期刊论文详细信息
BMC Biotechnology
Repair of large segmental bone defects: BMP-2 gene activated muscle grafts vs. autologous bone grafting
Oliver B Betz2  Volker M Betz2  Christian Schröder2  Rainer Penzkofer1  Michael Göttlinger1  Susanne Mayer-Wagner2  Peter Augat1  Volkmar Jansson2  Peter E Müller2 
[1] Institute of Biomechanics, Trauma Center Murnau, Prof.-Küntscher-Str. 8, Murnau, 82418, Germany
[2] Department of Orthopedic Surgery, Laboratory for Biomechanics and Experimental Orthopedics, University Hospital Grosshadern, Ludwig-Maximilians-University Munich, Marchioninistrasse 23, Munich, 81377, Germany
关键词: Tissue engineering;    In vivo;    Autologous bone grafts;    BMP-2;    Gene transfer;    Muscle grafts;    Large bone defects;    Bone regeneration;   
Others  :  1089665
DOI  :  10.1186/1472-6750-13-65
 received in 2013-04-19, accepted in 2013-08-05,  发布年份 2013
PDF
【 摘 要 】

Background

Common cell based strategies for the treatment of osseous defects require the isolation and expansion of autologous cells. Since this makes such approaches time-consuming and expensive, we developed a novel expedited technology creating gene activated muscle grafts. We have previously shown that large segmental bone defects in rats can be regenerated by implantation of muscle tissue fragments activated by BMP-2 gene transfer.

Results

In the present study, we compared the bone healing capacities of such gene activated muscle grafts with bone isografts, mimicking autologous bone grafting, the clinical gold standard for treatment of bone defects in patients. Two of 14 male, syngeneic Fischer 344 rats used for this experiment served as donors for muscle and bone. Muscle tissue was harvested from both hind limbs and incubated with an adenoviral vector carrying the cDNA encoding BMP-2. Bone was harvested from the iliac crest and long bone epiphyses. Bone defects (5 mm) were created in the right femora of 12 rats and were filled with either BMP-2 activated muscle tissue or bone grafts. After eight weeks, femora were evaluated by radiographs, micro-computed tomography (μCT), and biomechanical testing. In the group receiving BMP-2 activated muscle grafts as well as in the bone-grafting group, 100% of the bone defects were healed, as documented by radiographs and μCT-imaging. Bone volume was similar in both groups and biomechanical stability of the two groups was statistically indistinguishable.

Conclusions

This study demonstrates that treatment of large bone defects by implantation of BMP-2 gene activated muscle tissue leads to similar bone volume and stability as bone isografts, mimicking autologous bone grafting.

