Injectable Hyaluronan-Based Thermoresponsive Hydrogels for Dermatological Applications

Most marketed HA-based dermal fillers use chemical cross-linking to improve mechanical properties and extend their lifetime in vivo; however, stiffer products with higher elasticity require an increased extrusion force for injection in clinical practice. To balance longevity and injectability, we propose a thermosensitive dermal filler, injectable as a low viscosity fluid that undergoes gelation in situ upon injection. To this end, HA was conjugated via a linker to poly(N-isopropylacrylamide) (pNIPAM), a thermosensitive polymer using "green chemistry", with water as the solvent. HA-L-pNIPAM hydrogels showed a comparatively low viscosity (G' was 105.1 and 233 for Candidate1 and Belotero Volume^®, respectively) at room temperature and spontaneously formed a stiffer gel with submicron structure at body temperature. Hydrogel formulations exhibited superior resistance against enzymatic and oxidative degradation and could be administered using a comparatively lower injection force (49 N and >100 N for Candidate 1 and Belotero Volume^®, respectively) with a 32G needle. Formulations were biocompatible (viability of L929 mouse fibroblasts was >100% and ~85% for HA-L-pNIPAM hydrogel aqueous extract and their degradation product, respectively), and offered an extended residence time (up to 72 h) at the injection site. This property could potentially be exploited to develop sustained release drug delivery systems for the management of dermatologic and systemic disorders.