# Personalized Bone Reconstruction and Regeneration in the Treatment of Craniosomiasis
## 2 Biomaterials and Tissue Engineering Approaches
### Bioactive Compounds and Delivery Systems
\begin{table}
\begin{tabular}{c c c c c c c} \hline \hline
**Type of Polymer(s)** & **Synthesis** & **Molecular** & **Cell Types** & **Testing Model:** & **Testing Model:** & **Reference** \\
**Scaffold Assembly** & **Conventionalization** & **Implemented** & **In Vitro** & **In Vivo** & **Reference** \\ \hline PLGA & & & & ASC/ & & & \\ (PLA:PGA & Solvent casting + & & & BM-MSC/ & & \\ (PLA:PGA & 85:15) & & - & Calvarial & - & FBV mice & [105] \\  & & & osteoblasts/ & & & \\  & & & dural cells & & & \\ \hline \multirow{6}{*}{\begin{tabular}{c} GelMA + \\ Matrigel + \\ COL-I \\ (M-GM) \\ \end{tabular} } & Gelatin with & & & & & & & \\ \cline{1-1}  & methacrylamide & & & & & \\ (GelMA) side & & & & & \\ \cline{1-1}  & groups cross-linked & & & & \\ \cline{1-1}  & by radical & - & Glil + MSCs & - & _Twist1+_/ mice & [108] \\ (M-GM) & polymerization via & & & & & \\ \cline{1-1}  & phootinization & & & & & \\ \cline{1-1}  & midrigel and COL-I & & & & & \\ \hline \hline \multirow{6}{*}{\begin{tabular}{c} Bioactive glass + \\ PLGA \\ (PLA:PGA \\ 80:20) \\ \end{tabular} } & Fiber assembly scaffolds & - & - & - & \begin{tabular}{c} Transgenic \\ FGFR2C/2F8/wt \\ murine \\ \end{tabular} & & & \\ \cline{1-1}  & & & & \begin{tabular}{c} murine \\ osteoblasts; \\ osteoprogenitor \\ cells from CS \\ patients \\ \end{tabular} & - & [111] \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & \\ \hline PEG hydrogel- & CAD extrusion & - & - & \begin{tabular}{c} MC3T3E1(C4) \\ murine \\ calvarial MSCs \\ \end{tabular} & - & [114] \\ \hline \multirow{2}{*}{\begin{tabular}{c} PS-TCP scaffold \\ \end{tabular} } & Custom-built, & & & & Rabbit/ & \\ \cline{1-1}  & direct-write 3D & dipyridamole & - & - & sheep & [120; 121; 122] \\ \cline{1-1}  & & & & & calvarial defects & \\ \hline PLGA & Solvent & & & & & Sprague- \\ nanoparticle & diffusion method & DEX & - & - & \begin{tabular}{c} Sparse- \\ Dawley rats \\ \end{tabular} & [132] \\ \hline Chitin-PLGA & \
\begin{tabular}{c} Chitin \\ composite \\ hydrogel \\ \end{tabular} &
\begin{tabular}{c} regeneration \\ technique \\ \end{tabular} & CaSO\({}_{4}\) and/or & & Rat adipose & & \\ \cline{1-1}  & FGF-18 & - & derived stem (rADSCs) & & \\ \hline \hline \end{tabular}
\end{table} 
Table 4: Tissue engineering approaches for bone regeneration in calvarial defects. osteogenic differentiation of adipose tissue-derived stromal (ADS) cells in a dose-dependent and reversible manner [140]. Pitfalls may pose criticisms, as the inability of bio-compounds to be appropriately and stably delivered by scaffolds, due to short-half life, poor tissue penetration, instability/lability, and large molecular size. To overcome such limitations, the research has pushed the development of molecular \"carriers\" able to deliver and to maintain the bioactive compounds in the suture site. The efficacy of vehicles is dependent on the type of material, the biocompatibility, the non-toxicity, the biodegradability, the encapsulation, and the concentration of biomolecules incorporated within the material, along with the release kinetics [141] (see Table 5). Rapid developments in nanotechnology and controlled drug delivery have triggered exceptional growth in treating various bone diseases [142]. Most bone tissue engineering approaches rely on the implementation/functionalization of osteeconductive scaffolds with bioactive compounds, able to modify host tissue homeostasis upon grafting. Several studies have reported that the size variation of drug carriers in the nanoscale range (1-100 nm) provides various advantages for drug delivery purposes, such as enhanced transport across cell membranes, thus reducing clearance from the body and providing a selective targeted drug delivery; greater surface area-volume and subsequently more surface reactivity, thus increasing drug loading ability, providing controlled dissolution rates and drug bioavailability; and size similarity to natural tissue components, thus enabling better tissue acceptance by biomimicking tissue architecture [143; 144; 145].