Skip to main content

Bone Grafting in the Regenerative Reconstruction of Critical-Size Long Bone Segmental Defects

  • 203 Accesses

Abstract

Regenerative reconstruction of critical-size long bone segmental defects (LBSD) arising from high-energy traumas or tumor resections presents a formidable clinical challenge and imposes tremendous burdens to the healthcare systems worldwide. Standard treatment modalities like autologous cancellous bone grafting and allogenic cortical bone grafting are inadequate for LBSD due to limited supplies and suboptimal in vivo resorption of the former and poor fixation/tissue integration of the latter, respectively. These limitations have inspired the design of new synthetic bone grafts that integrate osteoinductivity and osteoconductivity with desired handling characteristics and controlled biodegradability. This chapter first outlines periosteal surface engineering strategies aimed at improving the in vivo performance of structural allografts, then reviews recent advances in synthetic bone grafts composed of demineralized bone matrices, titanium mesh cages, bioceramics, natural polymers, or synthetic polymers and composites. The discussions are centered around their applications for the regenerative repair of critical-size LBSD, contrasting their functional regeneration outcomes (e.g. restoration of mechanical integrity, quantification of new bone formation), whenever possible, with those achieved by clinical standards or to health controls.

Keywords

  • Long bone segmental defect (LBSD)
  • Critical-size defect
  • Scaffold-guided bone regeneration
  • Synthetic bone grafts
  • Three-dimensional (3D) printing
  • Synthetic degradable polymers
  • Natural biopolymers
  • Hydrogels

This is a preview of subscription content, access via your institution.

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-3-030-92014-2_8
  • Chapter length: 27 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   169.00
Price excludes VAT (USA)
  • ISBN: 978-3-030-92014-2
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Hardcover Book
USD   219.99
Price excludes VAT (USA)
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

3D printing:

Three-dimensional printing

ACS:

Absorbable collagen sponge

ADSC:

Adipose-derived stem cell

BMP:

Bone morphogenetic protein

BMSC:

Bone marrow-derived stromal cell

CAD:

Computer-assisted design

CaP:

Calcium phosphate

CT:

Computer tomography

DBM:

Demineralized bone matrix

ECM:

Extracellular matrix

FDA:

Food and Drug Administration

FGF23:

Fibroblast growth factor 23

HA:

Hyaluronic acid

hAFSC:

Human amniotic fluid-derived stem cell

HAp:

Hydroxyapatite

HDB:

Heterogeneous deproteinized bone

Ihh:

Indian hedgehog

LBSD:

Long bone segmental defect

MSC:

Mesenchymal stem cell

mSSC:

Mouse skeletal stem cell

OVX:

Ovariectomy

PCL:

Polycaprolactone

PEG:

Poly(ethylene glycol)

PEGDA:

Poly(ethylene glycol) diacrylate

PELGA:

Poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)

PGA:

Poly(glycolic acid)

PLGA:

Poly(lactic-co-glycolic acid)

PLA:

Poly(lactic acid)

PLA-DX-PEG:

Poly d,l-lactic acid-p-dioxanone-polyethylene glycol block copolymer

PVA:

Poly(vinyl alcohol)

rAAV:

Recombinant adeno-associated virus

RANKL:

Receptor activator of nuclear factor κB ligand

rhBMP-2:

Recombinant human bone morphogenetic protein-2

rhBMP-2/7:

Recombinant human bone morphogenetic protein-2/7 heterodimer

rt:

Room temperature

TCP:

Tricalcium phosphate

TEP:

Tissue-engineered periosteum

VEGF:

Vascular endothelial growth factor

WSF:

Wistar skin fibroblast

β-TCP:

β-Tricalcium phosphate

μ-CT:

Micro-computed tomography

References

  1. Bauer TW, Muschler GF. Bone graft materials: an overview of the basic science. Clin Orthop Relat Res. 2000;371:10–27.

    Google Scholar 

  2. Urist MR. 23 Physiologic basis of bone-graft surgery, with special reference to the theory of induction. Clin Orthop Relat Res. 1953;1:207–16.

