Modulation of the immune response in strategies for bone regeneration

Abstract

Transplantation of autologous (patient's own) bone is the gold standard in the repair of large bone defects. However, the limited amount of transplantable bone and the increased surgery time are major drawbacks of this technique. Several biological and synthetic off-the-shelf bone substitutes are available, but are still considered inferior to autologous bone. As the role of biomaterials for orthopedic applications is evolving from a structural role to a bioactive role to actively promote regeneration, the properties of these biomaterials are fine-tuned to direct the optimal tissue response. Study of the normal bone healing mechanisms shows that local factors expressed during the acute inflammatory response contribute to different processes needed for new bone formation. This generates the hypothesis that the modulation of the early inflammatory environment could be beneficial for the outcome. The aim of this thesis was to identify and test the feasibility of immune-modulatory strate­gies to enhance new bone formation. The results show that the incorporation of pro-inflammatory cytokines such as TNF-α or IL-17 into bone scaffolds can enhance bone formation in rabbits. Similarly, bacteria or specific components they hold, can induce immune responses that favor bone formation in rabbits. As an explanation for their bone-stimulating action, we show that pro-inflammatory mediators interact with bone-related growth factors to stimulate the formation of mature bone cells from progenitor cells. In summary, animal models were used to demonstrate that the local and short-lived delivery of pro-inflammatory cytokines is a potentially safe strategy to improve the efficacy of bone substitutes. Furthermore, selective bacterial ligands could have therapeutic merit in strategies for bone regeneration when the systemic effects can be controlled. To further explore the clinical relevance, the pro-in­flammatory stimuli with osteo-stimulatory potential should next be confirmed in larger, functional animal models.