Advertisement

Der Unfallchirurg

, Volume 109, Issue 9, pp 715–732 | Cite as

Die Überbrückung von posttraumatischen Knochendefekten

Bewährtes und Neues
  • M. Schieker
  • W. Mutschler
Leitthema

Zusammenfassung

Knochendefekte können durch Hochrasanztraumen, Sturz auf Osteoporose-geschwächten Knochen oder nach Resektion betroffener Knochenabschnitte zur Therapie angeborener oder erworbener Erkrankungen des Stütz- und Bewegungsapparates oder posttraumatischer Folgezustände entstehen. Daraus ergibt sich eine Vielzahl von Defektlokalisationen, Defektausprägungen, Knochen- und Weichteilkonditionen sowie Patientengegebenheiten.

Eine sinnvolle, praxisrelevante Einteilung der Defekte erfolgt in die vier Grundtypen: Wirbelsäulendefekt, metaphysärer Defekt, Halb- und Vollschaftdefekt von Röhrenknochen. Für diese Defekte liegen verschiedene Therapieoptionen vor. Das Ziel ist dabei, einen dauerhaften und belastungsstabilen Defektverschluß zu erreichen, Achsen und Längen wiederherzustellen und die Gelenkfunktionen zu gewährleisten.

Neben den klassischen Verfahren der autogenen und allogenen Knochentransplantation können Knochenersatzmaterialien in großer Variation eingesetzt werden. Weitere Behandlungsmöglichkeiten ergeben sich durch aufwändige Rekonstruktionsverfahren wie Segmenttransport oder vaskularisierte Knochentransplantation. Nicht zuletzt werden große Hoffnungen in neue regenerative Strategien im Rahmen des Tissue Engineerings sowie der Stammzell- und Gentherapie gesetzt. Ziel der vorliegenden Übersichtsarbeit ist es, unter Einbeziehung der biologischen und mechanischen Kenngrößen eine Rangfolge für die Therapie posttraumatischer Defekte abzuleiten.

Schlüsselwörter

Knochendefekte Posttraumatisch Knochentransplantation Regenerative Therapie 

Bridging posttraumatic bony defects

Established and new methods

Abstract

Bony defects as a result of injury or disease can be caused by a variety of conditions such as acute injury, fall fractures in osteoporotic patients or tumours and congenital malformations of the musculoskeletal system which necessitate the resection of affected parts of the bone.

This results in a multitude of defects concerning localisation and specificity as well as a number of conditions involving both hard and soft tissue structures and various situations of different patients. A reasonable classification of defects which is relevant for practical purposes includes four basic types: defects of the spine, metaphyseal defects as well as partial and complete diaphyseal defects of long bones. A variety of options exists for the treatment of these conditions. The aim of all efforts is to reinstall the integrity of affected structures long-lastingly and dependably and at the same time guarantee the normal function of joints involved. In addition to classical treatment strategies which involve the use of autogenous and allogenous corticocancellous bone grafts a great number of bone substitute materials can also be used. Further options lie in complex reconstructive methods such as the transport of whole segments or the transplantation of vascularised bone grafts. The field of new regenerative strategies including tissue engineering as well as stem cell and gene therapy holds great promise for the future.

The aim of this review is to derive a ranking from the evaluation of biological and mechanical characteristics for the treatment of posttraumatic defects.

Keywords

Bony defects Posttraumatic Bone transplantation Regenerative therapy 

Notes

Danksagung

Die Autoren danken Frau Hella Thun, Multimedialabor der Chirurgischen Klinik Innenstadt, Klinikum der LMU sehr für die professionelle Erstellung der Graphiken und Zusammenstellung der Abbildungen. Die Bilder und Grafiken in Abb. 7 wurden mit Genehmigung des Springer-Verlags in modifizierter Form aus Baumgart et al. 2005 [4] übernommen. Die Röntgenbilder in Abb. 8 wurden freundlicherweise von Herrn Prof. Dr. W. Stock, Ltd. Arzt der Hand- und Plastischen Chirurgie, Chirurgische Klinik Innenstadt, Klinikum der LMU München zur Verfügung gestellt.

