Nanoforming Hyaluronan-Based Thermoresponsive Hydrogels: Optimized and Tunable Functionality in Osteoarthritis Management

Abstract

Hyaluronic acid (HA) constitutes a versatile chemical framework for the development of osteoarthritis pain treatment by means of injection in the joints, so-called viscosupplementation. Without appropriate physico-chemical tuning, such preparations are inherently hindered by prompt in vivo degradation, mediated by hyaluronidases and oxidative stress. To prolong hydrogel residence time and confer optimized product functionality, novel thermoresponsive nanoforming HA derivatives were proposed and characterized. Combined use of sulfo-dibenzocyclooctyne-PEG4-amine linkers and poly(N-isopropylacrylamide) in green chemistry process enabled the synthesis of HA-based polymers, with in situ obtention of appropriate viscoelastic properties. Spontaneous and reversible thermoformation of nanoparticles above 30 °C was experimentally confirmed. Lead formulations were compared to a commercially available HA-based product and shown significantly better in vitro resistance to enzymatic and oxidative degradation, required half the injection force with optimal viscoelastic hydrogel properties in equine synovial fluids. Results highlighted the vast potential of appropriately engineered HA-based systems as next-generation long-acting viscosupplementation products for osteoarthritic patients.

Engineering Hyaluronic Acid for the Development of New Treatment Strategies for Osteoarthritis

“…Delivering HA as micro- and nanogels is another approach to enhance HA retention and joint lubrication [ 64 , 65 , 66 , 67 ]. For instance, injectable and thermoresponsive HA nanogels can be fabricated by conjugating poly(N-isopropylacrylamide) (PNIPAM) chains onto the backbone of HA [ 64 , 66 ].…”

“…Delivering HA as micro- and nanogels is another approach to enhance HA retention and joint lubrication [ 64 , 65 , 66 , 67 ]. For instance, injectable and thermoresponsive HA nanogels can be fabricated by conjugating poly(N-isopropylacrylamide) (PNIPAM) chains onto the backbone of HA [ 64 , 66 ]. PNIPAM is a polymer that demonstrates thermoreversible properties, where it undergoes a phase transition from solution to gel as the temperature is increased above its lower critical solution temperature (LCST) of around 32 °C [ 68 ], which is tunable by modulating the hydrophobicity and hydrophilicity of the copolymer [ 69 , 70 ].…”

Thermo-Responsive Hyaluronan-Based Hydrogels Combined with Allogeneic Cytotherapeutics for the Treatment of Osteoarthritis

“…Therefore, exogenous HA-based hydrogels (i.e., polymeric network dissolved/dispersed in an aqueous solvent) have been extensively investigated as optimal synthetic SF substitutes designed for pain reduction and enhanced mobility recovery. Based on clinical reports of progressive physiological HA functional degradation and molecular weight (MW) distribution shifts in ageing patients, many therapeutic HA-based injectables for mild to moderate knee OA were developed using high-MW linear polymers of various origins [ 13 , 14 ]. However, the available aggregated clinical evidence suggested an absence of significant efficacy of classical HA-based viscosupplementation products in OA [ 15 , 16 , 17 , 18 ].…”

“…Notwithstanding the conflicting published reports on the clinical efficacy of HA-based knee viscosupplementation interventions in OA patients, the corresponding injectable products remain in standard rheumatology practice and are constantly being redeveloped by experienced industrial manufacturers. Therefore, hydrogel product efficacy optimization may rely on various HA chemical modifications (e.g., polymer crosslinking, chemical functionalization) or on the incorporation of appropriate excipients (e.g., carbohydrates, antioxidants) designed for physico-chemical attribute (e.g., product stability) enhancement or intra-joint residence-time improvement [ 10 , 14 , 20 , 24 , 25 , 26 , 27 , 28 ]. Similarly, the use of smart polymers has been extensively reported for potentially optimized hydrogel-based OA management, with leveraging of both technical and functional attributes of such products.…”

“…In particular, water-soluble thermo-responsive polymers may transition from hydrophilic to hydrophobic as the system is heated above the ad hoc transition temperature (i.e., the lower critical solution temperature, LCST) [ 31 ]. Among such polymers, PNIPAM has been extensively exploited in diverse biomedical applications [ 14 , 25 , 26 ]. This is partly due to an LCST value of 32 °C, close to the human body temperature, and a low sensitivity of the phase transition to the local environmental conditions [ 14 , 27 , 31 ].…”