# Personalized Bone Reconstruction and Regeneration in the Treatment of Craniosomiasis
## 2 Biomaterials and Tissue Engineering Approaches
### Bioactive Compounds and Delivery Systems
PLGA polymer is a primary candidate in regenerative medicine due to its biocompatibility, controlled structural and mechanical proprieties and tailored degradation rates, being also suitable for growth factor delivery. PLGA may be fabricated in various forms, including sheets, blocks, microspheres, and nanofibers [162; 163; 164; 165; 166; 167]. Given the long-term need for cranial suture regulation throughout the development of the skull in early childhood, PLGA microspheres offer great advantage in comparison with other release systems, due to their potential for prolonged release as well as injectable dimensions [168]. A demonstration of biological replacement of a complex anatomic structure in an in vivo model using autologous cells and drug delivery approach consisting of PLGA microspheres was reported by [PERSON] and coworkers [166]. The researchers used autologous BM-MSCs co-seeded in a collagen carrier with TGF\(\beta\)3 encapsulated within PLGA microspheres in order to generate a cranial suture engineered tissue. The construct was applied during craniectomy in the same rat that had earlier donated the bone marrow sample. The analysis demonstrated a biologically derived bone-soft tissue-bone interface compared with the ossified suture derived after the treatment without autologous BM-MSCs. This type of scaffold in CS would be advantageous for both promoting formation of skull suture tissue and inhibiting the fusion of the suture [169; 170]. Other polymers may be used to form blend materials of optimized properties, such as improved mechanical strength, and defined degradation rates, i.e., PEG-PLGA composites, PLGA-Poly(isoprene) PI, or PLGA-PCL [171]. These polymers may be also used in the absence of PLGA to produce alternative systems able to release desired bioactive compounds. An interesting study by [PERSON] and coworkers [172] employed a PEG based hydrogel containing anti-angiogenic compounds such as anti-vascular endothelial growth factor A (VEGFA)-antibody or hypoxia inducible factor 1c-inhibitor topotecan. The Authors were able to demonstrate that these compounds can be incorporated into a spontaneously polymerizing hydrogel and remain active over 14 days in both in vitro and in vivo murine models. Specifically, bone formation was delayed by inhibiting neovascularization, suggesting a possible use as a therapeutic approach to control re-synostosis following suturectomies where rapid osteogenesis is not desired [172]. A further study investigated an injectable in situ crosslinking hydrogel composed of two mutually reactive poly(ethylene glycol) macromolecules for controlled delivery of Gremlin1, an inhibitor of BMPs, in order to treat cranial defect of weanling mice. The Authors demonstrated that the hydrogel with Gremlin1 was able to delay, for up to 14 days, the rapid post-operative bone growth that occurs within the pathological suture. However, the results from the long-term study showed that this therapeutic strategy was unable to completely prevent the re-synostosis over a long period and therefore would require repeated injections or changes in the kinetic release of bioactive molecules [173]. Recently, [PERSON] and coworkers studied the effect of glypicans 3 (GPC3) released by titanium nanotubular implant (TNT/Ti) to prevent re-synostosis in a murine model of Crouzon syndrome [174]. GPC3 is an antagonist of BMP pathways with a long-termpotential in controlling post-operative suture ossification in CS patients, compared with noggin [141; 156; 175; 176]. The system delivery was fabricated with self-ordering electrochemical process and has some specific advantages, namely, outstanding structural properties (mechanical strength), excellent biocompatibility, high in vivo stability, non-toxicity, and tailorable drug loading. These properties enable controllable therapy that does not require surgical removal after implantation [177]. Furthermore, chitosan coating may be used to extend the duration of drug elution and to improve biocompatibility in orthopedic implants [129; 147].