Interessenkonflikt

Es besteht kein Interessenkonflikt. Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen. Die Präsentation des Themas ist unabhängig und die Darstellung der Inhalte produktneutral.

Literatur

  1. 1.
    Ahsan T, Nerem RM (2005) Bioengineered tissues: the science, the technology, and the industry. Orthod Craniofac Res 8: 134–140CrossRefPubMedGoogle Scholar
  2. 2.
    Bauer TW, Smith ST (2002) Bioactive materials in orthopaedic surgery: overview and regulatory considerations. Clin Orthop Relat Res 395: 11–22CrossRefPubMedGoogle Scholar
  3. 3.
    Baumgart R, Burklein D, Hinterwimmer S et al. (2005) The management of leg-length discrepancy in Ollier’s disease with a fully implantable lengthening nail. J Bone Joint Surg Br 87: 1000–1004CrossRefPubMedGoogle Scholar
  4. 4.
    Baumgart R, Hinterwimmer S, Kettler M et al. (2005) Central bone transport system optimizes reconstruction of bone defects. Results of 40 treatments. Unfallchirurg 108: 1011–1020CrossRefPubMedGoogle Scholar
  5. 5.
    Baumgart R, Hinterwimmer S, Krammer M, Mutschler W (2004) Central cable system – fully automatic, continuous distraction osteogenesis for the lengthening treatment of large bone defects. Biomed Tech (Berl) 49: 202–207Google Scholar
  6. 6.
    Baumgart R, Kettler M, Zeiler C et al. (1997) Possibilities of osteotomy. Osteotomy and corticotomy techniques. Unfallchirurg 100: 797–804CrossRefPubMedGoogle Scholar
  7. 7.
    Beredjiklian PK, Hotchkiss RN, Athanasian EA et al. (2005) Recalcitrant nonunion of the distal humerus: treatment with free vascularized bone grafting. Clin Orthop Relat Res 435: 134–139CrossRefPubMedGoogle Scholar
  8. 8.
    Berven S, Tay BK, Kleinstueck FS, Bradford DS (2001) Clinical applications of bone graft substitutes in spine surgery: consideration of mineralized and demineralized preparations and growth factor supplementation. Eur.Spine J 10(Suppl 2): 169–177CrossRefGoogle Scholar
  9. 9.
    Boden SD, Zdeblick TA, Sandhu HS, Heim SE (2000) The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 25: 376–381CrossRefPubMedGoogle Scholar
  10. 10.
    Boileau P, Sinnerton RJ, Chuinard C, Walch G (2006) Arthroplasty of the shoulder. J Bone Joint Surg Br 88: 562–575CrossRefPubMedGoogle Scholar
  11. 11.
    Boontheekul T, Mooney DJ (2003) Protein-based signaling systems in tissue engineering. Curr Opin Biotechnol 14: 559–565CrossRefPubMedGoogle Scholar
  12. 12.
    Bramlage CP, Haupl T, Kaps C et al. (2005) Bone morphogenetic proteins in the skeletal system. Z Rheumatol 64: 416–422CrossRefPubMedGoogle Scholar
  13. 13.
    Burkus JK, Transfeldt EE, Kitchel SH et al. (2002) Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine 27: 2396–2408CrossRefPubMedGoogle Scholar
  14. 14.
    Burton AW, Rhines LD, Mendel E (2005) Vertebroplasty and kyphoplasty: a comprehensive review. Neurosurg Focus 18: 1Google Scholar
  15. 15.
    Caplan AI, Goldberg VM (1999) Principles of tissue engineered regeneration of skeletal tissues. Clin Orthop 367: 12–16CrossRefGoogle Scholar
  16. 16.
    Chapekar MS (2000) Tissue engineering: challenges and opportunities. J Biomed Mater Res 53: 617–620CrossRefPubMedGoogle Scholar
  17. 17.
    Chapovsky F, Kelly JD (2005) Osteochondral allograft transplantation for treatment of glenohumeral instability. Arthroscopy 21: 1007PubMedGoogle Scholar
  18. 18.