    CAS  Google Scholar 

  3. Mauffrey C, Barlow BT, Smith W. Management of segmental bone defects. J Am Acad Orthop Surg. 2015;23(3):143–53.

    PubMed  Google Scholar 

  4. Bostrom MPG, Seigerman DA. The clinical use of allografts, demineralized bone matrices, synthetic bone graft substitutes and osteoinductive growth factors: a survey study. HSS J. 2005;1(1):9–18.

    PubMed  PubMed Central  Google Scholar 

  5. Zhang M, Matinlinna JP, Tsoi JKH, Liu W, Cui X, Lu WW, Pan H. Recent developments in biomaterials for long-bone segmental defect reconstruction: a narrative overview. J Orthop Transl. 2019;22:26–33.

    Google Scholar 

  6. Supová M. Problem of hydroxyapatite dispersion in polymer matrices: a review. J Mater Sci Mater Med. 2009;20:1201–13.

    PubMed  Google Scholar 

  7. Geiger M, Li RH, Friess W. Collagen sponges for bone regeneration with rhBMP-2. Adv Drug Deliv Rev. 2003;55(12):1613–29.

    CAS  PubMed  Google Scholar 

  8. McKay WF, Peckham SM, Badura JM. A comprehensive clinical review of recombinant human bone morphogenetic protein-2 (INFUSE (R) bone graft). Int Orthop. 2007;31(6):729–34.

    PubMed  PubMed Central  Google Scholar 

  9. Glatt V, Bartnikowski N, Quirk N, Schuetz M, Evans C. Reverse dynamization: influence of fixator stiffness on the mode and efficiency of large-bone-defect healing at different doses of rhBMP-2. J Bone Joint Surg Am. 2016;98(8):677–87.

    PubMed  PubMed Central  Google Scholar 

  10. Makhni MC, Caldwell J-ME, Saifi C, Fischer CR, Lehman RA, Lenke LG, Lee FY. Tissue engineering advances in spine surgery. Regen Med. 2016;11(2):211–22.

    CAS  PubMed  Google Scholar 

  11. Zara JN, Siu RK, Zhang X, Shen J, Ngo R, Lee M, Li W, Chiang M, Chung J, Kwak J, Wu BM, Ting K, Soo C. High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. Tissue Eng Part A. 2011;17(9–10):1389–99.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Baldwin P, Li DJ, Auston DA, Mir HS, Yoon RS, Koval KJ. Autograft, allograft, and bone graft substitutes: clinical evidence and indications for use in the setting of orthopaedic trauma surgery. J Orthop Trauma. 2019;33(4):203–13.

    PubMed  Google Scholar 

  13. van de Vijfeijken SE, Münker TJ, Spijker R, Karssemakers LH, Vandertop WP, Becking AG, Ubbink DT, Becking A, Dubois L, Karssemakers L. Autologous bone is inferior to alloplastic cranioplasties: safety of autograft and allograft materials for cranioplasties, a systematic review. World Neurosurg. 2018;117(443–452):e8.

    Google Scholar 

  14. Hopp SG, Dahners LE, Gilbert JA. A study of the mechanical strength of long bone defects treated with various bone autograft substitutes: an experimental investigation in the rabbit. J Orthop Res. 1989;7(4):579–84.

    CAS  PubMed  Google Scholar 

  15. Lauthe O, Soubeyrand M, Babinet A, Dumaine V, Anract P, Biau D. The indications and donor-site morbidity of tibial cortical strut autografts in the management of defects in long bones. Bone Joint J. 2018;100(5):667–74.

    PubMed  Google Scholar 

  16. Buser Z, Brodke DS, Youssef JA, Rometsch E, Park J-B, Yoon ST, Wang JC, Meisel H-J. Allograft versus demineralized bone matrix in instrumented and noninstrumented lumbar fusion: a systematic review. Global Spine J. 2018;8(4):396–412.

    PubMed  Google Scholar 

  17. Mankin HJ, Fogelson FS, Thrasher AZ, Jaffer F. Massive resection and allograft transplantation in the treatment of malignant bone tumors. N Engl J Med. 1976;294(23):1247–55.

