Bone fracture healing: Cell therapy in delayed unions and nonunions

Bone

Volumn 70, Issue , 2015, Pages 93-101

  Gómez Barrena, Enrique ^a   Rosset, Philippe ^b,c   Lozano, Daniel ^d   Stanovici, Julien ^b,c   Ermthaller, Christian ^e   Gerbhard, Florian ^e  

^a UNIVERSIDAD AUTÓNOMA DE MADRID   (Spain)

^b UNIVERSITÉ DE TOURS   (France)

^c UNIVERSITÉ DE NANTES   (France)

^d Servicio Madrileño de Salud Red de Investigación en Servicios de Salud en Enfermedades Crónicas   (Spain)

^e UNIVERSITY HOSPITAL ULM   (Germany)

Author keywords

Bone healing; Cell therapy; Clinical trials; MSCs; Nonunion

Indexed keywords

BIOMATERIAL; BONE MORPHOGENETIC PROTEIN;

BIOMECHANICS; BONE ATROPHY; BONE CELL; BONE DEVELOPMENT; BONE GRAFT; BONE REMODELING; CELL THERAPY; CLINICAL EFFECTIVENESS; FRACTURE HEALING; FRACTURE NONUNION; HUMAN; HYPERTROPHY; LONG BONE; MEDICAL RESEARCH; MOLECULAR BIOLOGY; NONHUMAN; PATIENT SAFETY; RADIODIAGNOSIS; REVIEW; THERAPY EFFECT; TREATMENT RESPONSE; CLINICAL TRIAL (TOPIC); DRUG EFFECTS; FRACTURES, UNUNITED; STEM CELL TRANSPLANTATION;

BIOCOMPATIBLE MATERIALS; CLINICAL TRIALS AS TOPIC; FRACTURE HEALING; FRACTURES, UNUNITED; HUMANS; STEM CELL TRANSPLANTATION;

EID: 84918537363     PISSN: 87563282     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bone.2014.07.033     Document Type: Review

References (86)

