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

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 encapsulation strategy for fabricating crosslinked HA-poly(l-lactic acid) (PLLA) composite hydrogels (CHPs), optimized an L (4) 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 (') 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 encapsulation exhibited superior enzymatic resistance, with degradation rates lower than PMD counterparts. This work establishes 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.