    CAS  PubMed  Google Scholar 

  18. Samsell B, Softic D, Qin X, McLean J, Sohoni P, Gonzales K, Moore MA. Preservation of allograft bone using a glycerol solution: a compilation of original preclinical research. Biomater Res. 2019;23(1):5.

    PubMed  PubMed Central  Google Scholar 

  19. Boyce T, Edwards J, Scarborough N. Allograft bone: the influence of processing on safety and performance. Orthop Clin. 1999;30(4):571–81.

    CAS  Google Scholar 

  20. Sorger JI, Hornicek FJ, Zavatta M, Menzner JP, Gebhardt MC, Tomford WW, Mankin HJ. Allograft fractures revisited. Clin Orthop Relat Res. 2001;382:66–74.

    Google Scholar 

  21. Ito H, Koefoed M, Tiyapatanaputi P, Gromov K, Goater JJ, Carmouche J, Zhang X, Rubery PT, Rabinowitz J, Samulski RJ. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med. 2005;11(3):291–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang X, Awad HA, O’Keefe RJ, Guldberg RE, Schwarz EM. A perspective: engineering periosteum for structural bone graft healing. Clin Orthop Relat Res. 2008;466(8):1777–87.

    PubMed  PubMed Central  Google Scholar 

  23. Wang T, Zhai Y, Nuzzo M, Yang X, Yang Y, Zhang X. Layer-by-layer nanofiber-enabled engineering of biomimetic periosteum for bone repair and reconstruction. Biomaterials. 2018;182:279–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang B, Filion TM, Kutikov AB, Song J. Facile stem cell delivery to bone grafts enabled by smart shape recovery and stiffening of degradable synthetic periosteal membranes. Adv Funct Mater. 2017;27(5):1604784.

    Google Scholar 

  25. Zhang B, DeBartolo JE, Song J. Shape recovery with concomitant mechanical strengthening of amphiphilic shape memory polymers in warm water. ACS Appl Mater Interfaces. 2017;9(5):4450–6.

    CAS  PubMed  Google Scholar 

  26. Chang H, Knothe Tate ML. Concise review: the periosteum: tapping into a reservoir of clinically useful progenitor cells. Stem Cells Transl Med. 2012;1(6):480–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang ZX, Chen C, Zhou Q, Wang XS, Zhou G, Liu W, Zhang Z-Y, Cao Y, Zhang WJ. The treatment efficacy of bone tissue engineering strategy for repairing segmental bone defects under osteoporotic conditions. Tissue Eng Part A. 2015;21(17–18):2346–55.

    CAS  PubMed  Google Scholar 

  28. Ng MH, Duski S, Tan KK, Yusof MR, Low KC, Mohamed Rose I, Mohamed Z, Bin Saim A, Idrus RBH. Repair of segmental load-bearing bone defect by autologous mesenchymal stem cells and plasma-derived fibrin impregnated ceramic block results in early recovery of limb function. Biomed Res Int. 2014;2014:345910.

    PubMed  PubMed Central  Google Scholar 

  29. Hertlein H, Mittlmeier T, Piltz S, Schürmann M, Kauschke T, Lob G. Spinal stabilization for patients with metastatic lesions of the spine using a titanium spacer. Eur Spine J. 1992;1(2):131–6.

    CAS  PubMed  Google Scholar 

  30. Hollowell JP, Vollmer DG, Wilson CR, Pintar FA, Yoganandan N. Biomechanical analysis of thoracolumbar interbody constructs: how important is the endplate? Spine (Phila Pa 1976). 1996;21(9):1032–6.

    CAS  Google Scholar 

  31. Cobos JA, Lindsey RW, Gugala Z. The cylindrical titanium mesh cage for treatment of a long bone segmental defect: description of a new technique and report of two cases. J Orthop Trauma. 2000;14(1):54–9.

    CAS  PubMed  Google Scholar 

  32. Attias N, Thabet A, Prabhakar G, Dollahite J, Gehlert R, DeCoster T. Management of extra-articular segmental defects in long bone using a titanium mesh cage as an adjunct to other methods of fixation: a multicentre report of 17 cases. Bone Joint J. 2018;100(4):646–51.

