Treatment of critical-sized bone defects: clinical and tissue engineering perspectives

  • Erika Roddy
  • Malcolm R. DeBaun
  • Adam Daoud-Gray
  • Yunzhi P. Yang
  • Michael J. Gardner
General Review • BONE - TRAUMA


Critical-sized bone defects are defined as those that will not heal spontaneously within a patient’s lifetime. Current treatment options include vascularized bone grafts, distraction osteogenesis, and the induced membrane technique. The induced membrane technique is an increasingly utilized method with favorable results including high rates of union. Tissue engineering holds promise in the treatment of large bone defects due to advancement of stem cell biology, novel biomaterials, and 3D bioprinting. In this review, we provide an overview of the current operative treatment strategies of critical-sized bone defects as well as the current state of tissue engineering for such defects.


Critical bone defects Bone tissue engineering Bone healing Fracture healing 



Generous support from Kent Thiry and Denise O’Leary, Boswell Foundation, NIH R01AR057837 (NIAMS), and NIH 1U01AR069395 (NIAMS).

Compliance with ethical standards

Conflict of interest

Drs. Roddy, DeBaun, Daoud, and Yang have no conflicts of interest to declare. Dr. Gardner reports personal fees from DePuy-Synthes, personal fees from KCI, personal fees from Miami Medical, personal fees from Biocomposites, personal fees from Pacira, outside the submitted work.


  1. 1.
    Accadbled F, Mazeau P, Chotel F, Cottalorda J, Sales de Gauzy J, Kohler R (2013) Induced-membrane femur reconstruction after resection of bone malignancies: three cases of massive graft resorption in children. Orthop Traumatol Surg Res OTSR 99:479–483. doi: 10.1016/j.otsr.2013.01.008 PubMedCrossRefGoogle Scholar
  2. 2.
    Ackermann PW, Hart DA (2013) Influence of comorbidities: neuropathy, vasculopathy, and diabetes on healing response quality. Adv Wound Care 2:410–421. doi: 10.1089/wound.2012.0437 CrossRefGoogle Scholar
  3. 3.
    Aho OM, Lehenkari P, Ristiniemi J, Lehtonen S, Risteli J, Leskela HV (2013) The mechanism of action of induced membranes in bone repair. J Bone Jt Surg Am 95:597–604. doi: 10.2106/JBJS.L.00310 CrossRefGoogle Scholar
  4. 4.
    Apard T, Bigorre N, Cronier P, Duteille F, Bizot P, Massin P (2010) Two-stage reconstruction of post-traumatic segmental tibia bone loss with nailing. Orthop Traumatol Surg Res OTSR 96:549–553. doi: 10.1016/j.otsr.2010.02.010 PubMedCrossRefGoogle Scholar
  5. 5.
    Aponte-Tinao L, Farfalli GL, Ritacco LE, Ayerza MA, Muscolo DL (2012) Intercalary femur allografts are an acceptable alternative after tumor resection. Clin Orthop Relat Res 470:728–734. doi: 10.1007/s11999-011-1952-5 PubMedCrossRefGoogle Scholar
  6. 6.
    Arai K, Toh S, Tsubo K, Nishikawa S, Narita S, Miura H (2002) Complications of vascularized fibula graft for reconstruction of long bones. Plast Reconstr Surg 109:2301–2306PubMedCrossRefGoogle Scholar
  7. 7.
    Ardeshirylajimi A et al (2015) Enhanced osteoconductivity of polyethersulphone nanofibres loaded with bioactive glass nanoparticles in in vitro and in vivo models. Cell Prolif 48:455–464. doi: 10.1111/cpr.12198 PubMedCrossRefGoogle Scholar
  8. 8.
    Ardeshirylajimi A, Hosseinkhani S, Parivar K, Yaghmaie P, Soleimani M (2013) Nanofiber-based polyethersulfone scaffold and efficient differentiation of human induced pluripotent stem cells into osteoblastic lineage. Mol Biol Rep 40:4287–4294. doi: 10.1007/s11033-013-2515-5 PubMedCrossRefGoogle Scholar
  9. 9.
    Aronson J (1997) Limb-lengthening, skeletal reconstruction, and bone transport with the Ilizarov method. J Bone Jt Surg Am 79:1243–1258CrossRefGoogle Scholar
  10. 10.
    Aronson J, Harrison B, Boyd CM, Cannon DJ, Lubansky HJ (1988) Mechanical induction of osteogenesis: the importance of pin rigidity. J Pediatr Orthop 8:396–401PubMedCrossRefGoogle Scholar
  11. 11.
    Aronson J, Harrison B, Boyd CM, Cannon DJ, Lubansky HJ, Stewart C (1988) Mechanical induction of osteogenesis. Prelim Stud Ann Clin Lab Sci 18:195–203Google Scholar
  12. 12.
    Aronson J, Johnson E, Harp JH (1989) Local bone transportation for treatment of intercalary defects by the Ilizarov technique. Biomechanical and clinical considerations. Clin Orthop Relat Res 243:71–79Google Scholar
  13. 13.
    Bauer TW, Muschler GF (2000) Bone graft materials. An overview of the basic science. Clin Orthop Relat Res 371:10–27CrossRefGoogle Scholar
  14. 14.
