Abstract
The importance of the menisci to the well-being of the normal knee is well-documented. However, there is no ideal repair or reconstructive approach for damaged menisci. Gene therapy provides one promising alternative strategy, especially when combined with injectable tissue engineering to achieve minimally invasive clinical application. We asked whether the introduction of human insulin-like growth factor 1 (hIGF-1) gene could improve the repair of full-thickness meniscal defects. We created full-thickness meniscal defects in the “white area” of the anterior horn in 48 goats. Bone marrow stromal cells with the transfection of hIGF-1 gene and injectable calcium alginate gel were mixed together to repair the defects; three control groups included cells without transfection, gel without cells, and defects left empty. After 4, 8, and 16 weeks, the animals were euthanized and the excised defects were examined by macroscopic assessment, histological analysis, electron microscopy, proteoglycan determination, and MRI. Sixteen weeks after surgery the repaired meniscal defects were filled with white tissue similar to that in normal meniscal fibrocartilage. The repair tissue was composed of cells embedded within matrix that filled the spaces of the fibers. The proteoglycan content in the gene-enhanced tissue engineering group was higher than those in the control groups, and less than that in the normal meniscus. The results suggest full-thickness meniscal defects in regions without blood supply can be reconstructed with hIGF-1-enhanced injectable tissue engineering.
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References
Adams SB Jr, Randolph MA, Gill TJ. Tissue engineering for meniscus repair. J Knee Surg. 2005;18:25–30.
Arnoczky SP, Warren RF, Spivak JM. Meniscal repair using an exogeneous fibrin clot. An experimental study in dogs. J Bone Joint Surg Am. 1988;70:1209–1217.
Becker TA, Kipke DR, Brandon T. Calcium alginate gel: a biocompatible and mechanically stable polymer for endovascular embolization. J Biomed Mater Res. 2001;54:76–86.
Bhargava MM, Hidaka C, Hannafin JA, Doty S, Warren RF. Effects of hepatocyte growth factor and platelet-derived growth factor on the repair of meniscal defects in vitro. In Vitro Cell Dev Biol Anim. 2005;41:305–310.
Bradley MP, Fadale PD, Hulstyn MJ, Muirhead WR, Lifrak JT. Porcine small intestine submucosa for repair of goat meniscal defects. Orthopedics. 2007;30:650–656.
Brindle T, Nyland J, Johnson DL. The meniscus: review of basic principles with application to surgery and rehabilitation. J Athl Train. 2001;36:160–169.
DeHaven KE, Sebastianelli WJ. Open meniscus repair. Indications, technique, and results. Clin Sports Med. 1990;9:577–587.
Dupont J, Holzenberger M. Biology of insulin-like growth factors in development. Birth Defects Res C Embryo Today. 2003;69:257–271.
Evans CH, Ghivizzani SC, Smith P, Shuler FD, Mi Z, Robbins PD. Using gene therapy to protect and restore cartilage. Clin Orthop Relat Res. 2000;379(1):S214–S219.
Evans CH, Gouze JN, Gouze E, Robbins PD, Ghivizzani SC. Osteoarthritis gene therapy. Gene Ther. 2004;11:379–389.
Fabbriciani C, Lucania L, Milano G, Schiavone Panni A, Evangelisti M. Meniscal allografts: cryopreservation vs deep-frozen technique. An experimental study in goats. Knee Surg Sports Traumatol Arthrosc. 1997;5:124–134.
Garrett JC, Steensen RN. Meniscal transplantation in the human knee: a preliminary report. Arthroscopy. 1991;7:57–62.
Goodrich LR, Hidaka C, Robbins PD, Evans CH, Nixon AJ. Genetic modification of chondrocytes with insulin-like growth factor-1 enhances cartilage healing in an equine model. J Bone Joint Surg Br. 2007;89:672–685.
Goto H, Shuler FD, Lamsam C. Transfer of LacZ marker gene to the meniscus. J Bone Joint Surg Am. 1999;81:918–925.
