RESEARCH PROGRESS OF TISSUE ENGINEERED LIGAMENT_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

SUNZhengyu ,  LIJian

Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P. R. China;

Corresponding author：

LIJian, Email: hxlijian.china@163.com

Keywords：

Tissue engineered ligament; Fibroblasts; Mesenchymal stem cells; Scaffold material; Growth factor

DOI：

10.7507/1002-1892.20150251

Video：

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Objective To review the research progress of tissue engineered ligament. Methods The literature in recent years on tissue engineered ligament in repair of anterior cruciate ligament (ACL) injury was extensively reviewed, including cell sources, scaffold materials, growth factors, and mechanical stimulation in tissue engineered ligament. Results Tissue engineered ligament constructed by mesenchymal stem cells and ACL fibroblasts has been successfully used in animal experiments. It is crucial for qualified tissue engineered ligament to choose appropriate seed cells, scaffold, mechanical stimulation, and essential cytokines. To further optimize culture condition and how to realize the tissue engineered ligament in vivo better survival and prognosis need to be further studied. Conclusion Enormous progress has been made in tissue engineered ligament for repair and regeneration of ACL. With the development of biochemistry and scaffold materials, tissue engineered ligament will be used in clinic in the near future.

Citation： SUNZhengyu, LIJian. RESEARCH PROGRESS OF TISSUE ENGINEERED LIGAMENT. Chinese Journal of Reparative and Reconstructive Surgery, 2015, 29(9): 1160-1166. doi: 10.7507/1002-1892.20150251 Copy

