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Published in: Clinical Orthopaedics and Related Research® 9/2014

01-09-2014 | CORR ORS Richard A. Brand Award for Outstanding Orthopaedic Research

CORR® ORS Richard A. Brand Award for Outstanding Orthopaedic Research: Engineering Flexor Tendon Repair With Lubricant, Cells, and Cytokines in a Canine Model

Authors: Chunfeng Zhao, MD, Yasuhiro Ozasa, MD, PhD, Ramona L. Reisdorf, BS, Andrew R. Thoreson, MS, Gregory D. Jay, MD, PhD, Kai-Nan An, PhD, Peter C. Amadio, MD

Published in: Clinical Orthopaedics and Related Research® | Issue 9/2014

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Abstract

Background

Adhesions and poor healing are complications of flexor tendon repair.

Questions/purposes

The purpose of this study was to investigate a tissue engineering approach to improve functional outcomes after flexor tendon repair in a canine model.

Methods

Flexor digitorum profundus tendons were lacerated and repaired in 60 dogs that were followed for 10, 21, or 42 days. One randomly selected repair from either the second or fifth digit in one paw in each dog was treated with carbodiimide-derivatized hyaluronic acid, gelatin, and lubricin plus autologous bone marrow stromal cells stimulated with growth and differentiation factor 5; control repair tendons were not treated. Digits were analyzed by adhesion score, work of flexion, tendon-pulley friction, failure force, and histology.

Results

In the control group, 35 of 52 control tendons had adhesions, whereas 19 of 49 treated tendons had adhesions. The number of repaired tendons with adhesions in the control group was greater than the number in the treated group at all three times (p = 0.005). The normalized work of flexion in treated tendons was 0.28 (± 0.08), 0.29 (± 0.19), and 0.32 (± 0.22) N/mm/° at Day 10, Day 21, and Day 42 respectively, compared with the untreated tendons of 0.46 (± 0.19) at Day 10 (effect size, 1.5; p = 0.01), 0.77 (± 0.49) at Day 21 (effect size, 1.4; p < 0.001), and 1.17 (± 0.82) N/mm/° at Day 42 (effect size, 1.6; p < 0.001). The friction data were comparable to the work of flexion data at all times. The repaired tendon failure force in the untreated group at 42 days was 70.2 N (± 8.77), which was greater than the treated tendons 44.7 N (± 8.53) (effect size, 1.9; p < 0.001). Histologically, treated repairs had a smooth surface with intrinsic healing, whereas control repairs had surface adhesions and extrinsic healing.

Conclusions

Our study provides evidence that tissue engineering coupled with restoration of tendon gliding can improve the quality of tendon healing in a large animal in vivo model.

