Basile Patrick, Dadali Tulin, Jacobson Justin, Hasslund Sys, Ulrich-Vinther Michael, Søballe Kjeld, Nishio Yasuhiko, Drissi M Hicham, Langstein Howard N, Mitten David J, O'Keefe Regis J, Schwarz Edward M, Awad Hani A
Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, New York 14642, USA.
Mol Ther. 2008 Mar;16(3):466-73. doi: 10.1038/sj.mt.6300395. Epub 2008 Jan 8.
Tendon reconstruction using grafts often results in adhesions that limit joint flexion. These adhesions are precipitated by inflammation, fibrosis, and the paucity of tendon differentiation signals during healing. In order to study this problem, we developed a mouse model in which the flexor digitorum longus (FDL) tendon is reconstructed using a live autograft or a freeze-dried allograft, and identified growth and differentiation factor 5 (Gdf5) as a therapeutic target. In this study we have investigated the potential of rAAV-Gdf5 -loaded freeze-dried tendon allografts as "therapeutically endowed" tissue-engineering scaffolds to reduce adhesions. In reporter gene studies we have demonstrated that recombinant adeno-associated virus (rAAV)-loaded tendon allografts mediate efficient transduction of adjacent soft tissues, with expression peaking at 7 days. We have also demonstrated that the rAAV-Gdf5 vector significantly accelerates wound healing in an in vitro fibroblast scratch model and, when loaded onto freeze-dried FDL tendon allografts, improves the metatarsophalangeal (MTP) joint flexion to a significantly greater extent than the rAAV-lacZ controls do. Collectively, our data demonstrate the feasibility and efficacy of therapeutic tendon allograft processing as a novel paradigm in tissue engineering in order to address difficult clinical problems such as tendon adhesions.
使用移植物进行肌腱重建常常会导致粘连，从而限制关节的屈曲。这些粘连是由炎症、纤维化以及愈合过程中肌腱分化信号的缺乏所引发的。为了研究这个问题，我们构建了一种小鼠模型，其中使用活自体移植物或冻干同种异体移植物重建趾长屈肌（FDL）肌腱，并确定生长和分化因子5（Gdf5）作为治疗靶点。在本研究中，我们研究了负载rAAV-Gdf5的冻干肌腱同种异体移植物作为“具有治疗功能的”组织工程支架以减少粘连的潜力。在报告基因研究中，我们证明负载重组腺相关病毒（rAAV）的肌腱同种异体移植物可介导对相邻软组织的有效转导，表达在7天时达到峰值。我们还证明，rAAV-Gdf-5载体在体外成纤维细胞划痕模型中可显著加速伤口愈合，并且当负载到冻干的FDL肌腱同种异体移植物上时，与rAAV- lacZ对照相比，能在更大程度上改善跖趾（MTP）关节的屈曲。总体而言，我们的数据证明了治疗性肌腱同种异体移植物处理作为组织工程中的一种新范例，用于解决诸如肌腱粘连等棘手临床问题的可行性和有效性。