1.	Myer GD, Ford KR, Hewett TE. Rationale and clinical techniques for anterior cruciate ligament injury prevention among female athletes. J Athl Train, 2004, 39(4):352-364.
2.	Jørgensen U, Bak K, Ekstrand J, et al. Reconstruction of the anterior cruciate ligament with the iliotibial band autograft in patients with chronic knee instability. Knee Surg Sports Traumatol Arthrosc, 2001, 9(3):137-145.
3.	Murray MM, Fleming BC. Use of a bioactive scaffold to stimulate anterior cruciate ligament healing also minimizes posttraumatic osteoarthritis after surgery. Am J Sports Med, 2013, 41(8):1762-1770.
4.	Vavken P, Fleming BC, Mastrangelo AN, et al. Biomechanical outcomes after bioenhanced anterior cruciate ligament repair and anterior cruciate ligament reconstruction are equal in a porcine model. Arthroscopy, 2012, 28(5):672-680.
5.	Boisgard S, Levai JP, Geiger B, et al. Study of the varations in length of the anterior cruciate ligament during flexion of the knee:use of a 3D model reconstructed from MRI sections. Surg Radiol Anat, 1999, 21(5):313-317.
6.	Van Eijk F, Saris DB, Riesle J, et al. Tissue engineering of ligaments: a comparison of bone marrow stromal cells, anterior cruciate ligament, and skin fibroblasts as cell source. Tissue Eng, 2004, 10(5-6):893-903.
7.	Cooper JA Jr, Bailey LO, Carter JN, et al. Evaluation of the anterior cruciate ligament, medial collateral ligament, achilles tendon and patellar tendon as cell sources for tissue-engineered ligament. Biomaterials, 2006, 27(13):2747-2754.
8.	Brune T, Borel A, Gilbert TW, et al. In vitro comparison of human fibroblasts from intact and ruptured ACL for use in tissue engineering. Eur Cell Mater, 2007, 14:78-90.
9.	Murray MM, Spector M. The migration of cells from the ruptured human anterior cruciate ligament into collagen-glycosaminoglycan regeneration templates in vitro. Biomaterials, 2001, 22(17):2393-2402.
10.	Via AG, Frizziero A, Oliva F. Biological properties of mesenchymal Stem Cells from different sources. Muscles Ligaments Tendons J, 2012, 2(3):154-162.
11.	Fu WL, Zhang JY, Fu X, et al. Comparative study of the biological characteristics of mesenchymal stem cells from bone marrow and peripheralblood of rats.Tissue Eng Part A, 2012, 18(17-18):1793-1803.
12.	Caplan AI. New era of cell-based orthopedic therapies. Tissue Eng Part B Rev, 2009, 15(2):195-200.
13.	Steinert AF, Kunz M, Prager P, et al. Mesenchymal stem cell characteristics of human anterior cruciate ligament outgrowth cells. Tissue Eng Part A, 2011, 17(9-10):1375-1388.
14.	Cheng MT, Yang HW, Chen TH, et al. Isolation and characterization of multipotent stem cells from human cruciate ligaments. Cell Prolif, 2009, 42(4):448-460.
15.	Nau T, Teuschl A. Regeneration of the anterior cruciate ligament: Current strategies in tissue engineering. World J Orthop, 2015, 6(1): 127-136.
16.	Ksiazek K. A comprehensive review on mesenchymal stem cell growth and senescence. Rejuvenation Res, 2009, 12(2):105-116.
17.	Luo Q, Song G, Song Y, et al. Indirect co-culture with tenocytes promotes proliferation and mRNA expression of tendon/ligament related genes in rat bone marrow mesenchymal stem cells. Cytotechnology, 2009, 61(1-2):1-10.
18.	Ball SG, Shuttleworth AC, Kielty CM. Direct cell contact influences bone marrow mesenchymal stem cell fate. Int J Biochem Cell Biol, 2004, 36(4):714-727.
19.	Schneider PR, Buhrmann C, Mobasheri A, et al. Three-dimensional high-density coculture with primary tenocytes induces tenogenic differentiation in mesenchymal stem cells. J Orthop Res, 2011, 29(9): 1351-1360.
20.	Proffen BL, Haslauer CM, Harris CE, et al. Mesenchymal stem cells from the retropatellar fat pad and peripheral blood stimulate ACL fibroblast migration, proliferation, and collagen gene expression. Connect Tissue Res, 2013, 54(1):14-21.
21.	Canseco JA, Kojima K, Penvose AR, et al. Effect on ligament marker expression by direct-contact co-culture of mesenchymal stem cells and anterior cruciate ligament cells. Tissue Eng Part A, 2012, 18(23-24):2549-2558.
22.	Hoogduijn MJ, Popp F, Verbeek R, et al. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol, 2010, 10(12):1496-1500.