Clinical Relevance

Tissue engineering may enhance intrinsic tendon healing and thus improve the functional outcomes of flexor tendon repair.
Literature
1.
go back to reference Chai W, Ni M, Rui YF, Zhang KY, Zhang Q, Xu LL, Chan KM, Li G, Wang Y. Effect of growth and differentiation factor 6 on the tenogenic differentiation of bone marrow-derived mesenchymal stem cells. Chin Med J (Engl). 2013;126:1509–1516.PubMed Chai W, Ni M, Rui YF, Zhang KY, Zhang Q, Xu LL, Chan KM, Li G, Wang Y. Effect of growth and differentiation factor 6 on the tenogenic differentiation of bone marrow-derived mesenchymal stem cells. Chin Med J (Engl). 2013;126:1509–1516.PubMed
2.
go back to reference Clayton RA, Court-Brown CM. The epidemiology of musculoskeletal tendinous and ligamentous injuries. Injury. 2008;39:1338–1344.PubMedCrossRef Clayton RA, Court-Brown CM. The epidemiology of musculoskeletal tendinous and ligamentous injuries. Injury. 2008;39:1338–1344.PubMedCrossRef
3.
go back to reference Crovace A, Lacitignola L, Rossi G, Francioso E. Histological and immunohistochemical evaluation of autologous cultured bone marrow mesenchymal stem cells and bone marrow mononucleated cells in collagenase-induced tendinitis of equine superficial digital flexor tendon. Vet Med Int. 2010;2010:250978.PubMedCentralPubMedCrossRef Crovace A, Lacitignola L, Rossi G, Francioso E. Histological and immunohistochemical evaluation of autologous cultured bone marrow mesenchymal stem cells and bone marrow mononucleated cells in collagenase-induced tendinitis of equine superficial digital flexor tendon. Vet Med Int. 2010;2010:250978.PubMedCentralPubMedCrossRef
4.
go back to reference Filomeno P, Dayan V, Tourino C. Stem cell research and clinical development in tendon repair. Muscles Ligaments Tendons J. 2012;2:204–211.PubMedCentralPubMed Filomeno P, Dayan V, Tourino C. Stem cell research and clinical development in tendon repair. Muscles Ligaments Tendons J. 2012;2:204–211.PubMedCentralPubMed
5.
go back to reference Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44:25–32.PubMedCrossRef Godwin EE, Young NJ, Dudhia J, Beamish IC, Smith RK. Implantation of bone marrow-derived mesenchymal stem cells demonstrates improved outcome in horses with overstrain injury of the superficial digital flexor tendon. Equine Vet J. 2012;44:25–32.PubMedCrossRef
6.
go back to reference Hayashi M, Zhao C, AN K, Amadio P. The effects of growth and differentiation factor 5 on bone marrow stromal cell transplants in an in vitro tendon healing model. J Hand Surg Eur Vol. 2011;36:271–279.PubMedCentralPubMedCrossRef Hayashi M, Zhao C, AN K, Amadio P. The effects of growth and differentiation factor 5 on bone marrow stromal cell transplants in an in vitro tendon healing model. J Hand Surg Eur Vol. 2011;36:271–279.PubMedCentralPubMedCrossRef
7.
go back to reference James R, Kumbar SG, Laurencin CT, Balian G, Chhabra AB. Tendon tissue engineering: adipose-derived stem cell and GDF-5 mediated regeneration using electrospun matrix systems. Biomed Mater. 2011;6:025011.PubMedCentralPubMedCrossRef James R, Kumbar SG, Laurencin CT, Balian G, Chhabra AB. Tendon tissue engineering: adipose-derived stem cell and GDF-5 mediated regeneration using electrospun matrix systems. Biomed Mater. 2011;6:025011.PubMedCentralPubMedCrossRef
8.
go back to reference Manning CN, Schwartz AG, Liu W, Xie J, Havlioglu N, Sakiyama-Elbert SE, Silva MJ, Xia Y, Gelberman RH, Thomopoulos S. Controlled delivery of mesenchymal stem cells and growth factors using a nanofiber scaffold for tendon repair. Acta Biomater. 2013;9:6905–6914.PubMedCentralPubMedCrossRef Manning CN, Schwartz AG, Liu W, Xie J, Havlioglu N, Sakiyama-Elbert SE, Silva MJ, Xia Y, Gelberman RH, Thomopoulos S. Controlled delivery of mesenchymal stem cells and growth factors using a nanofiber scaffold for tendon repair. Acta Biomater. 2013;9:6905–6914.PubMedCentralPubMedCrossRef