    Beris AE, Lykissas MG, Korompilias AV, Vekris MD, Mitsionis GI, Malizos KN, Soucacos PN (2011) Vascularized fibula transfer for lower limb reconstruction. Microsurgery 31:205–211. doi: 10.1002/micr.20841 PubMedCrossRefGoogle Scholar
  15. 15.
    Bilic R et al (2006) Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis. Int Orthop 30:128–134. doi: 10.1007/s00264-005-0045-z PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Blum AL, BongioVanni JC, Morgan SJ, Flierl MA, dos Reis FB (2010) Complications associated with distraction osteogenesis for infected nonunion of the femoral shaft in the presence of a bone defect: a retrospective series. J Bone Jt Surg Br 92:565–570. doi: 10.1302/0301-620X.92B4.23475 CrossRefGoogle Scholar
  17. 17.
    Bullens PH, Minderhoud NM, de Waal Malefijt MC, Veth RP, Buma P, Schreuder HW (2009) Survival of massive allografts in segmental oncological bone defect reconstructions. Int Orthop 33:757–760. doi: 10.1007/s00264-008-0700-2 PubMedCrossRefGoogle Scholar
  18. 18.
    Ceruso M, Taddei F, Bigazzi P, Manfrini M (2008) Vascularised fibula graft inlaid in a massive bone allograft: considerations on the bio-mechanical behaviour of the combined graft in segmental bone reconstructions after sarcoma resection. Injury 39(Suppl 3):S68–74. doi: 10.1016/j.injury.2008.05.014 PubMedCrossRefGoogle Scholar
  19. 19.
    Cha JK, Lee JS, Kim MS, Choi SH, Cho KS, Jung UW (2014) Sinus augmentation using BMP-2 in a bovine hydroxyapatite/collagen carrier in dogs. J Clin Periodontol 41:86–93. doi: 10.1111/jcpe.12174 PubMedCrossRefGoogle Scholar
  20. 20.
    Chaddha M, Gulati D, Singh AP, Singh AP, Maini L (2010) Management of massive posttraumatic bone defects in the lower limb with the Ilizarov technique. Acta Orthop Belg 76:811–820PubMedGoogle Scholar
  21. 21.
    Chakkalakal DA (2005) Alcohol-induced bone loss and deficient bone repair. Alcohol Clin Exp Res 29:2077–2090PubMedCrossRefGoogle Scholar
  22. 22.
    Chotel F, Nguiabanda L, Braillon P, Kohler R, Berard J, Abelin-Genevois K (2012) Induced membrane technique for reconstruction after bone tumor resection in children: a preliminary study. Orthop Traumatol Surg Res OTSR 98:301–308. doi: 10.1016/j.otsr.2011.11.008 PubMedCrossRefGoogle Scholar
  23. 23.
    Claes L, Recknagel S, Ignatius A (2012) Fracture healing under healthy and inflammatory conditions Nature reviews. Rheumatology 8:133–143. doi: 10.1038/nrrheum.2012.1 PubMedGoogle Scholar
  24. 24.
    Conway JD (2010) Autograft and nonunions: morbidity with intramedullary bone graft versus iliac crest bone graft. Orthop Clin N Am 41:75–84. doi: 10.1016/j.ocl.2009.07.006 (table of contents) CrossRefGoogle Scholar
  25. 25.
    Cuthbert RJ, Churchman SM, Tan HB, McGonagle D, Jones E, Giannoudis PV (2013) Induced periosteum a complex cellular scaffold for the treatment of large bone defects. Bone 57:484–492. doi: 10.1016/j.bone.2013.08.009 PubMedCrossRefGoogle Scholar
  26. 26.
    Daftari TK, Whitesides TE Jr, Heller JG, Goodrich AC, McCarey BE, Hutton WC (1994) Nicotine on the revascularization of bone graft. Exp Study Rabbits Spine 19:904–911Google Scholar
  27. 27.
    de Boer HH, Wood MB (1989) Bone changes in the vascularised fibular graft. J Bone Jt Surg Br 71:374–378CrossRefGoogle Scholar
  28. 28.
    de Boer HH, Wood MB, Hermans J (1990) Reconstruction of large skeletal defects by vascularized fibula transfer. Factors that influenced the outcome of union in 62 cases. Int Orthop 14:121–128PubMedCrossRefGoogle Scholar
  29. 29.
    Dimitriou R, Mataliotakis GI, Angoules AG, Kanakaris NK, Giannoudis PV (2011) Complications following autologous bone graft harvesting from the iliac crest and using the RIA: a systematic review. Injury 42(Suppl 2):S3–15. doi: 10.1016/j.injury.2011.06.015 PubMedCrossRefGoogle Scholar
  30. 30.
    Dimitriou R, Tsiridis E, Giannoudis PV (2005) Current concepts of molecular aspects of bone healing. Injury 36:1392–1404. doi: 10.1016/j.injury.2005.07.019 PubMedCrossRefGoogle Scholar
  31. 31.
    Emara KM, Ghafar KA, Al Kersh MA (2011) Methods to shorten the duration of an external fixator in the management of tibial infections. World J Orthop 2:85–92. doi: 10.5312/wjo.v2.i9.85
  32. 32.
    Eward WC, Kontogeorgakos V, Levin LS, Brigman BE (2010) Free vascularized fibular graft reconstruction of large skeletal defects after tumor resection. Clin Orthop Relat Res 468:590–598. doi: 10.1007/s11999-009-1053-x PubMedCrossRefGoogle Scholar
  33. 33.
