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Article
A Novel Bi-Directional and Bi-Temporal Delivery System for Enhancing Intrasynovial Tendon Repair
Yidan Chen 1,, Seth Kinoshita 2,, Emily Yan 3, Min Hao 3,, Hua Shen 4,, Richard Gelberman 4,, Stavros Thomopoulos 5,, and Younan Xia 2,3,*,
1 School of Materials Science and Engineering, Georgia Institute of Technology, Atlanta, GA 30332, USA
2 School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA
3 The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA
4 Department of Orthopedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA
5 Department of Orthopedic Surgery, Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
* Correspondence: younan.xia@bme.gatech.edu
Received: 24 September 2024; Revised: 8 October 2024; Accepted: 14 October 2024; Published: 18 October 2024
Abstract: Flexor tendon injuries are common and often require surgical repair and prolonged rehabilitation. Successful clinical outcomes depend on the concurrent suppression of adhesions (caused by inflammation) at the tendon surface and promotion of matrix synthesis inside the tendon. Herein, we report a bi-directional and bi-temporal drug delivery system designed to target both the initial inflammatory phase and the subsequent proliferative and remodeling phases of healing to improve outcomes after flexor tendon repair. The system features a multi-layered design with anti-adhesion and pro-matrix factors encapsulated in separate layers of hyaluronate films crosslinked to different degrees to control their direction and rate of release. After validating drug delivery under controlled release, cell culture experiments involving tendon fibroblasts and a Transwell system are conducted to demonstrate the system’s efficacy in modulating local cellular responses. The promising results from this study lay the groundwork for moving this system toward in vivo testing and clinical translation.
Keywords:
flexor tendon repair sodium hyaluronate drug delivery controlled release Transwell cell cultureReferences
- Griffin, M.; Hindocha, S.; Jordan, D.; Saleh, M.; Khan, W. An Overview of the Management of Flexor Tendon Injuries. Open J. Orthop. 2012, 6, 28–35. https://doi.org/10.2174/1874325001206010028.
- Thomopoulos, S.; Das, R.; Silva, M.J.; Sakiyama-Elbert, S.; Harwood, F.L.; Zampiakis, E.; Kim, H.M.; Amiel, D.; Gelberman, R.H. Enhanced Flexor Tendon Healing through Controlled Delivery of PDGF-BB. J. Orthop. Res. 2009, 27, 1209–1215. https://doi.org/10.1002/jor.20875.
- Shen, H.; Gelberman, R.H.; Silva, M.J.; Sakiyama-Elbert, S.E.; Thomopoulos, S. BMP12 Induces Tenogenic Differentiation of Adipose-Derived Stromal Cells. PLoS ONE 2013, 8, e77613. https://doi.org/10.1371/journal.pone.0077613.
- Hayashi, M.; Zhao, C.; Thoreson, A.R.; Chikenji, T.; Jay, G.D.; An, K.-N.; Amadio, P.C. The Effect of Lubricin on the Gliding Resistance of Mouse Intrasynovial Tendon. PLoS ONE 2013, 8, e83836. https://doi.org/10.1371/journal.pone.0083836.
- Zhao, C.; Ozasa, Y.; Reisdorf, R.L.; Thoreson, A.R.; Jay, G.D.; An, K.-N.; Amadio, P.C. Engineering Flexor Tendon Repair with Lubricant, Cells, and Cytokines in a Canine Model. Clin. Orthop. Relat. Res. 2014, 472, 2569–2578. https://doi.org/10.1007/s11999-014-3690-y.
- Abate, M.; Pulcini, D.; Di Iorio, A.; Schiavone, C. Viscosupplementation with Intra-Articular Hyaluronic Acid for Treatment of Osteoarthritis in the Elderly. Curr. Pharm. Des. 2010, 16, 631–640. https://doi.org/10.2174/138161210790883859.
- Zhao, C.; Sun, Y.-L.; Amadio, P.C.; Tanaka, T.; Ettema, A.M.; An, K.-N. Surface Treatment of Flexor Tendon Autografts with Carbodiimide-Derivatized Hyaluronic Acid. An in Vivo Canine Model. J. Bone Jt. Surg. 2006, 88, 2181–2191. https://doi.org/10.2106/JBJS.E.00871.
- Liu, Y.; Skardal, A.; Shu, X.Z.; Prestwich, G.D. Prevention of Peritendinous Adhesions Using a Hyaluronan-Derived Hydrogel Film Following Partial Thickness Flexor Tendon Injury. J. Orthop. Res 2008, 26, 562–569. https://doi.org/10.1002/jor.20499.
