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Disputing Hyaluronic Acid Information I wish to respond to the article titled “Hyaluronic Acid in Fillers and Creams” (Baumann L. Skin & Aging. 2004; 12(1):86-88.). This piece contains numerous errors concerning the manufacture of Restylane and the physical chemical nature of this product. The author incorrectly says Restylane is a highly crosslinked material. In fact, Restylane is very lightly crosslinked. The total crosslinking is between 0.5% and 1% of the total disaccharide subunits. The level of crosslinking in the material used is very important; too little can prevent particle formation and reduce implant stability, while too much can result in decreased biocompatibility. Restylane is far less crosslinked than the other injectable HA gels cited in the article. The reference to the stiffness and hardness of Restylane results in some incorrect conclusions. The difference in the rheology of the products (flow characteristics) cited are only partially a result of the crosslinking process. While Hylaform and Restylane have a similar number of particles per ml and particle sizes, Hylaform contains 5.5 mg/ml of HA, while Restylane contains 20 mg/ml of HA. The higher level of HA in Restylane may increase the rheology slightly, but it may also increase the duration of the correction. The conclusion that the stiffness of the product makes it more difficult to “wash” out the residual crosslinking agent and proteins is also incorrect. HA is a highly hydroscopic molecule, and the HA in Restylane is fully in solution. Minimal crosslinking agent is used in the manufacturing process, and residual BDDE has been analytically determined to be below normal detection limits. That is, the level is below 1.5 parts per billion or almost free of residual BDDE. Also, protein levels are controlled and never exceed published limits of 6 ppm. The typical batch released is below 1.5 ppm. All of these levels are far lower than other products referred to in this article. The evidence of the purity of Restylane is reflected in the vastly reduced number of possible hypersensitization reactions reported. In 2002, and the first half of 2003, the rate was below 1 in 8,300 patients treated. Arnold William Klein, M.D. Clinical Professor of Dermatology University of California, Los Angeles Author Response Due to a lot of misinformation regarding the newly approved HA fillers, it is vital to rely on facts from patents, publications in peer-reviewed journals, FDA submissions and panel meetings rather than what the marketing brochures say. I will try to clarify some of the points that are raised in Dr. Klein’s letter. Amount of Crosslinking The Restylane patent number 5,827,937 in the second paragraph under the heading “Summary of the Invention” says that the object of the Restylane patent “is to provide a process for preparing a cross-linked polysaccharide gel composition, the biocompatibility of which can be retained in spite of a high degree of crosslinking or polymerization.” In addition, an article published in the Journal of the European Academy of Dermatology compared the properties of Hylaform and Restylane found Hylaform to contain 25% of the amount of crosslinks as did Restylane.1 Rheologic Properties The rheological properties (deformation and flow) of the material are what are important when evaluating which products are going to be best for the patient. I agree with Dr. Klein that Restylane is a stiffer than Hylaform, and I agree that this is partially due to the concentration of HA in the product. However, as mentioned in the letter, only 0.5% to 1% of these chains of HA are crosslinked. This leaves a large portion of the product as uncrosslinked, unmodified HA. The half-life of uncrosslinked HA is approximately 12 hours,2 so the presence of this extra HA is transient and would not serve to increase the duration of the product. Another fact is that the length of the HA chains used in Restylane are not as long as those used in Hylaform. The longer chains allow it to bind more water per molecular weight and may contribute to its softness. Residual BDDE and Protein As was presented at the FDA panel meeting,3 there is less than 2 parts per million of BDDE in Restylane. (Note that it is parts per million, not parts per billion.) This small residual should not pose a health risk. Also, at the FDA meeting, residual protein levels in Restylane were stated to be 6 parts per million. The problem comes up because each company uses its own system for determining protein levels and this makes it difficult to compare protein levels between products. At this time there are no published studies comparing protein loads in Juvederm, Hylaform and Restylane, so it is unfounded to say that “All of these (protein) levels are far lower than other products referred to in this article or on the market elsewhere.” I agree that the safety of Restylane has been established, as has the safety of Hylaform and Juvederm. The stiffness of Restylane is a downside in my opinion because it leads to increased swelling, longer down time, lumps and a less natural feel. I prefer the softer, more natural feel of the other products based on my clinical experience. My experience was garnered as a clinical investigator for the Hylaform and Juvederm Phase III FDA trials, and I was present at the FDA panel meeting that led to approval of both Hylaform and Restylane. Leslie Baumann, M.D., Associate Professor University of Miami, Department of Dermatology