    Farfalli GL, Aponte-Tinao L, Lopez-Millan L, Ayerza MA, Muscolo DL (2012) Clinical and functional outcomes of tibial intercalary allografts after tumor resection. Orthopedics 35:e391–396. doi: 10.3928/01477447-20120222-25 PubMedCrossRefGoogle Scholar
  34. 34.
    Foulk DA, Szabo RM (1995) Diaphyseal humerus fractures: natural history and occurrence of nonunion. Orthopedics 18:333–335PubMedGoogle Scholar
  35. 35.
    Fourman MS, Borst EW, Bogner E, Rozbruch SR, Fragomen AT (2014) Recombinant human BMP-2 increases the incidence and rate of healing in complex ankle arthrodesis. Clin Orthop Relat Res 472:732–739. doi: 10.1007/s11999-013-3261-7 PubMedCrossRefGoogle Scholar
  36. 36.
    Friedlaender GE et al (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Jt Surg Am 83-A(Suppl 1):S151–S158Google Scholar
  37. 37.
    Friedrich JB, Moran SL, Bishop AT, Wood CM, Shin AY (2008) Free vascularized fibular graft salvage of complications of long-bone allograft after tumor reconstruction. J Bone Jt Surg Am 90:93–100. doi: 10.2106/JBJS.G.00551 CrossRefGoogle Scholar
  38. 38.
    Garrison KR et al (2010) Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD006950.pub2 PubMedGoogle Scholar
  39. 39.
    Gaston MS, Simpson AH (2007) Inhibition of fracture healing. J Bone Jt Surg Br 89:1553–1560. doi: 10.1302/0301-620X.89B12.19671 CrossRefGoogle Scholar
  40. 40.
    Giannoudis PV, Dinopoulos H, Tsiridis E (2005) Bone substitutes: an update. Injury 36(Suppl 3):S20–27. doi: 10.1016/j.injury.2005.07.029 PubMedCrossRefGoogle Scholar
  41. 41.
    Giannoudis PV, Faour O, Goff T, Kanakaris N, Dimitriou R (2011) Masquelet technique for the treatment of bone defects: tips-tricks and future directions. Injury 42:591–598. doi: 10.1016/j.injury.2011.03.036 PubMedCrossRefGoogle Scholar
  42. 42.
    Goel A, Sangwan SS, Siwach RC, Ali AM (2005) Percutaneous bone marrow grafting for the treatment of tibial non-union. Injury 36:203–206. doi: 10.1016/j.injury.2004.01.009 PubMedCrossRefGoogle Scholar
  43. 43.
    Goulet JA, Senunas LE, DeSilva GL, Greenfield ML (1997) Autogenous iliac crest bone graft. Complications and functional assessment. Clin Orthop Relat Res 339:76–81CrossRefGoogle Scholar
  44. 44.
    Gouron R, Deroussen F, Plancq MC, Collet LM (2013) Bone defect reconstruction in children using the induced membrane technique: a series of 14 cases. Orthop Traumatol Surg Res OTSR 99:837–843. doi: 10.1016/j.otsr.2013.05.005 PubMedCrossRefGoogle Scholar
  45. 45.
    Gouron R, Petit L, Boudot C, Six I, Brazier M, Kamel S, Mentaverri R (2014) Osteoclasts and their precursors are present in the induced-membrane during bone reconstruction using the Masquelet technique. J Tissue Eng Regen Med. doi: 10.1002/term.1921 PubMedGoogle Scholar
  46. 46.
    Govender S et al (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Jt Surg Am 84-A:2123–2134CrossRefGoogle Scholar
  47. 47.
    Green SA (1994) Skeletal defects. A comparison of bone grafting and bone transport for segmental skeletal defects. Clin Orthop Relat Res 301:111–117Google Scholar
  48. 48.
    Haverstock BD, Mandracchia VJ (1998) Cigarette smoking and bone healing: implications in foot and ankle surgery. J Foot Ankle Surg 37:69–74 (discussion 78) PubMedCrossRefGoogle Scholar
  49. 49.
    Heitmann C, Erdmann D, Levin LS (2002) Treatment of segmental defects of the humerus with an osteoseptocutaneous fibular transplant. J Bone Jt Surg Am 84-A:2216–2223CrossRefGoogle Scholar
  50. 50.
    Henrich D et al (2013) Establishment and characterization of the Masquelet induced membrane technique in a rat femur critical-sized defect model. J Tissue Eng Regen Med. doi: 10.1002/term.1826 PubMedGoogle Scholar
  51. 51.
    Hernandez RK, Do TP, Critchlow CW, Dent RE, Jick SS (2012) Patient-related risk factors for fracture-healing complications in the United Kingdom general practice research database. Acta Orthop 83:653–660. doi: 10.3109/17453674.2012.747054 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hernigou P, Mathieu G, Poignard A, Manicom O, Beaujean F, Rouard H (2006) Percutaneous autologous bone-marrow grafting for nonunions. Surgical technique. J Bone Jt Surg Am 88(Suppl 1 Pt 2):322–327. doi: 10.2106/JBJS.F.00203 CrossRefGoogle Scholar
  53. 53.
    Higgins TF, Casey V, Bachus K (2007) Cortical heat generation using an irrigating/aspirating single-pass reaming vs conventional stepwise reaming. J Orthop Trauma 21:192–197. doi: 10.1097/BOT.0b013e318038d952 PubMedCrossRefGoogle Scholar
  54. 54.