23.	Leong NL, Petrigliano FA, McAllister DR. Current tissue engineering strategies in anterior cruciate ligament reconstruction. J Biomed Mater Res A, 2014, 102(5):1614-1624.
24.	Dunn MG, Liesch JB, Tiku ML, et al. Development of fibroblastseeded ligament analogs for ACL reconstruction. J Biomed Mater Res, 1995, 29(11):1363-1371.
25.	Bellincampi LD, Closkey RF, Prasad R, et al. Viability of fibroblastseeded ligament analogs after autogenous implantation. J Orthop Res, 1998, 16(4):414-420.
26.	Murray MM, Spector M. The migration of cells from the ruptured human anteriorcruciate ligament into collagenglycosaminoglycan regeneration templates in vitro. Biomaterials, 2001, 22(17):2393-2402.
27.	Caruso AB, Dunn MG. Changes in mechanical properties and cellularity during long-term culture of collagen fiber ACL reconstruction scaffolds. J Biomed Mater Res A, 2005, 73(4):388-397.
28.	Walters VI, Kwansa AL, Freeman JW. Design and analysis of braidtwist collagen scaffolds. Connect Tissue Res, 2012, 53(3):255-266.
29.	Altman GH, Horan RL, Lu HH, et al. Silk matrix for tissue engineered anterior cruciate ligaments. Biomaterials, 2002, 23(20): 4131-4141.
30.	Murphy AR, St John P, Kaplan DL. Modification of silk fibroin using diazonium coupling chemistry and the effects on hMSC proliferation and differentiation. Biomaterials, 2008, 29(19):2829-2838.
31.	Horan RL, Toponarski I, Boepple HE, et al. Design and characterization of a scaffold for anterior cruciate ligament engineering. J Knee Surg, 2009, 22(1):82-92.
32.	Fan H, Liu H, Toh SL, et al. Anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold in large animal model. Biomaterials, 2009, 30(28):4967-4977.
33.	Cristino S, Grassi F, Toneguzzi S, et al. Analysis of mesenchymal stem cells grown on a three-dimensional HYAFF 11-based prototype ligament scaffold. J Biomed Mater Res A, 2005, 73(3):275-283.
34.	Hansson A, Hashom N, Falson F, et al. In vitro evaluation of an RGD-functionalized chitosan derivative for enhanced cell adhesion. Carbohydr Polym, 2012, 90(4):1494-1500.
35.	Majima T, Funakosi T, Iwasaki N, et al. Alginate and chitosan polyion complex hybrid fibers for scaffolds in ligament and tendon tissue engineering. J Orthop Sci, 2005, 10(3):302-307.
36.	Buma P, Kok HJ, Blankevoort L, et al. Augmentation in anterior cruciate ligament reconstruction-a histological and biomechanical study on goats. Int Orthop, 2004, 28(2):91-96.
37.	Lu HH, Cooper JA, Manuel S, et al. Anterior cruciate ligament regeneration using braided biodegradable scaffolds:In vitro optimization studies. Biomaterials, 2005, 26(23):4805-4816.
38.	Freeman JW, Woods MD, Cromer DA, et al. Tissue engineering of the anterior cruciate ligament:The viscoelastic behavior and cell viability of a novel braid-twist scaffold. J Biomater Sci Polym Ed, 2009, 20(12):1709-1728.
39.	Cardwell RD, Dahlgren LA, Goldstein AS. Electrospun fibre diameter, not alignment, affects mesenchymal stem cell differentiation into the tendon/ligament lineage. J Tissue Eng Regen Med, 2014, 8(12):937-945.
40.	Panas-Perez E, Gatt CJ, Dunn MG. Development of a silk and collagen fiber scaffold for anterior cruciate ligament reconstruction. J Mater Sci Mater Med, 2013, 24(1):257-265.
41.	Chung AS, Hwang HS, Das D, et al. Lamellar stack formation and degradative behaviors of hydrolytically degraded poly (e-caprolactone) and poly (glycolide-e-caprolactone) blended fibers. J Biomed Mater Res B Appl Biomater, 2012, 100(1):274-284.
42.	Sahoo S, Toh SL, Goh JC. A bFGF-releasing silk/PLGA-based biohybrid scaffold for ligament/tendon tissue engineering using mesenchymalprogenitor cells. Biomaterials, 2010, 31(11):2990-2998.
43.	Anitua E, Sánchez M, Orive G, et al. The potential impact of the preparation rich in growth factors (PRGF) in different medical flelds. Biomaterials, 2007, 28(31):4551-4560.
44.	Wang Y, Tang Z, Xue R, et al. TGF-β1 promoted MMP-2 mediated wound healing of anterior cruciate ligament fibroblasts through NF-κB. Connect Tissue Res, 2011, 52(3):218-225.
