## 4 Discussion  
Porous and non-porous HA granules, combined with autologous BMA, was able to successfully regenerate bone in all subjects. However, porous HA regenerated a significantly greater amount of bone at 8- and 13-week time points (44% and 82% more, respectively). It is generally understood that greater porosity of a scaffold is advantageous in tissue engineering and that material properties must be considered based on the clinical application [20; 21; 22]. In the present study, both bone void fillers had similar features, but key differences were the amount of surface area available for cell retention and the total and interconnected porosity for tissue and vascular infiltration. Previously, monolithic porous HA scaffolds were synthesized using similar methods and demonstrated bone growth and vascular infiltration, but were custom-made based on pre-determined defect dimensions [4; 5; 23]. These approaches achieved bone regeneration in a non-critically-sized canine mandibular defect (36.4% volume) and a critically-sized rabbit radial defect (40 mm\({}^{3}\) new bone). By utilizing a microparticle-based formulation, it would be possible to capitalize on the osteogenic properties of the scaffold material, though it should be done in a moldable formulation. This approach would not only increase clinical ease of use in geometrically complex defects, but also the total surface area of the materials, which may alter degradation rates allowing for faster implant incorporation [24]. Greater porosity and surface area would be created by replacing a single porous scaffold with hundreds of smaller (<2 mm) porous scaffolds. Non-porous granules were found to be able to mold and pack the defects but encompassed significantly less surface area and porosity. The significant differences in residual scaffold volume between porous and non-porous HA is not surprising, considering the differences in the porosity of the materials. The increased rate of material resorption in porous HA is hypothesized to be due to its greater surface area for contacting biological fluids and tissue that could increase the mechanical stress on its thin struts, leading to physical degradation of the material and potentially accelerating biological or osteoclastic breakdown of the HA. It is also possible that faster osteoinduction within and around the scaffolds accelerated the natural remodeling and turnover of the porous material. No correlation between TNC or MSC concentrations in the graft preparations and the degradation rates of the implants was observed. The present study utilized autologous BMA as a source of progenitor cells to be co-implanted with the scaffolds. The choice of non-cultured, autologous cells was made for two reasons. Firstly, the use of autologous cells at the point-of-care is safe (minimal risk of contamination, prevents possible immune based reactions to allogeneic cells or culture medium proteins), and is easily translatable based on regulatory statutes. Secondly, other studies have demonstrated the increased potency, on a per-cell basis, of fresh or non-cultured bone marrow stromal cells compared to culture-expanded cell lines [25; 26]. The contribution of MSCs had an apparent positive effect on bone formation. This was seen for both materials, but more so for the non-porous HA particles. The more interesting result was the reduction in differences between the porous and non-porous HA new bone volumes with increasing mesenchymal cell content (Figure 4D). As CFU-F/mL increased, the amount of bone generated in non-porous HA implants increased more than in porous HA grafts. This effect may be elucidated using the value determined by [PERSON] et al. to be the critical concentration of MSCs for healing non-union fractures (1500 CFU-F/mL) [17]. At 13 weeks, rabbits with >1500 CFU-F/mL regeneratedan average of 30.0 mm\({}^{3}\) (porous) and 17.3 mm\({}^{3}\) (non-porous) new bone, compared to rabbits with \(<\)1500 CFU-F/mL that regenerated 28.1 mm\({}^{3}\) (porous) and 11.5 mm\({}^{3}\) (non-porous) new bone (\(p<0.05\)).