Enhance bone regeneration and implant fixation by novel substitute with combined angiogenic and osteogenic factors in animal models

Bone regeneration is attracting an increasing level of interest in the field of basic orthopaedic research due to the prediction of increasing fracture incidence resulting from a growing elderly population coupled with the need for a sustainable and unlimited method to ensure optimal bone healing. The clinical need for such an application is increasing, with the aim of ensuring fewer complications and shorter immobilisation periods for bone fracture patients.

The current method of bone regeneration used in larger bone defects is an allograft harvested from the bone of a donor after the insertion of arthroplasties, or from cadavers. However, this method is associated with the risk of disease transmission and immunogenicity. Furthermore, the bone bank storage of allografts cannot keep up with the clinical demand.

In the present work, biomaterials were used in an attempt to develop an alternative to these complications. The theory behind this design was to enhance critical factors in the bone remodelling process with an influence of angiogenic stimulation, but with a focus on bone growth only. This theory was tested via the natural development of animal studies from rodent to large animal models.

We started by testing the theory in a severe combined immunodeficient (SCID) mouse ectopic bone model in Study 1 using mesenchymal stem cells (MSC) in combination with vascular endothelial growth factor (VEGF) at different time points. We evaluated if MSC combined VEGF was better at enhancing bone than MSC alone. Several pilot studies were performed to give an indication of the optimal dosages of MSC and VEGF in SCID mice and to evaluate a suitable time for the delivery of VEGF in this design. The study demonstrated that the optimal time of VEGF administration was within the first 14 and/or 21 days after operation in combination with MSC when compared to MSC alone (p<0.01).

Study 2 then attempted the same combination of MSC and VEGF, except in a femoral implant gap model in sheep. Sheep have proven to be a good model in the field of orthopaedic research due to their body weight, bone content and bone metabolism. A pilot study provided an indication of the amount of MSCs that would be preferable to administer with VEGF. In the primary study, we tested different doses of VEGF combined with MSC and compared them to the allograft method. Notably, we found no difference in bone formation in our gap between both groups (p<0.05).

Study 3 investigated further research and development (R&D) purposes and attempted to determine whether current progress within this field suggests that the stimulation of VEGF alone was sufficient for optimal bone formation. While this study clearly serves as a stepping stone for future project designs, a systematic literature search found no conclusive results regarding whether VEGF alone is sufficient for promoting bone growth.

In conclusion, the importance of blood vessels in the environment is an essential factor in enhancing bone regeneration. Furthermore, stimulating both angiogenic and osteogenic properties in bone healing using the right methods can heal a critical size defect (CSD) with the same amount and quality as an allograft. This provides another indication for the use of VEGF in the field of bone regeneration for patients with osteoporosis and avascular necrosis, with further investigations being required to expand on this topic. By further studying with the focus of human applications in the near future, this technique could facilitate optimised bone ingrowth and the stabilisation of general osteosynthesis.