Innovations and personal experiences/preferences in subcutaneous filler applications

Soft tissue augmentation is the placement of various fillers on the dermis, subcutaneous tissue and periosteum, and is an ideal treatment alternative for static wrinkles. Fillers are used effectively to fill scar and atrophic areas apart from wrinkles, to correct mild structural asymmetries and small post-surgical defects. Non-surgical, minimally invasive procedures accounted for 83% of the 11 million cosmetic procedures performed in the USA in 2006. 1,2 In the selection of filler, the continuation of the aesthetic effect, the injection technique of the product and the suitability of the product to the applied face area must be considered. should be taken into account. Careful patient selection and patient expectation before the treatment, as well as procedural problems, are as important as the selection of the filler. It is expected that these products will be toxic, non-carcinogenic, non-immunogenic, do not cause foreign body reaction, cause minimal pain during application, do not migrate to another area, are ready to use and are easy to inject, and are inexpensive to apply. Today, however, there are no fillers with all these properties.3 Firms have offered many fillers to the world market by constantly renewing their technologies and producing new products in order to reach the ideal filler. If we classify the fillers from the past to the present; SOURCES OF COLLAGEN Endogenous collagen acts as the main structural element that provides strength and support to the skin. Collagen-based products currently used are derived from bovine, human and, most recently, pork.

BOTTLE-SOURCED COLLAGEN The first bovine collagen products (Zyderm-1, Zyderm-2, Zyplast; McGhan Medical Corporation, Fremont, CA, USA) received FDA approval in the mid-1980s for the correction of soft tissue deformities. 4,5 Endogenous injected materials The cosmetic improvement achieved due to its degradation by collagenases is limited to a period of approximately 2-4 months. With the introduction of Glutaraldehyde, which enables the cross-linking of collagen fibers, enzymatic destruction was delayed and the cosmetic effect increased. The life of the chemically cross-linked collagen form is approximately 4-6 months.4,5 Bovine collagen has a risk of hypersensitivity. For this reason, a collagen test injection is made to the forearm volar face 1 month before the treatment. If erythema, edema, itching, and induration are observed in the test area, the skin test is interpreted as positive. In order for the skin test result to be considered negative, the patient should be followed for 4 to 6 weeks. In patients with a negative skin test, the probability of post-injection hypersensitivity is between 0.5 and 5%. The disadvantages of these products are that they have to be kept in the refrigerator, short duration of action and skin test. The emergence of more effective, easy-to-use and inexpensive preparations has limited the popularity and use of these products.4,5 It has been used before in our country, but it is still not used.

COLLAGEN FROM HUMAN FIBROBLAST There are 2 products containing uncross-linked collagen derived from human fibroblasts, developed in parallel with bovine collagen; Cosmoderm-1 (35 mg/ml) and Cosmoderm-2 (65 mg/ml) (Allergan, Inc., Santa Barbara, CA,USA). The cross-linked form of human-derived collagen is Cosmoplast (35mg/ml).6 There is no need for allergy testing with human-derived collagen products. The obtained cosmetic effect lasts shorter than bovine collagen. The product formulation also contains 0.3% lidocaine in order to provide anesthesia during the application. While the expected effect is about 3 months for Cosmoderm, this period is about 4-7 months for Cosmoplast.7 Allergan company has announced that it will limit product production as of 2010, and it is thought that this situation arises as a result of economic reasons independent of product effectiveness. .7 It is not used in our country.

PIRGY SOURCED COLLAGEN The first swine-derived agent is Fibrel (Mentor Corp, Goleta, Calif, USA). It consists of three structures; porcine gelatin, Ɛ-aminocaproic acid, and plasma of the treated patient. Fibrel is one of the least popular filling materials today, due to the need to collect blood from the patient and mix the porcine collagen with the plasma obtained after centrifugation. It is injected intradermally. Trauma when this gelatin matrix is ​​injected intradermally causes a pooling of clotting factors for wound healing. Therefore, it should not be administered to patients receiving anticoagulant therapy. Fibrel, Zyderm and Zyplast are a good alternative filling material for patients with hypersensitivity. Evolence (Colbar LifeScience Ltd, Herzliya, Israel) containing 3.5% (35 mg/ml) cross-linked porcine collagen received FDA approval in June 2008 for the correction of medium-heavy facial wrinkles and nasolabial grooves. This product, obtained from pig tendons, was developed to replace human collagen. Although it is from porcine collagen, it does not require skin testing because the antigenic part of the molecule is removed during the enzymatic digestion that occurs during the procedure. The duration of action varies between 6-12 months. As a result of excessive cross-linking of collagen with the natural sugar metabolite by the method called Glymatrix technology, the continuity of the cosmetic effect can be increased over 12 months.2,7,8 It is not used in our country.