1. Fong K., Truong V., Foote C.J., Petrisor B., Williams D., Ristevski B., et al. Predictors of nonunion and reoperation in patients with fractures of the tibia: an observational study. BMC Musculoskelet Disord 2013, 14:103.
2. Nonunion following intramedullary nailing of the femur with and without reaming Results of a multicenter randomized clinical trial. J Bone Joint Surg Am 2003, 85-A:2093-2096.
3. WHO The global burden of disease: 2004 update 2008, World Health Organisation, Geneva.
4. Caplan A.I. Mesenchymal stem cells. J Orthop Res 1991, 9:641-650.
5. Gomez-Barrena E., Rosset P., Muller I., Giordano R., Bunu C., Layrolle P., et al. Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology. J Cell Mol Med 2011, 15:1266-1286.
6. Arvidson K., Abdallah B.M., Applegate L.A., Baldini N., Cenni E., Gomez-Barrena E., et al. Bone regeneration and stem cells. J Cell Mol Med 2011, 15:718-746.
7. Einhorn T.A. The cell and molecular biology of fracture healing. Clin Orthop Relat Res 1998, S7-S21.
8. Babhulkar S., Pande K., Babhulkar S. Nonunion of the diaphysis of long bones. Clin Orthop Relat Res 2005, 50-56.
9. Claes L.E., Heigele C.A., Neidlinger-Wilke C., Kaspar D., Seidl W., Margevicius K.J., et al. Effects of mechanical factors on the fracture healing process. Clin Orthop Relat Res 1998, 355(Suppl.: S):132-147.
10. Augat P., Burger J., Schorlemmer S., Henke T., Peraus M., Claes L. Shear movement at the fracture site delays healing in a diaphyseal fracture model. J Orthop Res 2003, 21:1011-1017.
11. Carter D.R., Blenman P.R., Beaupre G.S. Correlations between mechanical stress history and tissue differentiation in initial fracture healing. J Orthop Res 1988, 6:736-748.
12. Claes L.E., Heigele C.A. Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. J Biomech 1999, 32:255-266.
13. Augat P., Margevicius K., Simon J., Wolf S., Suger G., Claes L. Local tissue properties in bone healing: influence of size and stability of the osteotomy gap. J Orthop Res 1998, 16:475-481.
14. Hak D.J. Management of aseptic tibial nonunion. J Am Acad Orthop Surg 2011, 19:563-573.
15. Romano C.L., Romano D., Logoluso N. Low-intensity pulsed ultrasound for the treatment of bone delayed union or nonunion: a review. Ultrasound Med Biol 2009, 35:529-536.
16. Bashardoust Tajali S., Houghton P., MacDermid J.C., Grewal R. Effects of low-intensity pulsed ultrasound therapy on fracture healing: a systematic review and meta-analysis. Am J Phys Med Rehabil 2012, 91:349-367.
17. Bishop J.A., Palanca A.A., Bellino M.J., Lowenberg D.W. Assessment of compromised fracture healing. J Am Acad Orthop Surg 2012, 20:273-282.
18. Hobby B., Lee M.A. Managing atrophic nonunion in the geriatric population: incidence, distribution, and causes. Orthop Clin N Am 2013, 44:251-256.
19. Struijs P.A., Poolman R.W., Bhandari M. Infected nonunion of the long bones. J Orthop Trauma 2007, 21:507-511.
20. Bischoff M., Bischoff G., Buck A., von Baer A., Pauls S., Scheffold F., et al. Integrated FDG-PET-CT: its role in the assessment of bone and soft tissue tumors. Arch Orthop Trauma Surg 2010, 130:819-827.
21. Stecker F.F., Schierz J.H., Opfermann T., Driesch D., Hofmann G.O., Winkens T., et al. Early dynamic 18F-FDG PET/CT to diagnose chronic osteomyelitis following lower extremity fractures. A pilot study. Nuklearmedizin 2013, 52.
22. Giannoudis P.V., Einhorn T.A., Marsh D. Fracture healing: the diamond concept. Injury 2007, 38(Suppl. 4):S3-S6.
23. Schindeler A., McDonald M.M., Bokko P., Little D.G. Bone remodeling during fracture repair: the cellular picture. Semin Cell Dev Biol 2008, 19:459-466.
24. Deschaseaux F., Sensebe L., Heymann D. Mechanisms of bone repair and regeneration. Trends Mol Med 2009, 15:417-429.
25. Lenas P., Moos M., Luyten F.P. Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part I: from three-dimensional cell growth to biomimetics of in vivo development. Tissue Eng Part B Rev 2009, 15:381-394.
26. Lenas P., Moos M., Luyten F.P. Developmental engineering: a new paradigm for the design and manufacturing of cell-based products. Part II: from genes to networks: tissue engineering from the viewpoint of systems biology and network science. Tissue Eng Part B Rev 2009, 15:395-422.
27. Fang J., Hall B.K. Chondrogenic cell differentiation from membrane bone periostea. Anat Embryol (Berl) 1997, 196:349-362.
28. Marsh D.R., Li G. The biology of fracture healing: optimising outcome. Br Med Bull 1999, 55:856-869.
29. Phillips A.M. Overview of the fracture healing cascade. Injury 2005, 36(Suppl. 3):S5-S7.
30. Kon T., Cho T.J., Aizawa T., Yamazaki M., Nooh N., Graves D., et al. Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing. J Bone Miner Res 2001, 16:1004-1014.
31. Vo T.N., Kasper F.K., Mikos A.G. Strategies for controlled delivery of growth factors and cells for bone regeneration. Adv Drug Deliv Rev 2012, 64:1292-1309.
32. Sinha K.M., Zhou X. Genetic and molecular control of osterix in skeletal formation. J Cell Biochem 2013, 114:975-984.
