Lip augmentation with a new filler (agarose ): a 3-year follow-up study Antonio Scarano, DDS, MD, MS,a Francesco Carinci, DDS, MD,b and Adriano Piattelli, MD, DDS,c Chieti and Ferrara, Italy UNIVERSITY OF CHIETI-PESCARA AND UNIVERSITY OF FERRARA

Background. Many fillers have been used to augment . Agarose gel is a new and absorbable filler indicated for the correction of soft tissues and . Objective. This article reviews the results of 68 cases that have undergone lip augmentation with this new filler in the last 3 years. Study design. A total of 68 patients received agarose gel for treatment for lip augmentation in a 3-year period from 2005 to 2008. Each of the patients signed an informed consent form. The patients were between 35 and 70 years of age. Three patients were male, and 65 were female. A volume of 0.5-1.0 mL of agarose gel was sufficient for each lip. A bigger volume may result in a dense mass and pain. All patients were successfully treated with injections of agarose gel. Results. Clinical improvement was noted immediately, and only mild bruising was recorded. All of the the patients returned to the clinic 10 days after treatment for follow-up, and all felt that an excellent cosmetic result was obtained. The patients were told to return after an additional month for follow-up and possible reinjection. The results lasted approximately 5 months with a gradual decline to baseline. The agarose gel was very well tolerated with only a few mild adverse reactions that resolved spontaneously. Conclusion. During 3 years of clinical use, agarose gel proved to be a reliable and predictable treatment for lip augmentation. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:e11-e15)

Agarose gel is an absorbable filler indicated for the strate of choice in numerous biocompatible tests, such correction of soft tissues and for lip augmentation.1 It is as cytotoxity, genotoxicity,2 mutagenesis,3 sensitivity,4 made from a gel of injectable agarose and is painless and subcutaneous implants.5 Furthermore, the gel is because it is isotonic. It is a sterile, apyrogenic, vis- used in bioengineering for 3-dimensional tissue growth coelastic, clear, colorless, and transparent gel. Agarose and as a substrate for controlled release of pharmaco- gel is a polysaccharide formed by repeating units of logic substances. 3,6-anhydrous L-galactose and D-galactose. There is no Soft tissue augmentation with injectable filling specific enzyme in the human organism which is able to agents in the perioral region is rapidly increasing in degrade agarose. Therefore the agarose is first trans- popularity.6 In addition, the proven safety of these ported from the application site by the action of mac- products has also been a factor in their increased use. rophages and then subjected to enzymatic destruction Although only rarely, complications do occur.7 A novel of the polymer by means of galactosidase. Agarose is use for filling agents is to exploit their volume-occu- metabolized in the pentose cycle at the level of the pying properties to replace lost subdermal fat and re- macrophages, platelets, and endothelial reticulum. Aga- modeled maxillary and mandibular bone. The “push- rose gel has been chosen owing to its characteristics as fill” restores the youthful characteristics of the face a biocompatible vehicle in a wide range of preclinical without “pull” , with less inconvenience and and clinical applications. Agarose is used as the sub- few complications.8 It is used to support the cosmetic application of such agents and helps define the adverse aResearcher, Dental School, University of Chieti-Pescara. event profile. bChief, Maxillofacial Surgery, University of Ferrara. Using fillers for facial rejuvenation requires not only c Professor of Oral Pathology and Medicine, Dental School, Univer- knowledge of specific fillers but also insight into the sity of Chieti-Pescara. Supported in part by the National Research Council (CNR), Rome, process and anatomy of aging. The scientific support Italy, and by the Ministry of Education, University, and Research for the application of a substance for soft tissue aug- (M.I.U.R.), Rome, Italy. mentation is critical. One of the central tenets of soft Received for publication Jan. 26, 2009; returned for revision Mar. 18, tissue augmentation is the concept of the 3-dimensional 2009; accepted for publication Apr. 16, 2009. face. A youthful face has a soft, full appearance, as 1079-2104/$ - see front matter © 2009 Published by Mosby, Inc. opposed to the flat, pulled, 2-dimensional look often doi:10.1016/j.tripleo.2009.04.025 achieved by more traditional surgical approaches. In-