45.	Xie J, Jiang J, Zhang Y, et al. Up-regulation expressions of lysyl oxidase family in anterior cruciate ligament and medial collateral ligament fibroblasts induced by transforming growth factor-beta 1. Int Orthop, 2012, 36(1):207-213.
46.	Hashimoto Y, Naka Y, Fukunaga K, et al. ACL reconstruction using bone-tendon-bone graft engineered from the semitendinosus tendon by injection of recombinant BMP-2 in a rabbit model. J Orthop Res, 2011, 29(12):1923-1930.
47.	Schwarting T, Benölken M, Ruchholtz S, et al. Bone morphogenetic protein-7 enhances bone-tendon integration in a murine in vitro coculture model. Int Orthop, 2015, 39(4):799-805.
48.	Dong Y, Zhang Q, Li Y, et al. Enhancement of tendon-bone healing for anterior cruciate ligament (ACL) reconstruction using bone marrow-derived mesenchymal stem cells infected with BMP-2. Int J Mol Sci, 2012, 13(10):13605-13620.
49.	Kurtz CA, Loebig TG, Anderson DD, et al. Insulin-like growth factor I accelerates functional recovery from Achilles tendon injury in a rat model. Am J Sports Med, 1999, 27(3):363-369.
50.	Sahoo S, Ang LT, Cho-Hong Goh J, et al. Bioactive nanofibers for fibroblastic differentiation of mesenchymal precursor cells for ligament/tendon tissue engineering applications. Differentiation, 2010, 79(2):102-110.
51.	Haddad-Weber M, Prager P, Lunz M, et al. BMP12 and BMP13 gene transfer induce ligamentogenic differentiation in mesenchymal progenitor and anteriorcruciate ligament cells. Cytotherapy, 2010, 12(4):505-513.
52.	Wei XL, Lin L, Hou Y, et al. Construction of recombinant adenovirus co-expression vector carrying the human transforming growth factor-beta1 and vascular endothelial growth factor genes and its effect on anterior cruciate ligament fibroblasts. Chin Med J (Engl), 2008, 121(15):1426-1432.
53.	Woo YK, Kwon SY, Lee HS, et al. Proliferation of anterior cruciate ligament cells in vitro by photo-immobilized epidermal growth factor. J Orthop Res, 2007, 25(1):73-80.
54.	Li F, Jia H, Yu C. ACL reconstruction in a rabbit model using irradiated Achilles allograft seeded with mesenchymal stem cells or PDGF-B gene-transfected mesenchymal stem cells. Knee Surg Sports Traumatol Arthrosc, 2007, 15(10):1219-1227.
55.	Murray MM, Palmer M, Abreu E, et al. Platelet-rich plasma alone is not sufficient to enhance suture repair of the ACL in skeletally immature animals:an in vivo study. J Orthop Res, 2009, 27(5):639-645.
56.	Yuan T, Zhang CQ, Wang JH. Augmenting tendon and ligament repair with latelet-rich plasma (PRP). Muscles Ligaments Tendons J, 2013, 3(3):139-149.
57.	Figueroa D, Figueroa F, Cavlo R, et al. Platelet-rich plasma use in anterior cruciate ligament surgery:systematic review of the literature. Arthroscopy, 2015, 31(5):981-988.
58.	Benhardt HA, Cosgriff-Hernandez EM. The role of mechanical loading in ligament tissue engineering.Tissue Eng Part B Rev, 2009, 15(4):467-475.
59.	Altman GH, Horan RL, Martin I, et al. Cell differentiation by mechanical stress. FASEB J, 2002, 16(2):270-272.
60.	Subramony SD, Su A, Yeager K, et al. Combined effects of chemical priming and mechanical stimulation on mesenchymal stem cell differentiation on nanofiber scaffolds. J Biomech, 2014, 47(9):2189-2196.
61.	Moreau JE, Bramono DS, Horan RL, et al. Sequential biochemical and mechanical stimulation in the development of tissue-engineered ligaments. Tissue Eng Part A, 2008, 14(7):1161-1172.
62.	Park SA, Kim IA, Lee YJ, et al. Biological responses of ligament fibroblasts and gene expression profiling on micropatterned silicone substrates subjected to mechanical stimuli. J Biosci Bioeng, 2006, 102(5):402-412.
63.	Kreja L, Liedert A, Schlenker H, et al. Effects of mechanical strain on human mesenchymal stem cells and ligament fibroblasts in a textured poly (L-lactide) scaffold for ligament tissue engineering. J Mater Sci Mater Med, 2012, 23(10):2575-2582.
64.	Henshaw DR, Attia E, Bhargava M, et al. Canine ACL fibroblast integrin expression and cell alignment in response to cyclic tensile strain in three-dimensional collagen gels. J Orthop Res, 2006, 24(3): 481-490.
65.	Berry CC, Cacou C, Lee DA, et al. Dermal fibroblasts respond to mechanical conditioning in a strain profile dependent manner. Biorheology, 2003, 40(1-3):337-345.

