**6. References**

268 Recent Advances in Arthroplasty

nociception stems from the finding that eating is impaired in patients with TMD (Haketa, Kino, Sugisaki, Amemori, Ishikawa, Shibuya, Sato & Yoshida, 2006) and from a clinical study of juvenile rheumatoid arthritic children (Harper, Brown, Triplett, Villasenor & Gatchel, 2000) that examined chewing performance as an objective measure of masticatory function. It showed that the juvenile rheumatoid arthritic children with TMD symptoms changed their chewing habits presumably to "guard" against pain. Most recently, meal duration in the rat was shown to be increased over the course of a week following pulp exposures demonstrating meal duration can also be used as a measure of tooth nociception

Gelatin microcapsules are one type of sustained drug release mechanism that incorporates a shell of gelatin around a core of oil containing drug. One advantage of gelatin is it has been shown to be a safe means for sustained drug delivery because in vivo there is no inflammatory response (Brown, Leong, Huang, Dalal, Green, Haimes, Jimenez & Bathon, 1998; Tuncay, Calis, Kas, Ercan, Peksoy & Hincal, 2000) consistent with our result in the TMJ of a rat that showed injection of microcapsules did not increase the nociceptive response nor increased IL-1β levels in the TMJ. Studies using a shell of gelatin encapsulating oil containing drug demonstrated that uncrosslinked gelatin was effective when given orally (Jizomoto, Kanaoka, Sugita & Hirano, 1993). A previous pharmacokinetic study injecting gelatin microspheres containing NSAID show that the intra-articular concentration of NSAID was 8-fold higher 8 hours after injection versus the concentration of NSAID in a joint injected with a non-encapsulated solution of NSAID (Lu, Zhang, Sun & Zhong, 2007). Another recent study in a rabbit model indicated that intra-articular delivery of basic fibroblast growth factor or platelets via gelatin microspheres improved knee joint swelling, proteoglycan expression, and histological appearance of arthritic knee tissue (Inoue, Takahashi, Arai, Tonomura, Sakao, Saito, Fujioka, Fujiwara, Tabata & Kubo, 2006; Saito, Takahashi, Arai, Inoue, Sakao, Tonomura, Honjo, Nakagawa, Inoue, Tabata & Kubo, 2009). Our work is consistent with these results demonstrating microcapsule drug release can ameliorate arthritic TMJ pain. Future work would focus on encapsulating alternative drugs shown to be effective in relieving TMJ pain, such as mepivacaine (Zuniga, Ibanez &

Thickness of the microcapsule wall can be varied and the timing of drug release would be based on the capsule cell wall thickness. What is important to keep in mind is that the microcapsules for this application need to be injectable and thus the diameter should not exceed the inner bore of the needle (e.g. 165 µM for a 29 gauge needle). As the wall of the bead becomes thicker the amount of loaded drug decreases thus, you inject less drug when using beads with a thicker wall diameter. Thus, a balance between the amount of time you want before drug release and the total amount of drug administered must be obtained. The diameter of the sphere is also important, with spheres greater than 26 µM remaining in the interstitial fluid of the tissue because they are not phagocytosed by cells (e.g., macrophages) (Horisawa, Kubota, Tuboi, Sato, Yamamoto, Takeuchi & Kawashima, 2002). The optimal size range for intra-articular drug delivery systems is application specific (Horisawa, Hirota, Kawazoe, Yamada, Yamamoto, Takeuchi & Kawashima, 2002; Horisawa, Kubota, Tuboi, Sato, Yamamoto, Takeuchi & Kawashima, 2002; Liggins, Cruz, Min, Liang, Hunter & Burt,

(Bellinger, He & Kramer, 2010).

Kozacko, 2007).

**5.2 Sustained drug release by gelatin is safe and effective** 

**5.3 Microcapsule size and thickness for in vivo injection** 


Cross-Linked Gelatin Microcapsules for Drug Delivery in a Arthritic TMJ 271

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**Part 3** 

**Loosening** 

