We believe that fusion and current disc prostheses have failed to meet their promise because they do not restore the natural behavior of the disc, which is only one part of the complex structure in our spines. The natural disc is a complex structure that deforms, absorbs and stores energy, working together with other spinal elements. Recently, we created a novel prosthesis (BioAID) mimicking the structure and deformation properties of the natural disc, i.e. a biomimetic disc. The novelty of this biomimetic disc lies in the fact that it is composed of a hydrogel core restricted by a stiff fiber jacket, creating overall mechanical properties which are more similar to the natural intervertebral disc. Although the principal and performance of the design was demonstrated, biomimetic integration as well as in vivo proof-of-concept remain necessary for acceptance of this technology and availability of a truly biomimetic artificial intervertebral disc to alleviate back/neck pain.

The aim of the project is to demonstrate that a completely biomimetic artificial disc can be produced, become incorporated into adjacent vertebrae and return proper function to the spine. To this end, a 2nd generation prototype biomimetic artificial disc has been machine manufactured using current technology and designed according to medical device standards. The main objective of the project is to demonstrate proof of concept of primary stability and induction of biomimetic integration of the 2nd generation artificial disc with adjacent vertebrae. A secondary outcome will be the integrity of the hydrogel core within the biomimetic prosthesis.

• S.A. (Seyed) Kamali PhD
• prof. dr. Keita Ito
• prof. dr. M.A. (Marianna) Tryfonidou

• dr. A. Abdelgawad (Maastricht University); dr. S. Ghazanfari (Maastricht University); PhD candidate Celien A.M. Jacobs (TU Eindhoven); Prof. S. Jockenhövel (Aachen University); dr. H. Smelt (DSM)

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.

• dr. M. (Michelle) Teunissen
• prof. dr. P.R. (René) van Weeren
• 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.

In Western societies, osteoarthritis (OA) and chronic low back pain caused by intervertebral disc degeneration are the musculoskeletal diseases with most impact, resulting in decreased productivity and high health costs. Anti-Inflammatory Agents (AIA) are effective but have systemic side effects or limited duration of local activity. The ArIADNE consortium will develop slow release systems of anti-inflammatory drugs for the long term inhibition of inflammation, thus enhancing regeneration. Furthermore, in order to fine-tune these systems for clinical application, the local side effects of high local and prolonged doses of AIAs will be studied, as well as the in vivo release kinetics of AIA in relation to the implantation site and biomaterial degradation . Alongside, ArIADNE will study the role of inflammation in regeneration and kartogenin and caveolin-1 in particular as possible new regenerative compounds.

• dr. A.R. (Anna) Tellegen
• prof. dr. M.A. (Marianna) Tryfonidou

• dr LB Creemers (UMC Utrecht)
• I Jansen (UMC Utrecht)
• Nina Voike (DSM)
• George Mihov (DSM)
• Jens Thies (DSM)
• Ingrid Lether (Dutch Arthritis Foundation)

Low back pain is a widespread disorder, with tremendous socioeconomical impact. While this condition is multifactorial, intervertebral disc degeneration is one of its main causes. Actual treatments are only symptomatic (to alleviate pain) and new therapies are needed. Disc degeneration is characterized by the inability of the resident cells to keep the disc tissue intact due to a change of their phenotype and their decreasing number. Thus, delivery of exogenous cells may help. The disc originally contains two distinct cell populations: the nucleus pulposus cells (NPCs, chondrocyte-like cells) and the notochordal cells (NCs). Because NCs do not exist in human adults, regenerative therapies have only focused on using chondrocyte-like cells, e.g. adult mesenchymal stem cells (MSCs). However, their transplantation has been of limited success as disc degeneration was only inhibited and not reversed. We believe that this failure is in part due to inability of the transplanted cells to produce enough/appropriate disc matrix to restore tissue properties.

Using an innovative approach, we propose to mimic the natural cell combination of a developing disc, i.e. NCs and NPCs/MSCs, when the largest amount of matrix is produced. Different approaches will be tested for their efficacy using a succession of model systems moving from higher volume:cost ratio systems to more realistic but lower volume:costs systems. Another novelty of our approach will be to use the canine model in which disc degeneration is a frequent spontaneous spinal disease and whose NCs, NPCs and MSCs are readily available.

First, canine NCs, NPCs and MSCs (used to complement the decreasing disc cell population) will be combined in different co-culture systems to compare the ability of various cell combinations to stimulate the production of an appropriate disc matrix. We will also determine if the NCs directly contribute to matrix production or regulate other cells through biochemical signals. The most successful concepts will be further developed pre-clinically in experimental dogs with early stage spontaneous disc degeneration. Finally as proof of principle, a clinical study will be performed in client-owned canine patients with disc disease as the basis for a trial to be set up in human patients. In parallel with this sequential approach, the applicability of our findings to human cells will be demonstrated and if the NC regulatory effects are mediated through soluble factors, these will be identified for further exploitation. This project will (1) provide new and important insights on the role of NCs in disc regeneration and (2) may provide a new biological therapy to treat one of the most common disorders in modern society.

• dr. F.C. (Frances) Bach
• F.M. (Frank) Riemers MSc
• prof. dr. M.A. (Marianna) Tryfonidou

• Prof. dr. Keita Ito (TU/e)
• dr. Laura Creemers (UMCU)
• Ing. Stefan de Vries (TU/e)
• Ing. Irene Arkensteijn (TU/e)
• dr. Esther Potier (TU/e)

Do not remove…

The spinal column has a heavy task. It protects our spinal cord and its nerves, carries our body weight, supports the head and absorbs the shocks resulting from physical exercise. No wonder that lower back pain is a very common problem. Two out of three Dutch people will be confronted with this problem during their lifetime. Some people have chronic lower back pain. An important cause of chronic back pain is wear and tear of the intervertebral disc, the soft disc between the vertebrae that together form the spinal column. This degeneration of the intervertebral disc develops due to a previously incurred hernia or gradual wear and tear. Current treatments for lower back pain require the replacement of afflicted vertebrae with bone from elsewhere in the body, or replacement by intervertebral disc prostheses. In both cases, the entire intervertebral disc is removed and only the symptoms are suppressed. These operations also carry risks, such as further damage to the adjacent intervertebral disc, and persistent pain at the sites where the bone was removed.

... but repair

The purpose of this study is to determine how the function of the degenerated intervertebral disc can be repaired instead of removed. If the degeneration of a vertebral disc is not far advanced, a treatment could consist of injectable, biodegradable materials that release drugs over a longer period of time, thereby stimulating the self-recovery of the intervertebral disc. The materials for the incorporation and release of these compounds may be watery gels, very small spheres (microparticles) or a combination of these two. Next to this, methods are being developed to repair the outside of the intervertebral disc to ensure the injected materials will not diffuse out of the disc. These methods are based on a biodegradable plaster.

A unique aspect of this project is the investigation into the ethical aspects of these new self-repair methods and the moral guidelines for implementing these techniques in patients.

• prof. dr. M.A. (Marianna) Tryfonidou
• dr. N. (Nicole) Willems
• dr. A.R. (Anna) Tellegen
• F.M. (Frank) Riemers MSc

• dr LB Creemers
• prof dr K Ito
• prof dr T Smit
• InGell BV.
• DSM
• TNO