1. Myer GD, Ford KR, Hewett TE. Rationale and clinical techniques for anterior cruciate ligament injury prevention among female athletes. J Athl Train, 2004, 39(4):352-364.
2. Jørgensen U, Bak K, Ekstrand J, et al. Reconstruction of the anterior cruciate ligament with the iliotibial band autograft in patients with chronic knee instability. Knee Surg Sports Traumatol Arthrosc, 2001, 9(3):137-145.
3. Murray MM, Fleming BC. Use of a bioactive scaffold to stimulate anterior cruciate ligament healing also minimizes posttraumatic osteoarthritis after surgery. Am J Sports Med, 2013, 41(8):1762-1770.
4. Vavken P, Fleming BC, Mastrangelo AN, et al. Biomechanical outcomes after bioenhanced anterior cruciate ligament repair and anterior cruciate ligament reconstruction are equal in a porcine model. Arthroscopy, 2012, 28(5):672-680.
5. Boisgard S, Levai JP, Geiger B, et al. Study of the varations in length of the anterior cruciate ligament during flexion of the knee:use of a 3D model reconstructed from MRI sections. Surg Radiol Anat, 1999, 21(5):313-317.
6. Van Eijk F, Saris DB, Riesle J, et al. Tissue engineering of ligaments: a comparison of bone marrow stromal cells, anterior cruciate ligament, and skin fibroblasts as cell source. Tissue Eng, 2004, 10(5-6):893-903.
7. Cooper JA Jr, Bailey LO, Carter JN, et al. Evaluation of the anterior cruciate ligament, medial collateral ligament, achilles tendon and patellar tendon as cell sources for tissue-engineered ligament. Biomaterials, 2006, 27(13):2747-2754.
8. Brune T, Borel A, Gilbert TW, et al. In vitro comparison of human fibroblasts from intact and ruptured ACL for use in tissue engineering. Eur Cell Mater, 2007, 14:78-90.
9. Murray MM, Spector M. The migration of cells from the ruptured human anterior cruciate ligament into collagen-glycosaminoglycan regeneration templates in vitro. Biomaterials, 2001, 22(17):2393-2402.
10. Via AG, Frizziero A, Oliva F. Biological properties of mesenchymal Stem Cells from different sources. Muscles Ligaments Tendons J, 2012, 2(3):154-162.
11. Fu WL, Zhang JY, Fu X, et al. Comparative study of the biological characteristics of mesenchymal stem cells from bone marrow and peripheralblood of rats.Tissue Eng Part A, 2012, 18(17-18):1793-1803.
12. Caplan AI. New era of cell-based orthopedic therapies. Tissue Eng Part B Rev, 2009, 15(2):195-200.
13. Steinert AF, Kunz M, Prager P, et al. Mesenchymal stem cell characteristics of human anterior cruciate ligament outgrowth cells. Tissue Eng Part A, 2011, 17(9-10):1375-1388.
14. Cheng MT, Yang HW, Chen TH, et al. Isolation and characterization of multipotent stem cells from human cruciate ligaments. Cell Prolif, 2009, 42(4):448-460.
15. Nau T, Teuschl A. Regeneration of the anterior cruciate ligament: Current strategies in tissue engineering. World J Orthop, 2015, 6(1): 127-136.
16. Ksiazek K. A comprehensive review on mesenchymal stem cell growth and senescence. Rejuvenation Res, 2009, 12(2):105-116.
17. Luo Q, Song G, Song Y, et al. Indirect co-culture with tenocytes promotes proliferation and mRNA expression of tendon/ligament related genes in rat bone marrow mesenchymal stem cells. Cytotechnology, 2009, 61(1-2):1-10.
18. Ball SG, Shuttleworth AC, Kielty CM. Direct cell contact influences bone marrow mesenchymal stem cell fate. Int J Biochem Cell Biol, 2004, 36(4):714-727.
19. Schneider PR, Buhrmann C, Mobasheri A, et al. Three-dimensional high-density coculture with primary tenocytes induces tenogenic differentiation in mesenchymal stem cells. J Orthop Res, 2011, 29(9): 1351-1360.
20. Proffen BL, Haslauer CM, Harris CE, et al. Mesenchymal stem cells from the retropatellar fat pad and peripheral blood stimulate ACL fibroblast migration, proliferation, and collagen gene expression. Connect Tissue Res, 2013, 54(1):14-21.
21. Canseco JA, Kojima K, Penvose AR, et al. Effect on ligament marker expression by direct-contact co-culture of mesenchymal stem cells and anterior cruciate ligament cells. Tissue Eng Part A, 2012, 18(23-24):2549-2558.
22. Hoogduijn MJ, Popp F, Verbeek R, et al. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. Int Immunopharmacol, 2010, 10(12):1496-1500.