    Houdek MT, Wagner ER, Stans AA, Shin AY, Bishop AT, Sim FH, Moran SL (2016) What is the outcome of allograft and intramedullary free fibula (capanna technique) in pediatric and adolescent patients with bone tumors? Clin Orthop Relat Res 474:660–668. doi: 10.1007/s11999-015-4204-2 PubMedCrossRefGoogle Scholar
  55. 55.
    Huddleston PM, Steckelberg JM, Hanssen AD, Rouse MS, Bolander ME, Patel R (2000) Ciprofloxacin inhibition of experimental fracture healing. J Bone Jt Surg Am 82:161–173CrossRefGoogle Scholar
  56. 56.
    Ja K (1934) The effect of a local calcium depot on osteogenesis and healing of fractures. J Bone Jt Surg Am 16:176–184Google Scholar
  57. 57.
    Jin HH, Kim DH, Kim TW, Shin KK, Jung JS, Park HC, Yoon SY (2012) In vivo evaluation of porous hydroxyapatite/chitosan-alginate composite scaffolds for bone tissue engineering. Int J Biol Macromol 51:1079–1085. doi: 10.1016/j.ijbiomac.2012.08.027 PubMedCrossRefGoogle Scholar
  58. 58.
    Jun SH, Lee EJ, Jang TS, Kim HE, Jang JH, Koh YH (2013) Bone morphogenic protein-2 (BMP-2) loaded hybrid coating on porous hydroxyapatite scaffolds for bone tissue engineering. J Mater Sci Mater Med 24:773–782. doi: 10.1007/s10856-012-4822-0 PubMedCrossRefGoogle Scholar
  59. 59.
    Kanakaris NK et al (2009) Application of bone morphogenetic proteins to femoral non-unions: a 4-year multicentre experience. Injury 40(Suppl 3):S54–S61. doi: 10.1016/S0020-1383(09)70013-0 PubMedCrossRefGoogle Scholar
  60. 60.
    Kaneda K, Kurakami C, Minami A (1988) Free vascularized fibular strut graft in the treatment of kyphosis. Spine 13:1273–1277PubMedCrossRefGoogle Scholar
  61. 61.
    Kang Y, Scully A, Young DA, Kim S, Tsao H, Sen M, Yang Y (2011) Enhanced mechanical performance and biological evaluation of a PLGA coated beta-TCP composite scaffold for load-bearing applications. Eur Polym J 47:1569–1577. doi: 10.1016/j.eurpolymj.2011.05.004 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Karger C, Kishi T, Schneider L, Fitoussi F, Masquelet AC, French Society of Orthopaedic S, Traumatology (2012) Treatment of posttraumatic bone defects by the induced membrane technique. Orthop Traumatol Surg Res OTSR 98:97–102. doi: 10.1016/j.otsr.2011.11.001 PubMedCrossRefGoogle Scholar
  63. 63.
    Keating JF, Simpson AH, Robinson CM (2005) The management of fractures with bone loss. J Bone Jt Surg Br 87:142–150CrossRefGoogle Scholar
  64. 64.
    Kim DH et al (2009) Prospective study of iliac crest bone graft harvest site pain and morbidity. Spine J 9:886–892. doi: 10.1016/j.spinee.2009.05.006 PubMedCrossRefGoogle Scholar
  65. 65.
    Kline AJ, Gruen GS, Pape HC, Tarkin IS, Irrgang JJ, Wukich DK (2009) Early complications following the operative treatment of pilon fractures with and without diabetes. Foot Ankle Int 30:1042–1047. doi: 10.3113/FAI.2009.1042 PubMedCrossRefGoogle Scholar
  66. 66.
    Kyro A, Usenius JP, Aarnio M, Kunnamo I, Avikainen V (1993) Are smokers a risk group for delayed healing of tibial shaft fractures? Ann Chir Gynaecol 82:254–262PubMedGoogle Scholar
  67. 67.
    Lee KS, Han SB, Baek JR (2004) Free vascularized osteocutaneous fibular graft to the tibia in 51 consecutive cases. J Reconstr Microsurg 20:277–284. doi: 10.1055/s-2004-824884 PubMedCrossRefGoogle Scholar
  68. 68.
    Li J, Wang Z, Guo Z, Chen GJ, Fu J, Pei GX (2010) The use of allograft shell with intramedullary vascularized fibula graft for intercalary reconstruction after diaphyseal resection for lower extremity bony malignancy. J Surg Oncol 102:368–374. doi: 10.1002/jso.21620 PubMedCrossRefGoogle Scholar
  69. 69.
    Li Z, Ramay HR, Hauch KD, Xiao D, Zhang M (2005) Chitosan-alginate hybrid scaffolds for bone tissue engineering. Biomaterials 26:3919–3928. doi: 10.1016/j.biomaterials.2004.09.062 PubMedCrossRefGoogle Scholar
  70. 70.
    Liang K, Xiang Z, Chen S, Cen S, Zhong G, Yi M, Huang F (2012) Folded free vascularized fibular grafts for the treatment of subtrochanteric fractures complicated with segmental bone defects. J Trauma Acute Care Surg 72:1404–1410. doi: 10.1097/TA.0b013e31824473ce PubMedCrossRefGoogle Scholar
  71. 71.
