Regenerative Medicine Utrecht


22 March 2018
Academie Gebouw

Michiel Croes

Thesis: Modulation of the immune response in strategies for bone regeneration

Promotors: prof.dr. F.C. Oner, prof dr, W.J.A. Dhert
Copromotors: dr. J. Alblas, dr. M.C. Kruyt
Defense date: 22 March 2018

Advanced bone reconstruction techniques are required when the natural bone healing mechanism fails. To date, the gold standard method to restore bone defects is to transplant patient-own or donor-derived bone. The huge demand for bone grafts makes bone the most transplanted tissue worldwide, leaving blood aside. There is a great need for alternatives, as bone transplantations inevitably lead to serious concerns in terms of safety, efficacy and costs.

Identifying novel bone-promoting strategies can lead to the formulation of advanced bone replacements. In this thesis, we investigated the feasibility of inducing a controlled inflammatory response to instigate bone regeneration. Study of the normal bone healing process shows that local factors expressed during acute inflammation contribute to different processes needed for new bone formation, including the recruitment of competent cells, osteogenesis, chondrogenesis and/or angiogenesis. During disease, inflammatory processes can also be linked to excessive new bone formation. We hypothesized that, under the right conditions, local delivery of pro-inflammatory stimuli can lead to a favourable osteogenic response.

In rabbit models of bone formation, we found that pro-inflammatory cytokines involved in the normal bone healing response (i.e. TNF-α, IL-17) can improve the effectiveness of osteogenic scaffolds. In vitro experiments showed that their stimulatory effects are mediated in part by potentiating the growth factor bone morphogenetic protein 2. This possibly mimics the natural crosstalk between inflammatory and osteoinductive cues during bone healing.

Following the clinical observation that certain infectious conditions lead to a tremendous amount of new bone, we demonstrated that the complex tissue response induced by killed bacteria, bacterial cell wall fragments, or single bacterial ligands can be harnessed to stimulate osteogenesis. Accordingly, the diverse responses induced by different bacterial ligands can serve as model compounds to advance our understanding of immune responses involved in bone regeneration. Bacterial ligands may also have therapeutic merit in strategies for bone regeneration, but only when the choice of the ligand and its delivery method leads to a controlled and local response.

In conclusion, we have pinpointed different classes of pro-inflammatory stimuli with osteo-stimulatory potential, which should next be confirmed in relevant locations and/or functional models.