    PubMed  Google Scholar 

  33. Drosos GI, Touzopoulos P, Ververidis A, Tilkeridis K, Kazakos K. Use of demineralized bone matrix in the extremities. World J Orthop. 2015;6(2):269–77.

    PubMed  PubMed Central  Google Scholar 

  34. Grob D, Daehn S, Mannion AF. Titanium mesh cages (TMC) in spine surgery. Eur Spine J. 2005;14(3):211–21.

    PubMed  Google Scholar 

  35. Attias N, Lindsey RW. Management of large segmental tibial defects using a cylindrical mesh cage. Clin Orthop Relat Res. 2006;450:259–66.

    PubMed  Google Scholar 

  36. Pobloth A-M, Checa S, Razi H, Petersen A, Weaver JC, Schmidt-Bleek K, Windolf M, Tatai AÁ, Roth CP, Schaser K-D. Mechanobiologically optimized 3D titanium-mesh scaffolds enhance bone regeneration in critical segmental defects in sheep. Sci Transl Med. 2018;10(423):eaam8828.

    PubMed  Google Scholar 

  37. Chung W-J, Kwon K-Y, Song J, Lee S-W. Evolutionary screening of collagen-like peptides that nucleate hydroxyapatite crystals. Langmuir. 2011;27(12):7620–8.

    CAS  PubMed  Google Scholar 

  38. Nancollas GH, Henneman ZJ. Calcium oxalate: calcium phosphate transformations. Urol Res. 2010;38(4):277–80.

    CAS  PubMed  Google Scholar 

  39. Kasten P, Vogel J, Geiger F, Niemeyer P, Luginbühl R, Szalay K. The effect of platelet-rich plasma on healing in critical-size long-bone defects. Biomaterials. 2008;29(29):3983–92.

    CAS  PubMed  Google Scholar 

  40. Marcacci M, Kon E, Moukhachev V, Lavroukov A, Kutepov S, Quarto R, Mastrogiacomo M, Cancedda R. Stem cells associated with macroporous bioceramics for long bone repair: 6-to 7-year outcome of a pilot clinical study. Tissue Eng. 2007;13(5):947–55.

    CAS  PubMed  Google Scholar 

  41. Patel KD, Buitrago JO, Parthiban SP, Lee J-H, Singh RK, Knowles JC, Kim H-W. Combined effects of nanoroughness and ions produced by electrodeposition of mesoporous bioglass nanoparticle for bone regeneration. ACS Appl Bio Mater. 2019;2(11):5190–203.

    CAS  PubMed  Google Scholar 

  42. Tölli H, Kujala S, Levonen K, Jämsä T, Jalovaara P. Bioglass as a carrier for reindeer bone protein extract in the healing of rat femur defect. J Mater Sci Mater Med. 2010;21(5):1677–84.

    PubMed  Google Scholar 

  43. Gabbai-Armelin PR, Wilian Kido H, Fernandes KR, Fortulan CA, Muniz Renno AC. Effects of bio-inspired bioglass/collagen/magnesium composites on bone repair. J Biomater Appl. 2019;34(2):261–72.

    CAS  PubMed  Google Scholar 

  44. Bougioukli S, Jain A, Sugiyama O, Tinsley BA, Tang AH, Tan MH, Adams DJ, Kostenuik PJ, Lieberman JR. Combination therapy with BMP-2 and a systemic RANKL inhibitor enhances bone healing in a mouse critical-sized femoral defect. Bone. 2016;84:93–103.

    CAS  PubMed  Google Scholar 

  45. Friess W, Uludag H, Foskett S, Biron R, Sargeant C. Characterization of absorbable collagen sponges as recombinant human bone morphogenetic protein-2 carriers. Int J Pharm. 1999;185(1):51–60.

    CAS  PubMed  Google Scholar 

  46. Lissenberg-Thunnissen SN, de Gorter DJJ, Sier CFM, Schipper IB. Use and efficacy of bone morphogenetic proteins in fracture healing. Int Orthop. 2011;35(9):1271–80.

