Zusammenfassung
Neben stabilisierenden Osteosynthesetechniken und der autologen Knochentransplantation spielen Orthobiologika bei der Behandlung von Knochenheilungsstörungen eine zunehmende Rolle. Derzeit kommen hierbei v. a. Wachstumsfaktoren zum Einsatz. Zudem mehren sich Berichte, dass Zelltherapeutika die lokale Knochenregeneration fördern. Aus ethischen und biologischen Gründen ist die klinische Anwendung von Progenitorzellen am Bewegungsapparat zurzeit auf autologe, postpartale Stammzellen beschränkt. Dabei zeigte v. a. die intraoperative einzeitige Zelltherapie mit autologen Progenitorzellen in ersten klinischen Studien positive Ergebnisse. Anhand einer Literaturrecherche sowie eigenen Erfahrungen an 75 Patienten mit Knochendefekten oder -heilungsstörungen wird eine aktuelle Übersicht über die biologischen Hintergründe und die Besonderheiten der klinischen Anwendung einer Zelltherapie zur Behandlung ossärer Substanzdefekte gegeben. Die meisten klinischen Studien berichteten über eine erfolgreiche Knochenregeneration nach Applikation von Mischzellpopulationen aus Knochenmark.
Abstract
In addition to stabilizing osteosynthesis and autologous bone transplantation, so-called orthobiologics are playing an increasing role in the treatment of bone-healing disorders. Besides the application of different growth factors, new data in the literature suggest that cell therapeutic agents promote local bone regeneration. Due to ethical and biological considerations, clinical application of progenitor cells for the musculoskeletal system is limited to autologous postpartum stem cells. Here in particular, cell therapy with autologous progenitor cells in one surgical session has delivered first promising results. Based on a review of the literature and on our own experience with 75 patients, this article reviews the rationale and characteristics of the clinical application of cell therapy for the treatment of bony substance defects. Most clinical trials report successful bone regeneration after the application of mixed cell populations from bone marrow.
Literatur
Alsousou J, Thompson M, Hulley P et al (2009) The biology of platelet-rich plasma and its application in trauma and orthopaedic surgery: a review of the literature. J Bone Joint Surg Am 91:987–996
Amann B, Luedemann C, Ratei R et al (2009) Autologous bone marrow cell transplantation increases leg perfusion and reduces amputations in patients with advanced critical limb ischemia due to peripheral artery disease. Cell Transplant 18:371–380
Au A, Boehm CA, Mayes AM et al (2007) Formation of osteogenic colonies on well-defined adhesion peptides by freshly isolated human marrow cells. Biomaterials 28:1847–1861
Baksh D, Song L, Tuan RS (2004) Adult mesenchymal stem cells: characterization, differentiation and application in cell and gene therapy. J Cell Mol Med 8:301–316
Cahill R, Jones O, Klemperer M et al (2004) Replacement of recipient stromal/mesenchymal cells after bone marrow transplantation using bone fragments and cultured osteoblast-like cells. Biol Blood Marrow Transplant 10:709–717
Cahill R, Wenkert D, Perlman S et al (2007) Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab 92:2923–2930
Coipeau P, Rosset P, Langonne A et al (2009) Impaired differentiation potential of human trabecular bone mesenchymal stromal cells from elderly patients. Cytotherapy 11:584
Connolly JF, Guse R, Tiedeman J et al (1991) Autologous marrow injection as a substitute for operative grafting of tibial nonunions. Clin Orthop 266:259–270
Dahl JA, Duggal S, Coulston N et al (2008) Genetic and epigenetic instability of human bone marrow mesenchymal stem cells expanded in autologous serum or fetal bovine serum. Int J Dev Biol 52:1033–1042
Dallari D, Savarino L, Stagni C et al (2007) Enhanced tibial osteotomy healing with use of bone grafts supplemented with platelet gel or platelet gel and bone marrow stromal cells. J Bone Joint Surg Am 89:2413–2420
Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317
Driessen GJ, Gerritsen EJ, Fischer A et al (2003) Long-term outcome of haematopoietic stem cell transplantation in autosomal recessive osteopetrosis: an EBMT report. Bone Marrow Transplant 32:657–663
El Tamer MK, Reis Rl (2009) Progenitor and stem cells for bone and cartilage regeneration. J Tissue Eng Regen Med 3:327–337
Gan Y, Dai K, Zhang P et al (2008) The clinical use of enriched bone marrow stem cells combined with porous beta-tricalcium phosphate in posterior spinal fusion. Biomaterials 29:3973–3982
Gangji V, Hauzeur JP (2009) Cellular-based therapy for osteonecrosis. Orthop Clin North Am 40:213–221
Gangji V, Hauzeur JP, Matos C et al (2004) Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. A pilot study. J Bone Joint Surg Am 86-A:1153–1160
Gangji V, Toungouz M, Hauzeur JP (2005) Stem cell therapy for osteonecrosis of the femoral head. Expert Opin Biol Ther 5:437–442
Giannini S, Buda R, Vannini F et al (2009) One-step bone marrow-derived cell transplantation in talar osteochondral lesions. Clin Orthop 467:3307–3320
Gowda B, Kurkalli S, Gurevitch O et al (2009) Repair of bone defect using bone marrow cells and demineralized bone matrix supplemented with polymeric materials. Curr Stem Cell Res Ther Oct 7.[Epub ahead of print]
Granchi D, Ochoa G, Leonardi E et al (2009) Gene expression patterns related to osteogenic differentiation of bone marrow-derived mesenchymal stem cells during ex vivo expansion. Tissue Eng Part C Methods Aug 17.[Epub ahead of print]
Hendrich C, Engelmaier F, Waertel G et al (2009) Safety of autologous bone marrow aspiration concentrate (BMAC) transplantation: first experiences in 101 patients. Orthop Rev 1(2):e32:99–103
Hermann PC, Huber Sl, Herrler T et al (2008) Concentration of bone marrow total nucleated cells by a point-of-care device provides a high yield and preserves their functional activity. Cell Transplant 16:1059–1069
Hernigou P, Beaujean F (2002) Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop 405:14–23
Hernigou P, Beaujean F, Lambotte JC (1999) Decrease in the mesenchymal stem-cell pool in the proximal femur in corticosteroid-induced osteonecrosis. J Bone Joint Surg Br 81:349–355
Hernigou P, Poignard A, Beaujean F et al (2005) Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 87:1430–1437
Hernigou P, Mathieu G, Poignard A et al (2006) Percutaneous autologous bone-marrow grafting for nonunions. Surgical technique. J Bone Joint Surg Am [Suppl 1 Pt 2] 88:322–327
Hernigou P, Daltro G, Filippini P et al (2008) Percutaneous implantation of autologous bone marrow osteoprogenitor cells as treatment of bone avascular necrosis related to sickle cell disease. Open Orthop J 2:62–65
Hernigou P, Poignard A, Zilber S et al (2009) Cell therapy of hip osteonecrosis with autologous bone marrow grafting. Indian J Orthop 43:40–45
Hoeppner LH, Secreto F, Jensen ED et al (2009) Runx2 and bone morphogenic protein 2 regulate the expression of an alternative Lef1 transcript during osteoblast maturation. J Cell Physiol 221:480–489
Horwitz EM, Prockop DJ, Fitzpatrick LA et al (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313
Horwitz EM, Prockop DJ, Gordon Pl et al (2001) Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97:1227–1231
Horwitz EM, Le Blanc K, Dominici M et al (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395
Jackson WM, Aragon AB, Djouad F et al (2009) Mesenchymal progenitor cells derived from traumatized human muscle. J Tissue Eng Regen Med 3:129–138
Jäger M (2010) Gelenkerhaltende Operationen bei atraumatischer Femurkopfnekrose. Osteologie in press
Jäger M, Wild A, Lensing-Höhn S et al (2003) Influence of different culture solutions on osteoblastic differentiation in cord blood and bone marrow derived progenitor cells. Biomed Tech 48:241–244
Jäger M, Herten M, Jelinek EM et al (2009) Bone marrow concentrate – Optimal for bone repair! Langenbecks Arch Surg 394:940
