Despite hyaluronidase being widely used in aesthetic medicine, clinicians know the outcomes are not always consistent. In some patients, the injected gel seems to disappear rapidly, while in others, repeat injections achieve only partial softening. This variability is explained mainly by the structure of the hyaluronic acid (HA) filler itself, as clearly demonstrated in a recent study published in the Journal of Cosmetic Dermatology [1].

The authors set out to answer a pragmatic clinical question: why do some fillers respond readily to enzymatic degradation, whereas others appear relatively resistant? To address this, they combined in vitro and in vivo experiments, comparing biphasic and monophasic gels at varying hyaluronidase concentrations and delivery approaches. They also evaluated how long meaningful enzyme activity persists in tissue — an aspect with direct implications for time-sensitive complication management.

One of the most clinically relevant findings was the distinct difference in response between biphasic and monophasic fillers. Biphasic gels, with a more granular architecture and lower cohesivity, showed rapid hydration and breakdown even at relatively low hyaluronidase concentrations. In contrast, monophasic fillers, characterized by a more uniform, dense matrix and a higher degree of crosslinking, proved substantially more resistant. Their degradation required higher enzyme doses, longer contact time, and, in many situations, repeat injections.

How the enzyme is delivered to the gel also matters. The study confirmed that surrounding a filler deposit with hyaluronidase solution is less effective than providing the enzyme directly into the filler mass. This performance gap was particularly pronounced with monophasic fillers, where limited enzyme diffusion through a dense gel structure can markedly reduce the effect of superficial administration.

The pharmacokinetic aspect is equally essential for real-world decision-making. In the in vivo model, hyaluronidase activity in tissue dropped sharply within the first 30 minutes after administration, which helps explain why delayed or “fractionated” attempts at dissolution may underperform. A control experiment with normal saline further showed that simple hydration does not equate to degradation, reinforcing the need for enzymatic action rather than dilution for accurate filler breakdown.

The authors also emphasize safety considerations, noting the risk of hypersensitivity reactions, particularly with higher doses [2]. This is especially relevant in cases of vascular complications, where aggressive hyaluronidase regimens are often recommended to restore perfusion rapidly [3, 4]. For injectors, a solid understanding of the pathophysiology of vascular events after filler injections—and how to intervene promptly—remains a core requirement of safe practice [5].

Clinical takeaways for practitioners [1]

1. Hyaluronidase response is filler‑dependent: biphasic gels tend to dissolve faster at lower doses, while monophasic fillers often require higher cumulative enzyme exposure.
2. When treating monophasic fillers, plan upfront for repeat injections and a longer timeline to reach the desired clinical endpoint.
3. Direct intralesional delivery into the filler mass is the most effective technique, particularly for dense, highly cohesive gels.
4. The short tissue activity window makes early, adequately dosed intervention essential, especially in vascular compromise.
5. Normal saline should not be considered an alternative to hyaluronidase for dissolution, as it does not induce enzymatic degradation of HA.
6. With high-dose use, anticipate an increased hypersensitivity risk and be prepared for immediate management.

References

1. Hong G.-W., Hu H., Wan J. et al. How should we use hyaluronidase for dissolving hyaluronic acid fillers? J Cosmet Dermatol 2025; 24: e16783. DOI:10.1111/jocd. 16783.
2. Jung H. Hyaluronidase: an overview of its properties, applications, and side effects. Arch Plast Surg 2020; 47(4): 297–300.
3. Kroumpouzos G., Treacy P. Hyaluronidase for dermal filler complications: review of applications and dosage recommendations. JMIR Dermatol 2024; 7: e50403.
4. King M., Convery C., Davies E. This month’s guideline: the use of hyaluronidase in aesthetic practice (v2.4). J Clin Aesthet Dermatol 2018; 11(6): E61–E68.
5. DeLorenzi C. Complications of injectable fillers, part 2: vascular complications. Aesthetic Surg J 2014; 34(4): 584–600.