    PubMed  PubMed Central  Google Scholar 

  47. Kuttappan S, Mathew D, Nair MB. Biomimetic composite scaffolds containing bioceramics and collagen/gelatin for bone tissue engineering—a mini review. Int J Biol Macromol. 2016;93:1390–401.

    CAS  PubMed  Google Scholar 

  48. Guda T, Walker JA, Singleton BM, Hernandez JW, Son J-S, Kim S-G, Oh DS, Appleford MR, Ong JL, Wenke JC. Guided bone regeneration in long-bone defects with a structural hydroxyapatite graft and collagen membrane. Tissue Eng Part A. 2012;19(17–18):1879–88.

    PubMed  PubMed Central  Google Scholar 

  49. Yamamoto M, Takahashi Y, Tabata Y. Enhanced bone regeneration at a segmental bone defect by controlled release of bone morphogenetic protein-2 from a biodegradable hydrogel. Tissue Eng. 2006;12(5):1305–11.

    CAS  PubMed  Google Scholar 

  50. Mano JF, Silva GA, Azevedo HS, Malafaya PB, Sousa RA, Silva SS, Boesel LF, Oliveira JM, Santos TC, Marques AP, Neves NM, Reis RL. Natural origin biodegradable systems in tissue engineering and regenerative medicine: present status and some moving trends. J R Soc Interface. 2007;4(17):999–1030.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Collins MN, Birkinshaw C. Hyaluronic acid based scaffolds for tissue engineering—a review. Carbohydr Polym. 2013;92(2):1262–79.

    CAS  PubMed  Google Scholar 

  52. Han SH, Jung SH, Lee JH. Preparation of beta-tricalcium phosphate microsphere-hyaluronic acid-based powder gel composite as a carrier for rhBMP-2 injection and evaluation using long bone segmental defect model. J Biomater Sci Polym Ed. 2019;30(8):679–93.

    CAS  PubMed  Google Scholar 

  53. Gibbs DM, Black CR, Dawson JI, Oreffo RO. A review of hydrogel use in fracture healing and bone regeneration. J Tissue Eng Regen Med. 2016;10(3):187–98.

    CAS  PubMed  Google Scholar 

  54. Shoichet MS, Li RH, White ML, Winn SR. Stability of hydrogels used in cell encapsulation: an in vitro comparison of alginate and agarose. Biotechnol Bioeng. 1996;50(4):374–81.

    CAS  PubMed  Google Scholar 

  55. Kolambkar YM, Dupont KM, Boerckel JD, Huebsch N, Mooney DJ, Hutmacher DW, Guldberg RE. An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects. Biomaterials. 2011;32(1):65–74.

    CAS  PubMed  Google Scholar 

  56. Boerckel JD, Kolambkar YM, Dupont KM, Uhrig BA, Phelps EA, Stevens HY, García AJ, Guldberg RE. Effects of protein dose and delivery system on BMP-mediated bone regeneration. Biomaterials. 2011;32(22):5241–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Krebs MD, Salter E, Chen E, Sutter KA, Alsberg E. Calcium phosphate-DNA nanoparticle gene delivery from alginate hydrogels induces in vivo osteogenesis. J Biomed Mater Res A. 2010;92(3):1131–8.

    PubMed  Google Scholar 

  58. Oest ME, Dupont KM, Kong HJ, Mooney DJ, Guldberg RE. Quantitative assessment of scaffold and growth factor-mediated repair of critically sized bone defects. J Orthop Res. 2007;25(7):941–50.

    CAS  PubMed  Google Scholar 

  59. Boerckel JD, Dupont KM, Kolambkar YM, Lin AS, Guldberg RE. In vivo model for evaluating the effects of mechanical stimulation on tissue-engineered bone repair. J Biomech Eng. 2009;131(8):084502.

    PubMed  Google Scholar 

  60. Alsberg E, Kong H, Hirano Y, Smith M, Albeiruti A, Mooney D. Regulating bone formation via controlled scaffold degradation. J Dent Res. 2003;82(11):903–8.