    Coskunfirat OK, Wei FC, Huang WC et al. (2005) Microvascular free tissue transfer for treatment of osteoradionecrosis of the maxilla. Plast Reconstr Surg 115: 54–60PubMedGoogle Scholar
  19. 19.
    Crow SA, Chen L, Lee JH, Rosenwasser MP (2005) Vascularized bone grafting from the base of the second metacarpal for persistent distal radius nonunion: a case report. J Orthop Trauma 19: 483–486CrossRefPubMedGoogle Scholar
  20. 20.
    DaFonseca K, Baier M, Grafe I et al. (2006) Balloon kyphoplasty in the treatment of vertebral fractures. Unfallchirurg 109: 391–400CrossRefPubMedGoogle Scholar
  21. 21.
    Dailiana ZH, Malizos KN, Zachos V et al. (2006) Vascularized bone grafts from the palmar radius for the treatment of waist nonunions of the scaphoid. J Hand Surg Am 31: 397–404CrossRefPubMedGoogle Scholar
  22. 22.
    DeCoster TA, Gehlert RJ, Mikola EA, Pirela-Cruz MA (2004) Management of posttraumatic segmental bone defects. J Am Acad Orthop Surg 12: 28–38PubMedGoogle Scholar
  23. 23.
    Deramond H, Depriester C, Galibert P, Le Gars D (1998) Percutaneous vertebroplasty with polymethylmethacrylate. Technique, indications, and results. Radiol Clin North Am 36: 533–546CrossRefPubMedGoogle Scholar
  24. 24.
    Erdmann D, Giessler GA, Bergquist GE et al. (2004) Free fibula transfer. Analysis of 76 consecutive microsurgical procedures and review of the literature. Chirurg 75: 799–809CrossRefPubMedGoogle Scholar
  25. 25.
    Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV (1966) Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 16: 381–390PubMedGoogle Scholar
  26. 26.
    Fuchs B, Steinmann SP, Bishop AT (2005) Free vascularized corticoperiosteal bone graft for the treatment of persistent nonunion of the clavicle. J Shoulder Elbow Surg 14: 264–268CrossRefPubMedGoogle Scholar
  27. 27.
    Garcia-Cimbrelo E, Marti-Gonzalez JC (2004) Circular external fixation in tibial nonunions. Clin Orthop Relat Res 419: 65–70CrossRefPubMedGoogle Scholar
  28. 28.
    Giannoudis PV, Dinopoulos H, Tsiridis E (2005) Bone substitutes: an update. Injury 36(Suppl 3): 20–27CrossRefGoogle Scholar
  29. 29.
    Green SA (1994) Skeletal defects. A comparison of bone grafting and bone transport for segmental skeletal defects. Clin Orthop Relat Res 301: 111–117PubMedGoogle Scholar
  30. 30.
    Griffith LG, Naughton G (2002) Tissue engineering – current challenges and expanding opportunities. Science 295: 1009–1014CrossRefPubMedGoogle Scholar
  31. 31.
    Gross AE, Shasha N, Aubin P (2005) Long-term followup of the use of fresh osteochondral allografts for posttraumatic knee defects. Clin Orthop Relat Res 435: 79–87CrossRefPubMedGoogle Scholar
  32. 32.
    Haynesworth SE, Goshima J, Goldberg VM, Caplan AI (1992) Characterization of cells with osteogenic potential from human marrow. Bone 13: 81–88CrossRefPubMedGoogle Scholar
  33. 33.
    Heiss C, Meissner SA, Hoesel LM et al. (2006) Posteromedial approach to proximal tibia for corticotomy in callus distractions. Clin Orthop Relat Res (in press)Google Scholar
  34. 34.
    Hing KA (2004) Bone repair in the twenty-first century: biology, chemistry or engineering? Philos Transact A Math Phys Eng Sci 362: 2821–2850CrossRefPubMedGoogle Scholar
  35. 35.
    Hofmann GO, Kirschner MH (2000) Clinical experience in allogeneic vascularized bone and joint allografting. Microsurgery 20: 375–383CrossRefPubMedGoogle Scholar
  36. 36.
