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Daniel Cassuto,1,2 Gilberto Bellia,3 Chiara Schiraldi4 1Private Practice, Tel Aviv, Israel; 2Private Practice, Milan, Italy; 3IBSA Farmaceutici Italia Srl, Lodi, Italy; 4Department of Experimental Medicine, School of Medicine, University of Campania “Luigi Vanvitelli”, Naples, ItalyCorrespondence: Daniel Cassuto Email daniel.cassuto@gmail.comAbstract: Hyaluronic acid (HA)-based injectable filling agents are at the forefront of the current demand for noninvasive dermatological procedures for the correction of age-related soft tissue defects. The present review aims to summarize currently available HA-based products and critically appraise their differences in rheological nature and clinical application. Linear HA (LHA) gels may be supplemented with amino acids, lipoic acid, vitamins, nucleosides, or minerals for synergistic antiaging and antioxidant benefits (polycomponent LHA). HA hydrogels can be generated via chemical or physical crosslinking, which increases their elasticity and decreases viscosity. The performance of crosslinked fillers depends on HA concentration, degree of crosslinking, elastic modulus, cohesivity, and type of crosslinking agent employed. PEG-crosslinked LHA displays improved elasticity and resistance to degradation, and lower swelling rates as compared to BDDE-crosslinked LHA. Physical crosslinking stabilizes HA hydrogels without employing exogenous chemical compounds or altering hyaluronans’ natural molecular structure. Thermally stabilized hybrid cooperative HA complexes (HCC) are a formulation of high- and low-molecular-weight (H-HA and L-HA) hyaluronans, achieving high HA concentration, low viscosity with optimal tissue diffusion, and a duration comparable to weakly cross-linked gel. Our critical analysis evidences the importance of understanding different fillers’ properties to assist physicians in selecting the most appropriate filler for specific uses and for predictable and sustainable results.Keywords: hyaluronic acid, filler, hydrogel, crosslinking

Adele Sparavigna,1 Annalisa La Gatta,2 Gilberto Bellia,3 Laura La Penna,1 Andrea Maria Giori,4 Gabriele Vecchi,4 Beatrice Tenconi,1 Chiara Schiraldi2 1DERMING Srl., Milan, Italy; 2Department of Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, School of Medicine, University of Campania “L. Vanvitelli”, Naples, Italy; 3Medical Affairs, IBSA Farmaceutici Italia, Lodi, Italy; 4Research and Development, IBSA Farmaceutici Italia, Lodi, ItalyCorrespondence: Adele SparavignaDERMING Srl, Clinical Research and Bioengineering Institute, Via Valassina, 24, Milano, ItalyTel +39 2 2318 3475Email adele.sparavigna@derming.comPurpose: The primary aim of this study was to evaluate the performance of the study product, in terms of volumizing activity as well as the duration of the effect, in women with age-related midfacial volume defects. In addition, the study allowed the evaluation of the tolerability of the product by both volunteers and investigators.Patients and Methods: Twenty-two female volunteers, aged 42– 60 years, participated in this study, which was performed under dermatological control in a single center. After an initial visit at baseline to verify adherence to the protocol criteria, volunteers received an injection of Aliaxin® SV (IBSA Farmaceutici Italia Srl), followed 3– 4 weeks later by a second touch-up treatment to treat eventual asymmetries. Four subsequent visits, the last performed 9 months from the first injection, were performed to evaluate clinically and instrumentally the efficacy of the treatment.Results: Clinical and statistically significant improvement in cheek volume was recorded after the first postinjection visit, and the effect was maintained until the end of the study period. A clinically measurable amelioration of wrinkle severity was also observed. By 3D picture recording and subsequent quantitative analysis, it was possible to determine the efficacy in terms of increased facial volume, which was already appreciable at the first visit, was further increased at the second and third visits and was maintained at the fourth and last visits. The injections were very well tolerated by the volunteers, as determined by their self-evaluation questionnaires.Conclusion: The results of the study confirm the esthetic performance of the study product on age-related midfacial volume defects. The very strong high-volumizing activity of the study product was not only properly determined by the investigators but also confirmed by self-evaluation by the volunteers. These effects were obtained with no appreciable undesired effects.Keywords: midfacial aging, crosslinked hyaluronic acid, clinical assessment, instrumental assessment

