Orthogonal design-driven in situ encapsulation of hyaluronic acid-poly (lactic acid) composite hydrogels: mechanically tunable dermal fillers with enhanced enzymatic resistance

Abstract

Injectable hyaluronic acid (HA) – based hydrogels face limitations in clinical longevity due to enzymatic degradation and insufficient mechanical stability. To address these challenges, this study developed a novel in situ encapsulation strategy for fabricating crosslinked HA-poly(L-lactic acid) (PLLA) composite hydrogels (CHPs), optimized via an L₁₆ (4³) orthogonal experimental design. Three critical parameters – PLLA loading (0–10% w/v), 1,4-butanediol diglycidyl ether (BDDE) concentration (0.5–2% w/v), and crosslinking time (8–72 h) – were systematically evaluated to balance viscoelasticity, injectability, and biocompatibility. The optimized formulation (3% PLLA, 1.0% BDDE, 48 h crosslinking) achieved a storage modulus (G′) of 790 Pa, demonstrating 2.3-fold enhancement over conventional post-mixing dispersion (PMD) hydrogels. Mechanistic studies revealed hydrogen bonding between HA hydroxyl/carboxyl groups and PLLA carbonyl moieties, which compensated for steric hindrance-induced crosslinking inefficiency at moderate PLLA loading. CHPs fabricated via in situ encapsulation exhibited superior enzymatic resistance, with degradation rates lower than PMD counterparts. This work establishes in situ encapsulation as a scalable methodology for engineering HA-PLLA composites, offering a transformative platform in designing durable, biocompatible dermal fillers with tunable mechanical and degradation profiles.