# The Emerging Role of Cyclodextrin Metal-Organic Frameworks in Ostheotherapetics
## 3 Cyclodextrin-Based MOFs
### \(\gamma\)-CD-MOFs Loaded with Anti-Inflammatory Agents for the Management of Osteoarthritis
#### 3.2.2 Application to Periosteum Bone  
A recent work on the application of \(\gamma\)-CD-MOF-derived gel particles employed diphenyl carbonate as the crosslinking agent. This linker formed short-chained carbonate bridges between the units of \(\gamma\)-CD (Figure 6). Note that, to speed up the reaction process, triethylamine (TEA) was added as a catalyst, allowing the crosslinking reaction to be achieved in as little as 4 h [43]. While expected to have a lower ability of swelling because of the tight linking units, this process is advantageous because the preparation time of the gel is greatly reduced (from the three days reported by [PERSON] _et al._[41] to a few hours).  
Figure 5: Overview of the preparation steps for the K\({}^{+}\)-\(\gamma\)-CD-MOF and its derived cubic-shaped gel: (**i**) the MOF is prepared from K\({}^{+}\) and \(\gamma\)-CD by crystallisation; (**ii**) \(\gamma\)-CD-MOF crystals are treated with the cross-linking agent (L); (**iii**) K\({}^{+}\) ions are removed to obtain the gel particles, which retain the cubic shape as demonstrated by its SEM image (right). Reprinted with permission from [PERSON] _et al._[41].  
The cross-linked cubic gel was loaded with iodine by immersion into a solution of KI\({}_{3}\) for 2 h, affording a load of _c.a._ 30% (_w/w_). The particles of the gel were observed by SEM to show that, as expected, they did not significantly increase in size with the loading process, remaining within 5-20 \(\upmu\)m and having an average size of 11.8 \(\upmu\)m. Envisioning application of the gel as a carrier for local delivery in the buccal cavity, its release properties were studied _in vitro_ using artificial saliva. Results showed that roughly half of the load in iodine was released in the first 12 h of immersion, followed by a period with practically no further iodine release. The therapeutic effect _in vivo_ was evaluated in rats using a periodontitis model, comparing the iodine-loaded gel with a model drug, minocycline. Both the gel and minocycline were administered every three days for a total period of four weeks, and both showed similar results in the symptomatic relief of periodontitis. Histological examination of the periodontium confirmed these results: in contrast with non-treated rats, which exhibited a large number of infiltrating inflammatory cells and osteolytic osteoclast cells into the bone tissue, the tissue of rats treated with iodine-loaded gel or with a minocycline ointment revealed a low number of infiltrated inflammatory cells, meaning that both treatments were able to reduce tissue inflammation. In addition, the connective tissue arrangement was returned to normal, with lack of osteoclasts in the periosteum and osteoblasts being observed instead (Figure 7). These histological changes signified that following the four-week treatment with minocycline or with iodine-loaded gel the morphology of periodontal gingival tissue was restored to that which is typically observed in the healthy rat [44].  
Figure 6: Reaction conditions and structural representation of the formation of a cross-linked cubic gel starting from \(\upgamma\)-CD-MOF, depicted for one of its (\(\upgamma\)-CD)\({}_{6}\) cubic units and highlighting the kind of chemical links formed. Reproduced from [PERSON] _et al._[43] under a Creative Commons Attribution 3.0 Unported Licence (2017).