9.
go back to reference Manske PR, Gelberman RH, Lesker PA. Flexor tendon healing. Hand Clin. 1985;1:25–34.PubMed Manske PR, Gelberman RH, Lesker PA. Flexor tendon healing. Hand Clin. 1985;1:25–34.PubMed
10.
go back to reference Martinello T, Bronzini I, Perazzi A, Testoni S, De Benedictis GM, Negro A, Caporale G, Mascarello F, Iacopetti I, Patruno M. Effects of in vivo applications of peripheral blood-derived mesenchymal stromal cells (PB-MSCs) and platlet-rich plasma (PRP) on experimentally injured deep digital flexor tendons of sheep. J Orthop Res. 2013;31:306–314.PubMedCrossRef Martinello T, Bronzini I, Perazzi A, Testoni S, De Benedictis GM, Negro A, Caporale G, Mascarello F, Iacopetti I, Patruno M. Effects of in vivo applications of peripheral blood-derived mesenchymal stromal cells (PB-MSCs) and platlet-rich plasma (PRP) on experimentally injured deep digital flexor tendons of sheep. J Orthop Res. 2013;31:306–314.PubMedCrossRef
11.
go back to reference May EJ, Silfverskiold KL. Rate of recovery after flexor tendon repair in zone II: a prospective longitudinal study of 145 digits. Scand J Plast Reconstr Surg Hand Surg. 1993;27:89–94.PubMedCrossRef May EJ, Silfverskiold KL. Rate of recovery after flexor tendon repair in zone II: a prospective longitudinal study of 145 digits. Scand J Plast Reconstr Surg Hand Surg. 1993;27:89–94.PubMedCrossRef
12.
go back to reference Moran SL, Ryan CK, Orlando GS, Pratt CE, Michalko KB. Effects of 5-fluorouracil on flexor tendon repair. J Hand Surg Am. 2000;25:242–251.PubMedCrossRef Moran SL, Ryan CK, Orlando GS, Pratt CE, Michalko KB. Effects of 5-fluorouracil on flexor tendon repair. J Hand Surg Am. 2000;25:242–251.PubMedCrossRef
13.
go back to reference Morizaki Y, Zhao C, An KN, Amadio PC. The effects of platelet-rich plasma on bone marrow stromal cell transplants for tendon healing in vitro. J Hand Surg Am. 2010;35:1833–1841.PubMedCentralPubMedCrossRef Morizaki Y, Zhao C, An KN, Amadio PC. The effects of platelet-rich plasma on bone marrow stromal cell transplants for tendon healing in vitro. J Hand Surg Am. 2010;35:1833–1841.PubMedCentralPubMedCrossRef
14.
go back to reference Moro-oka T, Miura H, Mawatari T, Kawano T, Nakanishi Y, Higaki H, Iwamoto Y. Mixture of hyaluronic acid and phospholipid prevents adhesion formation on the injured flexor tendon in rabbits. J Orthop Res. 2000;18:835–840.PubMedCrossRef Moro-oka T, Miura H, Mawatari T, Kawano T, Nakanishi Y, Higaki H, Iwamoto Y. Mixture of hyaluronic acid and phospholipid prevents adhesion formation on the injured flexor tendon in rabbits. J Orthop Res. 2000;18:835–840.PubMedCrossRef
15.
go back to reference Muttini A, Salini V, Valbonetti L, Abate M. Stem cell therapy of tendinopathies: suggestions from veterinary medicine. Muscles Ligaments Tendons J. 2012;2:187–192.PubMedCentralPubMed Muttini A, Salini V, Valbonetti L, Abate M. Stem cell therapy of tendinopathies: suggestions from veterinary medicine. Muscles Ligaments Tendons J. 2012;2:187–192.PubMedCentralPubMed
16.
go back to reference Nagy K, Sung HK, Zhang P, Laflamme S, Vincent P, Agha-Mohammadi S, Woltjen K, Monetti C, Michael IP, Smith LC, Nagy A. Induced pluripotent stem cell lines derived from equine fibroblasts. Stem Cell Rev. 2011;7:693–702.PubMedCentralPubMedCrossRef Nagy K, Sung HK, Zhang P, Laflamme S, Vincent P, Agha-Mohammadi S, Woltjen K, Monetti C, Michael IP, Smith LC, Nagy A. Induced pluripotent stem cell lines derived from equine fibroblasts. Stem Cell Rev. 2011;7:693–702.PubMedCentralPubMedCrossRef