    Hofmann GO, Kirschner MH, Gonschorek O, Buhren V (1999) Allogeneic vascularized transplantation in cases of bone and joint defects. Unfallchirurg 102: 458–465CrossRefPubMedGoogle Scholar
  37. 37.
    Huo MH, Gilbert NF (2005) What’s new in hip arthroplasty. J Bone Joint Surg Am 87: 2133–2146CrossRefPubMedGoogle Scholar
  38. 38.
    Ilizarov GA (1989) The tension-stress effect on the genesis and growth of tissues. Part I. The influence of stability of fixation and soft-tissue preservation. Clin Orthop Relat Res 238: 249–281PubMedGoogle Scholar
  39. 39.
    Isogai N, Landis W, Kim TH et al. (1999) Formation of phalanges and small joints by tissue-engineering. J Bone Joint Surg Am 81: 306–316CrossRefPubMedGoogle Scholar
  40. 40.
    Jager M, Westhoff B, Wild A, Krauspe R (2005) Bone harvesting from the iliac crest. Orthopade 34: 976–992CrossRefPubMedGoogle Scholar
  41. 41.
    Jamali AA, Emmerson BC, Chung C et al. (2005) Fresh osteochondral allografts. Clin Orthop Relat Res 437: 176–185CrossRefPubMedGoogle Scholar
  42. 42.
    Jiang Y, Jahagirdar BN, Reinhardt RL et al. (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418: 41–49CrossRefPubMedGoogle Scholar
  43. 43.
    Jones DL, Westby MD, Greidanus N et al. (2005) Update on hip and knee arthroplasty: current state of evidence. Arthritis Rheum 53: 772–780CrossRefPubMedGoogle Scholar
  44. 44.
    Kanayama M, Hashimoto T, Shigenobu K et al. (2006) A prospective randomized study of posterolateral lumbar fusion using osteogenic protein-1 (OP-1) versus local autograft with ceramic bone substitute: emphasis of surgical exploration and histologic assessment. Spine 31: 1067–1074CrossRefPubMedGoogle Scholar
  45. 45.
    Kowalski RJ, Ferrara LA, Benzel EC (2001) Biomechanics of bone fusion. Neurosurg. Focus 10: 2Google Scholar
  46. 46.
    Langer R, Vacanti JP (1993) Tissue engineering. Science 260: 920–926PubMedGoogle Scholar
  47. 47.
    Laurencin C, Khan Y, El Amin SF (2006) Bone graft substitutes. Expert Rev Med Devices 3: 49–57CrossRefPubMedGoogle Scholar
  48. 48.
    Linhart W, Briem D (2001) Bone substitutes 2000 to 2010. Current status and innovation in therapy of bone defects. Orthopade 30: 189–192CrossRefPubMedGoogle Scholar
  49. 49.
    Lysaght MJ, Hazlehurst AL (2004) Tissue engineering: the end of the beginning. Tissue Eng 10: 309–320CrossRefPubMedGoogle Scholar
  50. 50.
    Malinin T, Temple HT, Buck BE (2006) Transplantation of osteochondral allografts after cold storage. J Bone Joint Surg Am 88: 762–770CrossRefPubMedGoogle Scholar
  51. 51.
    McAuliffe JA (2003) Bone graft substitutes. J Hand Ther 16: 180–187PubMedGoogle Scholar
  52. 52.
    Meeder PJ, DaFonseca K, Hillmeier J et al. (2003) Kyphoplasty and vertebroplasty in fractures in the elderly: effort and effect. Chirurg 74: 994–999CrossRefPubMedGoogle Scholar
  53. 53.
    Meehan R, McFarlin S, Bugbee W, Brage M (2005) Fresh ankle osteochondral allograft transplantation for tibiotalar joint arthritis. Foot Ankle Int 26: 793–802PubMedGoogle Scholar
  54. 54.
    Melton LJ III (1995) How many women have osteoporosis now? J Bone Miner Res 10: 175–177PubMedGoogle Scholar
  55. 55.
    Morag G, Kulidjian A, Zalzal P et al. (2006) Total knee replacement in previous recipients of fresh osteochondral allograft transplants. J Bone Joint Surg Am 88: 541–546CrossRefPubMedGoogle Scholar
  56. 56.
    Muscolo DL, Ayerza MA, Aponte-Tinao LA, Ranalletta M (2005) Use of distal femoral osteoarticular allografts in limb salvage surgery. J Bone Joint Surg Am 87: 2449–2455CrossRefPubMedGoogle Scholar