OTOLOGUE COLLAGEN PRODUCTS Autologen is a filling material consisting of intact collagen fibers prepared as a result of processing the skin tissue of the person to be filled in the laboratory. The resected skin tissue is frozen and sent to Collagenesis Inc. for processing. sent to the laboratory. Depending on the anatomical location, different concentrations of the product are prepared from the unit skin amount (0.6 ml from 1 gram of abdominal skin, 0.44 ml from 1 gram of eyelid skin). Preparation time is 4-6 weeks. The collagen in Autolagen is structurally different from other injectable collagen forms because it contains natural cross-links. In addition to its advantages such as being autologous, no risk of disease transmission, being able to be stored for 6 months, and not requiring skin testing, it also has disadvantages such as requiring 4-6 weeks for preparation and painful injection. In addition, since the source of autologous tissue is limited, it does not have continuity like other fillings.9 It is not used in our country. Isolagen is an autologous fibroblast solution. The aim is to increase local collagen production by using the patient’s own fibroblast repair system. The material is the skin tissue of the recipient, which is usually taken from the skin of the postauricular region with a 3 mm punch biopsy. The biopsy material is sent to the laboratory that has the certificate to carry out this production with the cold chain. In the laboratory, cells are propagated using appropriate tissue culture techniques. After six weeks, 1-1.5 ml of sterile cultured fibroblast material is returned to the doctor in syringes. The solution should be injected within 24 hours. The viability of cells decreases to 85% in 48 hours and to 65% in 72 hours. It takes 3-4 months to produce new collagen from the given fibroblast. Its effect gradually increases; this period is completed in 16-18 months.9 Plasmagel is an autologous product prepared by adding ascorbic acid and lidocaine to the blood plasma of the patient to be administered. It is prepared in the Fresenius laboratory in France. It is used for wrinkles, contour defects, acne scars and lip augmentation.

9 ALLOGENIC PRODUCTS FROM HUMAN CADAVERS These allogeneic products originating from cadaver; Dermolagen (Collagenesis Laboratory, Beverly, Massachusetts, USA), Alloderm (Life Cell Inc., Woodlands, Texas, USA), Cymetra (Life Cell Inc., Branchburg, NJ, USA), and Fascian (Fascia Biosystems, Los Angeles, USA). These products are not used in our country.10 Dermolagen is an acellular product consisting of collagen, elastin and glycosaminoglycans. Normal human collagen type I, III and IV fibers constitute the majority of the collagen it contains. It is obtained from human cadavers under the responsibility of the Musculoskeletal Transplantation Organization of the American Tissue Bank Association. Unlike bovine collagen, it should be taken out of the refrigerator 1 hour before the injection and brought to room temperature. In addition, unlike bovine collagen, it is sufficient to perform the skin test once. In addition to all these, it is at least as permanent as bovine collagen. However, since the autumn of 2001, it cannot be produced due to its lack of continuity.10 Alloderm has been applied to more than 3500 patients since 1992, when it was first used. It is an acellular human dermal allograft obtained from tissue bank sources under the control of the American tissue bank association and FDA. Once implanted, the alloderm acts like an autograft and is reshaped with the aid of the host’s tissue. Progressive increase of fibroblasts within two weeks following neovascularization and 5-8. Integration with the host collagen takes place within weeks. It can be stored in the refrigerator for up to two years.10 Cymetra is a micronized or injectable form of Alloderm. This FDA-approved product has a shelf life of 2 years and should be stored in the refrigerator.10Fascian first used Burres as a filler in 1994 in the treatment of acne scars and named it ‘recollagenization’. Graft material is prepared from the gastrocnemius fascia of human cadavers or from the tensor fascia lata.10 BIOSynthetic POLYMERS The need for long-acting non-absorbable agents has emerged to replace the short-acting agents that are absorbed over time. While biological products such as collagen and hyaluronic acid provide an immediate improvement with their volume-building feature, synthetic fillers can provide a more permanent effect with their effects on increasing fibroblast proliferation in the extracellular matrix.11,12 ‘Poly-L-lactic acid’,’calcium Synthetic facial fillers such as hydroxylapatite and polymethylmethacrylate are combined with liquid injectable carriers. The long-term effects of permanent synthetic compounds such as Bio-Alcamid and Aquamid are still unknown. While there are non-permanent fillers that are more reliable and give known results, the use of long-term permanent fillers is still a matter of debate.12,13 RADIESSE (MERZ AESTHETICS., FRANKSVILLE, WI, USA, IMPORTER COMPANY: ASSOS İLAÇ) Prepared in sodium carboxymethylcellulose gel. – The musk consists of ‘calcium hydroxylapatite’ globules of 25-45µm at a rate of 30%. This substance is the same as the mineral component in teeth and bone. FDA-approved for the correction of lipoatrophy and moderate-to-severe facial wrinkles in HIV patients, this product is also used in vocal cord augmentation and as a radiological tissue marker. It is not recommended for use on the lips due to the risk of submucosal nodule formation. Since it is an inert substance, it does not require skin testing. However, it has disadvantages such as being radio-opaque and visible on direct radiographs. After the injection, the gel part is phagocytized and ‘calcium hydroxylapatite’ microspheres settle in the surrounding soft tissue. Due to the slow destruction of microspheres and collagen proliferation, a prolonged effect of up to 2 years is expected. No allergy test is required for its use. Radiesse is completely synthetic. It does not contain any substance of human or animal origin. In the removal of nasolabial grooves for aesthetic purposes, in the revision of