    Lin CH, Wei FC, Chen HC, Chuang DC (1999) Outcome comparison in traumatic lower-extremity reconstruction by using various composite vascularized bone transplantation. Plast Reconstr Surg 104:984–992PubMedCrossRefGoogle Scholar
  72. 72.
    Ling XF, Peng X (2012) What is the price to pay for a free fibula flap? A systematic review of donor-site morbidity following free fibula flap surgery. Plast Reconstr Surg 129:657–674. doi: 10.1097/PRS.0b013e3182402d9a PubMedCrossRefGoogle Scholar
  73. 73.
    Liu H, Hu G, Shang P, Shen Y, Nie P, Peng L, Xu H (2013) Histological characteristics of induced membranes in subcutaneous, intramuscular sites and bone defect. Orthop Traumatol Surg Res OTSR 99:959–964. doi: 10.1016/j.otsr.2013.08.009 PubMedCrossRefGoogle Scholar
  74. 74.
    Liu Y, Ming L, Luo H, Liu W, Zhang Y, Liu H, Jin Y (2013) Integration of a calcined bovine bone and BMSC-sheet 3D scaffold and the promotion of bone regeneration in large defects. Biomaterials 34:9998–10006. doi: 10.1016/j.biomaterials.2013.09.040 PubMedCrossRefGoogle Scholar
  75. 75.
    Loder RT (1988) The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res 232:210–216Google Scholar
  76. 76.
    Lowe JA, Della Rocca GJ, Murtha Y, Liporace FA, Stover MD, Nork SE, Crist BD (2010) Complications associated with negative pressure reaming for harvesting autologous bone graft: a case series. J Orthop Trauma 24:46–52. doi: 10.1097/BOT.0b013e31819c0ccb PubMedCrossRefGoogle Scholar
  77. 77.
    Lyons FG, Gleeson JP, Partap S, Coghlan K, O'Brien FJ (2014) Novel microhydroxyapatite particles in a collagen scaffold: a bioactive bone void filler? Clin Orthop Relat Res 472(4):1318–1328Google Scholar
  78. 78.
    Maeda M, Bryant MH, Yamagata M, Li G, Earle JD, Chao EY (1988) Effects of irradiation on cortical bone and their time-related changes. A biomechanical and histomorphological study. J Bone Jt Surg Am 70:392–399CrossRefGoogle Scholar
  79. 79.
    Malizos KN, Zalavras CG, Soucacos PN, Beris AE, Urbaniak JR (2004) Free vascularized fibular grafts for reconstruction of skeletal defects. J Am Acad Orthop Surg 12:360–369PubMedCrossRefGoogle Scholar
  80. 80.
    Marcacci M, Kon E, Moukhachev V, Lavroukov A, Kutepov S, Quarto R, Mastrogiacomo M, Cancedda R (2007) Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study. Tissue Eng 13(5):947–955Google Scholar
  81. 81.
    Mariner PD, Wudel JM, Miller DE, Genova EE, Streubel SO, Anseth KS (2013) Synthetic hydrogel scaffold is an effective vehicle for delivery of INFUSE (rhBMP2) to critical-sized calvaria bone defects in rats. J Orthop Res 31:401–406. doi: 10.1002/jor.22243 PubMedCrossRefGoogle Scholar
  82. 82.
    Masquelet AC (2003) Muscle reconstruction in reconstructive surgery: soft tissue repair and long bone reconstruction Langenbeck’s archives of surgery / Deutsche Gesellschaft fur. Chirurgie 388:344–346. doi: 10.1007/s00423-003-0379-1 Google Scholar
  83. 83.
    Masquelet AC, Begue T (2010) The concept of induced membrane for reconstruction of long bone defects. Orthop Clin N Am 41:27–37. doi: 10.1016/j.ocl.2009.07.011 (table of contents) CrossRefGoogle Scholar
  84. 84.
    Masquelet AC, Fitoussi F, Begue T, Muller GP (2000) Reconstruction of the long bones by the induced membrane and spongy autograft. Ann Chir Plast Esthet 45:346–353PubMedGoogle Scholar
  85. 85.
    McBride JCM, Banks RE, Taylor D, Ryan J (1993) Healing of segmental bone defects in goat tibia. J Invest Surg 6:369Google Scholar
  86. 86.
    McCullen SD, Chow AG, Stevens MM (2011) In vivo tissue engineering of musculoskeletal tissues. Curr Opin Biotechnol 22:715–720. doi: 10.1016/j.copbio.2011.05.001 PubMedCrossRefGoogle Scholar
  87. 87.
    Mercado-Pagan AE, Kang Y, Ker DF, Park S, Yao J, Bishop J, Yang Y (2013) Synthesis and characterization of novel elastomeric poly(D, L-lactide urethane) maleate composites for bone tissue engineering. Eur Polym J 49:3337–3349. doi: 10.1016/j.eurpolymj.2013.07.004 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Mercado-Pagan AE, Stahl AM, Shanjani Y, Yang Y (2015) Vascularization in bone tissue engineering constructs. Ann Biomed Eng 43:718–729. doi: 10.1007/s10439-015-1253-3 PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Minami A, Kasashima T, Iwasaki N, Kato H, Kaneda K (2000) Vascularised fibular grafts. An experience of 102 patients. J Bone Jt Surg Br 82:1022–1025CrossRefGoogle Scholar
  90. 90.
