From extra-skeletal bone growth to re-osseointegration: Osteoinduction and mechanical disruption in bone repair

Abstract

The effort to preserve the integrity and function of the skeletal system has driven scientific innovation for centuries. Clinical challenges—such as tooth loss, joint failure, limb amputation, and large bone voids caused by congenital defects, trauma, disease, or surgery—can be addressed with biomaterials. However, no single material can fully replicate the biological and mechanical complexity of bone across diverse anatomical locations. This thesis investigates two aspects of bone regeneration using clinically relevant biomaterials: (i) the capacity of calcium phosphates (CaPs) to induce heterotopic bone formation both in association with and distant from the skeleton (Papers I-II) and (ii) the biological response to mechanical overload in osseointegrated titanium (Ti) implants, with a focus on re-osseointegration (Papers III-IV). Bone formation, remodelling, and repair processes were studied in two animal models—sheep and rats—and three anatomical locations: the occipital bone, soft tissue, and long bone, using complementary histological, microscopic, and spectroscopic techniques. Papers I and II investigated bone formation in response to multicomponent CaPs composed of monetite, β-tricalcium phosphate, and calcium pyrophosphate (Ca-PP). In Paper I, CaP constructs implanted on the occipital bone of sheep induced bone formation via endochondral and intramembranous ossification. The newly formed bone resembled native bone in structure and composition and showed signs of long-term remodelling. In Paper II, subcutaneous implantation revealed that while increasing Ca-PP content did not inhibit bone formation or accelerate material degradation, it negatively affected bone quality. The long-term persistence of heterotopic bone appeared to be dependent on the continued presence of the CaP material. While CaPs are widely used in non-load-bearing bone repair, metal implants remain the clinical standard for load-bearing skeletal reconstruction. Papers III and IV investigated the impact of mechanical overload on Ti implants and the potential for re-osseointegration. In Paper III, a new rat model simulated overload via snap-disruption of osseointegrated Ti implants. Four weeks after disruption, re-osseointegration was confirmed, with restored biomechanical stability. Paper IV examined the biological cascade following overload, revealing a staged regenerative process leading to re-osseointegration. This thesis demonstrates how CaPs promote bone formation beyond the skeletal envelope and how Ti implants can re-osseointegrate after mechanical failure. These findings offer valuable insights into the adaptive capacity of bone to improve bone-biomaterial performance and support regenerative and reconstructive applications in clinical settings.