17.
go back to reference Omae H, Sun YL, An KN, Amadio PC, Zhao C. Engineered tendon with decellularized xenotendon slices and bone marrow stromal cells: an in vivo animal study. J Tissue Eng Regen Med. 2012;6:238–244.PubMedCentralPubMedCrossRef Omae H, Sun YL, An KN, Amadio PC, Zhao C. Engineered tendon with decellularized xenotendon slices and bone marrow stromal cells: an in vivo animal study. J Tissue Eng Regen Med. 2012;6:238–244.PubMedCentralPubMedCrossRef
18.
go back to reference Omae H, Zhao C, Sun YL, Zobitz ME, Moran SL, Amadio PC. The effect of tissue culture on suture holding strength and degradation in canine tendon. J Hand Surg Eur Vol. 2009;34:643–650.PubMedCentralPubMedCrossRef Omae H, Zhao C, Sun YL, Zobitz ME, Moran SL, Amadio PC. The effect of tissue culture on suture holding strength and degradation in canine tendon. J Hand Surg Eur Vol. 2009;34:643–650.PubMedCentralPubMedCrossRef
19.
go back to reference Pacini S, Spinabella S, Trombi L, Fazzi R, Galimberti S, Dini F, Carlucci F, Petrini M. Suspension of bone marrow-derived undifferentiated mesenchymal stromal cells for repair of superficial digital flexor tendon in race horses. Tissue Eng. 2007;13:2949–2955.PubMedCrossRef Pacini S, Spinabella S, Trombi L, Fazzi R, Galimberti S, Dini F, Carlucci F, Petrini M. Suspension of bone marrow-derived undifferentiated mesenchymal stromal cells for repair of superficial digital flexor tendon in race horses. Tissue Eng. 2007;13:2949–2955.PubMedCrossRef
20.
go back to reference Rosberg HE, Carlsson KS, Hojgard S, Lindgren B, Lundborg G, Dahlin LB. What determines the costs of repair and rehabilitation of flexor tendon injuries in zone II? A multiple regression analysis of data from southern Sweden. J Hand Surg Eur Vol. 2003;28:106–112.CrossRef Rosberg HE, Carlsson KS, Hojgard S, Lindgren B, Lundborg G, Dahlin LB. What determines the costs of repair and rehabilitation of flexor tendon injuries in zone II? A multiple regression analysis of data from southern Sweden. J Hand Surg Eur Vol. 2003;28:106–112.CrossRef
21.
go back to reference Schneider LH, Hunter JM, Norris TR, Nadeau PO. Delayed flexor tendon repair in no man’s land. J Hand Surg Am. 1977;2:452–455.PubMedCrossRef Schneider LH, Hunter JM, Norris TR, Nadeau PO. Delayed flexor tendon repair in no man’s land. J Hand Surg Am. 1977;2:452–455.PubMedCrossRef
22.
go back to reference Smith RK. Mesenchymal stem cell therapy for equine tendinopathy. Disabil Rehabil. 2008;30:1752–1758.PubMedCrossRef Smith RK. Mesenchymal stem cell therapy for equine tendinopathy. Disabil Rehabil. 2008;30:1752–1758.PubMedCrossRef
23.
go back to reference Smith RK, Korda M, Blunn GW, Goodship AE. Isolation and implantation of autologous equine mesenchymal stem cells from bone marrow into the superficial digital flexor tendon as a potential novel treatment. Equine Vet J. 2003;35:99–102.PubMedCrossRef Smith RK, Korda M, Blunn GW, Goodship AE. Isolation and implantation of autologous equine mesenchymal stem cells from bone marrow into the superficial digital flexor tendon as a potential novel treatment. Equine Vet J. 2003;35:99–102.PubMedCrossRef
24.
go back to reference Strickland JW. Development of flexor tendon surgery: twenty-five years of progress. J Hand Surg Am. 2000;25:214–235.PubMedCrossRef Strickland JW. Development of flexor tendon surgery: twenty-five years of progress. J Hand Surg Am. 2000;25:214–235.PubMedCrossRef