e11 OOOOE e12 Scarano, Carinci, and Piattelli August 2009 jectable filling agents can augment and even, at times, were occasionally introduced into the lateral orbicularis replace pulling. Additionally, with the lip as the focal oris muscle to attempt lip eversion. A flattened philtrum center of the lower face, subtle lip enhancement is here can be raised effectively by two vertical injections of to stay, and is, in fact, the primary indication for in- agarose gel starting from below, e.g., from the two jectable fillers. Dermal fillers are commonly catego- corners of the Cupid’s bow within the white roll. Under rized by duration of effect: temporary, semipermanent no circumstances should the microdroplet (duration is often Ͼ18 months but the exact time frame technique be used in the lips. A volume of 0.5-1.0 mL is unknown), and permanent options. Doctors today agarose gel was sufficient for each lip. A bigger volume have a much larger armamentarium of techniques and may result in a dense mass and pain; therefore, the lips materials with which to improve facial contours, ame- should always be augmented in stages. If agarose gel liorate wrinkles, and provide esthetic rejuvenation to was well tolerated and lips were soft after 3 months, the face. more agarose-gel could be added to the same pocket. The present article briefly presents the first use of a Only rarely did the dislodge into the surround- temporary alloplastic injectable soft tissue filler, aga- ing tissue during implantation. In such a case, it became rose gel, for lip augentation. The aim of this article was necessary to mold the implant between 2 fingers into to evaluate the results in 68 cases that have undergone the philtrum or the white roll. Injection should be lip augmentation in the last 3 years. performed by linear threading. Patients were told to return after an additional month for follow-up and possible reinjection to correct asym- MATERIALS AND METHODS A total of 68 patients received agarose gel (Easy- metry or lack of desired fullness. These touch-ups were Filler [Ghimas, Casalecchio di Reno, Bologna, Italia] performed later, usually after 1 or 4 weeks, with 0.1-0.2 or Easy-Agarose [Sifarma, Milano, Italy]) for lip aug- mL agarose gel. Patients who received a further injec- mentation in a 3-year period (2005-2008). The agarose tion (0.1 mL) 3-4 weeks after the first injection only gel used in this study contained 2.5% agarose and needed an additional injection after 8-12 months to 97.5% saline solution. Patients with acute or chronic maintain the desired results. skin pathologies or direct involvement in or around the Finger compression of the angular artery and di- area to be treated were excluded. After the patients read rect compression with cotton gauze were immedi- the brochure and discussed the risks and benefits of the ately applied to reduce bruising. Following hemosta- procedure and the risks and benefits of alternatives, and sis, the area was compressed with ice for 3-4 minutes after having all of their questions answered, all of them to reduce swelling. Patients were warned not to drink signed the informed consent form. In the consent form hot tea or coffee until effects wore off. the possible complications of bruising, swelling, and Afterward, no special instructions were needed, and granuloma formation were outlined. To reduce bruis- the patients returned to work immediately. The sat- ing, patients were reminded not to take any salicylates, isfaction or dissatisfaction experienced by the pa- ibuprofen, or vitamin E for 2 weeks before treatment. tients was evaluated through the use of a subjective Patients were between 35 and 70 years of age. Median analog scale from 1 to 10. age was 52 years. Three patients were male, and the other 65 were female. RESULTS Superficial anesthetic was recommended for the aug- All of the patients were successfully treated with mentation of the upper and lower lips. In all patients, injection of agarose gel. Clinical improvement was both lips were treated. To achieve a field block with noted immediately, and only mild bruising was re- dermal anesthetic cream (Emla; Astra, Westborough, corded. All of the patients returned to clinic 10 days MA) or xylocaine spray, 10% solution was after treatment for follow-up, and all of them felt to applied on the mucosa and skin of the upper and lower have obtained an excellent cosmetic result (Figs. 1-7). labiogingival fold. In some cases infiltration with local The mean score of satisfaction of cosmetic result was anesthesia was used. After 10-15 minutes, the needle 8-10 immediately after treatment, and the score de- can be directed into the correct plane of the vermilion creased after some months (Table I). border. Generally, 30-gauge needles with a 13-mm The results lasted ϳ5 months with a gradual decline length should be used. The esthetic evaluation was to baseline (Fig. 8). Agarose gel was very well tolerated performed at 1, 2, 4, 6, and 12 months after injection. with only a few mild adverse reactions which resolved Often, one-half of the “white roll” can be implanted by spontaneously. No major complication was observed. withdrawing the needle while injecting. Injections were No persistent ecchymosis, pain, itching, outbreaks of repeated along the vermilion border until the procedure herpes, infectious processes, palpable implants, uneven was complete. In a few patients, additional injections distribution, visible implants, overcorrection, undercor- OOOOE Volume 108, Number 2 Scarano, Carinci, and Piattelli e13