minor deformities after rhinoplasty, in the removal of marionette lines (lines extending from the edges of the lips), removal of wrinkles around the lips, fullness in the cheeks, to add volume to the dorsal face of the hands and also malar and used for mandibular augmentation. It is not used in the area called tear-through deformity located in the inner-lower parts of the lower eyelids, on the glabella line and on the red mucosa of the lip. It is injected into the deep dermis. It is applied with a 25-27 G needle and cannula. Injections require anesthesia. It is available in our country’s market and its use is increasing day by day. Contrary to expectations, it is easy and safe to use. We can prefer it when we want long lasting. The product is usually diluted with 0.5cc lidocaine.14-18 SCULPTRA (VALEANT AESTHETICS,NORTH AMERICA.,LLC) is also known as New-Fill in Europe. ‘Poly-L-lactic acid’ was not actually designed as a filler on its own. Just like Radiesse, carboxymethylcellulose is prepared in gel. Although it is indicated in HIV-associated lipoatrophy and is FDA-approved, it is widely used in cosmetic facial filling procedures off-label in the United States and within indications in many other countries. It is recommended to be implanted with a 26G needle into the deep dermis or subcutaneous tissue by linear retraction or tunneling. Although its mechanism of action cannot be fully determined, it is thought to activate type-1 collagen synthesis by triggering the formation of granulomatous reaction when injected into the subdermis. This effect starts in about 6 weeks, but it has been shown to last up to 2 years.11,19,20 It is not used in our country. ARTEPLAST, ARTECOLL, ARTEFILL (ARTECOLL: ROFIL MEDICAL INTERNATIONAL, HOLLAND) (ARTEFILL: SUNEVA MEDICAL, INC., SAN DIEGO, CA, USA) ‘polymethyl met- hicrylate’ (PMMA) microspheres used in bone cement are also used as tissue enhancers. The first developed PMMA preparation caused the development of a large number of granulomas because the Arteplast surface was not flat, carried electrostatic energy and was not pure. Later in 1994, Artecoll was developed, containing high purity and smooth surface PMMA microspheres. Artecoll, which received a CE certificate in Europe in 1996, was not accepted for use in the USA. Within 20 years, the preparation was further developed and received FDA approval under the name Artefill in 2003.1 Artefill contains ‘polymethyl methacrylate’ (PMMA) microspheres with 30-40µm diameters at a rate of 20% in 3.5% bovine collagen and 0.3% lidocaine. It is a non-resorbable sub-dermal filler. It received FDA approval in 2006 for the treatment of nasolabial grooves. As a result of experience, injection into the lip and thin skin is not recommended due to the possible risk of papule-nodule formation. As a result of the destruction of the collagen component within 1-4 months, a 50-75% reduction in cosmetic improvement can be observed. During this period, PMMA microspheres, which are resistant to phagocytosis and enzymatic degradation, become permanent by encapsulating with the surrounding connective tissue. This is the feature of surrounding the foreign body with fibrous tissue, which is a natural defense mechanism of the body. It has been experienced that the aesthetic effect lasts for more than 10 years. Although PMMA is associated with a granulomatous reaction, granuloma formation was not reported in a clinical study in the USA in which 251 patients were treated in 5 years.1-3,6,7,19,21 As a result of accidental intradermal administration of PMMA, only Nodule formation can be observed, which can be removed by surgical excision.11 It is not used in our country. SILICONE 1000 (ALCON LABORATORY, INC., FORT WORTH, TX, USA) ‘Silicon’ element is naturally found in the structure of mucopolysaccharides in the body. ‘Silicone’ or siloxane, which are used for medical purposes, are long polymers of ‘dimethylpolysiloxane’ formed by the bonding of ‘silicon’ and oxygen atoms to hydrocarbon groups to form chains. ‘Silicones’ are synthetic compounds not found in the natural environment. These polymers can be liquid, gel or solid according to their viscosity. Intraocular injection of high-viscosity Adatosil-5000 and Silicon-1000 in the treatment of retinal tamponade received FDA approval, but no FDA approval was given for the use of liquid silicone in soft tissue augmentation. However, as it is known, it is legal to use an off-label product with a patient consent form in other indications. ‘Silicon 1000’, a ‘dimethylpolysiloxane’ polymer, can also be used off-label as a subdermal filler. Within weeks, fibrous capsule formation is observed around each silicon microdroplet, providing augmentation. New collagen formation takes place at a rate of 50% at the end of the 1st month, 90% at the end of the 2nd month, and 100% at the end of the 3rd month and is self-limiting. Due to the slow development of collagen formation in this way, the results appear late. Therefore, subsequent treatments should be performed at intervals of at least 6 weeks.1,7,22 Injection into the glandular breast tissue and penis is one of the absolute contraindications. In addition, application of acne to ‘icepick’ scars and deep chickenpox scars that are connected with fibrotic bands downwards may not elevate them and may cause a bagel appearance. Since liquid silicone is not allergic, there is no need for a skin test before application. No carcinogenic effects were detected in human and animal studies. It does not change in the body, but it is phagocytized in low amounts and transported to the reticuloendothelial system, but its harmful effects have not been determined. The hypothesis that silicon slides down by gravity is against the laws of physics because silicon is lighter than water and human tissues. Complications such as inflammation, induration, ulceration, granuloma formation and discoloration limit the use of silicone as a filler. The most permanent tissue enhancing agent known is silicone. Good and bad results generally depend on the application technique.1,7,22 It is not used in our country. AQUAMID (CONTURA INTERNATIONAL, A/S) is a 2.5% cross-linked homogeneous ‘Polyacrylamide’ hydrogel. This molecule is insoluble in water, but it has a very high water-holding property. The water molecules that it holds give the volume it gains. Does not require skin testing. Aquamid R has a higher viscosity. It is administered subcutaneously with a 27G needle. It has CE certification since 2001. It is not FDA approved.12,13 It is not used in our country. BIO-ALCAMID (ASCENTE MEDICAL, ITALY) is a synthetic network polymer containing 4% Polyalkylimide and 96% water. It is an injectable endoprosthesis rather than a filler. After 4-8 weeks, it wraps around the body with a thin collagen capsule and isolates it. That’s why it doesn’t move. It does not cause an allergic reaction. It can be removed if desired. It has no FDA approval. It is applied after local anesthesia is performed. Does not require skin testing. It is administered subcutaneously. It is soft in texture. It is not noticeable by touch. Bio-alcamid lips form is used to correct the lip profile. Bio-alcamid face form has a darker consistency. It is used for mild to moderate wrinkles and volume losses. The body form is the same as the face form in terms of content, only the volumes are different. Being an expensive filler limits its use.12 It is not used in our country. This product containing GORE-TEX Polytetrafluoroethylene (PTFE) is inserted into the deep dermis with the help of a guide needle over a trocar under local anesthesia in cosmetic dermatology. Since the implants are removable, the implant can be removed if the patient is not satisfied with the result. There is no need for a skin test as it does not pose an allergy risk. If infection develops after implantation, the implant should be removed.12 It is not used in our country. HYALURONIC ACID DERIVATIVES; Hyaluronic acid (HA), which is naturally found in the human body, is a basic polysaccharide of the connective tissue extracellular matrix and is a glycosaminoglycan composed of repeating D-glucuronic acid and DN-acetic-glucosamine dimeric units. It stabilizes intercellular structures and creates a viscoelastic framework for the binding of collagen and elastin. Since it binds water potently, it provides softness and hydration by creating volume when injected into the skin. As the age progresses, the decrease in the amount of hyaluronic acid results in a decrease in skin hydration, elasticity and mobility. It increases the volume and elasticity of the dermis, thanks to its water-binding capacity of 1000 times its volume.7,13,23,24 In its natural form, hyaluronic acid is rapidly absorbed. Since it is destroyed by hyaluronidase, the life of the hyaluronic acid in the dermis is 1 day. As a result of cross-linking with chemical agents such as butanediol diglycidyl ether (Restylane, Juvederm etc.) or divinyl sulfone (Prevelle Silk, Captique, Hylaform etc.), preparations resistant to heat or enzymatic degradation have been obtained. This cross-linking gives each HA filler its characteristic properties. These properties determine the behavior and effectiveness of each HA product. The crosslinking process enables the production of HA in ‘particulate’ and ‘non-particle’ forms, but it has not been determined which form leads to a better result. The effect and duration of the particulate form (Restylane, etc.) is proportional to the particle size, and the particle size in the gel determines the volume-filling feature. In addition, the density of HA particles per milliliter determines the permanence and stability of the product. The volume-filling power of the non-particulate form (Juvederm etc.) depends on the number of crosslinks it makes. The ideal level of crosslinking is unknown, it has been suggested that excessive crosslinking can significantly reduce the hydrophilic properties of hyaluronic acid.1,3,7,23,24 Hyaluronic acid fillers are ‘biphasic’ (combination of cross-linked and uncrosslinked HA) according to their characteristics. (Restylane etc.) and ‘monophasic’ (wholly cross-linked HA chains) (Juvederm, Teosyal etc.). While the biphasic form allows the application of HA with large particles, it is more difficult to apply. Since the monophasic form is homogeneous and has small particles, it can be applied more easily in theory.1,3,6,7,23,24 Another difference in biphasic filling is the monophasic gel particles. A scanning system is used to reach their concentration, which divides the filler into thousands of gel particles, depending on the desired volume. Therefore, biphasic fillers have the same concentration of hyaluronic acid and gel particles in different sizes.23-26 Hyaluronic acid products are easier to use than other filler products. Does not require skin testing. It does not need to be stored and transported in the cold chain. However, hyaluronic acid products should not come into contact with high temperatures. The monomers formed in this situation have the potential to develop inflammation.11 The advantages of HA far outweigh its disadvantages, increasing its use by 190% in the last decade in the USA. In 2011, 69% of all fillers injected in the USA were fillers containing HA. With the use of hyaluronidase, rapid recovery, being natural and safe, not containing animal products, obtaining cosmetic results immediately after application, and not showing antigenic properties are the advantages of hyaluronic acid over other fillers.23,24 Although manufacturers of hyaluronic acid Although he states that it is not necessary to apply a skin test before use for acid preparations, hyaluronin-related protein, which is present in varying amounts in fillers, theoretically carries a risk of hypersensitivity. Lowe et al. After the Hylaform and Restylane treatment they applied to 709 patients between 1996 and 2000, they followed the patients for 1 year. While delayed-type hypersensitivity reaction developed in three patients (0.042%), the reaction started 6-8 weeks after treatment in all three patients. Abscess formation was observed in all patients in the nasolabial region.3 HA application is contraindicated in pregnant women, lactating women, children under 12 years of age, those who are prone to keloid development, in the presence of bleeding diathesis, in the presence of active infection and inflammation. 