    Muramatsu K, Ihara K, Shigetomi M, Kawai S (2004) Femoral reconstruction by single, folded or double free vascularised fibular grafts. Br J Plast Surg 57:550–555. doi: 10.1016/j.bjps.2003.08.021 PubMedCrossRefGoogle Scholar
  91. 91.
    Muscolo DL (2012) Accurate 3-dimensional preoperative planning and resection in orthopedic oncology. Orthopedics 35:7–8. doi: 10.3928/01477447-20111122-01 PubMedCrossRefGoogle Scholar
  92. 92.
    Muscolo DL, Ayerza MA, Aponte-Tinao LA (2006) Massive allograft use in orthopedic oncology. Orthop Clin N Am 37:65–74. doi: 10.1016/j.ocl.2005.08.003 CrossRefGoogle Scholar
  93. 93.
    Ng VY (2012) Risk of disease transmission with bone allograft. Orthopedics 35:679–681. doi: 10.3928/01477447-20120725-04 PubMedCrossRefGoogle Scholar
  94. 94.
    Noaman HH (2013) Management of upper limb bone defects using free vascularized osteoseptocutaneous fibular bone graft. Ann Plast Surg 71:503–509. doi: 10.1097/SAP.0b013e3182a1aff0 PubMedCrossRefGoogle Scholar
  95. 95.
    Nusbickel FR, Dell PC, McAndrew MP, Moore MM (1989) Vascularized autografts for reconstruction of skeletal defects following lower extremity trauma. Rev Clin Orthop Relat Res 243:65–70Google Scholar
  96. 96.
    Ozaksar K, Sugun TS, Toros T, Gurbuz Y, Kayalar M, Ozerkan F (2012) Free vascularized fibular grafts in type 3 open tibia fractures. Acta orthopaedica et traumatologica turcica 46:430–437PubMedCrossRefGoogle Scholar
  97. 97.
    Palatnik Y, Rozbruch SR (2011) Femoral reconstruction using external fixation. Adv Orthop 2011:967186. doi: 10.4061/2011/967186 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Paley D (1990) Problems, obstacles, and complications of limb lengthening by the Ilizarov technique. Clin Orthop Relat Res 250:81–104Google Scholar
  99. 99.
    Paley D, Catagni M, Argnani F, Prevot J, Bell D, Armstrong P (1992) Treatment of congenital pseudoarthrosis of the tibia using the Ilizarov technique. Clin Orthop Relat Res 250:81–93Google Scholar
  100. 100.
    Paley D, Herzenberg JE, Paremain G, Bhave A (1997) Femoral lengthening over an intramedullary nail. A matched-case comparison with Ilizarov femoral lengthening. J Bone Jt Surg Am 79:1464–1480CrossRefGoogle Scholar
  101. 101.
    Paley D, Maar DC (2000) Ilizarov bone transport treatment for tibial defects. J Orthop Trauma 14:76–85PubMedCrossRefGoogle Scholar
  102. 102.
    Papakostidis C, Bhandari M, Giannoudis PV (2013) Distraction osteogenesis in the treatment of long bone defects of the lower limbs: effectiveness, complications and clinical results; a systematic review and meta-analysis. Bone Jt J 95-B:1673–1680. doi: 10.1302/0301-620X.95B12.32385 CrossRefGoogle Scholar
  103. 103.
    Pape HC, Zelle BA, Hildebrand F, Giannoudis PV, Krettek C, van Griensven M (2005) Reamed femoral nailing in sheep: does irrigation and aspiration of intramedullary contents alter the systemic response? J Bone Jt Surg Am 87:2515–2522. doi: 10.2106/JBJS.D.02024 Google Scholar
  104. 104.
    Patel RA, Wilson RF, Patel PA, Palmer RM (2013) The effect of smoking on bone healing: A systematic review. Bone Jt Res 2:102–111. doi: 10.1302/2046-3758.26.2000142 CrossRefGoogle Scholar
  105. 105.
    Pelissier P, Bollecker V, Martin D, Baudet J (2002) Foot reconstruction with the “bi-Masquelet” procedure. Ann Chir Plast Esthet 47:304–307PubMedCrossRefGoogle Scholar
  106. 106.
    Pelissier P, Masquelet AC, Bareille R, Pelissier SM, Amedee J (2004) Induced membranes secrete growth factors including vascular and osteoinductive factors and could stimulate bone regeneration. J Orthop Res 22:73–79. doi: 10.1016/S0736-0266(03)00165-7 PubMedCrossRefGoogle Scholar
  107. 107.
    Porter SE, Hanley EN Jr (2001) The musculoskeletal effects of smoking. J Ame Acad Orthop Surg 9:9–17CrossRefGoogle Scholar
  108. 108.
    Qi Y, Sun HT, Fan YG, Li FM, Lin ZS (2016) Do stress fractures induce hypertrophy of the grafted fibula? A report of three cases received free vascularized fibular graft treatment for tibial defects. Chin J Traumatol = Zhonghua chuang shang za zhi / Chin Med Assoc 19:179–181Google Scholar
  109. 109.
    Quinlan E, Thompson EM, Matsiko A, O'Brien FJ, Lopez-Noriega A (2015) Long-term controlled delivery of rhBMP-2 from collagen-hydroxyapatite scaffolds for superior bone tissue regeneration. J Control Release 207:112–119Google Scholar
  110. 110.
