An In Situ Hyaluronic Acid-Fibrin Hydrogel Containing Drug-Loaded Nanocapsules for Intra-Articular Treatment of Inflammatory Joint Diseases

Abstract

Intra-articular (IA) administration of drugs is an appealing route for the effective treatment of large joint diseases. However, a key limitation of this route is the premature elimination of the injected drugs from the synovial cavity. The objective of this work was to develop an easily injectable controlled release system intended to prolong the activity of anti-inflammatory drugs in the articular cavity. The system was an in situ forming hydrogel, made of fibrin and hyaluronic acid (HA), loaded with nanocapsules (NCs). The NCs, consisting of an olive oil core surrounded by a HA shell, were loaded with two different drugs, dexamethasone (DMX) and a galectin-3 inhibitor. They presented a particle size in the range of 122-135 nm and a surface charge of −29/−31 mV. The gelation time, rheological properties and porosity of the system could be adjusted by different parameters, such as addition of fibrin crosslinkers factor XIII and α2-antiplasmin. The non-crosslinked HA-fibrin hydrogels containing 30% (v/v) NCs showed the capacity to control the release of the encapsulated drug, DMX, for 72 h in simulated synovial fluid. The preliminary in vivo evaluation of the system containing a galectin-3 inhibitor in an acute synovitis rat model, showed a suppression of inflammation after IA administration compared with the non-treated control. In brief, this work shows the possibility to combine an in situ forming hydrogel and NCs as a drug delivery strategy for IA administration and suggests its potential for the treatment of arthropathies.

Hyaluronic Acid: A Key Ingredient in the Therapy of Inflammation

“…In vivo (acute synovitis rat model induced with carrageenan), after intra-articular administration, NC Gal-3i was found to reduce inflammation after 4h compared to the control group. Swelling was also effectively inhibited by the fibrin and HA hydrogel with NC Gal-3i compared to the control group [113].…”

Saturated Fatty Acid-Based In Situ Forming Matrices for Localized Antimicrobial Delivery

“…A liquid dosage form becomes semisolid or solid via various mechanisms, such as thermal trigger [ 1 , 2 ], pH change [ 3 ], solvent exchange [ 4 ], and chemical reaction [ 3 , 5 ]. The system has been focused on various application sites, such as the eyeball [ 6 ], periodontal pocket [ 7 ], articular joint [ 8 ], and muscle [ 9 ]. The solvent exchange or antisolvent processes are one of the simple mechanisms that suit any life form, given that the biological fluid is located in almost every part of the being.…”

Polymeric Hydrogels for Controlled Drug Delivery to Treat Arthritis

“…Notably, fibrin gel has presented low mechanical stiffness, faster degradation, and narrow stability (denaturation at high temperature and with the use of organic solvents), limiting its use as a single component hydrogel [ 23 , 24 ]. In order to overcome these drawbacks, fibrin is mostly used in combination with HA to prepare fibrin–HA hydrogel, delivering gapmers, cells, and even drug-loaded nanocapsules [ 25 , 26 , 27 ].…”