title: Efficacy study of two novel hyaluronic acid-based formulations for viscosupplementation therapy in an early osteoarthrosic rabbit model.
abstract: Viscosupplementation (VS) is a therapy for osteoarthrosis (OA) consisting of repetitive intra-articular injections of hyaluronic acid (HA). It is known to be clinically effective in relieving pain and increasing joint mobility by restoring joint homeostasis. In this study, the effects of two novel HA-based VS hydrogel formulations were assessed and challenged against a pure HA commercial formulation for the first time and this in a rabbit model of early OA induced by anterior cruciate ligament transection (ACLT). The first formulation tested was a hybrid hydrogel composed of HA and reacetylated chitosan, a biopolymer considered to be chondroprotective, assembled thanks to an ionic shielding. The second formulation consisted of a novel HA polymer grafted with antioxidant molecules (HA-4AR) aiming at decreasing OA oxidative stress and increasing HA retention time in the articulation. ACLT was performed on rabbits in order to cause structural changes comparable to traumatic osteoarthrosis. The protective effects of the different formulations were observed on the early phase of the pathology in a full randomized and blinded manner. The cartilage, synovial membrane, and subchondral bone were evaluated by complementary investigation techniques such as gross morphological scoring, scanning electron microscopy, histological scoring, and micro-computed tomography were used. In this study, ACLT was proven to successfully reproduce early OA articular characteristics found in humans. HA and HA-4AR hydrogels were found to be moderately protective for cartilage as highlighted by μCT. The HA-4AR was the only formulation able to decrease synovial membrane hypertrophy occurring in OA. Finally, the hybrid HA-reacetylated chitosan hydrogel surprisingly led to increased subchondral bone remodeling and cartilage defect formation. This study shows significant effects of two innovative HA modification strategies in an OA rabbit model, which warrant further studies toward more effective viscosupplementation formulations.
authors.affiliation: School of Pharmaceutical Sciences, University of Lausanne and Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland. Electronic address: sema.kaderli@unige.ch.
authors.forename: Sema
authors.initials: S
authors.lastname: Kaderli
authors.affiliation: UPSP ICE 2011.03.101, University of Lyon, VetAgro Sup, Veterinary Campus of Lyon, 69280 Marcy l'Etoile, Lyon, France. Electronic address: eric.viguier@vetagro-sup.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Viguier
authors.affiliation: UPSP ICE 2011.03.101, University of Lyon, VetAgro Sup, Veterinary Campus of Lyon, 69280 Marcy l'Etoile, Lyon, France. Electronic address: dorothee.watrelot@vetagro-sup.fr.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Watrelot-Virieux
authors.affiliation: UPSP ICE 2011.03.101, University of Lyon, VetAgro Sup, Veterinary Campus of Lyon, 69280 Marcy l'Etoile, Lyon, France. Electronic address: thierry.roger@vetagro-sup.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Roger
authors.affiliation: School of Pharmaceutical Sciences, University of Lausanne and Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland. Electronic address: robert.gurny@unige.ch.
authors.forename: Robert
authors.initials: R
authors.lastname: Gurny
authors.affiliation: School of Pharmaceutical Sciences, University of Lausanne and Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland. Electronic address: leonardo.scapozza@unige.ch.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Scapozza
authors.affiliation: School of Pharmaceutical Sciences, University of Lausanne and Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland. Electronic address: michael.moeller@unige.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Möller
authors.affiliation: UPSP ICE 2011.03.101, University of Lyon, VetAgro Sup, Veterinary Campus of Lyon, 69280 Marcy l'Etoile, Lyon, France. Electronic address: caroline.boulocher@vetagro-sup.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Boulocher
authors.affiliation: School of Pharmaceutical Sciences, University of Lausanne and Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland. Electronic address: olivier.jordan@unige.ch.
authors.forename: Olivier
authors.initials: O
authors.lastname: Jordan
mesh_terms: D000107:Acetylation; D000818:Animals; D000975:Antioxidants / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D003692:Delayed-Action Preparations / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D004195:Disease Models, Animal; D065546:Drug Liberation; D006820:Hyaluronic Acid / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D020100:Hydrogels; D007719:Knee Joint / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D011897:Random Allocation; D012118:Resorcinols / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D055675:Viscosupplements / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D003692:Delayed-Action Preparations; D020100:Hydrogels; D012118:Resorcinols; D055675:Viscosupplements; D006820:Hyaluronic Acid; D048271:Chitosan
keywords: 4-Aminoresorcinol (432827); Anterior cruciate ligament transection; Antioxidant; Chitosan; Chitosan (PubChem CID: 21896651); Hyaluronic acid; Hyaluronic acid (PubChem CID: 24728612); Osteoarthrosis; Rabbit; Viscosupplementation