Skinfill Carbonium: new product for the treatment of deep wrinkles and face contour remodelling Dr. Vannini Fulvio Aesthetic medicine aples Abstract A tissue augmentation product, based on cross-linked hyaluronic acid (HA), has been evaluated by Promoitalia Group S.p.A.’s scientific department in Naples, which has cooperated with various Italian research centers. The study involved 80 patients treated with one to two injections during a follow-up period of 7 months from September 2007 until April 2008. The treatment was completed when skin was levelled following one or two injections. No serious or permanent adverse reactions were noted during the test period. Introduction Aging skin is a challenge to every aesthetic therapist. Besides treatment with different cosmetic procedures, more profound wrinkles and folds of the face need more effective correction through tissue augmentation. For a long period of time products based on bovine collagen have been used. However, these products have been found to be sensitizing, short lasting, and also a potential source for the transmittance of certain viral diseases. To this date, a wide variety of other materials have been tested and used for the restoration of depressed contour deformities, for example silicone, and most recently, cross-linked versions of hyaluronic acid ( HA) (1,2,3,4,5,6,7,12). HA is a natural polymer with extraordinary biological compatibility. The substance is a constituent of all connective tissues in both humans and most other vertebrates and is biodegradable. Because of these favourable properties, the demand all over the world for HA based products in the practice of tissue augmentation of the aging skin is rising (1). However, the intradermal durability of a nonmodified HA preparation needs to be cross-linked in order to fulfil the demand for a long lasting product. Until today, commercial preparations of HA have not all been proven to have the properties of an optimal substance, such as pronounced tissue augmentation, transparency, non-toxicity, ease of injection and a long lasting intradermal durability combined with biodegradability. Most importantly, if the HA preparation is not highly purified, it can be potentially sensitizing to some individuals. Objective The primary objective of this limited study was to investigate the safety an efficacy, during and after the injection, of the cross-linked HA preparation, named Skinfill Carbonium, when injected intradermally to correct wrinkles, folds and increase the fullness of the lips. Material and method For this study, a volume of 1.6 to 3.2 ml of Skinfill Carbonium was used. Skinfill Carbonium is a sterile, non-pyrogenic, viscoelastic implant based on cross-linked HA. It is a clear, colorless and transparent gel packaged in a disposable syringe with a volume of 1.6 ml. Each box contains two syringes. The product is manufactured by cross-linking the glucoseamino-glucan molecule of HA using BDDE (1,4-butanediol diglycidyl ether 0.06 µg/ml), to get a product with a HA concentration of 10 mg/ml. The result is a polymer with a molecular network that resides in the intracellular matrix of the skin for 6 to 12 months. Skinfill Carbonium is a product by Promoitalia Group spa. In the present study, the product was implanted through needles of 27 Gauge ½” (0.4x13 mm). The injections were made intradermally using the linear threading technique. In cases of a remaining defect, the same procedure was repeated until the entire wrinkle or deformity was treated sufficiently. In most cases one to two syringes were used for every treated patient. Patients A total of 80 patients (100% females) participated in the study. Depending on the severity of the wrinkle and fold due to the age or the condition of the skin, some of the patients received a followup treatment two to three weeks after the initial treatment. The facial areas treated for these patients were limited to the glabellar lines, nasolabial folds, mouth angle wrinkles, cheeks, chin, upper lip and forehead giving a total of seven different facial areas treated. All patients were monitored for at least half an hour after the treatment in order to detect any occurrence of e.g. erythema, swelling, redness, itching, pain or tenderness. Any noticeable adverse event was carefully documented and followed up. Results Efficacy The three main parameters used for determining the results and the efficacy of the treatment were: 1. The degree of correction 2. The physician’s estimation of the degree of improvement, and 3. The patient’s assessment of the degree of improvement. In accordance with the above-mentioned parameters, the study shows that the product fulfilled the expected degree of correction, as evaluated by the physician, as well as the patient’s self-assessment of the degree of improvement. The combined evaluation showed that the product immediately filled out and lifted the wrinkles. Safety In a very small number of the treated patients there were minor injection-related reactions, as could be expected from the sensitizing study (13). Reactions related to an actual injection of the product were seen in a total of 2 cases (out of a total of 80). One case was an 81-year-old woman with very deep, over – folding wrinkles, who was treated once with only injection. In this case no improvement was noticeable. The other case was a lip enhancement treatment where the effect had disappeared after two to three weeks. No reactions or adverse events were found to be related to the actual implant of the product. The results described above could indicate that the use of this specific cross-linked HA preparation is not to be considered a risk to the patients. Discussion Generally, materials used for intradermal implantation, mainly