    Qvick LM, Ritter CA, Mutty CE, Rohrbacher BJ, Buyea CM, Anders MJ (2013) Donor site morbidity with reamer-irrigator-aspirator (RIA) use for autogenous bone graft harvesting in a single centre 204 case series. Injury 44:1263–1269. doi: 10.1016/j.injury.2013.06.008 PubMedCrossRefGoogle Scholar
  111. 111.
    Rabitsch K, Maurer-Ertl W, Pirker-Fruhauf U, Wibmer C, Leithner A (2013) Intercalary reconstructions with vascularised fibula and allograft after tumour resection in the lower limb. Sarcoma 2013:160295. doi: 10.1155/2013/160295 PubMedPubMedCentralGoogle Scholar
  112. 112.
    Reichert JC et al (2012) A tissue engineering solution for segmental defect regeneration in load-bearing long bones. Sci Transl Med 4:141ra193. doi: 10.1126/scitranslmed.3003720 CrossRefGoogle Scholar
  113. 113.
    Repo JP, Sommarhem A, Roine RP, Sintonen H, Halonen T, Tukiainen E (2016) Free vascularized fibular graft is reliable in upper extremity long-bone reconstruction with good long-term outcomes. J Reconstr Microsurg. doi: 10.1055/s-0036-1581075 Google Scholar
  114. 114.
    Retzepi M, Donos N (2010) The effect of diabetes mellitus on osseous healing. Clin Oral Implant Res 21:673–681. doi: 10.1111/j.1600-0501.2010.01923.x CrossRefGoogle Scholar
  115. 115.
    Rezwan K, Chen QZ, Blaker JJ, Boccaccini AR (2006) Biodegradable and bioactive porous polymer/inorganic composite scaffolds for bone tissue engineering. Biomaterials 27:3413–3431. doi: 10.1016/j.biomaterials.2006.01.039 PubMedCrossRefGoogle Scholar
  116. 116.
    Riebel GD, Boden SD, Whitesides TE, Hutton WC (1995) The effect of nicotine on incorporation of cancellous bone graft in an animal model. Spine 20:2198–2202PubMedCrossRefGoogle Scholar
  117. 117.
    Ronga M, Ferraro S, Fagetti A, Cherubino M, Valdatta L, Cherubino P (2014) Masquelet technique for the treatment of a severe acute tibial bone loss. Injury 45(Suppl 6):S111–115. doi: 10.1016/j.injury.2014.10.033 PubMedCrossRefGoogle Scholar
  118. 118.
    Roohani-Esfahani SI, Nouri-Khorasani S, Lu Z, Appleyard R, Zreiqat H (2010) The influence hydroxyapatite nanoparticle shape and size on the properties of biphasic calcium phosphate scaffolds coated with hydroxyapatite-PCL composites. Biomaterials 31:5498–5509. doi: 10.1016/j.biomaterials.2010.03.058 PubMedCrossRefGoogle Scholar
  119. 119.
    Sales de Gauzy J et al (2012) Traumatic diaphyseal bone defects in children. Orthop Traumatol Surg Res OTSR 98:220–226. doi: 10.1016/j.otsr.2012.01.001 PubMedCrossRefGoogle Scholar
  120. 120.
    Schmidmaier G, Herrmann S, Green J, Weber T, Scharfenberger A, Haas NP, Wildemann B (2006) Quantitative assessment of growth factors in reaming aspirate, iliac crest, and platelet preparation. Bone 39:1156–1163. doi: 10.1016/j.bone.2006.05.023 PubMedCrossRefGoogle Scholar
  121. 121.
    Schmitz JP, Hollinger JO (1986) The critical size defect as an experimental model for craniomandibulofacial nonunions. Clin Orthop Relat Res 205:299–308Google Scholar
  122. 122.
    Scholz AO, Gehrmann S, Glombitza M, Kaufmann RA, Bostelmann R, Flohe S, Windolf J (2015) Reconstruction of septic diaphyseal bone defects with the induced membrane technique. Injury 46(Suppl 4):S121–124. doi: 10.1016/S0020-1383(15)30030-9 PubMedCrossRefGoogle Scholar
  123. 123.
    Seebach C, Henrich D, Kahling C, Wilhelm K, Tami AE, Alini M, Marzi I (2010) Endothelial progenitor cells and mesenchymal stem cells seeded onto beta-TCP granules enhance early vascularization and bone healing in a critical-sized bone defect in rats. Tissue Eng Part A 16:1961–1970. doi: 10.1089/ten.TEA.2009.0715 PubMedCrossRefGoogle Scholar
  124. 124.
    Shekaran A, Garcia JR, Clark AY, Kavanaugh TE, Lin AS, Guldberg RE, Garcia AJ (2014) Bone regeneration using an alpha 2 beta 1 integrin-specific hydrogel as a BMP-2 delivery vehicle. Biomaterials 35:5453–5461. doi: 10.1016/j.biomaterials.2014.03.055 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Shi Y et al (2016) Evaluation of a novel HA/ZrO2-based porous bioceramic artificial vertebral body combined with a rhBMP-2/chitosan slow-release hydrogel. PLoS ONE 11:e0157698. doi: 10.1371/journal.pone.0157698 PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Song HR, Kale A, Park HB, Koo KH, Chae DJ, Oh CW, Chung DW (2003) Comparison of internal bone transport and vascularized fibular grafting for femoral bone defects. J Orthop Trauma 17:203–211PubMedCrossRefGoogle Scholar
  127. 127.