11 In general, Hyaluronic Acid derivatives, such as 27-30G thin It is applied by entering the skin at an angle of 33° with pointed needles. The effect is on average 6-12 months. A recent study in Europe showed a decrease in the correcting effect over time, and it was reported that there was a 98% reduction in the second week following treatment, 82% after three months, 69% after six months, and 66% after one year. 3,24 There are many HA-containing fillers in our country. Frequently used ones will be briefly mentioned here. Restylane (Galderma SA, Importer: Pharmexx): It was launched in 1996 as the first hyaluronic acid derivative of non-animal origin. This product, which was approved by the FDA in 2003, is also available in the market containing 0.3% lidocaine. The company produces hyaluronic acid with a non-animal origin method (bacterial fermentation). This method is called NASHA (Non animal source hyaluronic acid: non-animal source hyaluronic acid). After HA is produced by bacterial fermentation, it is cross-linked by adding 1,4-butanediol diglycidyl ether to increase the surface area and slow down the natural degradation of the product. All Restylane products contain between 4000 and 200,000 particles per milliliter. After the gel is homogenized, it is put into 1 ml pre-filled syringes. ‘Restylane Perlane’ contains approximately 8000 gel particles per milliliter. Compared to Restylane, it has a thicker consistency due to its larger particle sizes. Restylane can be injected with a 30G needle, while Perlane 27G with larger particles can be injected. Therefore, while Perlane is preferred for deeper wrinkles, Restylane can be used for more superficial wrinkles. Permanence varies between 6-12 months depending on the product scale.3,7,27 Restylane; Contains 20 mg/ml hyaluronic acid. It contains 100,000 particles per milliliter. Glabella can be applied to horizontal lines on the forehead, lip corners and lips (for contouring or fullness). It is applied to the middle dermis.3,7,27 Restylane Perlane; Contains 20 mg/ml hyaluronic acid. It contains 8,000 particles per milliliter. It is similar to Restylane but loses volume later as it contains larger particles. It is usually injected into deep wrinkles such as the naso-labial crease that occurs between the cheek and nose. It is among the fillings we frequently prefer for the nasolabial area. It is applied to the deep dermis.3,7,27 Restylane Vital/Vital light: Restylane Vital (20 mg/ml) is a product that repairs the skin structure and gives the skin its vitality rather than giving volume. Like mesotherapy, many superficial injections are made and 2-3 sessions are applied at four-week intervals. Since its effect is not permanent, it should be repeated twice a year. It is also available in Vital/light (12 mg/ml) product to provide high moisture to the newly formed wrinkles and skin.3,7,27 Restylane SUB-Q; It contains 1000 particles per milliliter. It is used for malar and mandibular augmentation. It is often preferred to create a volume. Applications are made deep subcutaneously or supraperiosteally.3,7,27 Juvederm (Allergan, USA, Importer: Allergan): It is a viscoelastic, gel-like monophasic hyaluronic acid preparation. It is obtained by bacterial fermentation. 1.4 Butanediol is cross-linked with diglycidylether (BDDE). Permanence is 8-12 months thanks to HV (high viscosity) technology. It is stated that it is the only hyaluronic acid-containing filler approved by the FDA to have an effect of 1 year. Juvederm ultra series of fillers contain lidocaine to relieve injection pain.3,7,23,24 Juvederm Ultra 2; 24 mg/ml, BDDE (++), It is a preferred filler especially for superficial wrinkles such as eye contour, forehead, glabella, cheek lines and slight nasolabial folds. It is applied to the upper-middle dermis.23,24 Juvederm Ultra 3; 24 mg/ml, BDDE (+++), It is a filler preferred in the treatment of medium-depth glabella, cheek wrinkles, nasolabial folds. It is also effectively used in nose, rim and lip volume restoration.23,24 Juvederm Ultra 4; 24 mg/ml, BDDE (++++), is a filler used for malar/mandibular augmentation as well as for filling deep depressions in the skin, deep nasolabial folds and marionette lines. It is applied to the middle and deep dermis.23,24 Juvederm Voluma; 24 mg/ml, BDDE (+++++), It is a filler that we frequently prefer for cheek and malar/mandibular augmentation that become dimpled due to weight loss or age-related reduction in facial adipose tissue. The lifting effect of voluma treatment can be seen for up to 18 months.23,28 Juvederm Volbella; 15 mg/ml, BDDE (++), is the new member of Juvederm fillers family. It is used for lip augmentation. Vycross technique, a special patented method of Allergan, is used in its production. In this way, it can last up to 12 months on the lips. There is a more natural appearance and less edema after the procedure.23,29 It is a product we frequently prefer in lip applications recently. Juvederm Ultra smile; 24 mg/ml, BDDE (+++), It is a filler used to plump the lip volume and reshape the oral contour. It is less preferred after volbella.23,24 Juvederm Hydrate; 13.5 mg/ml, BDDE (-) It is a hyaluronic acid designed to increase skin hydration and elasticity. It is used for mesolift purposes in the form of serial point technique at one cm intervals on the face, neck, hands and décolleté. It does not contain lidocaine.23,24 Teosyal (Teoxane, Geneva, Importer: Seltek): It is a permanent, non-animal origin, hyaluronic acid-containing filler. It is a monophasic hyaluronic acid. Contains 15-25 mg/ml HA. The permanence period is 6-12 months. There are Ultra Deep, Deep Lines, Global Action, First Lines, Kiss, Touch up, Ultimate and Meso (no cross-linking) forms.24 In addition, its two newest products: Teosyal Redensity I (Light filling): Mesotherapy and filling techniques It is a new concept among the skincare products, and with the HA, amino acids, vitamins and antioxidants it contains, both moisturizing and skin rejuvenation can be performed together. The expected effect is achieved in 3 sessions at 3-week intervals. Teosyal Redensity II (Under-eye light filling): It is a product that