Jäger M, Jelinek EM, Wess KM et al (2009) Bone marrow concentrate: a novel strategy for bone defect treatment. Curr Stem Cell Res Ther 4:34–43
Jethva R, Otsuru S, Dominici M et al (2009) Cell therapy for disorders of bone. Cytotherapy 11:3–17
Kahler RA, Galindo M, Lian J et al (2006) Lymphocyte enhancer-binding factor 1 (Lef1) inhibits terminal differentiation of osteoblasts. J Cell Biochem 97:969–983
Kitoh H, Kawasumi M, Kaneko H et al (2009) Differential effects of culture-expanded bone marrow cells on the regeneration of bone between the femoral and the tibial lengthenings. J Pediatr Orthop 29:643–649
Kode JA, Mukherjee S, Joglekar MV et al (2009) Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy 11:377–391
Lange C, Cakiroglu F, Spiess AN et al (2007) Accelerated and safe expansion of human mesenchymal stromal cells in animal serum-free medium for transplantation and regenerative medicine. J Cell Physiol 213:18–26
Lavoie JF, Biernaskie JA, Chen Y et al (2009) Skin-derived precursors differentiate into skeletogenic cell types and contribute to bone repair. Stem Cells Dev 18:893–906
Lin G, Garcia M, Ning H et al (2008) Defining stem and progenitor cells within adipose tissue. Stem Cells Dev 17:1053–1063
Mackay Dl, Tesar PJ, Liang LN et al (2006) Characterizing medullary and human mesenchymal stem cell-derived adipocytes. J Cell Physiol 207:722–728
Marlovits S, Striessnig G, Kutscha-Lissberg F et al (2005) Early postoperative adherence of matrix-induced autologous chondrocyte implantation for the treatment of full-thickness cartilage defects of the femoral condyle. Knee Surg Sports Traumatol Arthrosc 13:451–457
Marlovits S, Zeller P, Singer P et al (2006) Cartilage repair: generations of autologous chondrocyte transplantation. Eur J Radiol 57:24–31
Mayer B (2009) Quality management as a tool to improve translational research. Langenbecks Arch Surg 394:926
Miao Z, Jin J, Chen L et al (2006) Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell Biol Int 30:681–687
Muschler GF, Nitto H, Boehm CA et al (2001) Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res 19:117–125
Nakahara H, Misawa H, Hayashi T et al (2009) Bone repair by transplantation of hTERT-immortalized human mesenchymal stem cells in mice. Transplantation 88:346–353
Neen D, Noyes D, Shaw M et al (2006) Healos and bone marrow aspirate used for lumbar spine fusion: a case controlled study comparing healos with autograft. Spine 31:E636–E640
Nöth U, Reichert J, Reppenhagen S et al (2007) Cell based therapy for the treatment of femoral head necrosis. Orthopade 36:466–471
Pannenbecker A (2009) Stammzellbasierte Therapie am Bewegungsapparat. Rechtsrahmen nach GewebeG, VO (EG) Nr. 1394/2007 und der 15. AMG-Novelle für Tissue-Engineering Produkte aus mesenchymalen Stammzellen. In: DGOU (Hrsg) Stammzellbasierte Therapie am Bewegungsapparat. Expertenworkshop, DGOU, München
Park IH, Micic ID, Jeon IH (2008) A study of 23 unicameral bone cysts of the calcaneus: open chip allogeneic bone graft versus percutaneous injection of bone powder with autogenous bone marrow. Foot Ankle Int 29:164–170
Park J, Setter V, Wixler V et al (2009) Umbilical cord blood stem cells: induction of differentiation into mesenchymal lineages by cell-cell contacts with various mesenchymal cells. Tissue Eng Part A 15:397–406
Pradeep AR, Pai S, Garg G et al (2009) A randomized clinical trial of autologous platelet-rich plasma in the treatment of mandibular degree II furcation defects. J Clin Periodontol 36:581–588
Pradeep AR, Shetty SK, Garg G et al (2009) Clinical effectiveness of autologous platelet-rich plasma and peptide-enhanced bone graft in the treatment of intrabony defects. J Periodontol 80:62–71
Roth A, Jäger M, Maus U et al (2010) S1 Handlungsempfehlungen zur Diagnostik und Therapie der Atraumatischen Femurkopfnekrose des Erwachsenen. Osteologie in press
