Hyaluronic acid dermal fillers—also known as soft tissue implants, injectable gels, and wrinkle fillers—are medical devices formulated to effectively soften the appearance of wrinkles and lines. These implants can also be used to treat aesthetic imperfections such as undefined facial contours, sunken facial regions, scars, dehydration, and dullness.
Additionally, some fillers are also designed to non-surgically augment less than desirable facial features, like thin lips and crooked noses. Despite the popularity of dermal fillers in the field of aesthetic medicine, a 2013 report by the Department of Health (DOH) found that there is a lack of regulation surrounding the usage of these devices. In fact, dermal fillers are classified as devices instead of drugs in the United Kingdom and can be used for cosmetic purposes without being regulated by the European Commission (CE), EU General Product Safety Directive, and Care Quality Commission (CQC).
Most healthcare practitioners refer to the guidelines set by the U.S. Food and Drug Administration (FDA). Unfortunately, the FDA has only approved the use of 16 hyaluronic acid (HA)-based implants. Due to this, many practitioners have had to resort to their clinical expertise and judgement instead of relying on theFDA's guidelines.
Dermal filler rheology
Rheology is the in-depth study of the physical characteristics of a material and the way it behaves when it is acted upon by deforming forces. Dermal fillers are subjectto various forces (e.g. gravity, compression, shearing, vertical compression, and stretch from muscle movements) once they are administered into the skin. The following are the four major factors that influence the physical features of hyaluronic acid (HA) fillers:
- Cohesivity:The cohesiveness of a filler is directly proportional to the concentration of HA molecules and the degree of cross-linking force that holds the HA molecules together. A dermal filler with high cohesivity can maintain its vertical projection better than fillers with lower cohesivity.
- Elastic modulus (G’):The ability of a soft tissue implant to return to its original shape after undergoing shear deformation.
- Viscous modulus (G’’):The inability of a soft tissue implant to return to its original shape after undergoing shear deformation.
- Complex modulus (G*): The sum of the elastic modulus (G’) and viscous modulus (G’’) that refers to the total ability of a dermal filler to resist deformation.
It is imperative that aestheticians equip themselves with knowledge of dermal filler rheology, such as the mechanism of action of the implants and the different ways the implants behave when used in different facial regions. This allows physicians to select the most suitable dermal fillers for their patients and subsequently deliver the desired aesthetic results.
For example, physicians are recommended to choose a volumizing filler with low tissue spreading ability when treating the deep subdermal layers of the cheeks. On the other hand, the filler that is chosen to treat the superficial dermal layers must be able to spread easily through the tight connective tissues in the upper layers of the skin for the best outcome.
Detailed rheological properties of dermal fillers according to treatment areas are as follows:
- Fine lines/lips:Non-bulky fillers must be easily molded with high spreading ability in order to restore volume in intradermal and sub-dermal planes. Most lip and fine line plumping fillers, such as Belotero Balance, Juvederm Volbella, and Restylane Kysse, are of low viscosity, low-to-medium elasticity, and low cohesivity.
- Nose/chin:The implants used to correct the shape and structure of the nose and chin should only have minimal lateral spreading ability and maximum vertical projection. Suitable implants for these facial areas, such as Juvederm Voluma, Restylane Lyft, and Teosyal Ultimate, are of low viscosity, high elasticity, and high cohesivity.
- Mid-face:The soft tissue implants that are indicated for augmenting the mid-face region should be able to withstand compression and shear deformation. They must also be able to retain the molded shape without getting displaced from the original injection sites. Some examples of suitable fillers for this area are Restylane Lyft, Teosyal Ultimate, and Teosyal Ultra Deep. These fillers are considered suitable due to their rheological properties of low viscosity, high elasticity, and medium-to-high cohesivity. Once injected, the fillers will not only volumize the deep dermal or subdermal layer of the skin, but they will also achieve the desired projection.
- Lower face:The aesthetic fillers that are used to correct the lower face region must be easily malleable and non-palpable and create minimal projection once administered into the skin. This is to ensure adequate volume restoration in the deep dermal or subdermal planes. Examples of dermal implants suitable for the lower face region are Belotero Intense, Juvederm Volift, and Teosyal Global Action, which have the rheological properties of low viscosity, moderate elasticity, and low-to-medium cohesivity.
Complications of dermal filler injections
The administration of dermal fillers is not without health risks. Besides the usual inflammatory reactions such as bruising, redness, and swelling that are associated with the minimally-invasive injection process, there are other side effects that patients should be made aware of.
Infections, though an uncommon secondary effect of aesthetic filler implantation, can happen due to viruses, bacteria, fungi, or even biofilm. [21, 22] Pathogens can camouflage themselves within a biofilm and avoid detection by the immune system and antibiotics.  These pathogens can then lead to other serious side effects, such as nodules, granulomatous inflammation, abscesses, and recurrent infections. Since biofilms are resistant to the actions of antibiotics, patients may need to undergo surgical debridement or excision to remove the foreign materials.