    CAS  PubMed  Google Scholar 

  61. Boontheekul T, Kong H-J, Mooney DJ. Controlling alginate gel degradation utilizing partial oxidation and bimodal molecular weight distribution. Biomaterials. 2005;26(15):2455–65.

    CAS  PubMed  Google Scholar 

  62. Priddy LB, Chaudhuri O, Stevens HY, Krishnan L, Uhrig BA, Willett NJ, Guldberg RE. Oxidized alginate hydrogels for bone morphogenetic protein-2 delivery in long bone defects. Acta Biomater. 2014;10(10):4390–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Oryan A, Alidadi S, Bigham-Sadegh A, Moshiri A. Effectiveness of tissue engineered based platelet gel embedded chitosan scaffold on experimentally induced critical sized segmental bone defect model in rat. Injury. 2017;48(7):1466–74.

    PubMed  Google Scholar 

  64. LogithKumar R, KeshavNarayan A, Dhivya S, Chawla A, Saravanan S, Selvamurugan N. A review of chitosan and its derivatives in bone tissue engineering. Carbohydr Polym. 2016;151:172–88.

    CAS  PubMed  Google Scholar 

  65. Khanal D, Minami S, Rakshit S, Chandrakrachang S, Stevens W. Management of fracture with chitosan in dogs. Indian Vet J. 2000;77(12):1085–90.

    Google Scholar 

  66. Shuang F, Hou S, Zhao Y, Zhong H, Xue C, Zhu J, Bu G, Cao Z. Characterization of an injectable chitosan-demineralized bone matrix hybrid for healing critical-size long-bone defects in a rabbit model. Eur Rev Med Pharmacol Sci. 2014;18:740–52.

    CAS  PubMed  Google Scholar 

  67. Luca L, Rougemont AL, Walpoth BH, Boure L, Tami A, Anderson JM, Jordan O, Gurny R. Injectable rhBMP-2-loaded chitosan hydrogel composite: osteoinduction at ectopic site and in segmental long bone defect. J Biomed Mater Res A. 2011;96(1):66–74.

    PubMed  Google Scholar 

  68. Kim S, Bedigrew K, Guda T, Maloney WJ, Park S, Wenke JC, Yang YP. Novel osteoinductive photo-cross-linkable chitosan-lactide-fibrinogen hydrogels enhance bone regeneration in critical size segmental bone defects. Acta Biomater. 2014;10(12):5021–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Huang H, Tan Y, Ayers DC, Song J. Anionic and zwitterionic residues modulate stiffness of photo-cross-linked hydrogels and cellular behavior of encapsulated chondrocytes. ACS Biomater Sci Eng. 2018;4(5):1843–51.

    CAS  PubMed  Google Scholar 

  70. Tan Y, Huang H, Ayers DC, Song J. Modulating viscoelasticity, stiffness, and degradation of synthetic cellular niches via stoichiometric tuning of covalent versus dynamic noncovalent cross-linking. ACS Cent Sci. 2018;4(8):971–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Madl CM, Heilshorn SC. Engineering hydrogel microenvironments to recapitulate the stem cell niche. Annu Rev Biomed Eng. 2018;20:21–47.

    CAS  PubMed  Google Scholar 

  72. Xu X, Jerca FA, Jerca VV, Hoogenboom R. Covalent poly (2-isopropenyl-2-oxazoline) hydrogels with ultrahigh mechanical strength and toughness through secondary terpyridine metal-coordination crosslinks. Adv Funct Mater. 2019;29(48):1904886.

    CAS  Google Scholar 

  73. Hubbell JA. Synthetic biodegradable polymers for tissue engineering and drug delivery. Curr Opin Solid State Mater Sci. 1998;3(3):246–51.

    CAS  Google Scholar 

  74. Sonnet C, Simpson CL, Olabisi RM, Sullivan K, Lazard Z, Gugala Z, Peroni JF, Weh JM, Davis AR, West JL. Rapid healing of femoral defects in rats with low dose sustained BMP2 expression from PEGDA hydrogel microspheres. J Orthop Res. 2013;31(10):1597–604.