Annalisa La Gatta,1 Chiara Schiraldi,1 Giovanna Zaccaria,2 Daniel Cassuto2 1Department Experimental Medicine, Section of Biotechnology, Medical Histology and Molecular Biology, School of Medicine, University of Campania “L. Vanvitelli”, Naples 80138, Italy; 2Private Practice, Milan, ItalyCorrespondence: Chiara Schiraldi via De Crecchio 7, Naples 80138, ItalyTel +39 081 5667546Fax +39 081 5665897Email chiara.schiraldi@unicampania.itDaniel Cassuto Dr. Daniel Cassuto, Piazza V Giornate 1, Milan 20129, ItalyTel +39 02 36723960Email daniel.cassuto@gmail.comIntroduction: Hyaluronic Acid (HA) fillers are among the most used products in cosmetic medicine. Companies offer different formulations to allow full facial treatment and/or remodeling. Gels are being studied to establish the biophysical properties behind the specific clinical use and a correlation between the gel biophysical properties and their clinical performance. Clinicians’ awareness is growing about the potential benefit deriving from such biophysical characterization.Aim: The Aliaxin® line of HA dermal fillers is the object of this study. The study aimed to widen the biophysical characterization of these gels by investigating a variety of properties to better support their optimal use. Further, we aimed to provide some clinical findings to gain a deeper insight into the correlation between filler features and clinical outcome.Methods: The four gels of the line were investigated, for the first time, for their cohesivity and stability to Reactive Oxygen Species (ROS). Additional secondary rheological parameters; evidence of relative water-uptake ability; and some clinical findings on product safety, palpability and duration of the aesthetic effect are provided.Results and conclusion: The gels proved highly cohesive and sensitive to ROS action with stability declining with the decrease in the overall gel elasticity. The G* and complex viscosity values at clinically relevant frequencies and gel water-uptake ability are consistent with the relative clinical indication related to gel projection and hydration capacity. Clinical outcomes showed the safety of the products and a perception of palpability well correlating with the cohesive/viscosity properties of the gels. A similar duration of the aesthetic effect (up to 1 year) was observed despite the diverse in vitro gel stability. The results broaden our knowledge of these gels and may contribute to optimize their clinical use towards the improvement of patient safety and satisfaction. Initial clinical observation indicated that gel biophysical properties allow for a reliable prediction of gel palpability, while in vitro data on gel stability cannot be related to the duration of the observed skin improvement. The latter finding further corroborates the idea of a skin restoration process activated by the gels besides the physical volumetric action.Keywords: dermal filler, degradation, cohesivity, palpability

The capsular polysaccharide obtained from Escherichia coli K4 is a glycosaminoglycan-like molecule, similar to chondroitin sulphate, that has established applications in the biomedical field. Recent efforts focused on the development of strategies to increase K4 polysaccharide fermentation titers up to technologically attractive levels, but an aspect that has not been investigated so far, is how changes in the molecular machinery that produces this biopolymer affect its molecular weight. In this work, we took advantage of recombinant E. coli K4 strains that overproduce capsular polysaccharide, to study whether the inferred pathway modifications also influenced the size of the produced polymer. Fed-batch fermentations were performed up to the 22 L scale, in potentially industrially applicable conditions, and a purification protocol that allows in particular the recovery of high molecular weight unsulphated chondroitin, was developed next. This approach allowed to determine the molecular weight of the purified polysaccharide, demonstrating that kfoF overexpression increased polymer size up to 133 kDa. Higher polysaccharide titers and size were also correlated to increased concentrations of UDP-GlcA and decreased concentrations of UDP-GalNAc during growth. These results are interesting also in view of novel potential applications of higher molecular weight chondroitin and chondroitin sulphate in the biomedical field. [ABSTRACT FROM AUTHOR]