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Stimulation der Frakturheilung durch Wachstumsfaktoren und zellbasierte Technologien

Stimulation of fracture healing by growth factors and cell-based technologies

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Zusammenfassung

Knochen besitzt die besondere Fähigkeit, sich nach einem Trauma vollständig zu regenerieren. In der Regel gelingt es dem Gewebe, die geometrische Form und biomechanische Stabilität – dem prätraumatischen Zustand entsprechend – wiederzuerlangen. Im klinischen Alltag kommt es allerdings immer wieder zu einer Störung der Frakturheilung, bedingt durch eine unzureichende mechanische Stabilität und/oder insuffiziente biologische Prozesse im Bereich der Frakturregion. Durch intensive Erforschung der physiologischen Vorgänge im Rahmen der Frakturheilung sowie Herstellung und klinischen Einsatz von Wachstumsfaktoren besteht seit der Jahrtausendwende die Möglichkeit, lokale biologische Vorgänge durch Osteoinduktion in der Frakturregion zu verbessern. Trotz anfänglich vielversprechender klinischer Ergebnisse v. a. der „bone morphogenetic proteins“ konnten sich Wachstumsfaktoren jedoch in der klinischen Anwendung nicht uneingeschränkt etablieren. Aktuell werden weitere Wachstumsfaktoren im Hinblick auf ihre supportiven und osteoinduktiven Eigenschaften im Rahmen der Frakturheilung und deren mögliche Anwendung in der Klinik untersucht. Die Entwicklung zellbasierter Technologien ist ein weiterer vielversprechender Ansatz, um die Frakturheilung positiv zu beeinflussen. Neben dem Goldstandard der autologen (Kortiko‑)Spongiosatransplantation hat die Aspiration von mesenchymalen Stromazellen in den letzten Jahren zunehmend an Bedeutung gewonnen. Allogene Knochenzelltransplantationsverfahren und besonders die Gentherapie sind vielversprechende Ansätze für die Behandlung von Frakturheilungsstörungen. Die vorliegende Arbeit gibt einen Überblick über aktuelle und zukünftige Möglichkeiten der Modulation der Frakturheilung durch Wachstumsfaktoren und zellbasierte Technologien.

Abstract

Bone has the special capability to completely regenerate after trauma and to re-establish its original geometry and biomechanical stability corresponding to the pretrauma conditions. Nevertheless, in daily clinical practice impaired fracture healing and nonunions are regular complications as a result of inadequate mechanical stability and/or insufficient biological processes around the fracture region. Since the beginning of the millennium, intensive research on the physiological processes in bone healing as well as the production and clinical administration of growth factors have enabled the possibility to improve the local biological processes during fracture healing by osteoinduction. Although the initial clinical results, particularly of bone morphogenetic proteins, in fracture healing were promising, growth factors did not become established for unrestricted use in the clinical application. Currently, additional growth factors are being investigated with respect to the potential supportive and osteoinductive characteristics for enhancement of fracture healing and possible clinical applications. Furthermore, the development of cell-based technologies is another promising approach to positively stimulate fracture healing. In addition to the gold standard of autologous bone grafting, harvesting of mesenchymal stroma cells by aspiration has gained in importance in recent years. Allogeneic bone cell transplantation procedures and in particular gene therapy are promising new strategies for the treatment of disorders of fracture healing. This review gives an overview of present and future possibilities for modulation of fracture healing by growth factors and cell-based technologies.

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Literatur

  1. Balmayor ER, van Griensven M (2015) Gene therapy for bone engineering. Front Bioeng Biotechnol 3:9

    Article  Google Scholar 

  2. Becerikli M, Jaurich H, Schira J, Schulte M, Dobele C, Wallner C et al (2017) Age-dependent alterations in osteoblast and osteoclast activity in human cancellous bone. J Cell Mol Med 21(11):2773–2781

    Article  CAS  Google Scholar 

  3. Calori GM, Colombo M, Mazza EL, Mazzola S, Malagoli E, Mineo GV (2014) Incidence of donor site morbidity following harvesting from iliac crest or RIA graft. Injury 45(Suppl 6):S116–S120

