## 1 Introduction  
Critically-sized bone defects arise from traumatic injury, tumor resection, autologous bone graft harvesting, and surgical procedures, including spinal fusion. Autografts, considered the gold standard in bone substitutes, are impractical for use in larger defects, as graft size would be limited to patient sample availability. Additionally, pain and local donor site morbidity are commonly reported at the site of graft harvesting [1]. Nonetheless, autografts are successful in defect treatment because they combine a number of key components necessary for tissue growth. Bone regeneration requires contributions from all aspects of the \"tissue engineering paradigm\", including progenitor cells, which are a scaffold to guide tissue formation and remodeling, and biochemical/biomechanical stimuli. Significant research has investigated various biomaterials and scaffolding techniques with osteoconductive or osteoinductive properties. Among these biomaterials is hydroxyapatite (HA),the primary crystalized form of calcium phosphate comprising the inorganic portion of bones, which has consistently demonstrated the ability to promote bone growth in vivo [2; 3]. Monolithic scaffolds are commonly utilized, usually conforming to the pre-determined geometry of controlled defects created in animal models [4; 5]. In clinical application, this type of scaffold would be impractical. The implanted scaffold must span the full volume of the defect--thus, having a pre-sized scaffold would limit its application to defects of specific sizes, or require the physician to modify the graft or the graft site. Graft modification requires costly operating-room time and introduces the risk of damaging the biomaterial. Graft site modification could have deleterious effects to the patient, in that use of a reamer or burr causes heat generation and local tissue necrosis. Ultimately, a moldable formulation may reduce time in surgery and avoid additional bone loss or trauma to the surrounding tissue area [6]. It would therefore be advantageous for the scaffolding material to be moldable to irregular geometries presented in most clinical cases to completely fill the defect and bridge the native bone. There are, however, a number of physical characteristics of bone grafts that need to be retained. The inclusion of porosity in the HA scaffolds cannot be understated, as there is typically a correlation between the extent and interconnectivity of pores and the scaffold's ability to regenerate bone [7; 8; 9; 10]. Interconnected porosity encourages the in vivo infiltration of autologous cells and vasculature. High porosity may be achieved with ceramics by employing a granular or microparticle preparation. This approach has been validated in limited studies without specific tailoring of granule porosity or surface area, nor thorough characterization of the cellular component of the graft [11; 12; 13]. The contribution of cells is often overlooked in biomaterials-based approaches for orthopedic healing. However, it is ultimately the cells, whether they be transplanted with the graft or recruited endogenously, that are responsible for new tissue generation and remodeling [14; 15]. We recently reported that many Food and Drug Administration (FDA)-cleared or approved biomaterials for bone healing are not efficient at retaining bone marrow-derived cells and, in many instances, were cytotoxic, with pH values less than 7 or greater than 10 when reconstituted in plasma or saline [16]. Materials that were not easily soluble (allograft bone and calcium phosphates) were most successful at retaining bone marrow mesenchymal stem or stromal cells (MSCs) and inducing osteogenic gene expression in an in vitro simulation of surgical graft preparation. In addition to the effects of materials on cells, the source and number of cells must be considered. Many in vivo studies combine biomaterials with culture-expanded autologous or allogeneic cells as an implantable graft.