Targeting cartilage regeneration in joint and intervertebral disc diseases

S Grad, M Alini

Background

The aim of the project TargetCaRe (Targeting cartilage regeneration in joint and intervertebral disc diseases) was to achieve regeneration of damaged and degenerated cartilage and disc by employing targeting strategies tailored to the pathology and the tissues involved. Towards this aim ARI scientists collaborated with experts in advanced drug delivery carriers with dedicated targeting tools, state of the art imaging techniques, and cartilage or disc biology. Regeneration of diseased tissues was addressed by loading biologically active agents in state-of-the-art nanocarriers. 

 

Design of the study. Articular bovine chondrocytes, isolated from fetlock joints, were embedded into FB/HA hydrogels and subjected to mechanical stimulation for 14 days. In addition, FGF-18 was added to the culture medium

 

Results

A collaborative study aimed to test the interplay between mechanical and fibroblast growth factor (FGF)-18 mediated biochemical signals on the proliferation and differentiation of primary bovine articular chondrocytes embedded in a chondro-conductive Fibrin-Hyaluronan (FB/HA) based hydrogel. Chondrocytes seeded in a FB/HA hydrogel, with or without a chondro-inductive FGF18 variant were loaded within ARI's joint-mimicking bioreactor applying controlled, multi-axial movements, simulating the natural movements of articular joints. 

Under moderate loading, samples produced significant amounts of sulphated glycosaminoglycan (sGAG)/DNA compared to unloaded controls. There was no significant effect of FGF-18 on cartilage gene expression at rest. Following moderate multi-axial loading, FGF-18 upregulated the expression of Aggrecan, Cartilage Oligomeric Matrix Protein, type II collagen and Proteoglycan-4. Moreover, the combination of load and FGF-18, significantly downregulated Matrix Metalloproteinases-9 and -13, two of the most important factors contributing to joint destruction in osteoarthritis. Thus, biomimetic mechanical signals and FGF-18 may work in concert to support hyaline cartilage regeneration and repair.

 

Fund:

EU H2020-MSCA-ITN-2014 Marie Sklodowska-Curie Grant ARI Funding CHF 530'000, Period: 2015-2019

 

  • Publication

    Vainieri ML, Alini M, Yayon A, van Osch GJVM, Grad S. Mechanical stress inhibits early stages of endogenous cell mgration: A pilot study in an ex vivo osteochondral model. Polymers. 2020;12:1754

    Haeckel S, Zolfaghar M, Du J, Hoppe S, Benneker LM, Garstka N, Peroglio M, Alini M, Grad S, Yayon A, Li Z. Fibrin-hyaluronic acid hydrogel with Fibroblast Growth Factor-18 for in vitro 3D culture of human and bovine nucleus pulposus cells. Int. J. Mol. Sci. 11:20(20), 2019.

    Vainieri ML, Lolli A, Kops N, D'Atri D, Eglin D, Yayon A, Alini M, Grad S, Sivasubramaniyan K, van Osch GJVM. Evaluation of biomimetic hyaluronic-based hydrogels with enhanced endogenous cell recruitment and cartilage matrix formation. Acta Biomater. 2019 Nov 11. pii: S1742-7061(19)30755-X. doi: 10.1016/j.actbio.2019.11.015. [Epub ahead of print].

    Vainieri ML. Towards Cartilage Regeneration: Biomaterial-Assisted Cell-Free Approach in a Physiological Joint-like Environment. 2021 Erasmus University Rotterdam (G. van Osch, S. Grad) - PhD thesis

  • Presentation

    Haeckel S, Li Z, Zolfaghar M, Yayon A, Hoppe S, Benneker LM, Alini M, Grad S. One-way Street Disc Degeneration? An Investigation of Hydrogel and Fibroblast Growth Factor 18 (FGF-18) for Intervertebral Disc Regeneration. DKOU 2019, Berlin, DE (podium)

    S. Haeckel, Z. Li, A. Yayon, S. Hoppe, L. Benneker, M. Alini, S. Grad. One-way Street Disc Degeneration? An Investigation of Hydrogel and Fibroblast Growth Factor 18 (FGF-18) For Intervertebral Disc Regeneration. Global Spine Congress 2019, Toronto, CA (poster)

    ML Vainieri, A Lolli, K Sivasubramaniyan, D Eglin, A Yayon, M Alini, S Grad, G Van Osch. Biomimetic hyaluronic-based hydrogel enhances endogenous cell recruitment and healing process of osteochondral lesions. TERMIS-EU 2019, Rodos, GR (podium)

    Bernardo P. Antunes, M. Letizia Vainieri, Efrat Monsonego-Ornan, Mauro Alini, Sibylle Grad, Avner Yayon. Effects of mechanical stimulation combined with FGF-18 on bovine chondrocytes embedded in a novel Fibrin:Hyaluronan hydrogel. ORS 2019, US (poster)

    Sonja Häckel, Mona Zolfaghar, Jie Du, Sven Hoppe, Lorin M. Benneker, Marianna Peroglio, Mauro Alini, Sibylle Grad, Avner Yayon, Zhen Li. Fibrin-hyaluronic acid hydrogel and Fibroblast Growth Factor-18 for Intervertebral Disc Regeneration: an in vitro study on bovine and human nucleus pulposus cells. ORS PSRS 2019, Skytop, USA (poster)

  • Partner

    van Osch G (Prof), Erasmus University Medical Centre, NL

    Creemers L (PhD), University Medical Centre Utrecht, NL

    Machluf M (Prof), Technion-Israel Institute of Technology, IL

    Stevens M (Prof), Imperial College London, UK

    de Bari C (Prof), University of Aberdeen, UK

    Howard K (Prof), University of Aarhus, DK

    Heeren R (Prof), Fundamenteel onderzoek der Materie, NL

    Chan A (PhD), Percuros BV, NL

    Caterson B (Prof), Cardiff University, UK

    Yayon A (PhD), ProCore, IL

    Savelsberg R, Omics2Image, NL

    Lether I (MSc), Dutch Arthritis Foundation, NL

Completed