Injectable Hyaluronan-Based Thermoresponsive Hydrogels for Dermatological Applications

Abstract

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.

Dual Functionalization of Hyaluronan Dermal Fillers with Vitamin B3: Efficient Combination of Bio-Stimulation Properties with Hydrogel System Resilience Enhancement

“…Contrastingly, the remaining fractions of the loss moduli G ′′ were found to be significantly lower for the VOLBELLA ® product as compared to the other tested products (Figure 2B, Table S3). Of note, H 2 O 2 is the most common and simplest ROS generator to be used when evaluating the in vitro oxidative degradation of HA [25]. As previously mentioned, two major mechanisms that contribute to the degradatio of HA-based gels are oxidative reactions and enzymatic catabolism (i.e., primarily vi hyaluronidases).…”

“…Additionally, numerous studies evaluated and benchmarked various finished product bio-physical attributes (e.g., extrusion forces, cohesivity, and swelling ratio). Importantly, the hydrogel characterization methodologies were largely consistent across studies, with minimal variations in approaches and results [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. However, experimental unraveling of the degradation mechanisms in cross-linked HA-based fillers is highly complex and challenging.…”

“…However, experimental unraveling of the degradation mechanisms in cross-linked HA-based fillers is highly complex and challenging. Specifically, methodological variations (i.e., polymer breakdown model and analytical means) were reported for characterizing such HA-based system degradation processes [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”

Exploring the Formulation and Approaches of Injectable Hydrogels Utilizing Hyaluronic Acid in Biomedical Uses

“…Another study reported the in situ formation of a hydrogel of hyaluronic poly (N-isopropylacrylamide) prepared using click chemistry [46]. Termosensitive hyaluronic acid-based injectable hydrogels were recently reported through the conjugation of hyaluronic acid with poly (N-isopropyl acrylamide), the produced hydrogel exhibited in situ gelation at body temperature, and study results indicate good compatibility with prolonged residence at the injection site which is regarded crucial for e for ensuring the treatment's maximum efcacy [47].…”

Herbal Nano Formulations for Topical Drug Delivery: Prospective for Multiple Skin Disorders

“…However, paramount remains the imperative of rigorous research and clinical scrutiny to affirm the safety and efficacy of these formulations, setting the stage for evidence-driven practice in this dynamic domain. 13…”