  57. 57.
    Oberholzer A, Stahel P, Tschoke SK, Ertel W (2006) Role of gene therapy in trauma and orthopedic surgery. Unfallchirurg 109(7): 521–527CrossRefPubMedGoogle Scholar
  58. 58.
    Olivier V, Faucheux N, Hardouin P (2004) Biomaterial challenges and approaches to stem cell use in bone reconstructive surgery. Drug Discov Today 9: 803–811CrossRefPubMedGoogle Scholar
  59. 59.
    Owen M (1988) Marrow stromal stem cells. J Cell Sci 10(Suppl): 63–76Google Scholar
  60. 60.
    Paley D (1990) Problems, obstacles, and complications of limb lengthening by the Ilizarov technique. Clin Orthop Relat Res 250: 81–104PubMedGoogle Scholar
  61. 61.
    Parikh SN (2002) Bone graft substitutes: past, present, future. J Postgrad Med 48: 142–148PubMedGoogle Scholar
  62. 62.
    Pilitsis JG, Lucas DR, Rengachary SS (2002) Bone healing and spinal fusion. Neurosurg Focus 13: 1Google Scholar
  63. 63.
    Pittenger MF, Mackay AM, Beck SC et al. (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147CrossRefPubMedGoogle Scholar
  64. 64.
    Platz A, Werner CM, Kunzi W etal. (2004) Reconstruction of posttraumatic bony defects of the lower extremity: callotaxis or free vascularized fibula graft? Handchir Mikrochir Plast Chir 36: 397–404CrossRefPubMedGoogle Scholar
  65. 65.
    Pruss A, Kao M, von Garrel T et al. (2003) Virus inactivation in bone tissue transplants (femoral heads) by moist heat with the ‚Marburg bone bank system’. Biologicals 31: 75–82CrossRefPubMedGoogle Scholar
  66. 66.
    Pruss A, Knaepler H, Katthagen BD, Frommelt L (2005) Consequence of European Directive 2004/23/EC for bone banks in Germany. Orthopade 34: 1160–1168CrossRefPubMedGoogle Scholar
  67. 67.
    Pruss A, Seibold M, Benedix F et al. (2003) Validation of the ‚Marburg bone bank system‘ for thermodisinfection of allogenic femoral head transplants using selected bacteria, fungi, and spores. Biologicals 31: 287–294CrossRefPubMedGoogle Scholar
  68. 68.
    Radnay CS, Scuderi GR (2006) Management of bone loss: augments, cones, offset stems. Clin Orthop Relat Res 446: 83–92CrossRefPubMedGoogle Scholar
  69. 69.
    Rajan GP, Fornaro J, Trentz O, Zellweger R (2006) Cancellous allograft versus autologous bone grafting for repair of comminuted distal radius fractures: a prospective, randomized trial. J Trauma 60: 1322–1329PubMedGoogle Scholar
  70. 70.
    Raschke MJ, Mann JW, Oedekoven G, Claudi BF (1992) Segmental transport after unreamed intramedullary nailing. Preliminary report of a „Monorail“ system. Clin Orthop Relat Res 282: 233–240PubMedGoogle Scholar
  71. 71.
    Rodeo SA, Maher SA, Hidaka C (2004) What’s new in orthopaedic research. J Bone Joint Surg Am 86: 2085–2095PubMedGoogle Scholar
  72. 72.
    Rubel IF, Carrer A (2005) Fresh-frozen osteochondral allograft reconstruction of a severely fractured talus. A case report. J Bone Joint Surg Am 87: 625–629CrossRefPubMedGoogle Scholar
  73. 73.
    Rueger JM (1996) Bone substitutes. State of the art and: what lies ahead? Unfallchirurg 99: 228–236PubMedGoogle Scholar
  74. 74.
    Rueger JM (1998) Bone substitution materials. Current status and prospects. Orthopade 27: 72–79PubMedGoogle Scholar
  75. 75.
    Samartzis D, Khanna N, Shen FH, An HS (2005) Update on bone morphogenetic proteins and their application in spine surgery. J Am Coll Surg 200: 236–248CrossRefPubMedGoogle Scholar
  76. 76.