Satija NK, Singh VK, Verma YK et al (2009) Mesenchymal stem cell-based therapy: a new paradigm in regenerative medicine. J Cell Mol Med Jul 10.[Epub ahead of print]
Sauerbier S, Stricker A, Kuschnierz J et al (2009) In vivo comparison of hard tissue regeneration with human mesenchymal stem cells processed with either the FICOLL- or the BMAC-method. Tissue Eng May 27.[Epub ahead of print]
Segawa Y, Muneta T, Makino H et al (2009) Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament and articular chondrocytes share similar gene expression profiles. J Orthop Res 27:435–441
Siddiqi S, Mills J, Matushansky I (2009) Epigenetic remodeling of chromatin architecture: exploring tumor differentiation therapies in mesenchymal stem cells and sarcomas. Curr Stem Cell Res Ther Oct 7.[Epub ahead of print]
Sir M, Prochazka V, Gumulec J et al (2009) Our first experiences with autologous transplantation of bone marrow stem cells to treat pseudarthrosis, delayed fracture healing and long bone defects fracture. Vnitr Lek 55:187–189
Stark Z, Savarirayan R (2009) Osteopetrosis. Orphanet J Rare Dis 4:5
Steward CG, Pellier I, Mahajan A et al (2004) Severe pulmonary hypertension: a frequent complication of stem cell transplantation for malignant infantile osteopetrosis. Br J Haematol 124:63–71
Takada I, Kouzmenko AP, Kato S (2009) Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev 5:442–447
Tingart M, Beckmann J, Opolka A et al (2009) Analysis of bone matrix composition and trabecular microarchitecture of the femoral metaphysis in patients with osteonecrosis of the femoral head. J Orthop Res 27:1175–1181
Turnovcova K, Ruzickova K, Vanecek V et al (2009) Properties and growth of human bone marrow mesenchymal stromal cells cultivated in different media. Cytotherapy 11:874–885
Undale AH, Westendorf JJ, Yaszemski MJ et al (2009) Mesenchymal stem cells for bone repair and metabolic bone diseases. Mayo Clin Proc 84:893–902
Whyte M, Kurzberg J, Mcalister W et al (2003) Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 2003:624–636
Wright JG, Yandow S, Donaldson S et al (2008) A randomized clinical trial comparing intralesional bone marrow and steroid injections for simple bone cysts. J Bone Joint Surg Am 90:722–730
Yang J, Cao C, Wang W et al (2009) Proliferation and osteogenesis of immortalized bone marrow-derived mesenchymal stem cells in porous polylactic glycolic acid scaffolds under perfusion culture. J Biomed Mater Res 92A(3):817–882
Yin D, Wang Z, Gao Q et al (2009) Determination of the fate and contribution of ex vivo expanded human bone marrow stem and progenitor cells for bone formation by 2.3ColGFP. Mol Ther 17(11):1967–1978
Yoshimi R, Yamada Y, Ito K et al (2009) Self-assembling peptide nanofiber scaffolds, platelet-rich plasma and mesenchymal stem cells for injectable bone regeneration with tissue engineering. J Craniofac Surg 20:1523–1530
Zamzam MM, Abak AA, Bakarman KA et al (2008) Efficacy of aspiration and autogenous bone marrow injection in the treatment of simple bone cysts. Int Orthop 33(5):1353–1358
Zhang S, Muneta T, Morito T et al (2008) Autologous synovial fluid enhances migration of mesenchymal stem cells from synovium of osteoarthritis patients in tissue culture system. J Orthop Res 26:1413–1418
Zhang X, Tang T, Shi Q et al (2009) The immunologic properties of undifferentiated and osteogenic differentiated mouse mesenchymal stem cells and its potential application in bone regeneration. Immunobiology 214:179–186
Zilkens C, Lögters T, Bittersohl B et al (2009) Spinning around or stagnation – what do osteoblasts and chondroblast really like? Eur J Med Res 14:1–9
Zuk PA, Zhu M, Mizuno H et al (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211–228
Interessenkonflikt
Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jäger, M., Hernigou, P., Zilkens, C. et al. Zelltherapie bei Knochenheilungsstörungen. Orthopäde 39, 449–464 (2010). https://doi.org/10.1007/s00132-009-1583-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00132-009-1583-7