Over the past 60 years, hyaluronidase has been successfully utilized in ophthalmic surgery and is now being implemented in dermatosurgery as well as in other surgical disciplines. The enzyme is considered a “spreading factor” as it decomplexes hyaluronic acid (also called hyaluronan, HA), an essential component of the extracellular matrix (ECM). When applied as an adjuvant, hyaluronidase enhances the diffusion capacity and bioavailability of injected drugs. Therefore, the enzyme has been used as a local adjuvant to increase the diffusion capacity of local anesthetics, increasing the analgesic efficacy, and the anesthetized area particularly in the first minutes following injection, resulting in diminished intra- and postoperative pain. In aesthetic medicine, the off-label use of hyaluronidase is considered the gold standard for the management of HA-filler-associated complications. Here, we review the clinical use, underlying biological mechanisms, and future directions for the application of hyaluronidase in surgical and aesthetic medicine.

BACKGROUND: Hyaluronic acid (HA) fillers may differ in terms of gel characteristics and ease of use and it is of interest whether this might affect safety and duration of effect. OBJECTIVE: To compare the long-term safety and effect of 2 HA fillers produced by 2 different technologies for lip enhancement. MATERIALS AND METHODS: Subjects with very thin to moderately thick lips were randomized and treated with HA-RK (N = 31) or HA-JV (N = 29) to improve lip fullness by ≥ 1 grade on a 5-point scale, using a maximum of 3 mL of product. RESULTS: A smaller volume of HA-RK compared with HA-JV was required to improve lip fullness by ≥ 1 grade (mean: 1.54 mL vs 1.94 mL, p < .001). Despite the smaller volume, lip fullness and global aesthetic improvement were comparably sustained in both groups. At 6 months, 60.0% versus 57.7% of subjects (HA-RK vs HA-JV) had improved lip fullness. At 12 months, 71.4% versus 76.0% had aesthetic improvement (blinded evaluations) and 85.7% versus 86.2% felt more attractive. Both products were well tolerated. CONCLUSION: Both products achieved durable improvement in lip fullness and aesthetic appearance. A significantly smaller amount of HA-RK was required compared with HA-JV to achieve optimal treatment effect.

Hyaluronic acid (HA)-based fillers are widely used in aesthetic dermatology for their biocompatibility, reversibility, and safety; however, adverse events (AEs) may occur. This review evaluated the safety profile, focusing on short- and long-term AEs, of HA fillers manufactured with MACRO (MAtrix CROsslinking) Core Technology, encompassing both current saypha and former Princess products. A systematic PubMed search identified prospective clinical trials assessing safety outcomes following facial aesthetic use of these fillers. Eleven studies including 947 patients met the inclusion criteria. The most common short-term AEs were transient swelling, injection site pain, and bruising, which were predominantly mild to moderate and resolved within two weeks. Severe or serious treatment-related events were rare, with only one reported across all studies. Long-term AEs, such as delayed-onset nodules or inflammatory reactions, were infrequent and mild, with no granulomas, hypersensitivity responses, or vascular complications observed. Safety outcomes were consistent across formulations and between the legacy Princess and current saypha products. Overall, the saypha HA filler portfolio demonstrates a predictable and strong safety profile within the expected range reported in the broader literature, noting the limitations of cross-study comparisons. Most AEs were related to injection trauma rather than the filler itself, supporting its continued use in clinical aesthetic practice.