# Use of Hydrogels to Regulate Orthodontic Tooth Movement in Animal Models: A Systematic Review
## 4 Discussion
### Polymers  
Gelatin is a protein obtained by the hydrolysis of collagen from animal bones and skin and has been used for pharmaceutical and medical applications because of its biodegradability and biocompatibility in physiological environments [31]. [PERSON] et al. developed a gelatin hydrogel that was shown to be effective in prolonging the release of isedronate sodium by cross-linking as the gelatin hydrogel controlled the release and degradability by cross-linking through regulating the water content of the system [27]. The system was shown to be effective in prolonging the release of isedronate sodium when applied topically to a targeted area; furthermore, the hydrogel maintained the structure of the proteins during delivery and prevented their degradation or denaturation until they entered the intended area, a desirable property for possible use in clinical practice [24; 25]. According to [PERSON] et al., one of the desirable characteristics for extended release to take place is the drying of gelatin hydrogels because it influences the conformation of the gelatin network and interactions to result in a smoother microstructure [32]. However, despite being one of the main reasons affecting drug release in this type of hydrogel, none of the articles included in this review mention the drying process. On the other hand, [PERSON] et al. used two biocompatible hydrogels (4% _w/v_ chitosan and 10% _w/v_ gelatin); chitosan is one of the most widely used polymers in medicine. However, in the orthodontic area, this is the only report that exists regarding its use as a vehicle. They mention that, because of its sensitivity to pH and its mucoadhesive property, chitosan gels directly at physiological pH, which could favor its topical use in the oral cavity; they found no statistically significant difference between the groups of chitosan and gelatin, thus showing the importance of the active agent over the method of transport [20]. Another material used as a vehicle was a PEG derivative, which allows the hydrogel to be photo-crosslinked, providing greater mechanical stability. In particular, PEG exhibits high hydrophilicity, a bioinert structure and absence of toxic or immunogenic responses [14]. [PERSON] et al. used a thermosensitive PEG-PCL-PEG hydrogel to transport sclerostin; this hydrogel has the ability to switch from sol-gel-sol as the temperature increases [21]. According to [PERSON] et al. the sol-gel-sol transition behavior of copolymers depends on several factors, such as the hydrophilic/hydrophobic balance in the molecular structure and the composition of the hydrogel solution. They reported that in the lower-concentration hydrogels (20% vs. 30% by weight), the drug was released faster and achieved a higher cumulative release rate (98.2%) compared to the higher-concentration hydrogel (94.6%). The effect of the amount of initial drug loading on the release profile was also investigated,concluding that the effect of the amount of initial drug loading on the release profile was limited [33]. Of the eight included studies, two used hydrogels based on cellulose derivatives. [PERSON] et al. created a hydroxyethylcellulose hydrogel with RANKL, their PLGA-RANKL-HEC formulation released 14% of total RANKL at day 1 and reached 82% at day 28. The use of porous PLGA microspheres minimized the initial release of RANKL for a more stable release rate. They found that embedding the microspheres in HEC gel allowed better retention of RANKL delivery, despite a slightly higher initial RANKL release, indicating a quasi-Fickian diffusion of RANKL from their RANKL formulation [22]. For their part, [PERSON] et al., created a PTH-containing methylcellulose hydrogel, which showed a higher initial release than [PERSON] et al. In the first 12 h of incubation, about 40% of PTH was released into the MC gel and the rest was released gradually until 72 h of incubation [23].