    CAS  PubMed  Google Scholar 

  75. Shekaran A, García JR, Clark AY, Kavanaugh TE, Lin AS, Guldberg RE, García AJ. Bone regeneration using an alpha 2 beta 1 integrin-specific hydrogel as a BMP-2 delivery vehicle. Biomaterials. 2014;35(21):5453–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Webb AR, Yang J, Ameer GA. Biodegradable polyester elastomers in tissue engineering. Expert Opin Biol Ther. 2004;4(6):801–12.

    CAS  PubMed  Google Scholar 

  77. Lee K-W, Wang S, Lu L, Jabbari E, Currier BL, Yaszemski MJ. Fabrication and characterization of poly (propylene fumarate) scaffolds with controlled pore structures using 3-dimensional printing and injection molding. Tissue Eng. 2006;12(10):2801–11.

    CAS  PubMed  Google Scholar 

  78. Wada K, Yu W, Elazizi M, Barakat S, Ouimet MA, Rosario-Meléndez R, Fiorellini JP, Graves DT, Uhrich KE. Locally delivered salicylic acid from a poly(anhydride-ester): impact on diabetic bone regeneration. J Control Release. 2013;171(1):33–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Yan L, Jiang D-m. Study of bone-like hydroxyapatite/polyamino acid composite materials for their biological properties and effects on the reconstruction of long bone defects. Drug Des Devel Ther. 2015;9:6497.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ye H, Zhang K, Kai D, Li Z, Loh XJ. Polyester elastomers for soft tissue engineering. Chem Soc Rev. 2018;47(12):4545–80.

    CAS  PubMed  Google Scholar 

  81. Narayanan G, Vernekar VN, Kuyinu EL, Laurencin CT. Poly (lactic acid)-based biomaterials for orthopaedic regenerative engineering. Adv Drug Deliv Rev. 2016;107:247–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Kirker-Head CA, Gerhart TN, Armstrong R, Schelling SH, Carmel LA. Healing bone using recombinant human bone morphogenetic protein 2 and copolymer. Clin Orthop Relat Res. 1998;349:205–17.

    Google Scholar 

  83. Zhang Y, Wang J, Wang J, Niu X, Liu J, Gao L, Zhai X, Chu K. Preparation of porous PLA/DBM composite biomaterials and experimental research of repair rabbit radius segmental bone defect. Cell Tissue Bank. 2015;16(4):615–22.

    CAS  PubMed  Google Scholar 

  84. Kokubo S, Mochizuki M, Fukushima S, Ito T, Nozaki K, Iwai T, Takahashi K, Yokota S, Miyata K, Sasaki N. Long-term stability of bone tissues induced by an osteoinductive biomaterial, recombinant human bone morphogenetic protein-2 and a biodegradable carrier. Biomaterials. 2004;25(10):1795–803.

    CAS  PubMed  Google Scholar 

  85. Reichert JC, Wullschleger ME, Cipitria A, Lienau J, Cheng TK, Schütz MA, Duda GN, Nöth U, Eulert J, Hutmacher DW. Custom-made composite scaffolds for segmental defect repair in long bones. Int Orthop. 2011;35(8):1229–36.

    PubMed  Google Scholar 

  86. Reichert JC, Cipitria A, Epari DR, Saifzadeh S, Krishnakanth P, Berner A, Woodruff MA, Schell H, Mehta M, Schuetz MA, Duda GN, Hutmacher DW. A tissue engineering solution for segmental defect regeneration in load-bearing long bones. Sci Transl Med. 2012;4(141):141ra93.

    PubMed  Google Scholar 

  87. Reichert JC, Cipitria A, Epari DR, Saifzadeh S, Krishnakanth P, Berner A, Woodruff MA, Schell H, Mehta M, Schuetz MA. A tissue engineering solution for segmental defect regeneration in load-bearing long bones. Sci Transl Med. 2012;4(141):141ra93.