23. Leong NL, Petrigliano FA, McAllister DR. Current tissue engineering strategies in anterior cruciate ligament reconstruction. J Biomed Mater Res A, 2014, 102(5):1614-1624.
24. Dunn MG, Liesch JB, Tiku ML, et al. Development of fibroblastseeded ligament analogs for ACL reconstruction. J Biomed Mater Res, 1995, 29(11):1363-1371.
25. Bellincampi LD, Closkey RF, Prasad R, et al. Viability of fibroblastseeded ligament analogs after autogenous implantation. J Orthop Res, 1998, 16(4):414-420.
26. Murray MM, Spector M. The migration of cells from the ruptured human anteriorcruciate ligament into collagenglycosaminoglycan regeneration templates in vitro. Biomaterials, 2001, 22(17):2393-2402.
27. Caruso AB, Dunn MG. Changes in mechanical properties and cellularity during long-term culture of collagen fiber ACL reconstruction scaffolds. J Biomed Mater Res A, 2005, 73(4):388-397.
28. Walters VI, Kwansa AL, Freeman JW. Design and analysis of braidtwist collagen scaffolds. Connect Tissue Res, 2012, 53(3):255-266.
29. Altman GH, Horan RL, Lu HH, et al. Silk matrix for tissue engineered anterior cruciate ligaments. Biomaterials, 2002, 23(20): 4131-4141.
30. Murphy AR, St John P, Kaplan DL. Modification of silk fibroin using diazonium coupling chemistry and the effects on hMSC proliferation and differentiation. Biomaterials, 2008, 29(19):2829-2838.
31. Horan RL, Toponarski I, Boepple HE, et al. Design and characterization of a scaffold for anterior cruciate ligament engineering. J Knee Surg, 2009, 22(1):82-92.
32. Fan H, Liu H, Toh SL, et al. Anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold in large animal model. Biomaterials, 2009, 30(28):4967-4977.
33. Cristino S, Grassi F, Toneguzzi S, et al. Analysis of mesenchymal stem cells grown on a three-dimensional HYAFF 11-based prototype ligament scaffold. J Biomed Mater Res A, 2005, 73(3):275-283.
34. Hansson A, Hashom N, Falson F, et al. In vitro evaluation of an RGD-functionalized chitosan derivative for enhanced cell adhesion. Carbohydr Polym, 2012, 90(4):1494-1500.
35. Majima T, Funakosi T, Iwasaki N, et al. Alginate and chitosan polyion complex hybrid fibers for scaffolds in ligament and tendon tissue engineering. J Orthop Sci, 2005, 10(3):302-307.
36. Buma P, Kok HJ, Blankevoort L, et al. Augmentation in anterior cruciate ligament reconstruction-a histological and biomechanical study on goats. Int Orthop, 2004, 28(2):91-96.
37. Lu HH, Cooper JA, Manuel S, et al. Anterior cruciate ligament regeneration using braided biodegradable scaffolds:In vitro optimization studies. Biomaterials, 2005, 26(23):4805-4816.
38. Freeman JW, Woods MD, Cromer DA, et al. Tissue engineering of the anterior cruciate ligament:The viscoelastic behavior and cell viability of a novel braid-twist scaffold. J Biomater Sci Polym Ed, 2009, 20(12):1709-1728.
39. Cardwell RD, Dahlgren LA, Goldstein AS. Electrospun fibre diameter, not alignment, affects mesenchymal stem cell differentiation into the tendon/ligament lineage. J Tissue Eng Regen Med, 2014, 8(12):937-945.
40. Panas-Perez E, Gatt CJ, Dunn MG. Development of a silk and collagen fiber scaffold for anterior cruciate ligament reconstruction. J Mater Sci Mater Med, 2013, 24(1):257-265.
41. Chung AS, Hwang HS, Das D, et al. Lamellar stack formation and degradative behaviors of hydrolytically degraded poly (e-caprolactone) and poly (glycolide-e-caprolactone) blended fibers. J Biomed Mater Res B Appl Biomater, 2012, 100(1):274-284.
42. Sahoo S, Toh SL, Goh JC. A bFGF-releasing silk/PLGA-based biohybrid scaffold for ligament/tendon tissue engineering using mesenchymalprogenitor cells. Biomaterials, 2010, 31(11):2990-2998.
43. Anitua E, Sánchez M, Orive G, et al. The potential impact of the preparation rich in growth factors (PRGF) in different medical flelds. Biomaterials, 2007, 28(31):4551-4560.
44. Wang Y, Tang Z, Xue R, et al. TGF-β1 promoted MMP-2 mediated wound healing of anterior cruciate ligament fibroblasts through NF-κB. Connect Tissue Res, 2011, 52(3):218-225.
45. Xie J, Jiang J, Zhang Y, et al. Up-regulation expressions of lysyl oxidase family in anterior cruciate ligament and medial collateral ligament fibroblasts induced by transforming growth factor-beta 1. Int Orthop, 2012, 36(1):207-213.