    Sangkaew C (2005) Distraction osteogenesis for the treatment of post traumatic complications using a conventional external fixator. A novel technique. Injury 36: 185–193PubMedGoogle Scholar
  77. 77.
    Schieker M, Seitz H, Drosse I et al. (2006) Biomaterials as scaffold for bone tissue engineering. Europ J Trauma 32: 114–124CrossRefGoogle Scholar
  78. 78.
    Schnürer SM, Gopp U, Kuhn KD, Breusch SJ (2003) Knochenersatzwerkstoffe. Orthopäde 32: 2–10Google Scholar
  79. 79.
    Shasha N, Krywulak S, Backstein D et al. (2003) Long-term follow-up of fresh tibial osteochondral allografts for failed tibial plateau fractures. J Bone Joint Surg Am 85(Suppl 2): 33–39Google Scholar
  80. 80.
    Sotereanos DG, Darlis NA, Dailiana ZH et al. (2006) A capsular-based vascularized distal radius graft for proximal pole scaphoid pseudarthrosis. J Hand Surg Am 31: 580–587CrossRefPubMedGoogle Scholar
  81. 81.
    Sporer SM, O’Rourke M, Chong P, Paprosky WG (2006) The use of structural distal femoral allografts for acetabular reconstruction. Surgical technique. J Bone Joint Surg Am 88(Suppl 1 Pt 1): 92–99CrossRefGoogle Scholar
  82. 82.
    Sundfeldt M, Carlsson LV, Johansson CB et al. (2006) Aseptic loosening, not only a question of wear: a review of different theories. Acta Orthop 77: 177–197CrossRefPubMedGoogle Scholar
  83. 83.
    Urist MR (1965) Bone: formation by autoinduction. Science 150: 893–899PubMedGoogle Scholar
  84. 84.
    Vacanti CA, Bonassar LJ, Vacanti MP, Shufflebarger J (2001) Replacement of an avulsed phalanx with tissue-engineered bone. N Engl J Med 344: 1511–1514CrossRefPubMedGoogle Scholar
  85. 85.
    Vaccaro AR, Anderson DG, Patel T et al. (2005) Comparison of OP-1 Putty (rhBMP-7) to iliac crest autograft for posterolateral lumbar arthrodesis: a minimum 2-year follow-up pilot study. Spine 30: 2709–2716CrossRefPubMedGoogle Scholar
  86. 86.
    Verlaan JJ, Oner FC (2004) Operative compared with nonoperative treatment of a thoracolumbar burst fracture without neurological deficit. J Bone Joint Surg Am 86: 649–650PubMedGoogle Scholar
  87. 87.
    von Garrel T, Knaepler H, Gurtler L (1997) Inactivation of HIV-1 in human femur heads using a heat disinfection system (Lobator SD-1). Unfallchirurg 100: 375–381CrossRefPubMedGoogle Scholar
  88. 88.
    Weber M (1998) Segmenttransport des Knochens mittels Kabelrollen und flexiblem Draht – eine neue Technik am Ringfixateur. Med Orthop Tech 118: 134–140Google Scholar
  89. 89.
    Weng HH, Fitzgerald J (2006) Current issues in joint replacement surgery. Curr Opin Rheumatol 18: 163–169CrossRefPubMedGoogle Scholar
  90. 90.
    Whang PG, Wang JC (2003) Bone graft substitutes for spinal fusion. Spine J 3: 155–165CrossRefPubMedGoogle Scholar
  91. 91.
    Yazar S, Lin CH, Wei FC (2004) One-stage reconstruction of composite bone and soft-tissue defects in traumatic lower extremities. Plast Reconstr Surg 114: 1457–1466CrossRefPubMedGoogle Scholar
  92. 92.
    Zimmermann R, Gabl M, Lutz M et al. (2003) Injectable calcium phosphate bone cement Norian SRS for the treatment of intra-articular compression fractures of the distal radius in osteoporotic women. Arch Orthop Trauma Surg 123: 22–27PubMedGoogle Scholar

Copyright information

© Springer Medizin Verlag 2006

Authors and Affiliations

  1. 1.Experimentelle Chirurgie und Regenerative MedizinChirurgische Klinik Innenstadt Klinikum der UniversitätMünchenDeutschland

Personalised recommendations