The formation of nodules or granulomatous inflammation usually happens due to an abnormal tissue reaction. The latter is a type 4 hypersensitivity reaction that is mediated by T-cell or macrophage interaction.  Patients displaying this reaction may require triamcinolone acetonide injections, cortisone injections, or topical application of 5-florouracil.  Severe cases may need to be treated via surgical excision.
Additionally, anaphylactic reactions, though rare, are still possible. These must be treated immediately to avoid other life-threatening health complications. Injectors must be highly skilled, trained in the latest anaphylaxis management method(s), and have anaphylaxis equipment on hand in order to administer life-saving medications accurately if the need ever arises.
Dermal filler that is accidentally injected into the blood vessels can cause arterial embolization (AE) and dangerous disruption of blood flow, resulting in pain, mottling, blanching, tissue necrosis, and ulceration. Embolization of filler material is extremely risky, as it can lead to complications like blindness, stroke, and extensive necrosis.  Some of the strategies that can be followed to reduce the risk of intravascular injection are as follows:
- Physicians should aspirate the needle or cannula prior to injection, even if they are pre-filled with filler gel. A blood flashback confirms that the needle tip is located within a blood vessel and consequently must be repositioned.
- Physicians are advised to use a large diameter cannula instead of a fine gauge needle. This is because a blunt-tip cannula with a wide diameter has a lower risk of penetrating into the blood vessels and can aspirate better for a blood flashback.
- Physicians are recommended to inject small aliquots of implant material into one area. Intravascular injection of a large volume of filler will have devastating results.
- Filler must also be administered slowly to reduce pressure damage and the risk of accidental intravascular injection.
- It is safer to administer the filler material via retrograde injection than anterograde injection due to the former’s lower risk of intravascular injection.
Prior to conducting the aesthetic procedure, there are some important factors that must be considered by both physicians and patients. While most dermal fillers are considered safe, it is important that patients’ medical histories are thoroughly reviewed.
Patients with health conditions like known allergies to the filler material and/or its components, like lidocaine, and active infections are contraindicated from receiving dermal filler injections. Physical (e.g. diabetes, immunosuppression, autoimmune disease, dermatological issues, etc.) and psychological factors (e.g. anxiety, depression, body dysmorphia, etc.) that may influence the treatment session and the recovery process must be identified and managed accordingly.
Hyaluronic acid (HA)-based fillers
Hyaluronic acid is a glycosaminoglycan (GAG) polymer that is naturally abundant in the extracellular matrix of the body. The polymer is made of repeated disaccharide units of glucuronic acid and N-acetylglucosamine, and the length of the HA polymers varies extensively. The varying molecular weight of the HA polymers determines the different biological functions in the tissues.
For instance, polymers with high molecular mass help to curb tissue inflammation and angiogenesis, while polymers with low molecular mass work against the high molecular polymers by increasing inflammation and angiogenesis. About half of the body’s total HA is found in the skin, with one third of that amount synthesized daily due to rapid tissue metabolism. It is one of the integral dermal cells and acts as the framework for the extracellular matrix. HA molecules not onlyprovide rigidity, turgor, and adequate hydration, but also permit cellular growth and movement.
HA molecules also shield the skin from free radicals, such as UVA and UVB rays. The level of HA in the body is carefully balanced by the enzymes that create it (e.g. synthase HAS1, HAS2, and HAS3) and those that disintegrate it (e.g. hyaluronidases HYAL1, HYAL2, and HYAL3). Nowadays, hyaluronidase is harvested synthetically to be used in enhancing the absorption and penetration of various injectable solutions, including local anesthetic agents, infusions, and subcutaneous or intramuscular injections. It can also be used to reduce swelling.
That being said, hyaluronidase has also been used to prematurely dissolve HA-based fillers that deliver undesirable results. Though hyaluronidase enzymes originate from various sources,includingmammalian sources (endo-Beta- N-acetylhexosaminidase), microbial sources (Hyaluronate lyase), and leech/hookworm sources (endo-Beta-D-glucuronidase), the most commonly used preparation of hyaluronidase in the UK is Hyalase, which is made from sheep testes. That being said, microbial- and human-based hyaluronidases still deliver efficient results since they have superior safety profiles and reduced risk of immunogenic reactions.
Hyaluronic acid-based dermal fillers are made of long chains of HA polymers that are stabilized and cross-linked with each other through chemical reticulating agents, such as 1,4-butanediol diglycidyl ether (BDDE) for Belotero, Juvederm, and Restylane; 1,2,7,8-diepoxyoctane (DEO) for Puragen; and divinyl sulfone (DVX) for Hylaform. The resulting filler material is then reconstituted into a phosphate-buffered solution and processed into a homogenous gel or a suspension of HA molecules in a gel carrier.
