Granuloma Acnes Petechiae Injectable fillers have become an integral part of aesthetic medicine in recent years, and there is now a wide range of fillers on the market. Injectable fillers are rapidly evolving and getting closer to “perfect” products: long-lasting but not permanent, highly tolerable, with refined and natural cosmetic results, and reversible in case of adverse surgical outcomes. The fillers currently on the market are further divided into two categories: biodegradable and non-biodegradable. The choice of the product depends on the preference of the injection method, the expected result and the injection site. For an introduction to the filler category, Dr. Carruthers et al. of the University of British Columbia provided a review of fillers currently approved by the U.S. Food and Drug Administration and new filler products currently being tested in the United States, as published in a recent issue of Plastic and Reconstructive Surgery. Biodegradable fillers are non-permanent agents that maintain their effects for a longer period of time (sometimes up to 12 months), but are eventually metabolized by the body. Current biodegradable fillers stimulate the regeneration of collagen fibers to achieve long-lasting cosmetic improvements with a low risk of adverse prognostic reactions or outcomes. This agent is popular among physicians and patients because of its non-permanent and easily correctable characteristics. 1. Early injectables: fat and collagen The application of autologous soft tissue filler cases was first used in 1983 to repair facial scarring, and today fat filler is an adjunct to platelet-rich plasma and stem cell breast augmentation. There are many factors that influence the optimal outcome of lipofilling, including the method and type of fat obtained, the experience of the injector and the unpredictable or even transient outcome of the injections, which can last from a few months to several years. Side effects of fat grafting are more pronounced: fat transfer can prolong edema and ecchymosis, with the risk of infection and necrosis. Blindness and strokes have been reported with fat injections into the seal and nasolabial folds. Bovine collagen was the first facial filler approved by the U.S. Food and Drug Administration to correct irregular contours. Two factors limited the use of the protein: first, patient allergy to the product and second, the short-lived effect. Due to the production of facial injectable products that last longer and have fewer side effects, the demand for collagen is now drastically reduced. 2, hyaluronic acid Because of its natural appearance, ease of use, reversibility and low incidence of adverse reactions, hyaluronic acid has become a classic facial filler widely used around the world. Hyaluronic acid is rich in mucopolysaccharides and is a class of polymer. Commercially available cross-linking technology is used to extend the duration of the effects of these products. When injected into the skin or subdermis, hyaluronic acid can increase the volume of the skin with water molecules and the effect can last for 4-12 months. Recent studies have also shown that hyaluronic acid can lead to the regeneration of collagen fibers. Hyaluronic acid in the body is eventually degraded and cleared by hepatic metabolism. There are a variety of hyaluronic acid products on the market in the United States, the two most popular being hyaluronic acid and jojaderm. Hyaluronic acid was the first non-animal-derived anti-wrinkle product to be approved by the FDA in December 2003. Jayden was approved in 2013 for cheek augmentation fillers, and it has a higher volume carrying capacity than other products due to its greater resistance and viscosity when injected deeper. Innovative in its ability to fill the midface and restore volume to the face due to age-related decreases, Jayden can now also be used for deep wrinkle and facial contour restoration outside of indications. Hydrelle/Elevess and Prevelle Silk are other injectable formulations approved for use in the U.S. Hydrelle is produced by a coccidiofermentation process and maintains efficacy for 12 months, but reports of post-injection inflammatory and allergic reactions have limited its use; Prevelle Silk contains the lowest concentration of hyaluronic acid and has the least cross-linked structure. Prevelle Silk contains the lowest concentration of hyaluronic acid and has the least cross-linked structure, which means that it has a shorter duration of efficacy. Most hyaluronic acid-based products are used for the repair of moderate to severe facial wrinkles, but are also used for other areas of the face outside of their indications to restore skin volume and reduce wrinkles. Customers can choose the ideal injectable product for their needs, but sometimes the most satisfactory results may not be achieved in areas like the mouth where there is a lot of movement, as