Goto H, Shuler FD, Nivibizi C, Fu FH, Robbins PD, Evans CH. Gene therapy for meniscal injury: enhanced synthesis of proteoglycan and collagen by meniscal cells transduced with a TGFbeta(1)gene. Osteoarthritis Cartilage. 2000;8:266–271.
Guo X, Zhang Q, Yang S, Shao Z, Yuan Q, Pan Z, Tang S, Liu K, Quan D. Repair of full-thickness articular cartilage defects by cultured mesenchymal stem cells transfected with the transforming growth factor beta1 gene. Biomed Mater. 2006;1:206–215.
Hanks GA, Gause TM, Sebastianelli WJ, O’Donnell CS, Kalenak A. Repair of peripheral meniscal tears: open versus arthroscopic technique. Arthroscopy. 1991;7:72–77.
Heckmann TP, Barber-Westin SD, Noyes FR. Meniscal repair and transplantation: indications, techniques, rehabilitation, and clinical outcome. J Orthop Sports Phys Ther. 2006;36:795–814.
Helgren I, Drvota V, Pieper R, Enoksson S, Blomberg P, Islam KB. Highly efficient cell-mediated gene transfer using non-viral vectors and FuGene6: in vitro and in vivo studies. Cell Mol Life Sci. 2000;57:1326–1333.
Henning CE, Lynch MA, Yearout KM, Vequist SW, Stallbaumer RJ, Decker KA. Arthroscopic meniscal repair using an exogenous fibrin clot. Clin Orthop Relat Res. 1990;252:64–72.
Hidaka C, Ibarra C, Hannafin JA, Torzilli PA, Quitoriano M, Jen SS. Formation of vascularized meniscal tissue by combining gene therapy with tissue engineering. Tissue Eng. 2002;8:93–105.
Hoben GM, Athanasiou KA. Meniscal repair with fibrocartilage engineering. Sports Med Arthrosc. 2006;14:129–137.
Holte O, Tonnesen HH, Karlsen J. Measurement of diffusion through calcium alginate gel matrices. Pharmazie. 2006;61:30–34.
Itoh K, Suzuki S, Kuroda T. Effects of local administration of insulin-like growth factor-I on mandibular condylar growth in rats. J Med Dent Sci. 2003;50:79–85.
Ivkovic A, Pascher A, Hudetz D, Jelic M, Haspl M, Windhager R, Pecina M. Current concepts in gene therapy of the musculoskeletal system. Acta Chir Orthop Traumatol Cech. 2006;73:115–122.
Johnson TC, Evans JA, Gilley JA, Delee JC. Osteonecrosis of the knee after arthroscopic surgery for meniscal tears and chondral lesions. Arthroscopy. 2000;16:254–261.
Kollias SL, Fox JM. Meniscal repair. Where do we go from here? Clin Sports Med. 1996;15:621–630.
Kon E, Chiari C, Marcacci M, Delcogliano M, Salter DM, Martin I, Ambrosio L, Fini M, Tschon M, Tognana E, Plasenzotti R, Nehrer S. Tissue engineering for total meniscal substitution: animal study in sheep model. Tissue Eng Part A. 2008;14:1067–1080.
Leo AJ, Grande DA. Mesenchymal stem cells in tissue engineering. Cells Tissues Organs. 2006;183:112–122.
Loeser RF, Shanker G. Autocrine stimulation by insulin-like growth factor 1 and insulin-like growth factor 2 mediates chondrocyte survival in vitro. Arthritis Rheum. 2000;43:1552–1559.
Lozano J, Ma CB, Cannon WD. All-inside meniscus repair: a systematic review. Clin Orthop Relat Res. 2007;455:134–141.
Madry H, Cucchiarini M, Kaul G, Kohn D, Terwilliger EF, Trippel SB. Menisci are efficiently transduced by recombinant adeno-associated virus vectors in vitro and in vivo. Am J Sports Med. 2004;32:1860–1865.
Madry H, Trippel SB. Efficient lipid-mediated gene transfer to articular chondrocytes. Gene Ther. 2000;7:286–291.