    PubMed  Google Scholar 

  88. Kutikov AB, Song J. Biodegradable PEG-based amphiphilic block copolymers for tissue engineering applications. ACS Biomater Sci Eng. 2015;1(7):463–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kaito T, Myoui A, Takaoka K, Saito N, Nishikawa M, Tamai N, Ohgushi H, Yoshikawa H. Potentiation of the activity of bone morphogenetic protein-2 in bone regeneration by a PLA–PEG/hydroxyapatite composite. Biomaterials. 2005;26(1):73–9.

    CAS  PubMed  Google Scholar 

  90. Yasuda H, Yano K, Wakitani S, Matsumoto T, Nakamura H, Takaoka K. Repair of critical long bone defects using frozen bone allografts coated with an rhBMP-2-retaining paste. J Orthop Sci. 2012;17(3):299–307.

    CAS  PubMed  Google Scholar 

  91. Yoneda M, Terai H, Imai Y, Okada T, Nozaki K, Inoue H, Miyamoto S, Takaoka K. Repair of an intercalated long bone defect with a synthetic biodegradable bone-inducing implant. Biomaterials. 2005;26(25):5145–52.

    CAS  PubMed  Google Scholar 

  92. Kutikov AB, Gurijala A, Song J. Rapid prototyping amphiphilic polymer/hydroxyapatite composite scaffolds with hydration-induced self-fixation behavior. Tissue Eng Part C Methods. 2015;21(3):229–41.

    CAS  PubMed  Google Scholar 

  93. Kutikov AB, Skelly JD, Ayers DC, Song J. Templated repair of long bone defects in rats with bioactive spiral-wrapped electrospun amphiphilic polymer/hydroxyapatite scaffolds. ACS Appl Mater Interfaces. 2015;7(8):4890–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang B, Skelly JD, Maalouf JR, Ayers DC, Song J. Multifunctional scaffolds for facile implantation, spontaneous fixation, and accelerated long bone regeneration in rodents. Sci Transl Med. 2019;11(502):eaau7411.

    PubMed  Google Scholar 

  95. Kutikov A, Song J. An amphiphilic degradable polymer/hydroxyapatite composite with enhanced handling characteristics promotes osteogenic gene expression in bone marrow stromal cells. Acta Biomater. 2013;9(9):8354–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Koons GL, Mikos AG. Progress in three-dimensional printing with growth factors. J Control Release. 2019;295:50–9.

    CAS  PubMed  Google Scholar 

  97. Kang H-W, Lee SJ, Ko IK, Kengla C, Yoo JJ, Atala A. A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat Biotechnol. 2016;34(3):312–9.

    CAS  PubMed  Google Scholar 

  98. Keriquel V, Oliveira H, Rémy M, Ziane S, Delmond S, Rousseau B, Rey S, Catros S, Amédée J, Guillemot F. In situ printing of mesenchymal stromal cells, by laser-assisted bioprinting, for in vivo bone regeneration applications. Sci Rep. 2017;7(1):1–10.

    CAS  Google Scholar 

  99. Urciuolo A, Poli I, Brandolino L, Raffa P, Scattolini V, Laterza C, Giobbe GG, Zambaiti E, Selmin G, Magnussen M. Intravital three-dimensional bioprinting. Nat Biomed Eng. 2020;4(9):901–15.

    CAS  PubMed  Google Scholar 

  100. Chen Y, Zhang J, Liu X, Wang S, Tao J, Huang Y, Wu W, Li Y, Zhou K, Wei X. Noninvasive in vivo 3D bioprinting. Sci Adv. 2020;6(23):eaba7406.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work is supported by an Alex Lemonade Stand Foundation Innovation Grant and a BRIDGE Award from the University of Massachusetts Medical School.

Conflict of Interests

The authors declare there is no conflict of interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jie Song .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this chapter

Verify currency and authenticity via CrossMark

Cite this chapter

Xu, X., Song, J. (2022). Bone Grafting in the Regenerative Reconstruction of Critical-Size Long Bone Segmental Defects. In: Guastaldi, F.P., Mahadik, B. (eds) Bone Tissue Engineering. Springer, Cham. https://doi.org/10.1007/978-3-030-92014-2_8

Download citation