46. Hashimoto Y, Naka Y, Fukunaga K, et al. ACL reconstruction using bone-tendon-bone graft engineered from the semitendinosus tendon by injection of recombinant BMP-2 in a rabbit model. J Orthop Res, 2011, 29(12):1923-1930.
47. Schwarting T, Benölken M, Ruchholtz S, et al. Bone morphogenetic protein-7 enhances bone-tendon integration in a murine in vitro coculture model. Int Orthop, 2015, 39(4):799-805.
48. Dong Y, Zhang Q, Li Y, et al. Enhancement of tendon-bone healing for anterior cruciate ligament (ACL) reconstruction using bone marrow-derived mesenchymal stem cells infected with BMP-2. Int J Mol Sci, 2012, 13(10):13605-13620.
49. Kurtz CA, Loebig TG, Anderson DD, et al. Insulin-like growth factor I accelerates functional recovery from Achilles tendon injury in a rat model. Am J Sports Med, 1999, 27(3):363-369.
50. Sahoo S, Ang LT, Cho-Hong Goh J, et al. Bioactive nanofibers for fibroblastic differentiation of mesenchymal precursor cells for ligament/tendon tissue engineering applications. Differentiation, 2010, 79(2):102-110.
51. Haddad-Weber M, Prager P, Lunz M, et al. BMP12 and BMP13 gene transfer induce ligamentogenic differentiation in mesenchymal progenitor and anteriorcruciate ligament cells. Cytotherapy, 2010, 12(4):505-513.
52. Wei XL, Lin L, Hou Y, et al. Construction of recombinant adenovirus co-expression vector carrying the human transforming growth factor-beta1 and vascular endothelial growth factor genes and its effect on anterior cruciate ligament fibroblasts. Chin Med J (Engl), 2008, 121(15):1426-1432.
53. Woo YK, Kwon SY, Lee HS, et al. Proliferation of anterior cruciate ligament cells in vitro by photo-immobilized epidermal growth factor. J Orthop Res, 2007, 25(1):73-80.
54. Li F, Jia H, Yu C. ACL reconstruction in a rabbit model using irradiated Achilles allograft seeded with mesenchymal stem cells or PDGF-B gene-transfected mesenchymal stem cells. Knee Surg Sports Traumatol Arthrosc, 2007, 15(10):1219-1227.
55. Murray MM, Palmer M, Abreu E, et al. Platelet-rich plasma alone is not sufficient to enhance suture repair of the ACL in skeletally immature animals:an in vivo study. J Orthop Res, 2009, 27(5):639-645.
56. Yuan T, Zhang CQ, Wang JH. Augmenting tendon and ligament repair with latelet-rich plasma (PRP). Muscles Ligaments Tendons J, 2013, 3(3):139-149.
57. Figueroa D, Figueroa F, Cavlo R, et al. Platelet-rich plasma use in anterior cruciate ligament surgery:systematic review of the literature. Arthroscopy, 2015, 31(5):981-988.
58. Benhardt HA, Cosgriff-Hernandez EM. The role of mechanical loading in ligament tissue engineering.Tissue Eng Part B Rev, 2009, 15(4):467-475.
59. Altman GH, Horan RL, Martin I, et al. Cell differentiation by mechanical stress. FASEB J, 2002, 16(2):270-272.
60. Subramony SD, Su A, Yeager K, et al. Combined effects of chemical priming and mechanical stimulation on mesenchymal stem cell differentiation on nanofiber scaffolds. J Biomech, 2014, 47(9):2189-2196.
61. Moreau JE, Bramono DS, Horan RL, et al. Sequential biochemical and mechanical stimulation in the development of tissue-engineered ligaments. Tissue Eng Part A, 2008, 14(7):1161-1172.
62. Park SA, Kim IA, Lee YJ, et al. Biological responses of ligament fibroblasts and gene expression profiling on micropatterned silicone substrates subjected to mechanical stimuli. J Biosci Bioeng, 2006, 102(5):402-412.
63. Kreja L, Liedert A, Schlenker H, et al. Effects of mechanical strain on human mesenchymal stem cells and ligament fibroblasts in a textured poly (L-lactide) scaffold for ligament tissue engineering. J Mater Sci Mater Med, 2012, 23(10):2575-2582.
64. Henshaw DR, Attia E, Bhargava M, et al. Canine ACL fibroblast integrin expression and cell alignment in response to cyclic tensile strain in three-dimensional collagen gels. J Orthop Res, 2006, 24(3): 481-490.
65. Berry CC, Cacou C, Lee DA, et al. Dermal fibroblasts respond to mechanical conditioning in a strain profile dependent manner. Biorheology, 2003, 40(1-3):337-345.

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