Thanks to the variability in manufacturing processes, the HA fillers are differentiated based on their particle size, strength, and degree of cross-linking; in turn, these properties determine the effectiveness of the fillers.There are also stable complexes of HA that are cross-linked using hydrogen bonds. These fillers are considered safer than fillers cross-linked with chemical reticulating agents, as they pose less of a riskofof allergic reaction and are better tolerated by patients with sensitive immune systems.
Hyaluronic acid-based injectable fillers can be classified based on their gel textures, which are either monophasic or biphasic. Monophasic fillers are made of a single phase of HA molecules; they can be monodensified (e.g. Juvederm and Teosyal) or polydensified (e.g. Belotero) depending on the stages of cross-linking. On the other hand, biphasic implants, such as Restylane, are made of two phases of HA, with the cross-linked HA molecules suspended uniformly and non-crosslinked HA acting as the carrier gel.
There is no single type of HA filler that is superior to the others; physicians are recommended to choose a filler that is most suitable for their patients’ aesthetic indications, treatment areas, underlying medical conditions, and budgets.
Non-hyaluronic acid fillers
Besides HA, dermal fillers are also made of the following materials:
- Collagen:Collagen can be extracted from bovine, porcine and even human sources. Just like HA fillers, collagen implants are used to treat many aesthetic issues. For example, superficial injections of collagen fillers can help to soften the appearance of scars and wrinkles, while deep dermal injections can help to correct deep-set creases and facial contours. They can also be mixed with polymethylmethacrylate (PMMA) or other gel carriers for enhanced aesthetic improvements.
- Polymethylmethacrylate (PMMA):Polymethylmethacrylate (PMMA) is actually a polymer of acrylic. PMMA-based fillers exist as non-absorbable microspheres that will encourage the fibroblasts to encapsulate each PMMA microparticle, synthesize newer collagen fibers via neocollagenesis, and increase tissue volume via fibroplasia. An example of a PMMA filler is Artefill, which is the only PMMA-based filler that is approved by the FDA for use in correcting acne scars and nasolabial folds. It is made of PMMA microbeads that are uniformly suspended in bovine collagen. However, the original version of Artefill was infamous for its high rate (up to 2.5%) of post-injection granulomas. Patients must undergo skin testing prior to receiving Artefill injections to reduce the risk of allergic reactions associated with the bovine collagen. Compared to HA-based fillers that only offer non-permanent results, Artefill delivers permanent aesthetic enhancements, so they require surgical removal should there be any health complications or need for correction.
- Calcium Hydroxylapatite (CaHA):Calcium hydroxylapatite is a completely synthetic compound that shares a similar structure to bones and teeth. As of now, Radiesse is the only CaHA-based filler that is approved for use by the FDA. 30% of the product consists of CaHA microspheres that are suspended in an aqueous gel carrier, which makes up the remaining 70% of the product. Since it is synthetic and non-immunogenic, patients do not need to undergo skin patch tests. Once injected, the filler corrects aesthetic issues like moderate wrinkles and skin folds, with the corrective results lasting for about a year. Radiesse can also be used to correct facial lipoatrophy in patients with advanced Human Immunodeficiency Virus (HIV) infection.
- Poly-L-lactic Acid (PLLA):Just like PMMA fillers, PLLA implants are made of absorbable polymers that encourage the fibroblasts to regenerate healthier and stronger collagen fibers. Physicians are advised to give multiple iPLLA filler injections for optimal outcomes, which should last for approximately 2 years. However, the administration of a PLLA implant may result in the delayed formation of palpable nodules.A five-year prospective research study conducted by Woerle et al. among 300 patients demonstrated that the incidence of nodule formation is well below 1% if the filler is injected with proper handling of the vials, adequate dilution, a longer hydration time, and the addition of lidocaine. As of yet, Sculptra is the only FDA-approved PLLA-based implant that can be used for the treatment of facial lipoatrophy in HIV patients.
Besides the types of fillers listed above, there are other less common types of dermal fillers, such as dextran particles, autologous fat transfer, polycaprolactone, agarose gel, and polyacrylamide gel.
As stated earlier, HA is a naturally-occurring molecule that helps to maintain the health and functionality of skin. Hyaluronic acid molecules that are harvested for cosmetic purposes must be reticulated and stabilized with chemical cross-linking agents, such as 1,4-butanediol diglycidyl ether (BDDE). This important step allows HA fillers to resist premature degradation and provide durable aesthetic results once they are injected into the problematic areas.
Due to vast technological developments, these HA fillers are manufactured with varying degrees of strength andproperties thataddress a wide range of aesthetic issues. Non-HA implants also have their own advantages, including the ability to promote collagen synthesis in the body via neocollagenesis and a longer residence time. Aestheticians should discuss available treatment options with their patients and carefully choose the most suitable dermal filler on the basis of a patient’s skin conditions, budget, and desired outcome(s).
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