in the facial area, have differed widely over time. Because the skin is under constant transformation due to aging and other factors, permanent implants have shown to not be suitable or desirable for dermal correction, since these types of products will not degrade. In some cases, the injected product has migrated from the treated area, thus creating a lateral augmentation in a way that the wrinkle has been increased instead of being reduced. Other adverse events have been reported related to degradable materials, for example, for products deriving from bovine collagen (7, 11). The preparation used in this particular study is based on non-bacterial, natural HA, a substance that has several advantages compared to products based on bacterial HA. HA based products have already, in their non cross-linked form as an implant, been used for more than 30 years and in millions of individuals with a high efficacy and safety track record. The critical properties in relation to a HA based dermal filler is the source of the material and also the method of cross-linking of the preparation in order to prolong the durability of the implanted product. To ensure that the results given are the best possible, and to minimize any risk for adverse events, a non- bacterial and natural form of HA, deriving from rooster combs, has been chosen for the preparation used in this study. This HA has then been cross-linked using a low degree of BDDE (1,4-butanediol diglycidyl ether), a chemical cross-linking agent commonly used for dermal filler products based on HA. The product is then sterilized using steam sterilization. Furthermore, the roosters used for the preparation of this product are raised in selected farms. Seen the origin of the HA, it has a very high molecular weight compared to HA deriving from bacterial origin. Bacterial origin HA has a molecular weight that ranges from 1 000 000 to 2 500 000 Dalton (Low Molecular Weight, LMW) whereas HA deriving from rooster combs has a High Molecular Weight (HMW) equal 5 500 000 Daltons. It is thanks to this fact that the product has a high viscosity in spite of the low concentration of HA (10 mg/ml). Another characteristic of the product in object is the Easy-Flow technology, which means that a filler with an elevated molecular weight would have a higher shear thinning compared to those of bacterial origin with a lower molecular weight. Shear thinning means that a non-Newtonian fluid has the ability to transform its own state, from solid to liquid and vice versa; this is exactly what the Skinfill Carbonium product does meaning that it has elevated manageability and plasticity. The former thanks to the elevated product adaptation during the passage through the syringe and the latter due to the excellent adaptation in the dermis with immediate recovery of its viscosity and filling of the depression. The resulting product is a formation of intermolecular bonds of high viscosity with a high viscoelasticity and elasticity. Furthermore, the low cross-linking level means that the final product is similar to the natural occurring HA found in the human tissue, and is as such very well tolerated by the human skin cells and tissues (9, 10). Conclusions The results from the study shows that the examined product, used with the described injection technique, serves its purpose as a dermal filler to be used for corrections of wrinkles, folds and lip in an efficient and safe manner. It also has the advantage of being similar to the natural occurring HA present in the human body. References 1. Balazs EA, Leschchiner EA; Hyaluronan, its cross-linked derivative-hylan-and their medical applications. In Inagaki H, Phillips GO (ed): Cellulosics Utilization: Research and rewards in cellulosics. Tokyo: Elsevier, Applied Science Pubblications,pp. 233-241,1998. 2. Burton JL, Cunliff WJ: The subcutaneous fat: oil granuloma. In Rock A, Wilkinson DB, Ebling FJG, Champion RH, Burton JL (ed): Textbook of dermatology, Oxford: Blackwell, 1986, pp. 1870-1871,1986. 3. Donald PJ: Collagen grafts-here today gone tomorrow. Otolaryn-Head and Neck Surg., 95:607-614, 1986. 4. Ficher JC: Discussion of : DeLustro F, Smith STS, et al: Reaction to injectable collagen: Results in animal models and clinical use, (Plast.Reconstr. Surg. 79: 581-592, 1987), Plast. Reconstr. Surg. 79:593-594,1987 5. Jean Cukier MD, Richard A, Beauchamp MD, Joseph S, Spinder MD and David E: 6. Trentham association between bovine collagendermal implants and dermatomyositis or a polymyositislike syndrome, Ann Intern Med 118: 920-928, 1993. 7. McPherson JM, Ledger PW, Sawamura S, Conti A, Wade S, Reihanian H and Wallance DG: The preparation and physiochemical characterization of an injectable form of reconstituted glutaraldehyde cross-linked, bvovine corium collagen. J Biomed Mater 20: 7982, 1986 8. Reed RK, Laurent UBG, Frazer JRE and Laurent TC: Re-moval rate of (3H) hyaluronan injected subcutaneously in rabbits. Am J Physiol 259: H532-H535 1990. 9. Richter AW: Non –immunogenicity of purified hyaluronic acid preparations tested by passive cutaneous anaphylaxis. Int Arch Allergy Appl Immunol 47: 211-217, 1974. 10. Ritcher AW, Ryde EM and Zetterstrom EO: Non-immunogenicity of a purified sodium hyaluronic preparation in man. Int Arch Allergy Appl Immunol 59:45-48, 1979. 11. Ross A, Rames and Ian A Aaronson: Migration of polytef paste to the lung and brain following intravesical injection for the correction of reflux, Pediatr Surg Int 6:239-240, 1991. 12. Selmanowitz VJ, Orentreiich N: Medical-grade fluid silicone: a monographic review. J. Dermatol Surg Oncol: 597-611, 1977 13. Mdt-medical device testing, Report: Test for delayed-type hypersensitivity (Guinea Pig Maximisation Test) with Dermavisc degraded, 2006.