# The Emerging Role of Cyclodextrin Metal-Organic Frameworks in Ostheotherapetics
## 4 Overview and Future Outlook  
Metal-Organic Frameworks have been gaining interest as drug delivery vehicles because of their high loading ability and the flexibility of construction to obtain biocompatible and biodegradable materials. The use of cyclodext, either as building blocks or in coatings on the particles of these materials, is a strategy developed over the last two decades that contributes to ensure better biocompatibility and to a sustained release [31; 38; 39; 44]. Delivery of active pharmaceutical ingredients for osteheotherapeutics is an emerging, niche application for MOFs. The literature herein described and summarised present several promising development routes. Coating of MIL-88B with \(\beta\)-CD afforded a material able to release alendronate for as long as four weeks [31], which opens the possibility of a monthly treatment for osteoporosis, for instance, using this system as an _in vivo_ depot. Before this or other clinical applications come to light, further studies are needed to ensure _in vivo_ safety and degradability of MIL-88B with \(\beta\)-CD. MOFs built with \(\gamma\)-CD were shown, in several studies, to be good carriers for non-steroidal anti-inflammatory drugs. With diclofenac sodium, a sustained release was observed for up to 24 h in aqueous media simulating the gastro-intestinal track. Highlight goes to the non-conventional \(\gamma\)-CD-MOF built with iron metal centres which was further shown to  
Figure 7: Histology of the left upper jaw of rats in the normal periodontium (upper line), periodontitis-induced (negative control, second line from the top), minocycline treatment group (third line), and the group treated with iodine-loaded gel (l2@\(\gamma\)-CD-gel, bottom line). Samples were stained using the H&E (hematoxylin and eosin) dye mixture. Green, blue and orange arrows represent infiltrated inflammatory cells, osteoblasts and osteoclasts, respectively. Scale bar represents 100 \(\mu\)m, 20 \(\mu\)m for 10\(\times\), 40\(\times\), respectively. Reprinted with permission from [PERSON] _et al._ [44] (Copyright 2021, Elsevier Ltd.). increase _in vivo_ effectiveness of diclofenac sodium by almost three-fold when compared with that of the pure drug on the mouse paw edema model for inflammation [38]. Given the known safety of the carrier material [18; 19], this strategy offers the possibility of reducing the dosage of NSAIDs for osteoarthritis patients without compromising the activity. This will be extremely beneficial given the gastrointestinal and haematological side effects of the high dosages typically associated with this condition. So far, the potentiating effect has only been demonstrated for mice. Thus, clinical trials on human patients are needed to confirm its applicability in our species. Successful application of \(\gamma\)-CD-MOFs in periosteal bone, _i.e._, inside the buccal cavity, was achieved by generating cross-linked derivatives that do not degrade in aqueous media. One of these gels, when loaded with the biocidal iodine, showed equivalent activity to the antibiotic drug minocycline and contributed to bone tissue regeneration [44]. These results are quite exciting as they open way for application in the repair of bone fractures. The qualitative step towards application in an internal tissue still requires further development: the material should have a nanometric particle size to ensure haematological compatibility and it should degrade slowly enough to afford a sustained release of the therapeutic agents. These can comprise, for instance, a combination of steroidal drugs, for inflammation mitigation, and bisphosphonates, for bone growth promotion. The material cannot, however, be completely non-degradable because one has to ensure that it will, over a few weeks, be reabsorbed by the organism and give way to osteoblast migration and the growth of new bone at the fracture site.