Mahler S, Desille M, Fremond B, Chesne C, Guillouzo A, Campion JP. Hypothermic storage and cryopreservation of hepatocytes: the protective effect of alginate gel against cell damages. Cell Transplant. 2003;12:579–592.
McCarty EC, Marx RG, DeHaven KE. Meniscus repair: considerations in treatment and update of clinical results. Clin Orthop Relat Res. 2002;402:122–134.
McDermott ID, Amis AA. The consequences of meniscectomy. J Bone Joint Surg Br. 2006;88:1549–1556.
Mi Z, Ghivizzani SC, Lechman ER, Jaffurs D, Glorioso JC, Evans CH, Robbins PD. Adenovirus-mediated gene transfer of insulin-like growth factor 1 stimulates proteoglycan synthesis in rabbit joints. Arthritis Rheum. 2000;43:2563–2570.
Miller MD, Kline AJ, Jepsen KG. “All-inside” meniscal repair devices: an experimental study in the goat model. Am J Sports Med. 2004;32:858–862.
Miller MD, Ritchie JR, Gomez BA, Royster RM, DeLee JC. Meniscal repair. An experimental study in the goat. Am J Sports Med. 1995;23:124–128.
Neidel J, Schulze M, Sova L. Insulin-like growth factor I accelerates recovery of articular cartilage proteoglycan synthesis in culture after inhibition by interleukin 1. Arch Orthop Trauma Surg. 1994;114:43–48.
Nixon AJ, Haupt JL, Frisbie DD, Morisset SS, McIlwraith CW, Robbins PD, Evans CH, Ghivizzani S. Gene-mediated restoration of cartilage matrix by combination insulin-like growth factor-I/interleukin-1 receptor antagonist therapy. Gene Ther. 2005;12:177–186.
Nixon AJ, Saxer RA, Brower-Toland BD. Exogenous insulin-like growth factor-I stimulates an autoinductive IGF-1 autocrine/paracrine response in chondrocytes. J Orthop Res. 2001;19:26–32.
Noyes FR, Barber-Westin SD, Rankin M. Meniscal transplantation in symptomatic patients less than fifty years old. J Bone Joint Surg Am. 2004;86:1392–1404.
Oreffo RO, Cooper C, Mason C, Clements M. Mesenchymal stem cells: lineage, plasticity, and skeletal therapeutic potential. Stem Cell Rev. 2005;1:169–178.
Pagnotto MR, Wang Z, Karpie JC, Ferretti M, Xiao X, Chu CR. Adeno-associated viral gene transfer of transforming growth factor-beta1 to human mesenchymal stem cells improves cartilage repair. Gene Ther. 2007;14:804–813.
Ritchie JR, Miller MD, Bents RT, Smith DK. Meniscal repair in the goat model. The use of healing adjuncts on central tears and the role of magnetic resonance arthrography in repair evaluation. Am J Sports Med. 1998;26:278–284.
Rogachefsky RA, Dean DD, Howell DS, Altman RD. Treatment of canine osteoarthritis with insulin-like growth factor-1 (IGF-1) and sodium pentosan polysulfate. Osteoarthritis Cartilage. 1993;1:105–114.
Sakai S, Masuhara H, Yamada Y, Ono T, Ijima H, Kawakami K. Transition of mechanical property of porous alginate scaffold with cells during culture period. J Biosci Bioeng. 2005;100:127–129.
Schreiber RE, Ilten-Kirby BM, Dunkelman NS, Symons KT, Rekettye LM, Willoughby J, Ratcliffe A. Repair of osteochondral defects with allogeneic tissue engineered cartilage implants. Clin Orthop Relat Res. 1999;367(Suppl):S382–395.
Seedholm BB, Hargreaves DJ. Transmission of load in the knee joint with special reference to the role of the menisci. Part II. Experimental result, discussion and conclusion. Eng Med. 1979;8:220–229.
Stone KR, Steadman JR, Rodkey WG, Li ST. Regeneration of meniscal cartilage with use of a collagen scaffold. Analysis of preliminary data. J Bone Joint Surg Am. 1997;79:1770–1777.