25.
go back to reference Sun YL, Thoreson AR, Cha SS, Zhao C, An KN, Amadio PC. Temporal response of canine flexor tendon to limb suspension. J Appl Physiol. 2010;109:1762–1768.PubMedCentralPubMedCrossRef Sun YL, Thoreson AR, Cha SS, Zhao C, An KN, Amadio PC. Temporal response of canine flexor tendon to limb suspension. J Appl Physiol. 2010;109:1762–1768.PubMedCentralPubMedCrossRef
26.
go back to reference Sun YL, Yang C, Amadio PC, Zhao C, Zobitz ME, An KN. Reducing friction by chemically modifying the surface of extrasynovial tendon grafts. J Orthop Res. 2004;22:984–989.PubMedCrossRef Sun YL, Yang C, Amadio PC, Zhao C, Zobitz ME, An KN. Reducing friction by chemically modifying the surface of extrasynovial tendon grafts. J Orthop Res. 2004;22:984–989.PubMedCrossRef
27.
go back to reference Taguchi M, Sun Y, Zhao C, Zobitz M, Cha C, Jay G, An K, Amadio P. Lubricin surface modification improves tendon gliding after tendon repair in a canine model in vitro. J Orthop Res. 2009;27:257–263.PubMedCentralPubMedCrossRef Taguchi M, Sun Y, Zhao C, Zobitz M, Cha C, Jay G, An K, Amadio P. Lubricin surface modification improves tendon gliding after tendon repair in a canine model in vitro. J Orthop Res. 2009;27:257–263.PubMedCentralPubMedCrossRef
28.
go back to reference Tan SL, Ahmad RE, Ahmad TS, Merican AM, Abbas AA, Ng WM, Kamarul T. Effect of growth differentiation factor 5 on the proliferation and tenogenic differentiation potential of human mesenchymal stem cells in vitro. Cells Tissues Organs. 2012;196:325–338.PubMedCrossRef Tan SL, Ahmad RE, Ahmad TS, Merican AM, Abbas AA, Ng WM, Kamarul T. Effect of growth differentiation factor 5 on the proliferation and tenogenic differentiation potential of human mesenchymal stem cells in vitro. Cells Tissues Organs. 2012;196:325–338.PubMedCrossRef
29.
go back to reference Tanaka T, Amadio PC, Zhao C, Zobitz ME, Yang C, An KN. Gliding characteristics and gap formation for locking and grasping tendon repairs: a biomechanical study in a human cadaver model. J Hand Surg Am. 2004;29:6–14.PubMedCrossRef Tanaka T, Amadio PC, Zhao C, Zobitz ME, Yang C, An KN. Gliding characteristics and gap formation for locking and grasping tendon repairs: a biomechanical study in a human cadaver model. J Hand Surg Am. 2004;29:6–14.PubMedCrossRef
30.
31.
go back to reference Tang JB, Shi D. Subdivision of flexor tendon “no man’s land” and different treatment methods in each sub-zone: a preliminary report. Chin Med J (Engl). 1992;105:60–68.PubMed Tang JB, Shi D. Subdivision of flexor tendon “no man’s land” and different treatment methods in each sub-zone: a preliminary report. Chin Med J (Engl). 1992;105:60–68.PubMed
32.
go back to reference Tozer S, Duprez D. Tendon and ligament: development, repair and disease. Birth Defects Res C Embryo Today. 2005;75:226–236.PubMedCrossRef Tozer S, Duprez D. Tendon and ligament: development, repair and disease. Birth Defects Res C Embryo Today. 2005;75:226–236.PubMedCrossRef
33.
go back to reference Uchiyama S, Coert JH, Berglund L, Amadio PC, An KN. Method for the measurement of friction between tendon and pulley. J Orthop Res. 1995;13:83–89.PubMedCrossRef Uchiyama S, Coert JH, Berglund L, Amadio PC, An KN. Method for the measurement of friction between tendon and pulley. J Orthop Res. 1995;13:83–89.PubMedCrossRef
34.
go back to reference Watts AE, Yeager AE, Kopyov OV, Nixon AJ. Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model. Stem Cell Res Ther. 2011;2:4.PubMedCentralPubMedCrossRef Watts AE, Yeager AE, Kopyov OV, Nixon AJ. Fetal derived embryonic-like stem cells improve healing in a large animal flexor tendonitis model. Stem Cell Res Ther. 2011;2:4.PubMedCentralPubMedCrossRef