helps to solve problems around the eyes such as eye socket and bruise problems. Its permanence varies between 1 and 1.5 years. With the HA, amino acids, vitamins and antioxidants in its content, both moisturizing and skin regeneration can be performed together. Unlike Redensity I, HA contains light crosslinks. In this way, the correction of the under-eye pit continues for a long time. It is a product that we have frequently preferred recently to correct deformities of detention. Perfectha (ObvieLine, France, Importer: Mesoclinic): Cross-linked, non-animal, 3D Filling | It is a biphasic filling material produced with E-Bridge technology. It has CE approval. This filler is produced in 4 different forms: Perfectha Derm Fine Lines, Perfectha Derm, Perfectha Derm Deep, Perfectha Derm Subskin. Esthélis (Anteis SA, Switzerland, Importer: Sanovis) is a monophasic-polydensified filler produced with CPM (Cohesive Polydensified Matrix) technology. It is a non-animal origin filler. It has four forms: Soft, Esthelis Basic, Fortélis extra (Monophasic-monodensified) and Modelis. In addition, Mesolis and Mesolis plus (with glycerol added to it) are non-cross-linked products with lower concentrations of HA. Regenyal Idea/Bio-Expander(Phitocorp, Italy, Importer: Naturamed): Bio-Expander, an innovation in the balanced volumetric structuring of the face shape; It is formed by the combination of 3 different molecular weight HA (1 M Dalton, 2 M Dalton, 500 K Dalton). HA comes out of the product package in 3 different volumes of 1.1 ml. 1 and 2 M Dalton HAs are cross-linked and provide volume and structuring of the skin. On the other hand, HA of 500 K Dalton distributes freely and moisturizes the skin. Thus, augmentation and rejuvenation can be done together. We prefer this product when we want to create a fast and combined effect on the entire face. In addition, Idea/Regenyal Fillers have Idea for facial augmentation, Lips for lip augmentation and IAL system/ IAL system-ACP for bio-revitalization. HYDROPHILIC GEL DERIVATIVE Aquafilling(BIOMATRIX EUROPE, Czech Republic, Importer: Alesta) is a hydrophilic gel consisting of 2% synthetic linear polyamide and 98% saline. Its structure is based on multiple hydrogen bonds between carbonyl and amine groups. The presence of more than one active carboxylic group gives the polymer molecule its positive charge and provides high hydraulic structure and water solubility. It is a filler that can be used both for facial wrinkles and body aesthetics (breast augmentation, hip augmentation). It is produced in 2 different forms as faceline and bodyline. It is used in Faceline 1 cc pre-filled syringes and filling applications on the face. Bodyline, on the other hand, is used in 100 gr bags, in body shaping such as breast and hip enlargement. It is permanent for 5-8 years in body applications. As important as choosing the right and high quality product after choosing the patient to be filled, it is very important to apply the product to be applied with the right technique. APPLICATION TECHNIQUES AND RECOMMENDATIONS Most fillers are available in closed system, ‘disposable’ syringes that are pre-prepared and sterilized according to their viscosity. Fine wrinkles require superficial injection. For deeper wrinkles, it is placed in the mid-deep dermis or subdermis, depending on the application. The filler can be injected in 4 ways; (a) Serial Dot-Serial Puncture, (b) Tunneling-Linear Threading, (c) Fan-Fanning, (d) Cross Hatch-Cross Hatching (Fig. 1). In the 2 Serial Dot method, multiple points along the wrinkle line Filling material is applied by injection. Injection points should be kept as close as possible to obtain a consistent and uniform result. The remaining gaps can be corrected by applying massage. This technique is useful in non-surgical rhinoplasty applications with acne scarring, superficial forehead wrinkles, glabella and filtrum filling, and non-surgical rhinoplasty. In the method called ‘push-ahead technique’, filler is given while the needle is further advanced. There is a risk of damaging the vessels in this anterograde application. Another application technique in the tunneling method is to give the filling by pulling back slowly while the needle is completely in. This retrograde method provides a more homogeneous and safe application. The tunneling method is the best method for vermillon line and nasolabial groove repairs.2 Fan/Cross-Scan methods are variations of the Tunneling method that allow larger defects to be filled. In the fan method, the direction of the needle is changed by opening radial tunnels to form a fan with a single needle entry. In the cross-hatching method, tunnels are formed by making many entrances with the needle and crossing each other perpendicularly. Both techniques are useful in the applications of the malar region and the mouth commissure (Marionette). For example, while application control is easier with the serial point technique, the risk of multiple injections into the same place called ‘overlap’ is higher with this technique. Again, in the serial point method, it should be kept in mind that the pressure applied while removing the needle from the skin should be reduced so that superficial deposits do not form. Tunneling technique, on the other hand, requires more experience than others. Many physicians generally use a combination of these two techniques. According to the application areas, tunneling and/or serial point technique in the lips; The cross hatching technique is ideal for the oral commissure, marionette lines, and under the corners of the mouth. Serial point and linear retraction techniques can be used for the nasolabial region. Serial point technique is recommended for deep and wide wrinkles in the glabellar region. The serial point technique is recommended for forehead wrinkles.2,30 In addition to applying the fillers with the correct technique, the filler should be determined according to the needs of the application area and the application should be made after the depth is adjusted according to the product. On the contrary, in case of wrong product choice, the desired effect may not be achieved or an excessive effect may be created.