    Soucacos PN, Kokkalis ZT, Piagkou M, Johnson EO (2013) Vascularized bone grafts for the management of skeletal defects in orthopaedic trauma and reconstructive surgery. Injury 44(Suppl 1):S70–75. doi: 10.1016/S0020-1383(13)70016-0 PubMedCrossRefGoogle Scholar
  128. 128.
    Soucacos PN, Korompilias AV, Vekris MD, Zoubos A, Beris AE (2011) The free vascularized fibular graft for bridging large skeletal defects of the upper extremity. Microsurgery 31:190–197. doi: 10.1002/micr.20862 PubMedCrossRefGoogle Scholar
  129. 129.
    Stevenson S (1998) Enhancement of fracture healing with autogenous and allogeneic bone grafts. Clin Orthop Relat Res 355:S239–246CrossRefGoogle Scholar
  130. 130.
    Strong DM et al (1996) Immunologic responses in human recipients of osseous and osteochondral allografts. Clin Orthop Relat Res 326:107–114CrossRefGoogle Scholar
  131. 131.
    Tatara AM, Wong ME, Mikos AG (2014) In vivo bioreactors for mandibular reconstruction. J Dent Res 93:1196–1202. doi: 10.1177/0022034514547763 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Tierney CM, Haugh MG, Liedl J, Mulcahy F, Hayes B, O’Brien FJ (2009) The effects of collagen concentration and crosslink density on the biological, structural and mechanical properties of collagen-GAG scaffolds for bone tissue engineering. J Mech Behav Biomed Mater 2:202–209. doi: 10.1016/j.jmbbm.2008.08.007 PubMedCrossRefGoogle Scholar
  133. 133.
    Vail TP, Urbaniak JR (1996) Donor-site morbidity with use of vascularized autogenous fibular grafts. J Bone Jt Surg Am 78:204–211CrossRefGoogle Scholar
  134. 134.
    Villa MM, Wang L, Huang J, Rowe DW, Wei M (2015) Bone tissue engineering with a collagen-hydroxyapatite scaffold and culture expanded bone marrow stromal cells. J Biomed Mater Res B Appl Biomater 103(2):243–253 Google Scholar
  135. 135.
    Villemagne T, Bonnard C, Accadbled F, L’Kaissi M, de Billy B, de Gauzy SJ (2011) Intercalary segmental reconstruction of long bones after malignant bone tumor resection using primary methyl methacrylate cement spacer interposition and secondary bone grafting: the induced membrane technique. J Pediatr Orthop 31:570–576. doi: 10.1097/BPO.0b013e31821ffa82 PubMedCrossRefGoogle Scholar
  136. 136.
    Wong TM, Lau TW, Li X, Fang C, Yeung K, Leung F (2014) Masquelet technique for treatment of posttraumatic bone defects. TheScientificWorldJournal 2014:710302. doi: 10.1155/2014/710302 PubMedPubMedCentralGoogle Scholar
  137. 137.
    Wood MB, Bishop AT (2007) Massive bone defects of the upper limb: reconstruction by vascularized bone transfer. Hand Clin 23:49–56. doi: 10.1016/j.hcl.2007.01.002 PubMedCrossRefGoogle Scholar
  138. 138.
    Woon CY, Chong KW, Wong MK (2010) Induced membranes—a staged technique of bone-grafting for segmental bone loss: a report of two cases and a literature review. J Bone Jt Surg Am 92:196–201. doi: 10.2106/JBJS.I.00273 CrossRefGoogle Scholar
  139. 139.
    Yajima H, Tamai S, Mizumoto S, Ono H (1993) Vascularised fibular grafts for reconstruction of the femur. J Bone Jt Surg Br 75:123–128CrossRefGoogle Scholar
  140. 140.
    Zappaterra T et al (2011) Induced membrane technique for the reconstruction of bone defects in upper limb. A prospective single center study of nine cases. Chir Main 30:255–263. doi: 10.1016/j.main.2011.06.005 PubMedCrossRefGoogle Scholar
  141. 141.
    Zhen P, Hu YY, Luo ZJ, Liu XY, Lu H, Li XS (2010) One-stage treatment and reconstruction of Gustilo Type III open tibial shaft fractures with a vascularized fibular osteoseptocutaneous flap graft. J Orthop Trauma 24:745–751. doi: 10.1097/BOT.0b013e3181d88a07 PubMedCrossRefGoogle Scholar
  142. 142.
    Zigdon-Giladi H, Bick T, Lewinson D, Machtei EE (2015) Co-transplantation of endothelial progenitor cells and mesenchymal stem cells promote neovascularization and bone regeneration. Clin Implant Dent Relat Res 17:353–359. doi: 10.1111/cid.12104 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag France SAS 2017

Authors and Affiliations

  1. 1.School of MedicineUniversity of California, San Francisco (UCSF)San FranciscoUSA
  2. 2.Department of Orthopaedic SurgeryStanford UniversityStanfordUSA
  3. 3.School of MedicineStanford University School of MedicineStanfordUSA
  4. 4.Department of Orthopedic SurgeryStanford UniversityStanfordUSA
  5. 5.Department of BioengineeringStanford UniversityStanfordUSA
  6. 6.Department of Materials Science and EngineeringStanford UniversityStanfordUSA

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