35.
go back to reference Zhao C, Amadio PC, Paillard P, Tanaka T, Zobitz ME, Larson DR, An KN. Digital resistance and tendon strength during the first week after flexor digitorum profundus tendon repair in a canine model in vivo. J Bone Joint Surg Am. 2004;86:320–327.PubMed Zhao C, Amadio PC, Paillard P, Tanaka T, Zobitz ME, Larson DR, An KN. Digital resistance and tendon strength during the first week after flexor digitorum profundus tendon repair in a canine model in vivo. J Bone Joint Surg Am. 2004;86:320–327.PubMed
36.
go back to reference Zhao C, Chieh H-F, Bakri K, Ikeda J, Sun Y-L, Moran SL, An K-N, Amadio PC. The effects of bone marrow stromal cell transplants on tendon healing in vitro. Med Eng Phys. 2009;31:1271–1275.PubMedCentralPubMedCrossRef Zhao C, Chieh H-F, Bakri K, Ikeda J, Sun Y-L, Moran SL, An K-N, Amadio PC. The effects of bone marrow stromal cell transplants on tendon healing in vitro. Med Eng Phys. 2009;31:1271–1275.PubMedCentralPubMedCrossRef
37.
go back to reference Zhao C, Hsu CC, Moriya T, Thoreson AR, Cha SS, Moran SL, An KN, Amadio PC. Beyond the square knot: a novel knotting technique for surgical use. J Bone Joint Surg Am. 2013;5:1020–1027.CrossRef Zhao C, Hsu CC, Moriya T, Thoreson AR, Cha SS, Moran SL, An KN, Amadio PC. Beyond the square knot: a novel knotting technique for surgical use. J Bone Joint Surg Am. 2013;5:1020–1027.CrossRef
38.
go back to reference Zhao C, Sun YL, Amadio PC, Tanaka T, Ettema AM, An KN. Surface treatment of flexor tendon autografts with carbodiimide-derivatized hyaluronic acid: an in vivo canine model. J Bone Joint Surg Am. 2006;88:2181–2191.PubMedCentralPubMedCrossRef Zhao C, Sun YL, Amadio PC, Tanaka T, Ettema AM, An KN. Surface treatment of flexor tendon autografts with carbodiimide-derivatized hyaluronic acid: an in vivo canine model. J Bone Joint Surg Am. 2006;88:2181–2191.PubMedCentralPubMedCrossRef
39.
go back to reference Zhao C, Sun Y-L, Kirk RL, Thoreson AR, Jay GD, Moran SL, An KN, Amadio PC. Effects of a lubricin-containing compound on the results of flexor tendon repair in a canine model in vivo. J Bone Joint Surg Am. 2010;92:1453–1461.PubMedCentralPubMedCrossRef Zhao C, Sun Y-L, Kirk RL, Thoreson AR, Jay GD, Moran SL, An KN, Amadio PC. Effects of a lubricin-containing compound on the results of flexor tendon repair in a canine model in vivo. J Bone Joint Surg Am. 2010;92:1453–1461.PubMedCentralPubMedCrossRef
40.
go back to reference Zhao C, Sun YL, Jay GD, Moran SL, An KN, Amadio PC. Surface modification counteracts adverse effects associated with immobilization after flexor tendon repair. J Orthop Res. 2012;30:1940–1944.PubMedCentralPubMedCrossRef Zhao C, Sun YL, Jay GD, Moran SL, An KN, Amadio PC. Surface modification counteracts adverse effects associated with immobilization after flexor tendon repair. J Orthop Res. 2012;30:1940–1944.PubMedCentralPubMedCrossRef
Metadata
Title
CORR® ORS Richard A. Brand Award for Outstanding Orthopaedic Research: Engineering Flexor Tendon Repair With Lubricant, Cells, and Cytokines in a Canine Model
Authors
Chunfeng Zhao, MD
Yasuhiro Ozasa, MD, PhD
Ramona L. Reisdorf, BS
Andrew R. Thoreson, MS
Gregory D. Jay, MD, PhD
Kai-Nan An, PhD
Peter C. Amadio, MD
Publication date
01-09-2014
Publisher
Springer US
Published in
Clinical Orthopaedics and Related Research® / Issue 9/2014
Print ISSN: 0009-921X
Electronic ISSN: 1528-1132
DOI
https://doi.org/10.1007/s11999-014-3690-y

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