Fig. 1. Before lip augmentation with agarose gel. The white Fig. 4. The patient in Fig. 3 immediately after injection of cream at the upper left nasolabial fold is the dermal anesthetic agarose gel. cream Emla.

Fig. 2. The patient (female) in Fig. 1 immediately after Fig. 5. Female patient before injection.This patient never had injection of 1.5 mL agarose gel. a full lip.

Fig. 3. A 58-year-old patient with the typical signs of an aging lip before treatment. This patient had a full lip with a Fig. 6. The patient in Fig. 5 immediately after injection of vermilion curl that was lost with aging. agarose gel. OOOOE e14 Scarano, Carinci, and Piattelli August 2009

Fig. 7. Rejuvenation of lip with 1.5 mL agarse gel (same Fig. 8. After 6 months of lip augmentation with 1.5 mL patient as in Fig. 5, immediately after injection). The results agarose gel. The results lasted approximately 6 months with lasted approximately 4 months with a gradual decline to a gradual decline to baseline. baseline.

Table II. Esthetic indications for agarose gel Table I. Score of satisfaction of patients Lip augmentation Score Nasolabial wrinkles Immediately after treatment 8-10 Mentolabial folds 1 month 7-8 Facial outlines 2 months 6-8 Correction of facial depressions 4 months 4-5 Zygomatic augmentation 6 months 3-4 Chin augmentation 12 months 2-3

rection, , hypersensitivity reactions, or nodu- Enhancement of the vermilion border is one of the larity (permanent or transient based on the type of most rewarding indications for agarose gel. There is a implant and its depth) were observed. natural pocket between the vermilion border and the orbicularis oris muscle that should be filled. Agarose DISCUSSION gel is an excellent filler material to achieve minimally To our knowledge, this is the first study reported in invasive lasting improvement of facial wrinkles, fur- the literature of the use of agarose gel for lip augmen- rows, and other soft tissue contour deficiencies of sim- tation. Decreased skin laxity, along with habitual re- ilar size. There is a broad spectrum of well defined peated contraction of the underlying facial muscles, medical and esthetic indications for the use of agarose result in wrinkles or rhytids. In general, the aging gel outlined in Table II. The viscosity of agarose gel is process of the face is a process of atrophy. The ratio of lower than that of other fillers, and a low and constant type I to type III diminishes, and elastic fibers, pressure can be applied throughout the injection proce- which maintain the pattern of collagen bundles, become dure, depending on the tissue and depth of placement. thin and fragmented, resulting in an overall reduction in This simple addition to the technique is easily and the total amount of collagen. In addition to aging, quickly mastered. Agarose gel will give a long-lasting external processes, such as actinic damage, may accel- lip augmentation if implanted correctly. It is important erate this decline. Lips are the foundation on which the to place it into the deep dermal plane with slight over- remainder of the perioral region is centered. In modern correction. Local anesthetic might be not indicated, esthetics, full lips provide a youthful healthy appear- because there is slightly more discomfort during injec- ance. Visually, an aging lip is characterized by a de- tion, because the viscosity of agarose gel is lower than crease in the vermilion show, blunting of the Cupid’s that of other fillers, and because the patients tend to bow, and an attenuated white roll.9 Lip rejuvenation experience less postoperative pain. Moreover, agarose primarily for the treatment of perioral rhytids is a gel is injected in a more economic way, because there procedure commonly requested by patients who are is no loose material during implantation. typically Ͼ50 years of age and who smoke or are Patient satisfaction was very high. The rate of side former smokers. effects and complications after agarose gel treatment in OOOOE Volume 108, Number 2 Scarano, Carinci, and Piattelli e15

