Evaluation of Tissue Response to Coinjection Versus Individual Injection of Hyaluronic Acid Filler and Polycaprolactone Microsphere‐Based Filler in a Rabbit Model

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BACKGROUND: Cross-linked hyaluronic acid (HA) and polycaprolactone (PCL) are currently the two most representative dermal fillers. However, the tissue response and safety profiles of their combined administration are not fully elucidated. This study aims to evaluate the safety and tissue reactions following the injection of HA filler, PCL microsphere-based filler, and the mixture of HA/PCL filler. METHODS: The dermal filler was injected on the back of the rabbit. Five injection experimental groups were established: (1) HA filler alone, (2) PCL microsphere-based filler alone, (3) HA filler followed by PCL microsphere-based filler after 1 month, (4) PCL microsphere-based filler followed by HA filler after 1 month, and (5) premixed HA and PCL filler (1:1). Histological evaluation of tissue was conducted at 1, 2, and 3 months after injection. RESULTS: PCL microsphere-based filler alone induced a time-dependent increase in inflammatory response, with relatively notable inflammation observed around microspheres by month 3. In contrast, HA filler alone elicited minimal inflammation during the observation period. In all combined application groups (sequential and premixed), HA filler effectively improved the dispersion of PCL microspheres. Compared to PCL microsphere-based filler alone, these combined approaches demonstrated a mitigated initial inflammatory response. Collagen deposition was negligible in HA filler groups throughout the process. PCL microsphere-based filler alone stimulated mild collagen deposition by month 3, with notable Type III collagen generation. The presence of HA did not directly enhance collagen deposition. CONCLUSIONS: The combined or sequential injection of HA filler and PCL microsphere-based filler alleviated the initial inflammatory response and improved PCL microsphere dispersion compared to PCL microsphere-based filler injection alone, indicating a favorable safety profile. However, HA filler did not directly promote collagen deposition. These findings support the combined use of these materials as a safe approach with a modulated tissue reaction.

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