FILLING MATERIAL SELECTION ACCORDING TO THE APPLICATION AREA The most frequently intervened wrinkles on the upper part of the face; Forehead wrinkles formed by the movement of the frontalis muscle, vertical glabellar wrinkles formed by the depressor corrugator complex, and crow’s-oil wrinkles formed by the movement of the orbicularis oculi muscle. Horizontal forehead lines and lines appearing in the middle of the eyebrows create a harsh and unhappy expression in people with frowning eyebrows. Although such dynamic wrinkles respond very well to botulinum toxin treatment, intradermal application of low cross-linked or small-particle HA combined with botulinum toxin has been found to be successful in resistant cases. 6,31 The thinning of the skin and the collapse of the cheeks can be corrected by using fillers. Subcutaneous/supraperiosteal application of the largest particle or most cross-linked HA preparation or long-term permanent fillers is a good alternative to fat transfer for midface augmentation. During the treatment of ‘Tear Trough’ deformities, the patient should be ensured to sit upright in order to prevent gravitational displacement of the orbital fat tissue. A small amount of filler is injected very slowly, just outside the orbital rim and under the orbicularis oculi muscle, using the retrograde tunneling method. After the procedure, a light massage can be applied to ensure homogeneous distribution. The success of the procedure in this area is related to the selected product, the technique applied and the experience of the physician. In order to prevent ecchymosis, pressure and ice should be applied to the area after the injection. The interval between two injections should be at least 4 weeks. In the case of very superficial placement of hyaluronic acid, a blue color change is seen, which is called the ‘Tyndall Effect’. This discoloration, which tends to resolve spontaneously, can be treated with hyaluronidase injection or the use of Nd:YaG laser. 7,32 Another new area of ​​use for fillers is ‘Injection Rhinoplasty’, which saves patients from surgical procedures. A medium-sized filler should be applied to the fronto-nasal angle, nasal dorsum, nasolabial angle, and medium-deep dermis. Many patients expect the lines in this area to disappear completely in one session. Filling should be done in a few sessions, as overfilling in a single session makes the face swollen and expressionless. Since the nasolabial sulcus is deeper than other facial wrinkles, denser fillers should be applied to the mid-deep dermis. 6,7,31 The lower part of the face is volume loss with aging and the soft tissues collapse, with the mouth commissures facing down and the depressed anguli. Marionette lines develop as a result of excessive movement of the oris muscle. In lip augmentation, first of all, the lip contour (vermillon) should be filled, then the lip edges and perioral lines should be filled. Finally, if lip augmentation is desired, a submucosal injection is made in the middle 1/3 of the dry/wet mucosa junction and the filler is implanted. Movements of the orbicularis oris muscle cause perioral wrinkle formation, age-related atrophy causes volume loss with the lip vermillon border and loss of the upper lip fold called the ‘cupid bow’. Since treatments in this area are very painful, infraorbital and mental block with 2% lidocaine and 1:100,000 epinephrine is recommended. Starting from the oral commissure, the needle is advanced along the vermillion line (between the red and white lips), and the filler is implanted into the subdermal area during retrograde tunneling. Before lip augmentation procedures, patients with a history of herpes simplex should be given antiviral prophylaxis. Perioral lines can be treated with laser, dermabrasion, botulinum toxin and fillers. Although the use of filler alone in this area is not a very effective method, it is a safe and practical option.6,7,31 Deep marionette lines and downturned oral commissures can be reversed with many fillers. Fan and retrograde tunneling techniques are frequently used in this area.7 Minor repairs can be made to eliminate the changes that occur with aging in the jaw. The spectrum of fillers used for the chin is also large-particle or highly cross-linked, and parallels those used for the cheeks. Before the application, the area where the scar is located is stretched with two fingers, if there is improvement in the scar, it is understood that the filling will be beneficial. Today, the main areas of use of fillers in scar treatment are scars due to acne. However, due to the fibrous nature of pitted and ice-pick scars, the benefit of filling treatment is quite limited compared to sunken or wide-based scars. Acne scars that respond best to treatment with filler injection are atrophic and/or Rolling scars. Filling injection after subcutaneous fibrotic bands are cut with subcision before the application allows us to obtain better results. The most suitable scars for filler injection are the scars that have matured and become sequelae.21 In order to get good results in filler application, we must fulfill the requirements of all disciplines in all aspects. One of these disciplines is to choose the right patient and to inform the selected patient in the best possible way. PATIENT SELECTION AND INFORMATION What should be questioned and revealed primarily by the physician is how much the patient’s aesthetic concerns can benefit from the filling process and whether this is sufficient for the patient’s satisfaction. This evaluation should be made at the first consultation, and if necessary, the patient should be directed to different cosmetic procedures (resurfacing, recounturing, relaxation). If the procedure is decided, the patient’s detailed medical history should be taken in the second step. For those with active infection, the procedure should be postponed, and those using drugs such as aspirin and coumadin should be interrupted if possible. Although immunosuppression is not a contraindication for this procedure, the patient should be informed about the possible risk of infection. As the third step, the patient should be informed about the procedure. The patient should be included in the selection of the filler to be used, by giving information about the different fillers that can be used, their advantages and disadvantages, their duration of action, and the anesthesia to be used. Finally, all complications that may occur should be explained to the patient, and a signed consent form containing all these complications in terms of legal procedure must be obtained. who manages. FILLING MATERIAL COMPLICATIONS In addition to patient selection, it is very important to know which filler should be used and where it should not be used, and the depth of injection with the