# Personalized Bone Reconstruction and Regeneration in the Treatment of Craniosomiasis
## 2 Biomaterials and Tissue Engineering Approaches
### Bioactive Compounds and Delivery Systems
Moreover, the inherent properties of nanoscale materials (such as physical, chemical, mechanical, electrical, magnetic, and optical properties) can be utilized to improve the performance of the delivery systems [147; 148; 149]. For example, electrical properties of surfaces interact with drugs or biological systems to promote an even greater impact on drug biological activity, drug release kinetics, conjugation to targeting moieties, and transport in bone. For instance, cationic nanoparticles can localize in the cytoplasm and within mitochondria, while anionic nanoparticles remain in lysosomes [150]. These novel drug delivery systems involve different types of materials from 1D to 3D: polymers, metals, ceramics, semiconductors, and sol-gel with different geometries including particles, fibres, capsules, tubes, whiskers, and dendrimers [146]. Some of these delivery systems have been exploited for the confined administration of therapeutics in in vitro and in vivo models of CS. Collagen has been used in the form of films, hydrogels, pellets, shields, and sponges, for the delivery of specific inhibitors of the aberrant pathways involved in the molecular pathogenesis of CS [151; 152]. The collagen gel is an attractive vehicle because it can be easily inserted into a variety of spaces, it is extremely malleable, and can be introduced in a minimally invasive manner, though the release kinetics is variable, and often transient (i.e., lasting only a few weeks) [141]. The Bone Morphogenic Protein (BMP) signalling pathway represents a suitable target for the selected delivery of specific drugs able to interfere with the osteogenic program, being involved in the differentiation, both in syndromic and nonsyndromic CS [38; 153]. BMPs are members of the transforming growth factor beta (TGF\(\beta\)) super-family and are potent ostee-inductors [154]. Different studies have tested the role of BMP antagonists, namely, noggin, glypicans, or gremlin, for developing adjuvant treatments in CS management [138; 155; 156; 153]. Specifically, noggin loaded in a collagen-vehicle [155] or on a gel-foam scaffold with GFP-expressing cells [138] was administered topically at the site of suturectomy. This clearly reduced the re-ossification rate within pathological sutures in treated animals compared with untreated controls, demonstrating that the inhibition of post-operative re-synostosis was possible using biologically based therapies [138; 155]. More recently, [PERSON] and colleagues used a plasmid encoding TGF\(\beta\)3 delivered by a dense collagen-gel scaffold injected at suture sites in rats, to prevent programmed suture fusion in calvarial organotypic culture. The treatment enabled a 70% to 80% folds decrease of suture ossification compared with collagen controls, depending on suture sites [157]. Collagen sponges were used in an in vivo experiment of [PERSON] and [PERSON] [158]. The researchers supposed that skull suture can be engineered from autologous cells. In particular, the Authors suggested that re-synostosis in CS patients occurred lacking mesenchymal and fibrous interface between the gap created after craniectomy. They fabricated a composite tissue construct made by fibroblasts isolated from rabbits seeded in an absorbable gelatin-scaffold between two collagen sponges loaded with recombinant human BMP2 (rhBMP2). Surgically created full-thickness parietal defects were filled with the composite tissue implant in the same rabbits from which fibroblasts had been obtained. After four weeks of in vivo implantation, the treated cranial suture was still patent [158]. However, the biological introduction of rhBMP2 needs further studies due to the risks of developing premature suture fusion, osteolysis and malignant degeneration [159]. Nonetheless, some studies have shown that a few types of collagen-based vehicles are able to promote osteogenesis in rat cranial defects, making them unsuitable for bone inhibiting applications [160; 161; 141].