In his famous textbook “On the diseases of articulating surfaces” published in the year 1743, William Hunter wrote “If we consult the standard Chirurgical Writers from Hippocrates down to the present Age, we shall find, that an ulcerated Cartilage is universally allowed to be a very troublesome Disease; that it admits of a Cure with more Difficulty than carious Bone; and that, when destroyed, it is not recovered”. Up until now this sentence still dictates the vision of orthopedic surgeons how to deal with joint disorders like osteoarthritis and cartilage trauma.

Recent scientific developments have challenged the view of William Hunter. First, distraction of the joint for just 6 weeks is sufficient to stimulate complete regrowth of an eroded articular cartilage surface in animal models and human patients. Second, resident stem cell populations have been identified in joint tissue such as cartilage, the bone marrow compartment below the subchondral bone plate, the synovial membrane and freely floating in the synovial fluid. Evidence shows that these cells can migrate to cartilage defects and can be activated to induce a regenerative response. Indeed, most likely by exploiting the regenerative potential of these stem or progenitor cell populations, it was shown in preliminary experiments that focal cartilage defects can be repaired by a biomaterial approach only in orthotopic focal cartilage defect equine and rabbit models. In these animals, chondral defects were filled with an injectable in situ gelating hydrogel that activates locally resident stem or progenitor cells. Indeed in rabbits, after 10 weeks defects were completely repaired in a cell-free approach. In the equine model, histological examination demonstrated the ingrowth of cells in the hydrogel two weeks after the arthroscopically guided implantation of the hydrogel in the chondral defect. A substantial part of these cells showed typical chondrocyte features. Taken together multiple lines of evidence demonstrates that articular cartilage can repair itself once the proper microenvironment is offered which unleashes its regenerative potential.

These exciting new developments open up a complete new avenue for the treatment of focal cartilage defects and osteoarthritis. Primary osteoarthritis and secondary osteoarthritis as a consequence of cartilage trauma earlier in life are among the most prevalent diseases in the Western World for which no effective cure is available. This proposal aims at bringing together leading Dutch groups on osteoarthritis research, which are well known for their pioneering work on the potential of intrinsic cartilage repair, with Dutch SMEs active in developing innovative treatments for joint regeneration. The program is furthermore supported by the Dutch Arthritis Foundation.
Within this proposal we intend to develop multidisciplinary projects along two intrinsically related themes:

Theme 1 is focusing on studies to explore the cellular basis of intrinsic cartilage repair and the role of biomechanics: This could be either stem cell populations residing in the joint but might also be chondrocyte subpopulations or alternative cell sources. Once identified we will aim at two strategies that can exploit these cell populations: i) development of bioactive scaffolds that in a cell-free manner can induce regeneration of lost cartilage tissue by activating these resident stem or progenitor cell populations; ii) controlled release strategies that release bioactive components that activate the regenerative potential of these cells.

Theme 2 is focusing on studies to explore the molecular basis of joint homeostasis by assessing the composition of synovial fluid in opposing conditions (catabolic versus anabolic conditions). This may lead to new diagnostics but also to new drugs / biologicals that can restore joint homeostasis.

Both themes are intrinsically related. For example joint distraction changes the catabolic osteoarthritic milieu in the joint into an anabolic regenerative milieu. Likewise, cell attracting hydrogels that fill up cartilage defects induce a regenerative response while in control animals similar defects result in cartilage catabolism. These opposing experimental conditions thus provide excellent models to study the fundamentals of joint homeostasis that could lead to new biomarkers of disease as well as new therapeutic interventions.

• prof. dr. B.P. (Bjorn) Meij
• dr. M. (Michelle) Teunissen
• prof. dr. M.A. (Marianna) Tryfonidou

• dr. H.B.J. (Marcel) Karperien
• Prof. dr. G.J. van Osch
• Prof. dr. H. Weinans
• Prof. dr. F. Lafeber
• dr. P. van der Kraan
• dr P. Emans
• dr T. Welting
• Dutch Arthritis Foundation
• Hy2Care B.V.
• InGell B.V.
• Crystal Therapeutics B.V.
• QVQ B.V.
• Percuros B.V.