- Taguchi, M.; Zhao, C.; Sun, Y.-L.; Jay, G.D.; An, K.-N.; Amadio, P.C. The Effect of Surface Treatment Using Hyaluronic Acid and Lubricin on the Gliding Resistance of Human Extrasynovial Tendons In vitro. J. Hand Surg. 2009, 34, 1276–1281. https://doi.org/10.1016/j.jhsa.2009.04.011.
- Felson, D.T.; Anderson, J.J. Hyaluronate Sodium Injections for Osteoarthritis: Hope, Hype, and Hard Truths. Arch. Intern. Med. 2002, 162, 245–247. https://doi.org/10.1001/archinte.162.3.245.
- Chen, Q.; Zhu, C.; Huo, D.; Xue, J.; Cheng, H.; Guan, B.; Xia, Y. Continuous Processing of Phase-Change Materials into Uniform Nanoparticles for Near-Infrared-Triggered Drug Release. Nanoscale 2018, 10, 22312–22318. https://doi.org/10.1039/c8nr07027j.
- Vartanian, A.J.; Frankel, A.S.; Rubin, M.G. Injected Hyaluronidase Reduces Restylane-Mediated Cutaneous Augmentation. JAMA Facial Plast. Surg. 2005, 7, 231–237. https://doi.org/10.1001/archfaci.7.4.231.
- Ryu, C.; Lu, J.E.; Zhang-Nunes, S. Response of Twelve Different Hyaluronic Acid Gels to Varying Doses of Recombinant Human Hyaluronidase. J. Plast. Reconstr. Aesthet. Surg. 2021, 74, 881–889. https://doi.org/10.1016/j.bjps.2020.10.051.
- Golman, M.; Li, X.; Skouteris, D.; Abraham, A.A.; Song, L.; Abu-Amer, Y.; Thomopoulos, S. Enhanced Tendon-to-Bone Healing via IKKβ Inhibition in a Rat Rotator Cuff Model. Am. J. Sports Med. 2021, 49, 780–789. https://doi.org/10.1177/0363546520985203.
- Hu, M.; Sabelman, E.E.; Tsai, C.; Tan, J.; Hentz, V.R. Improvement of Schwann Cell Attachment and Proliferation on Modified Hyaluronic Acid Strands by Polylysine. Tissue Eng. 2000, 6, 585–593. https://doi.org/10.1089/10763270050199532.
- Zhao, X. Synthesis and Characterization of a Novel Hyaluronic Acid Hydrogel. J. Biomater. Sci. Polym. Ed. 2006, 17, 419–433. https://doi.org/10.1163/156856206776374115.
- Tomihata, K.; Ikada, Y. Crosslinking of Hyaluronic Acid with Water-Soluble Carbodiimide. J. Biomed. Mater. Res. 1997, 37, 243–251. https://doi.org/10.1002/(sici)1097-4636(199711)37:2<243::aid-jbm14>3.0.co;2-f.
- Lu, P.-L.; Lai, J.-Y.; Ma, D.H.-K.; Hsiue, G.-H. Carbodiimide Cross-Linked Hyaluronic Acid Hydrogels as Cell Sheet Delivery Vehicles: Characterization and Interaction with Corneal Endothelial Cells. J. Biomater. Sci. Polym. Ed. 2008, 19, 1–18. https://doi.org/10.1163/156856208783227695.
- van der Vusse, G.J. Albumin as Fatty Acid Transporter. Drug Metab. Pharmacokinet. 2009, 24, 300–307. https://doi.org/10.2133/dmpk.24.300.
- Manning, C.N.; Havlioglu, N.; Knutsen, E.; Sakiyama-Elbert, S.E.; Silva, M.J.; Thomopoulos, S.; Gelberman, R.H. The Early Inflammatory Response after Flexor Tendon Healing: A Gene Expression and Histological Analysis. J. Orthop. Res. 2014, 32, 645–652. https://doi.org/10.1002/jor.22575.
- Ajuebor, M.N.; Flower, R.J.; Hannon, R.; Christie, M.; Bowers, K.; Verity, A.; Perretti, M. Endogenous Monocyte Chemoattractant Protein-1 Recruits Monocytes in the Zymosan Peritonitis Model. J. Leukocyte Biol. 1998, 63, 108–116. https://doi.org/10.1002/jlb.63.1.108.
- Fingleton, B. Matrix Metalloproteinases as Regulators of Inflammatory Processes. Biochim. Biophys. Acta Mol. Cell Res. 2017, 1864, 2036–2042. https://doi.org/10.1016/j.bbamcr.2017.05.010.
- Gelberman, R.H.; Lane, R.A.; Sakiyama-Elbert, S.E.; Thomopoulos, S.; Shen, H. Metabolic Regulation of Intrasynovial Flexor Tendon Repair: The Effects of Dichloroacetate Administration on Early Tendon Healing in a Canine Model. J. Orthop. Res. 2023, 41, 278–289. https://doi.org/10.1002/jor.25354.