appropriate technique. However, minor and/or major complications may occur in patients in the early and late stages. Minor complications such as skin discoloration may occur. Often these appear the next morning. If the patient is under anticoagulant treatment or some vitamin (vitamin E, ginseng, gingko, ginger, garlic) supplements, the size of the ecchymosis may be deeper. It has been reported that ecchymosis can be reduced with some natural treatment methods such as echinacea. Interestingly, the fan method adopted by many practitioners is said to predispose to bleeding and ecchymosis.33 Temporary edema due to the irritation of the inserted foreign body is expected to subside in 24-72 hours. Sensitivity, which occurs as a result of needle trauma, also passes in similar times. Edema and tenderness are more prominent when long-acting fillers are used compared to short-acting ones. The pain seen after the application is probably due to the irritation of the cutaneous nerves in the skin, which is stretched by the effect of the putty material.19 Discoloration of the skin is common after injections of hyaluronic acid and calcium hydroxylapatite. Although this situation does not resemble a hypersensitivity reaction, it has been observed that mast cell release accompanies the color change.11 MAJOR COMPLICATIONS A significant portion of the patients who apply for the filling procedure come with a request for the removal of the asymmetry. The patient should be told from the very beginning that some asymmetry may still persist after the procedure. It is recommended to take pictures before and after the procedure to show the change. The lump formation after the injection can probably be removed with massage. However, the lumps that may form as a result of excessive superficial injection of medium-particle fillers can persist for months.33 Hematoma is a rare complication due to accidental rupture of blood vessels during the procedure. Especially the glabellar region is a region more prone to hematoma formation due to the supratrochlear artery and dense anastomosis network. Although rapid development of hypersensitivity after injection is not a common condition, it can be encountered with bovine collagen applications. Although infection at the injection site is rare, HSV reactivation may occur as a result of trauma.11 LATE-TERM COMPLICATIONS Minor Complications Delayed small lumps of unknown etiology may occur after HA, calcium hydroxylapatite, and poly-L-lactic acid, especially applied to the mid/deep dermis. Delayed hypersensitivity reaction is very rare when non-animal products are used.32 MAJOR COMPLICATIONS True granuloma formation is very rare. It is found in 0.1% of the patient population. Most of them are seen as a result of the use of medium-long-acting and permanent fillers. These granulomas, which are formed as a result of foreign body reaction, usually present with dermal nodule formation accompanied by mild erythema. Although these granulomas usually disappear spontaneously within 6 months after injection, persistent granulomas up to 14 months after PMMA injection have also been reported. Infection is usually an early complication caused by skin pathogens, especially S.aureus. However, in the later stages, the formation of fluctuating nodules, unlike granuloma, also suggests infection. Erythema, tenderness, and increased temperature accompany these nodules. Mycobacteria are accused of being able to infect in the delayed period (sterile abscess).33,34 Migration of the injected implant is another delayed complication. While this risk exists in permanent implants such as calcium hydroxylapatite and silicone, this is very rare for resorbing temporary fillings. Despite the risk, the migration of calcium hydroxylapatite could not be demonstrated in three different studies. In addition, it has been reported that calcium hydroxylapatite can cause a ‘popcorn lip’ appearance as a result of superficial migration if it is applied in lip augmentation. If the silicone is applied with the microdroplet technique, the risk of migration is much less. Conditions such as infection and granulomatous reaction may trigger migration.32 MANAGEMENT OF COMPLICATIONS Prevention The best way to deal with complications is to ensure that they never occur in the first place. For this, first of all, it is necessary to understand very well which filler material will be used in which region and the characteristics of the product. For example, the use of calcium hydroxylapatite, which is a versatile filler, on the lips carries the risk of nodularity. Although corticosteroid injection into the lip shrinks the nodules, there is a risk of atrophy in the lip. Before nasolabial sulcus implantations, 1 ml of 1% lidocaine injection containing 1/100,000 epinephrine ensures adequate constriction of the vessels and minimizes the risk of vessel damage. . Information should be given that the treatment plan may take several sessions. What the physician should determine is whether the resulting complication can go away on its own in time or whether it is necessary to intervene.11 TREATMENT Observation and supportive treatment are recommended for minor complications such as ecchymosis. A light massage application is beneficial for the bumps and moderate asymmetry that occur in the early period. In case of advanced asymmetry complication, additional injection planning may provide symmetry.19 In case of superficial papule formation, methods such as dermabrasion or laser resurfacing are beneficial, but if the implant is not permanent, needle aspiration method should be tried first. Injection of serum into the area will increase the efficiency of aspiration. Granulomas formed as a result of superficial implantation of HA can be successfully removed with hyaluronidase injection. Intralesional steroid injection is also widely used in the formation of implant-induced granuloma. However, it should not be applied above 10 mg/ml, as it may cause atrophy and erythema on the skin. In case of abscess formation, culture is taken from the aspiration material. Specific antibiotics should be started according to the culture results. However, in most cases, the culture result is negative. In the case of a sterile abscess, the patient should still be treated with antibiotics and drained of the abscess. If necessary, intralesional rifampicin injection can also be performed.33 Skin necrosis resulting from vascular injury or intravenous injection is the most feared complication. If there is fading and severe pain at the injection site, this is a sign of necrosis. In this case, hyaluro- nidase injection, massage with nitroglycerin pomade and systemic heparin injection should be applied to the filling area immediately. If necrosis has occurred, surgical procedures may be required.