Takahashi T, Ogasawara T, Kishimoto J, Liu G, Asato H, Nakatsuka T, Uchinuma E, Nakamura K, Kawaguchi H, Chung UI, Takato T, Hoshi K. Synergistic effects of FGF-2 with insulin or IGF-1 on the proliferation of human auricular chondrocytes. Cell Transplant. 2005;14:683–693.
Tavera C, Abribat T, Reboul P, Dore S, Brazeau P, Pelletier JP. IGF and IGF-binding protein system in the synovial fluid of osteoarthritic and rheumatoid arthritic patients. Osteoarthritis Cartilage. 1996;4:263–274.
Tomita T, Hashimoto H, Tomita N, Morishita R, Lee SB, Hayashida K. In vivo direct gene transfer into articular cartilage by intraarticular injection mediated by HVJ (Sendai virus) and liposomes. Arthritis Rheum. 1997;40:901–906.
Ueblacker P, Wagner B, Vogt S, Salzmann G, Wexel G, Krüger A, Plank C, Brill T, Specht K, Hennig T, Schillinger U, Imhoff AB, Martinek V, Gansbacher B. In vivo analysis of retroviral gene transfer to chondrocytes within collagen scaffolds for the treatment of osteochondral defects. Biomaterials. 2007;28:4480–4487.
Vacanti CA. The history of tissue engineering. J Cell Mol Med. 2006;10:569–576.
Van Arkel ER, de Boer HH. Survival analysis of human meniscal transplantations. J Bone Joint Surg Br. 2002;84:227–231.
Verdonk PC, Demurie A, Almgvist KF, Veys EM, Verbruggen G, Verdonk R. Transplantation of viable meniscal allograft. Survivorship analysis and clinical outcome of one hundred cases. J Bone Joint Surg Am. 2005;87:715–724.
Verdonk PC, Verstraete KL, Almgvist KF, De Cuyper K, Veys EM, Verbruggen G, Verdonk R. Meniscal allograft transplantation: long-term clinical results with radiological and magnetic resonance imaging correlations. Knee Surg Sports Traumatol Arthrosc. 2006;14:694–706.
Vinatier C, Guicheux J, Daculsi G, Layrolle P, Weiss P. Cartilage and bone tissue engineering using hydrogels. Biomed Mater Eng. 2006;16(Suppl):S107–S113.
Winter A, Breit S, Parsch D, Benz K, Steck E, Hauner H. Cartilage-like gene expression in differentiated human stem cell spheroids: a comparison of bone marrow-derived and adipose tissue-derived stromal cells. Arthritis Rheum. 2003;48:418–429.
Yamasaki T, Deie M, Shinomiya R, Yasunaga Y, Yanada S, Ochi M. Transplantation of meniscus regenerated by tissue engineering with a scaffold derived from a rat meniscus and mesenchymal stromal cells derived from rat bone marrow. Artif Organs. 2008;32:519–524.
Acknowledgments
We thank Dr Xiaokui Hou and Dr Yingzhen Wang for assistance with the manuscript. We also thank Dr Guanzhen Yang and Dr Xiangfu Wu for their technical assistance on molecular technology and Dr Chengyu Lv, Dr Xiaoming Xing, and Dr Wenjian Xu for their help with the histologic and imageologic analysis. We thank Hao Xu for his assistance on statistical analysis.
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Two of the authors (HZ, PL) received funding from the National Natural Science Foundation of China (No 30801167).
Each author certifies that he or she has no commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.
Each author certifies that his or her institution has approved the animal protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.
This work was performed at Department of Joint Surgery, The Affiliated Hospital of Tsingtao University, Tsingtao, China.
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Zhang, H., Leng, P. & Zhang, J. Enhanced Meniscal Repair by Overexpression of hIGF-1 in a Full-thickness Model. Clin Orthop Relat Res 467, 3165–3174 (2009). https://doi.org/10.1007/s11999-009-0921-8
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DOI: https://doi.org/10.1007/s11999-009-0921-8