TY - JOUR
T1 - Freeze-dried tendon allografts as tissue-engineering scaffolds for Gdf5 gene delivery
AU - Basile, Patrick
AU - Dadali, Tulin
AU - Jacobson, Justin
AU - Hasslund, Sys
AU - Ulrich-Vinther, Michael
AU - Søballe, Kjeld
AU - Nishio, Yasuhiko
AU - Drissi, M. Hicham
AU - Langstein, Howard N.
AU - Mitten, David J.
AU - O'Keefe, Regis J.
AU - Schwarz, Edward M.
AU - Awad, Hani A.
N1 - Funding Information:
P.B. and T.D. share first authorship as they contributed equally to the work. The authors thank Brendan Boyce for valuable advice and stimulating discussions, Denise Hocking for advice on the in vitro microwound assay, Gwynne Bragdon for advice on surgeries, Krista Scorsone for technical assistance with histology, David Reynolds for technical assistance with biomechanical testing, and Tony Chen for help with data analysis (all from the University of Rochester Medical Center). This work was supported in part by research grants from the National Institutes of Health (PHS AR054041, AR051469, DE017096), Whitaker Foundation, the Danish Medical Research Council, the Musculoskeletal Transplant Foundation, the Orthopaedic Research Education Foundation (OREF), and DePuy J&J.
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=39849105677&partnerID=8YFLogxK
U2 - 10.1038/sj.mt.6300395
DO - 10.1038/sj.mt.6300395
M3 - Article
C2 - 18180771
AN - SCOPUS:39849105677
SN - 1525-0016
VL - 16
SP - 466
EP - 473
JO - Molecular Therapy
JF - Molecular Therapy
IS - 3
ER -