【 授权许可】

   
2013 Betz et al.; licensee BioMed Central Ltd.

【 预 览 】
附件列表
Files Size Format View
20150126013427835.pdf 2719KB PDF download
Figure 4. 55KB Image download
Figure 3. 59KB Image download
Figure 2. 130KB Image download
Figure 1. 66KB Image download
【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】
  • [1]Arrington ED, Smith WJ, Chambers HG, Bucknell AL, Davino NA: Complications of iliac crest bone graft harvesting. Clin Orthop Relat Res 1996, 329(329):300-309.
  • [2]Colterjohn NR, Bednar DA: Procurement of bone graft from the iliac crest. An operative approach with decreased morbidity. J Bone Joint Surg Am 1997, 79(5):756-759.
  • [3]Kneser U, Schaefer DJ, Polykandriotis E, Horch RE: Tissue engineering of bone: the reconstructive surgeon’s point of view. J Cell Mol Med 2006, 10(1):7-19.
  • [4]Boden SD, Zdeblick TA, Sandhu HS, Heim SE: The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 2000, 25(3):376-381.
  • [5]Einhorn TA: Clinical applications of recombinant human BMPs: early experience and future development. J Bone Joint Surg Am 2003, 85-A Suppl 3:82-88.
  • [6]Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S: Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 2001, 83-A Suppl 1(Pt 2):S151-158.
  • [7]Mont MA, Ragland PS, Biggins B, Friedlaender G, Patel T, Cook S, Etienne G, Shimmin A, Kildey R, Rueger DC, et al.: Use of bone morphogenetic proteins for musculoskeletal applications. An overview. J Bone Joint Surg Am 2004, 86-A(Suppl 2):41-55.
  • [8]Reddi AH: Bone morphogenetic proteins: from basic science to clinical applications. J Bone Joint Surg Am 2001, 83-A Suppl 1(Pt 1):S1-6.
  • [9]Talwar R, Di Silvio L, Hughes FJ, King GN: Effects of carrier release kinetics on bone morphogenetic protein-2-induced periodontal regeneration in vivo. J Clin Periodontol 2001, 28(4):340-347.
  • [10]Uludag H, Gao T, Porter TJ, Friess W, Wozney JM: Delivery systems for BMPs: factors contributing to protein retention at an application site. J Bone Joint Surg Am 2001, 83-A Suppl 1(Pt 2):S128-135.
  • [11]Evans CH, Ghivizzani SC, Robbins PD: The 2003 Nicolas Andry Award. Orthopaedic gene therapy. Clin Orthop Relat Res 2004, 429:316-329.
  • [12]Lieberman JR, Daluiski A, Einhorn TA: The role of growth factors in the repair of bone. Biology and clinical applications. J Bone Joint Surg Am 2002, 84-A(6):1032-1044.
  • [13]Scaduto AA, Lieberman JR: Gene therapy for osteoinduction. Orthop Clin North Am 1999, 30(4):625-633.
  • [14]Betz OB, Betz VM, Nazarian A, Pilapil CG, Vrahas MS, Bouxsein ML, Gerstenfeld LC, Einhorn TA, Evans CH: Direct percutaneous gene delivery to enhance healing of segmental bone defects. J Bone Joint Surg Am 2006, 88(2):355-365.
  • [15]Betz VM, Betz OB, Glatt V, Gerstenfeld LC, Einhorn TA, Bouxsein ML, Vrahas MS, Evans CH: Healing of segmental bone defects by direct percutaneous gene delivery: effect of vector dose. Hum Gene Ther 2007, 18(10):907-915.
  • [16]Betz OB, Betz VM, Nazarian A, Egermann M, Gerstenfeld LC, Einhorn TA, Vrahas MS, Bouxsein ML, Evans CH: Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects. Gene Ther 2007, 14(13):1039-1044.
  • [17]Lieberman JR, Le LQ, Wu L, Finerman GA, Berk A, Witte ON, Stevenson S: Regional gene therapy with a BMP-2-producing murine stromal cell line induces heterotopic and orthotopic bone formation in rodents. J Orthop Res 1998, 16(3):330-339.
  • [18]Zachos T, Diggs A, Weisbrode S, Bartlett J, Bertone A: Mesenchymal stem cell-mediated gene delivery of bone morphogenetic protein-2 in an articular fracture model. Mol Ther 2007, 15(8):1543-1550.
  • [19]Dragoo JL, Choi JY, Lieberman JR, Huang J, Zuk PA, Zhang J, Hedrick MH, Benhaim P: Bone induction by BMP-2 transduced stem cells derived from human fat. J Orthop Res 2003, 21(4):622-629.
  • [20]Krebsbach PH, Gu K, Franceschi RT, Rutherford RB: Gene therapy-directed osteogenesis: BMP-7-transduced human fibroblasts form bone in vivo. Hum Gene Ther 2000, 11(8):1201-1210.
  • [21]Peng H, Wright V, Usas A, Gearhart B, Shen HC, Cummins J, Huard J: Synergistic enhancement of bone formation and healing by stem cell-expressed VEGF and bone morphogenetic protein-4. J Clin Invest 2002, 110(6):751-759.
  • [22]Shen HC, Peng H, Usas A, Gearhart B, Fu FH, Huard J: Structural and functional healing of critical-size segmental bone defects by transduced muscle-derived cells expressing BMP4. J Gene Med 2004, 6(9):984-991.
  • [23]Betz OB, Betz VM, Abdulazim A, Penzkofer R, Schmitt B, Schroder C, Augat P, Jansson V, Muller PE: Healing of large segmental bone defects induced by expedited bone morphogenetic protein-2 gene-activated, syngeneic muscle grafts. Hum Gene Ther 2009, 20(12):1589-1596.
  • [24]Deutinger M, Kuzbari R, Paternostro T, Todoroff B, Becker MH: Functional and esthetic assessment of donor site defects following transfer of the gracilis muscle. Handchir Mikrochir Plast Chir 1995, 27(2):90-92.
  • [25]Chen HC, Santamaria E, Chen HH, Cheng MH, Chang CJ, Tang YB: Microvascular vastus lateralis muscle flap for chronic empyema associated with a large cavity. Ann Thorac Surg 1999, 67(3):866-869.
  • [26]Kaplan J, Kaplan FS, Shore EM: Restoration of normal BMP signaling levels and osteogenic differentiation in FOP mesenchymal progenitor cells by mutant allele-specific targeting. Gene Ther 2011, 19(7):786-790.
  • [27]Benten D, Kumaran V, Joseph B, Schattenberg J, Popov Y, Schuppan D, Gupta S: Hepatocyte transplantation activates hepatic stellate cells with beneficial modulation of cell engraftment in the rat. Hepatology 2005, 42(5):1072-1081.
  • [28]Iida J, Yoshikawa T, Akahane M, Ohgushi H, Dohi Y, Takakura Y, Nonomura A: Osteogenic potential of cultured bone/ceramic construct: comparison with marrow mesenchymal cell/ceramic composite. Cell Transplant 2004, 13(4):357-365.
  • [29]Niranjan A, Fellows W, Stauffer W, Burton EA, Hong CS, Lunsford LD, Kondziolka D, Glorioso JC, Gobbel GT: Survival of transplanted neural progenitor cells enhanced by brain irradiation. J Neurosurg 2007, 107(2):383-391.
  • [30]Einhorn TA, Lane JM, Burstein AH, Kopman CR, Vigorita VJ: The healing of segmental bone defects induced by demineralized bone matrix. A radiographic and biomechanical study. J Bone Joint Surg Am 1984, 66(2):274-279.
  • [31]Meinel L, Fajardo R, Hofmann S, Langer R, Chen J, Snyder B, Vunjak-Novakovic G, Kaplan D: Silk implants for the healing of critical size bone defects. Bone 2005, 37(5):688-698.
  • [32]Rajagopalan S, Lu L, Yaszemski MJ, Robb RA: Optimal segmentation of microcomputed tomographic images of porous tissue-engineering scaffolds. J Biomed Mat Res 2005, 75(4):877-887.
  • [33]Hildebrand T, Laib A, Muller R, Dequeker J, Ruegsegger P: Direct three-dimensional morphometric analysis of human cancellous bone: microstructural data from spine, femur, iliac crest, and calcaneus. J Bone Miner Res 1999, 14(7):1167-1174.
  文献评价指标  
  下载次数:39次 浏览次数:19次