Abstract
In the present study, a series of four different scaffolds were comparatively evaluated in a goat calvarial critical size defect model. Such studies are only rarely reported in the literature. In our work, E1001(1k), a member of a large combinational library of tyrosine-derived polycarbonates (TyrPC), was used to prepare two calcium phosphate hybrid, biodegradable bone scaffolds. In one formulation, the widely used β-tricalcium phosphate (β-TCP) was incorporated into the polymer scaffold. In the second formulation, a coating of dicalcium phosphate dihydrate (DCPD, also known as brushite) was used as the mineral phase. These scaffolds were evaluated for bone regeneration in goat calvarial 20-mm critical size defects (CSD) after 16 weeks. Results were compared with chronOS (a clinically used product) and E1001(1k)/β-TCP scaffolds, augmented with 400 μg of recombinant human bone morphogenetic protein-2 (rhBMP-2). Microcomputed tomography (micro-CT) and histomorphometry were used to assess bone regeneration within the defects. Histomorphometry showed that rhBMP-2-augmented E1001(1k)/β-TCP scaffolds completely healed the defect in all animals within 16 weeks. Among the hybrid scaffolds that were not augmented with rhBMP-2, the degree of bone regeneration within the defect area was low for the clinically used chronOS, which is a poly(lactide co-ε-caprolactone)/β-TCP hybrid scaffold. Similar results were obtained for E1001(1k)/β-TCP scaffolds, indicating that replacing poly(lactide co-ε-caprolactone) with E1001(1k) does not improve bone regeneration is this model. However, a statistically significant improvement of bone regeneration was observed for E1001(1k)/DCPD scaffolds. These scaffolds resulted in significant levels of bone regeneration in all animals and in complete bridging of the defect in three of six tests. This is the first report of a synthetic bone scaffold being able to heal a critical size calvarial defect in a large animal model without the addition of exogenous growth factors.
Lay Summary
Reconstruction of large bone defects is a significant clinical problem. The overwhelming majority of all research results are obtained in vitro or in small animal models (mouse, rat, rabbit) that cannot predict the clinical outcomes in humans. We address this problem by conducting our studies in a goat calvarial critical size defect model, which is widely regarded as predictive of human outcomes. Among the three rhBMP-2-free scaffolds tested, only one specific formulation, E1001(1k)/DCPD, resulted in massive bone ingrowth into the center of the defect in all animals and in complete bridging of the defect 50% of the animals. This is the first time, a synthetic bone scaffold was able to heal a critical size calvarial defect in a large animal model without the addition of biological growth factors. Given the high cost of biologically enhanced bone grafts and the regulatory complexities of their FDA market clearance, the development of E1001(1k)/DCPD hybrid scaffolds addresses a significant clinical need.
Notch-Wnt signal crosstalk regulates proliferation and differentiation of osteoprogenitor cells during intramembranous bone healing