repetitive motion around the mouth can reduce the longevity of the injectable. Hyaluronic acid-based fillers are rarely associated with serious adverse reactions. The main common adverse reactions are temporary minor pain, edema and technically induced rashes. Hyaluronidase can be used to digest and remove the filler within 24-48 hours of injection if you are not satisfied with the results. This feature has made hyaluronic acid injectable products more popular with patients than other products. There are several hyaluronidase products available in North America that are purified from sheep testicles without the addition of preservatives, reducing the risk of adverse reactions. The dosage of the product depends on the case, ranging from a maximum of 15 U injected directly into or under the implant for microcosmetic corrections to up to 200 U for cases facing necrosis, with immediate injection when complications are detected. The exact dose to be injected has not yet been determined. However, it should be injected immediately after the complication occurs to the area where the blood supply is reduced. Factors affecting the action of hyaluronidase are the concentration of hyaluronic acid, the degree of cross-linking and binding of its molecules, viscosity; however, some products are even resistant to enzymatic degradation. 3, calcium hydroxyapatite Calcium hydroxyapatite (CaHA) consists of spherical particles similar to bone resuspended in a sodium carboxymethylcellulose gel, which allows the injection site to produce a new gel matrix that is maintained for 15 months or more and eventually metabolized normally by the body. 2006 FDA approved for the repair of moderate to severe wrinkles and AIDS-induced fat atrophy; indications outside of the CaHA is not indicated for lip, tear trough, seal and superficial injections. 4, polylactic acid Polylactic acid (PLLA) is a biodegradable product synthesized using alpha-hydroxy acids, which is injected into the skin to cause a subclinical inflammatory response and fibrin proliferation, eventually leading to progressive volume increase in skin tissue. This product will eventually be metabolized over time. The FDA approved the product in 2004 and 2009 for the treatment of AIDS-related lipoatrophy and the repair of moderate to severe wrinkles, respectively. In addition, off-indication applications include filling acne scars and correcting facial asymmetry. Multiple courses of injections are required at 3-4 week intervals to allow for gradual results and maintenance for up to 2 years. Most of the adverse reactions caused by PLA are common tiny palpable nodules, which are associated with poor product construction or product injection sites. In most cases these apparently palpable but invisible nodules do not require treatment, however, non-granulomatous visible nodules require treatment with hyaluronic acid until the nodule is spontaneously absorbed. This product should not be applied to dynamic areas such as the lips or around the eyes. Platelet Rich Plasma Platelet Rich Fibrin Matrix is derived from centrifugation of whole blood and is another FDA approved product of safe and rapid autologous origin for use in plastic surgery. This product can be used to fill scarring, anti-wrinkle but is accompanied by transient micro petechiae or edema. Its safety and efficacy need to be further studied. Non-biodegradable fillers Permanent fillers have good efficacy and long effect maintenance but the application is more risky and requires skilled operators, and of course the complications caused by them are more common and more difficult to deal with. 1, polymethyl methacrylate microspheres Bellevue is the third generation of polymethyl methacrylate (PMMA) fillers, approved by the FDA in 2006 and 2015 for nasolabial folds and moderate to severe acne scar repair. Continuous injections are usually required to achieve satisfactory results, and the product’s effects are not immediate, taking months or even a year to achieve cosmetic requirements. PMMA is mainly used for patients with high efficacy requirements for facial wasting, cheek hollows, nose irregularities, cheekbone filling and filling of deeper lines and wrinkles such as nasolabial folds, forehead wrinkles, acne scarring, etc. PMMA cannot be used on the lips. Skin allergy test is required before treatment. When applying PMMA, extra attention should be paid to the conservative injection location and method, and the interval between injections should be long enough. In general, the incidence of adverse reactions of PMMA third generation products is greatly reduced compared with the first two generations, and the types of adverse reactions are mainly nodules, beads, scar formation and delayed granuloma. 