Table III. Complications observed in litterature Filler Adverse reactions/side effects Outcome Collagen Lasting up to 6 months Autologous collagen harvested from Ecchymosis, possible ; no allergies/ Lasting up to 6 months the patient treated hypersensitivity reaction Rare allergic/hypersensitivity reactions; Lasting up to 6 months acneiform eruptions, granulomas L-Polylactic acid Hypersensitivity? Allergic reaction? Lasting up to 6 months Agarose gel Transitory bruising Lasting up to 6 days

this study was lower compared with the complications 3. Marczylo T, Arimoto-Kobayashi S, Hayatsu H. Protection observed with other filler injections.10 Agarose gel is against Trp-P-2 mutagenicity by purpurin: mechanism of in vitro not broken down by any enzyme, and therefore it antimutagenesis. Mutagenesis 2000;15:223-8. 4. Naziruddin B, Durriya S, Phelan D, Duffy BF, Olack B, Smith D, causes no hypersensitivity reactions or tissue harden- et al. HLA antibodies present in the sera of sensitized patients ing. The only complication observed in 3 patients in the awaiting renal transplant are also reactive to swine leukocyte present study was a severe bruising that lasted about 1 antigens. Transplantation 1998;66:1074-80. week after treatment. All 3 patients had forgotten to 5. Gu Y, Tabata Y, Kawakami Y, Balamurugan AN, Hori H, discontinue aspirin before treatment. No nodule ulcer- Nagata N, et al. Development of a new method to induce ation or scarring was observed. The complications ob- angiogenesis at subcutaneous site of streptozotocin-induced 11 diabetic rats for islet transplantation. Cell Transplant 2001;10: served by other authors are listed in Table III. The 453-7. present study confirmed the good results obtained in a 6. Andre P. Evaluation of the safety of a nonanimal stabilized previous study, where agarose gel was used for rejuve- hyaluronic acid (NASHAFQ-Medical, Sweden) in European nation of perioral tissues and lip augmentation, nasola- countries: a retrospective study from 1997 to 2001. J Eur Acad bial wrinkles, mentolabial folds, facial outlines, correc- Dermatol Venereol 2004;18:422-5. tion of facial depressions, zygomatic augmentation, and 7. Cohen JL. Understanding, avoiding, and managing dermal filler 1 complications. Dermatol Surg 2008;34:S92-9. chin augmentation. 8. Godin MS, Majmundar MV, Chrzanowski DS, Dodson KM. Use Furthermore, the molecule was saturated with water, of Radiesse in combination with Restylane for facial augmenta- meaning that there would be no additional water attrac- tion. Arch Fac Plast Surg 2006;8:92-7. tion in the tissues. 9. Maloney BP. Aesthetic surgery of the lip. In: Papel ID, editor. In conclusion, during 3 years of clinical use, agarose Facial plastic and reconstructive surgery. 2nd ed. New York: gel proved to be a reliable and predictable treatment for Thieme Medical; 2002. p. 344-52. 10. Salles AG, Lotierzo PH, Gemperli R, Besteiro JM, Ishida LC, lip augmentation. Gimenez RP, et al. Complications after polymethylmethacrylate injections: report of 32 cases. Plast Reconstr Surg 2008;121: The authors express their thanks to Dr Michela Marroni 1811-20. for linguistic assistance and Dr. Raffaella Scarano for the 11. Duffy DM. Complications of fillers: overview. Dermatol Surg psychologic assistance of patients. 2005;31:1626-33.

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