection of dermal filler. Retrograde injection is associated with a decreased risk of intravascular injection.
• Injecting the dermal filler slowly to reduce pressure damage.

Summary

Hyaluronic acid has the properties to make it function well as a biomaterial. However, to make hyaluronic acid a functional soft tissue augmentation agent, hyaluronic acid must be stabilised, usually through modification via cross-linking proteins, such as 1,4-BDDE. This results in hyaluronic acid being more resistant to degradation and improves its longevity of results.

Due to the various technologies used for manufacturing hyaluronic acid dermal fillers, dermal fillers with very different rheological and physical characteristics have emerged in the market. This diversity in dermal fillers is beneficial, as there is now a wide selection of fillers for the practitioner to choose from based on the aesthetic indication at hand. This allows them to optimize and tailor the treatment and get the best treatment and outcomes for their patients.

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