2.Liquid injectable silicone Liquid injectable silicone (LIS) was originally used in ophthalmic surgery, but was controversial because of the risk of long-term complications in cosmetic surgery. The product can also be used to treat AIDS-related facial fat atrophy, lip filler, facial contouring, repair of acne scarring and age-related wrinkles. Disfiguring nodules and granulomas have been reported as a result of injection migration and weeks to decades after injection. Granulomatous reactions can be managed clinically with injections of high concentrations of flourohydrogenated prednisone and topical imiquimod, and surgery is required for complete healing in most cases. However, most adverse reactions are due to poor technique or product contamination, so choosing the FDA-approved small-volume versions of silicone 1000 and ADATOSIL-ol 5000, along with the use of microdrip technology, minimizes the risk of complications. Unapproved Products In addition to those approved in the U.S. there are a large number of commercial cosmetic products, even those under development or in trials, however only a small number of products are close to FDA approval standards. The first product in the injectable gel category, Bio-Alcamid, was withdrawn from the Canadian and European markets due to significant negative publicity and long-term unmanageable complications. Another non-biodegradable product, long-acting hyaluronic acid containing 2.5% polyacrylamide hydrogel (PAAG), has been marketed in Europe for facial fillers and contouring since 2001 and is widely used in more than 40 countries worldwide, pending FDA approval. PAAG has been clinically evaluated in facial contouring and deep wrinkles and folds, and its effectiveness in facial fat atrophy repair is similar to that of non-biologic hyaluronic acid, with results lasting at least 1 year in the treatment of nasolabial folds. As with Bio-Alcamid, early clinical trials of PAAG found good efficacy and minimal side effects. However, delayed reactions including infection, granulomas and migration may occur after injection. Preventive dosing with antibiotics prior to injection can significantly reduce the incidence of inflammation. Since adverse reactions are difficult to manage and usually require surgery, proper skin preparation and sterilization are necessary. No other injectable agents have been identified to treat the adverse effects of PAAG. 2. Polycaprolactone particles Ellansé is a synthetic biodegradable dermal filler. The components of the product, polycaprolactone and sodium carboxymethylcellulose, are medically and pharmaceutically safe. In the UK, polycaprolactone particles have been used in deep dermal and epidermal injections to stimulate fiber regeneration and improve skin aesthetics for up to 4 years. The safety and efficacy have been clinically proven and satisfactory results have been obtained. 3. Cross-linked hyaluronic acid In Canada and the UK, the cross-linked hyaluronic acid products in use are Revanesse and Redexis. Revanesse contains five product lines with different levels of viscosity and hyaluronic acid content, and can be used to repair varying degrees of lines, lip fillers and contouring of the midface, chin and jaw. A non-cross-linked hyaluronic acid product is also used for skin hydration, and Redexis is used for facial contouring and deep crease correction, with results lasting from 6 to 42 months. 130 trials have demonstrated the safety and efficacy of this product, with relatively good aesthetic results and minimal and short-lived side effects. In 2011, another dermal filler called Emervel was introduced in Europe, with five formulations, of which two types, Classic Emervel and Advanced Emervel, have been submitted to the FDA for approval. The classic Emervel formulation is used for moderate dermal injections to treat moderate facial wrinkles such as nasolabial folds, with efficacy comparable to hyaluronic acid and longer-lasting results. Advanced Emervel formulations are used for deeper dermal injections to treat more severe wrinkles with better and longer-lasting results than hyaluronic acid. Serious Adverse Events Serious adverse events are usually rare but can occur immediately to weeks or even years after injection. Often bacterial infections, long-term injections, etc. can lead to inflammatory nodules. A more serious problem is blockage of blood vessels caused by injection, which is rare but extremely dangerous. Depending on the blocked blood vessel, this can lead to tissue necrosis, blindness or stroke. Adverse ischemic events have been reported regardless of the type of injectable filler. The high incidence of vascular blockage and tissue necrosis is in the nose, nasolabial folds, and the seal; and the high incidence of blindness is in the seal, nose, and forehead, especially when autologous fat injections are used. Although steps are taken to mitigate the risk of complications, vascular-type adverse reactions are always unpredictable and difficult to manage, so special care should be taken when injecting in the upper two-thirds.