Regenerative Medicine Utrecht


18 September 2018
Academie Gebouw

Marianne Koolen

Thesis: Building Better Bone

Promotoren: Prof.dr. H.H. Weinans, Prof.dr. F.C. Öner
Copromotoren: dr. O.P. van der Jagt, D. Gawlitta
Defense Date: 18 September 2018




The aim of this thesis is to provide a detailed overview of local bone regenerative options that would profit trauma, orthopedic and maxillofacial surgery.

In the first part of this thesis a “cell-based” method to regenerate bone is investigated. For this, mesenchymal stem cells (MSCs) are differentiated, and so-called pellets of cartilage are made. These pellets can develop into bone, comparable to endochondral ossification. At first, human chondrogenic pellets were placed in a bone defect of an immuno-incompetent rat. We saw significant bone formation, but this was donor dependent. Also, to translate this into the clinic, pellets need to be kept in the bone defect. Therefore, fibrin, a protein already present in natural bone healing, was used. In this second experiment, normal rats were used, which meant that there was a xenograft. We did indeed see an immune response of the rat against the MSCs. However, the xenogeneic cells also induced bone regeneration.

Subsequently, in the second part of this thesis the “material-based” bone regeneration method was investigated. First, fibrin was used in a non-union model, as its permeability to (bone)cells make it a good carrier. If we add a small amount of the growth factor bone morphogenetic protein (BMP) to fibrin, there was exceptional bone growth with remodeling of cortical bone in a short amount of time. Since fibrin itself does not give stability, other bone substitutes should be used in case stability is necessary. We showed that the more ductile porous pure titanium generated greater bone tissue, but was also less strong compared to porous titanium alloy. Furthermore, we showed that bone regeneration in titanium bone substitutes is improved when BMP is added to fibrin and placed into porous titanium scaffolds. The original hypothesis was that high molecular weight fibrin would enable better bone regeneration than the standard clinically applied fibrin (Tissucol), because it would improve cell migration and angiogenesis. However, it makes no difference which fibrin is used. No side effects were seen in any of the studies using BMP.

In the last part of this thesis we tested whether shockwave therapy is suitable as a “stimulus-based” method for bone regeneration. This method concerns the use of a device that produces a divergent shockwave, in other words electrohydraulically generated impulses. Three different porous bone substitutes were treated with shockwave therapy and more bone was visualised in both the bone substitute hydroxyapatite and in porous titanium. The bone substitute tricalcium phosphate, showed no positive effect of shockwaves. Also we noticed that shockwave therapy generated more bone around cortical screws and provided a stronger fixation of these screws, compared to cancellous placed screws. However, we also saw the formation of an extra cortex in some rats and the old cortex disappeared. Encouraged by these results we conducted a clinical pilot study to investigate if shockwave therapy could induce bone formation in patients without evoking side effects. The study showed there were indeed no side effects of shockwave therapy, but unfortunately there was no increase in bone density.