    Article  Google Scholar 

  4. Calori GM, Giannoudis PV (2011) Enhancement of fracture healing with the diamond concept: the role of the biological chamber. Injury 42(11):1191–1193

    Article  Google Scholar 

  5. Calori GM, Phillips M, Jeetle S, Tagliabue L, Giannoudis PV (2008) Classification of non-union: need for a new scoring system? Injury 39(Suppl 2):S59–S63

    Article  Google Scholar 

  6. Dawson J, Kiner D, Gardner W 2nd, Swafford R, Nowotarski PJ (2014) The reamer-irrigator-aspirator as a device for harvesting bone graft compared with iliac crest bone graft: union rates and complications. J Orthop Trauma 28(10):584–590

    Article  Google Scholar 

  7. Desai P, Hasan SM, Zambrana L, Hegde V, Saleh A, Cohn MR et al (2015) Bone mesenchymal stem cells with growth factors successfully treat nonunions and delayed unions. HSS J 11(2):104–111

    Article  Google Scholar 

  8. DiGiovanni CW, Lin SS, Baumhauer JF, Daniels T, Younger A, Glazebrook M et al (2013) Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/beta-TCP): an alternative to autogenous bone graft. J Bone Joint Surg Am 95(13):1184–1192

    Article  Google Scholar 

  9. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4):315–317

    Article  CAS  Google Scholar 

  10. Eastlack RK, Garfin SR, Brown CR, Meyer SC (2014) Osteocel Plus cellular allograft in anterior cervical discectomy and fusion: evaluation of clinical and radiographic outcomes from a prospective multicenter study. Spine 39(22):E1331–E1337

    Article  Google Scholar 

  11. Einhorn TA, Gerstenfeld LC (2015) Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 11(1):45–54

    Article  Google Scholar 

  12. Evans CH (2010) Gene therapy for bone healing. Expert Rev Mol Med 12:e18

    Article  Google Scholar 

  13. Feichtinger GA, Hofmann AT, Slezak P, Schuetzenberger S, Kaipel M, Schwartz E et al (2014) Sonoporation increases therapeutic efficacy of inducible and constitutive BMP2/7 in vivo gene delivery. Hum Gene Ther Methods 25(1):57–71

    Article  CAS  Google Scholar 

  14. Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF et al (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am 83-A(Suppl 1(Pt 2)):151–158

    Google Scholar 

  15. Garrison KR, Shemilt I, Donell S, Ryder JJ, Mugford M, Harvey I et al (2010) Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD006950.pub2

    Article  PubMed  Google Scholar 

  16. Giannoudis PV, Einhorn TA, Marsh D (2007) Fracture healing: the diamond concept. Injury 38(Suppl 4):S3–S6

    Article  Google Scholar 

  17. Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R 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 Joint Surg Am 84-A(12):2123–2134

    Article  Google Scholar 

  18. Hernigou P, Poignard A, Beaujean F, Rouard H (2005) Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 87(7):1430–1437

    PubMed  Google Scholar 

  19. Hollinger JO, Hart CE, Hirsch SN, Lynch S, Friedlaender GE (2008) Recombinant human platelet-derived growth factor: biology and clinical applications. J Bone Joint Surg Am 90(Suppl 1):48–54

    Article  Google Scholar 

  20. Hu K, Olsen BR (2016) The roles of vascular endothelial growth factor in bone repair and regeneration. Bone 91:30–38

    Article  CAS  Google Scholar 

  21. Kasten P, Beyen I, Egermann M, Suda AJ, Moghaddam AA, Zimmermann G et al (2008) Instant stem cell therapy: characterization and concentration of human mesenchymal stem cells in vitro. Eur Cell Mater 16:47–55

    Article  CAS  Google Scholar 

  22. Kawaguchi H, Nakamura K, Tabata Y, Ikada Y, Aoyama I, Anzai J et al (2001) Acceleration of fracture healing in nonhuman primates by fibroblast growth factor-2. J Clin Endocrinol Metab 86(2):875–880

    Article  CAS  Google Scholar 

  23. Kawaguchi H, Oka H, Jingushi S, Izumi T, Fukunaga M, Sato K et al (2010) A local application of recombinant human fibroblast growth factor 2 for tibial shaft fractures: A randomized, placebo-controlled trial. J Bone Miner Res 25(12):2735–2743

