# 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  
Osteoarthritis is a common age-related condition caused by wearing of the cartilage layer lining bone joints. The bone layer that lies beneath the affected cartilage usually suffers from sub-mineralisation and altered metabolism. Frequently, periosteal cells at the joint margin undergo excessive growth and cause the development of bony projections that bring pain to the patient [33; 34]. Osteoclasts, the cells responsible for the removal and recycling of mineralised bone tissue, are involved in the development of osteoarthritis, being associated with pain generation by forming microchannels that connect the subchondral marrow spaces with the cartilage tissue at the edge of the articulation. Without any bone tissue left to retain them, pro-inflammatory cytokines and algesic factors can, thus, easily migrate from the synovial fluid where they are present, going through the microchannels, reaching the subchondral nerves and triggering pain [35]. The inflammation process is known to further contribute to the progression and persistence of the disease [36]. It is, thus, important to administer anti-inflammatory drugs, typically of the non-steroidal kind (NSAIDs), not only to alleviate the symptoms of the patient but to control the cycle of inflammation and cartilage destruction. Oral intake of NSAIDs, while universally recommended by international guidelines for patients with persistent symptoms, brings some risks, namely the occurrence of gastrointestinal discomfort as an adverse effect and possible cardiovascular events, such as stroke. Moreover, these risks are now known to be dose-dependent, thus increasing with high-dose or prolonged intake of NSAIDs [37]. \(\gamma\)-CD-MOFs are interesting carrier systems for NSAIDs because of their well-known high loading capacity in combination with their controlled release properties. Entrapment of diclofenac sodium into three different kinds of \(\gamma\)-CD-MOFs, two having traditional metal centres such as Na\({}^{+}\) and K\({}^{+}\) and an innovative third one prepared from \(\gamma\)-CD and Fe\({}_{2}\)Cl\({}_{3}\), was reported [38]. Na-\(\gamma\)-CD-MOF, K-\(\gamma\)-CD-MOF and Fe-\(\gamma\)-CD-MOF all exhibited a high porosity, tallying well with previously reported values: the porous network was  
Figure 2: Representation of different aspects of the solid-state structure of the \(\gamma\)-CD-MOF with K\({}^{+}\) ions as metal centres: (**a**) one of the repeating (\(\gamma\)-CD)\({}_{6}\) units, each having a 1.7 nm diameter cavity, with \(\gamma\)-CD units depicted in the stick model and K\({}^{+}\) ions as purple spheres; (**b**) representation highlighting the porous network comprised of various large spherical cavities at the centres of the (\(\gamma\)-CD)\({}_{6}\) units, here depicted as large yellow spheres, while individual sugar units of the \(\gamma\)-CD ring are depicted by red spheres and the K\({}^{+}\) ions by blue spheres; (**c**) space-filling representation of the extended body-centred cubic packing, with each separate (\(\gamma\)-CD)\({}_{6}\) units having a different colour to highlight the body-centred cubic packing arrangement. Reproduced with permission from [PERSON] _et al._[32]. calculated to occupy 46%, 47% and 59% of the structure of Na-\(\gamma\)-CD-MOF, K-\(\gamma\)-CD-MOF and Fe-\(\gamma\)-CD-MOF, respectively. The three \(\gamma\)-CD-MOFs were subsequently used to load high quantities of diclofenac sodium, with entrapment efficacies of 49 \(\pm\) 0.109% for Na-\(\gamma\)-CD-MOF, 50 \(\pm\) 0.015% for K-\(\gamma\)-CD-MOF and 55 \(\pm\) 0.140% for Fe-\(\gamma\)-CD-MOF. All three \(\gamma\)-CD-MOFs exhibited sustained release properties for diclofenac sodium in a simulated GI tract experiment consisting of sequential immersion into three media: 2 h in 0.2 M HCl with 1.5% (\(\omega v/v\)) polysorbate 80 (to simulate gastric fluid), 4 h in PBS pH 7.4 (to simulate intestinal fluid) and 18 h in PBS with pH 6.8 (to simulate colonic fluid).