Abstract
Under pathological conditions, joints and skin are often affected by an imbalance in the breakdown and production of hyaluronic acid (HA). The unique biochemical and biomechanical properties provided by HA must be restored for the long-term lubrication and cushioning effects. To overcome the inconvenience of repeated injections and the rapid degradation of exogenous HA treatments, HA is conjugated to a thermosensitive polymer, enabling the spontaneous formation of nanoparticles (HA Nano) at body temperature. Three HA Nano preparations are tested for their injectability, sensitivity to enzymatic degradation and cytocompatibility. One of them is delivered via subcutaneous and intra-articular injections to healthy mice and tested in a murine osteoarthritis (OA) model. It is found to be biocompatible, to offer a prolonged residence time at the injection site, have the ability to protect cartilage, to reduce pro-inflammatory cytokines and to preserve epiphysis thickness. In this study, HA Nano spontaneously forms nanoparticles at body temperature in vivo and is a promising candidate for the next generation of the sustainable/long-lasting treatment of OA and potentially also dermatological conditions.
Highlights
Hydrogels, which are composed of hydrophilic homopolymer or copolymer networks that can swell in water and physiological fluids,[1] are important biomedical materials due to their high water content and tissue-like elasticity
The aromatic protons of DBCO allowed the calculation of the degree of substitution (DS) of the Hyaluronic acid (HA) conjugates (Fig. 1f) from their NMR spectra
The NMR data demonstrated the grafting efficacy of the reaction in water–DMSO from the native HA sodium salt used without previous modification.[9]
Summary
Hydrogels, which are composed of hydrophilic homopolymer or copolymer networks that can swell in water and physiological fluids,[1] are important biomedical materials due to their high water content and tissue-like elasticity. Injected HA does not HA alterations that confer thermosensitivity might help to prolong the in vivo lifetime/residence of HA To this end, the thermoresponsive poly(N-isopropylacrylamide) ( pNiPAM) polymer might be suitable because of its well-defined sol–gel transition.[10] pNiPAM can introduce physical cross-links via the association of hydrophobic domains and in situ hydrogel formation.[11,12] Below the lower critical solution temperature (LCST), the hydrophobic N-substituted groups of pNiPAM are hydrated by water molecules to form a homogeneous solution. The LCST, hydrophobic interactions between the N-substituted groups increase, and their strength surpasses their hydration energy, leading to the aggregation of hydrophobic polymer chains.[13,14] Besides, low molecular weight pNiPAM is biocompatible and undergoes renal clearance.[15,16] Previously, thermoreversible HA-pNiPAM hydrogels were formulated for various applications such as tissue engineering and drug delivery systems.
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