title: In vitro and in vivo evaluation of doxycycline-chondroitin sulfate/PCLmicrospheres for intraarticular treatment of osteoarthritis.
abstract: Osteoarthritis (OA) is a degenerative joint disease, which has no complete treatment with medication yet. Intraarticular hyaluronan (HA) injection can decrease pain and modify the natural course of OA. This study was designed to provide long term delivery of an MMP (matrix-metalloproteinase) inhibitor agent-doxycycline, together with matrix regenerative agent-chondroitin sulfate for treating OA which progress with matrix degenerations. Doxycycline (D) and doxycycline-chondroitin sulfate (D-CS) loaded poly-ɛ-caprolactone (PCL) microspheres (MS) were prepared as intraarticular delivery systems. Bio-effectiveness of developed microspheres was first evaluated with three-dimensional in vitro model of OA where both MS showed significant reduction in MMP-13 levels compared to untreated OA-chondrocytes at 15 and 24 days. Significant decrease was observed in GAG release into the media for both D MS and D-CS MS treated groups at 15 and 24 days. Second, the microspheres were injected to rabbit knee in hyaluronan (HA) to evaluate the effectiveness of the treatment. Radiographic scores of D MS and D-CS MS groups improved after 8 weeks when compared to OA group. Mankin-Pitzker histological scores similarly showed improvement with D MS and D-CSMS groups when compared to OA group. Ex vivo hardness tests of cartilages demonstrated superior hardness values with both doses of D-CSMS compared to OA group. D MS showed promising improvement of OA in histology results. Although, both MS groups had similar effects on cells in the in vitro model, D-CSMS had a positive contribution on all in vivo treatment outcomes and showed potential as a new strategy for treatment when applied to OA knee joints.
authors.affiliation: Department of Engineering Sciences, Middle East Technical University, 06800, Ankara, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Aydin
authors.affiliation: Department of Sports Medicine, Hacettepe University, Faculty of Medicine, 06100, Ankara, Turkey.
authors.forename: Feza
authors.initials: F
authors.lastname: Korkusuz
authors.affiliation: Department of Histology and Embryology, Hacettepe University, Faculty of Medicine, 06100, Ankara, Turkey.
authors.forename: Petek
authors.initials: P
authors.lastname: Korkusuz
authors.affiliation: Department of Engineering Sciences, Middle East Technical University, 06800, Ankara, Turkey.|BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, Ankara, 06800, Turkey.
authors.forename: Aysen
authors.initials: A
authors.lastname: Tezcaner
authors.affiliation: Department of Histology and Embryology, Hacettepe University, Faculty of Medicine, 06100, Ankara, Turkey.
authors.forename: Elif
authors.initials: E
authors.lastname: Bilgic
authors.affiliation: Department of Surgery, Faculty of Veterinary Medicine, Afyon Kocatepe University, 03200, Afyon, Turkey.
authors.forename: Volkan
authors.initials: V
authors.lastname: Yaprakci
authors.affiliation: Department of Engineering Sciences, Middle East Technical University, 06800, Ankara, Turkey.|BIOMATEN, Center of Excellence in Biomaterials and Tissue Engineering, Middle East Technical University, Ankara, 06800, Turkey.
authors.forename: Dilek
authors.initials: D
authors.lastname: Keskin
mesh_terms: D000818:Animals; D002809:Chondroitin Sulfates / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004318:Doxycycline / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D007270:Injections, Intra-Articular; D008863:Microspheres; D010003:Osteoarthritis / Q000188:drug therapy* / Q000473:pathology; D011817:Rabbits
chemical_list: D002809:Chondroitin Sulfates; D004318:Doxycycline
keywords: articular cartilage; chondroitin sulfate; drug delivery/release; matrix metalloproteinase; microspheres