## 4 Treating Bone Diseases: Evidence from Bone Imaging and Analysis
### Materials Science and Tissue Engineering Approaches  
Currently, almost all bone biomaterials studied/developed have only had their potential demonstrated in vitro or have been exclusively for repairing fracture or necrosis-induced defect(s). Discussed below are possible candidates to address bone pathologies.  
In autosomal dominant OI, gene defects in _COLIA1_ result in reduced collagen content [141]. Ceria nanoparticles may be a promising candidate to tackle this. Nanoceria/bioglass nanocomposite scaffolds can increase collagen production in vivo from human mesenchymal stem cells seeded onto the scaffold and promote their differentiation into osteoblasts [185]. More work is needed to examine the quality of the collagen produced as well as the collagen texture in neo-bone using appropriate in vivo models. Nanoceria with a mixture of 3+ and 4+ oxidation states have antioxidant and radical-scavenging capabilities, as evidenced by an in vitro study involving a co-culture of osteoblasts and macrophages [186]. Nanoceria used in osteoporosis treatment could neutralize the overproduction of reactive oxygen species in age-related osteoporosis pathology [139] and could promote osteogenesis. Additionally, nanoceria-loaded mesoporous silica nanoparticles have the advantage that they can be internalized by cells but cannot enter the nucleus, thus avoiding any unintended genetic modification [186].  
On the other end of the spectrum, patients with severely deformed bones or with pathological fractures would require revision surgeries, and bone implants are needed. Forinstance, for patients suffering from [PERSON]'s disease of the bone and skeletal deformities, total hip or knee replacement and internal fixation for pathological fractures are common surgical measures [187]. Following removal of the malformed bone, either metal/alloy fixations or tissue-engineered bone scaffolds are to be implanted. Tissue-engineered bone scaffolds are becoming increasingly investigated, with a surge in the number of new or modified designs over the last few years. Biomimetic tissue-engineered scaffolds can act as an internal fixation measure to support patient mobility, provided that there is satisfactory osseointegration and good mechanical performance of the scaffold to enable effective load transfer to host bone. Porous strontium-containing bioglass scaffolds, as a composite material, leverage the therapeutic effects of both Sr2+ ions and bioactive glass [188]. In an in vivo animal study, the Sr-loading led to enhanced and more rapid osseointegration compared to bioglass alone. In particular, the fibril organization of collagen improved drastically. The fibrils assemble in parallel layers to the lamellar bone in a strontium-containing bioglass scaffold, whereas the bioglass-only scaffold resulted in randomly oriented collagen bundles and irregularly shaped lacunae [188]. Of note, bone matrix NCPs can be incorporated into bone scaffolds through direct covalent incorporation into polymeric chains that make up the polymer-based scaffold via chemical modification of the implant surface or as soluble biologics that become loaded into the porous scaffold [61]. The incorporation of or modification with NCPs not only enables better mimicking of the microenvironment of the extracellular matrix of bone but also leverages the therapeutic potential of certain NCPs.  
When these bone biomaterials become implanted into the body at the pathological or defect site, ultrastructural imaging and nanoscale analysis can be used to examine the extent of repair mediated by these biomaterials and the organization of mineralized collagen around the implant [189]. Nanometric information against treatment time can be obtained to investigate the efficiency of bone repair if samples are sourced periodically following biomaterial implantation. Nanoscale imaging and analysis can be highly informative and can even become integrated into understanding the efficacy of new gene and cell therapies, pharmaceutical drugs, and bone bio-nanomaterials for treating bone disorders.