    Article  Google Scholar 

  24. Le ADK, Enweze L, DeBaun MR, Dragoo JL (2018) Current clinical recommendations for use of platelet-rich plasma. Curr Rev Musculoskelet Med 11(4):624–634

    Article  Google Scholar 

  25. Lieberman JR, Daluiski A, Einhorn TA (2002) The role of growth factors in the repair of bone. Biology and clinical applications. J Bone Joint Surg Am 84-A(6):1032–1044

    Article  Google Scholar 

  26. Moghaddam A, Thaler B, Bruckner T, Tanner M, Schmidmaier G (2016) Treatment of atrophic femoral non-unions according to the diamond concept: Results of one- and two-step surgical procedure. J Orthop 14(1):123–133

    Article  Google Scholar 

  27. Roffi A, Di Matteo B, Krishnakumar GS, Kon E, Filardo G (2017) Platelet-rich plasma for the treatment of bone defects: from pre-clinical rational to evidence in the clinical practice. A systematic review. Int Orthop 41(2):221–237

    Article  Google Scholar 

  28. Schmidmaier G, Herrmann S, Green J, Weber T, Scharfenberger A, Haas NP et al (2006) Quantitative assessment of growth factors in reaming aspirate, iliac crest, and platelet preparation. Bone 39(5):1156–1163

    Article  CAS  Google Scholar 

  29. Scott RT, Hyer CF (2013) Role of cellular allograft containing mesenchymal stem cells in high-risk foot and ankle reconstructions. J Foot Ankle Surg 52(1):32–35

    Article  Google Scholar 

  30. Seeherman H, Li R, Wozney J (2003) A review of preclinical program development for evaluating injectable carriers for osteogenic factors. J Bone Joint Surg Am 85-A(Suppl 3):96–108

    Article  Google Scholar 

  31. Simpson AH, Mills L, Noble B (2006) The role of growth factors and related agents in accelerating fracture healing. J Bone Joint Surg Br 88(6):701–705

    Article  CAS  Google Scholar 

  32. Toosi S, Behravan N, Behravan J (2018) Nonunion fractures, mesenchymal stem cells and bone tissue engineering. J Biomed Mater Res A 106(9):2552–2562

    Article  CAS  Google Scholar 

  33. Urist MR (1965) Bone: formation by autoinduction. Science 150(3698):893–899

    Article  CAS  Google Scholar 

  34. Wang W, Yeung KWK (2017) Bone grafts and biomaterials substitutes for bone defect repair: A review. Bioact Mater 2(4):224–247

    Article  Google Scholar 

  35. Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW et al (1988) Novel regulators of bone formation: molecular clones and activities. Science 242(4885):1528–1534

    Article  CAS  Google Scholar 

  36. Yang YQ, Tan YY, Wong R, Wenden A, Zhang LK, Rabie AB (2012) The role of vascular endothelial growth factor in ossification. Int J Oral Sci 4(2):64–68

    Article  CAS  Google Scholar 

  37. Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS et al (2008) Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 7(3):335–343

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Klinik für Unfall‑, Hand- und Wiederherstellungschirurgie, Universitätsklinikum Münster, Münster, Deutschland

    J. Everding, J. Stolberg-Stolberg & M. J. Raschke

  2. Abteilung für Regenerative Muskuloskelettale Medizin, Universitätsklinikum Münster, Münster, Deutschland

    R. Stange

  3. Institut für Muskuloskelettale Medizin (IMM), Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Deutschland

    R. Stange

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  1. J. Everding
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  2. J. Stolberg-Stolberg
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  3. M. J. Raschke
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Correspondence to R. Stange.

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J. Everding, J. Stolberg-Stolberg, M.J. Raschke und R. Stange geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

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Everding, J., Stolberg-Stolberg, J., Raschke, M.J. et al. Stimulation der Frakturheilung durch Wachstumsfaktoren und zellbasierte Technologien. Unfallchirurg 122, 534–543 (2019). https://doi.org/10.1007/s00113-019-0686-9

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