33. Champagne C.M., Takebe J., Offenbacher S., Cooper L.F. Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. Bone 2002, 30:26-31.
34. Lehmann W., Edgar C.M., Wang K., Cho T.J., Barnes G.L., Kakar S., et al. Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing. Bone 2005, 36:300-310.
35. Salinas A.J., Esbrit P., Vallet-Regi M. A tissue engineering approach based on the use of bioceramics for bone repair. Biomater Sci 2013, 1:40-51.
36. Boerckel J.D., Uhrig B.A., Willett N.J., Huebsch N., Guldberg R.E. Mechanical regulation of vascular growth and tissue regeneration in vivo. Proc Natl Acad Sci U S A 2011, 108:E674-E680.
37. Akeel S., El-Awady A., Hussein K., El-Refaey M., Elsalanty M., Sharawy M., et al. Recombinant bone morphogenetic protein-2 induces up-regulation of vascular endothelial growth factor and interleukin 6 in human pre-osteoblasts: role of reactive oxygen species. Arch Oral Biol 2012, 57:445-452.
38. Esbrit P., Alvarez-Arroyo M.V., De Miguel F., Martin O., Martinez M.E., Caramelo C. C-terminal parathyroid hormone-related protein increases vascular endothelial growth factor in human osteoblastic cells. J Am Soc Nephrol 2000, 11:1085-1092.
39. Zhang L., Richardson M., Mendis P. Role of chemical and mechanical stimuli in mediating bone fracture healing. Clin Exp Pharmacol Physiol 2012, 39:706-710.
40. Siddappa R., Martens A., Doorn J., Leusink A., Olivo C., Licht R., et al. cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. Proc Natl Acad Sci U S A 2008, 105:7281-7286.
41. Chen Y., Alman B.A. Wnt pathway, an essential role in bone regeneration. J Cell Biochem 2009, 106:353-362.
42. Kulkarni N.H., Wei T., Kumar A., Dow E.R., Stewart T.R., Shou J., et al. Changes in osteoblast, chondrocyte, and adipocyte lineages mediate the bone anabolic actions of PTH and small molecule GSK-3 inhibitor. J Cell Biochem 2007, 102:1504-1518.
43. Heath D.J., Chantry A.D., Buckle C.H., Coulton L., Shaughnessy J.D., Evans H.R., et al. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res 2009, 24:425-436.
44. Caetano-Lopes J., Lopes A., Rodrigues A., Fernandes D., Perpetuo I.P., Monjardino T., et al. Upregulation of inflammatory genes and downregulation of sclerostin gene expression are key elements in the early phase of fragility fracture healing. PLoS One 2011, 6:e16947.
45. Aspenberg P., Genant H.K., Johansson T., Nino A.J., See K., Krohn K., et al. Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res 2010, 25:404-414.
46. Peichl P., Holzer L.A., Maier R., Holzer G. Parathyroid hormone 1-84 accelerates fracture-healing in pubic bones of elderly osteoporotic women. J Bone Joint Surg Am 2011, 93:1583-1587.
47. Garrison K.R., Shemilt I., Donell S., Ryder J.J., Mugford M., Harvey I., et al. Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev 2010, CD006950.
48. Kawaguchi H., Oka H., Jingushi S., Izumi T., Fukunaga M., Sato K., et al. A local application of recombinant human fibroblast growth factor 2 for tibial shaft fractures: a randomized, placebo-controlled trial. J Bone Miner Res 2010, 25:2735-2743.
49. Goulet J.A., Senunas L.E., DeSilva G.L., Greenfield M.L. Autogenous iliac crest bone graft. Complications and functional assessment. Clin Orthop Relat Res 1997, 76-81.
50. Burchardt H. Biology of bone transplantation. Orthop Clin N Am 1987, 18:187-196.
51. Hernigou P., Pariat J., Queinnec S., Homma Y., Lachaniette C.H., Chevallier N., et al. Supercharging irradiated allografts with mesenchymal stem cells improves acetabular bone grafting in revision arthroplasty. Int Orthop 2014, [Epub ahead of print].
52. Fernandez-Bances I., Perez-Basterrechea M., Perez-Lopez S., Nunez Batalla D., Fernandez Rodriguez M.A., Alvarez-Viejo M., et al. Repair of long-bone pseudoarthrosis with autologous bone marrow mononuclear cells combined with allogenic bone graft. Cytotherapy 2013, 15:571-577.
53. Liao Y., Zhang X.L., Li L., Shen F.M., Zhong M.K. Stem cell therapy for bone repair: a systematic review and meta-analysis of preclinical studies with large animal model. Br J Clin Pharmacol 2014, [Epub ahead of print]. 10.1111/bcp.12382.
54. Laurencin C., Khan Y., El-Amin S.F. Bone graft substitutes. Expert Rev Med Devices 2006, 3:49-57.
55. Sen M.K., Miclau T. Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions?. Injury 2007, 38(Suppl. 1):S75-S80.
56. Lozano D., Feito M.J., Portal-Nunez S., Lozano R.M., Matesanz M.C., Serrano M.C., et al. Osteostatin improves the osteogenic activity of fibroblast growth factor-2 immobilized in Si-doped hydroxyapatite in osteoblastic cells. Acta Biomater 2012, 8:2770-2777.
57. Chai Y.C., Roberts S.J., Van Bael S., Chen Y., Luyten F.P., Schrooten J. Multi-level factorial analysis of Ca2+/Pi supplementation as bio-instructive media for in vitro biomimetic engineering of three-dimensional osteogenic hybrids. Tissue Eng Part C Methods 2012, 18:90-103.
58. Ryan G., Pandit A., Apatsidis D.P. Fabrication methods of porous metals for use in orthopaedic applications. Biomaterials 2006, 27:2651-2670.
59. Wysolmerski J.J. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab 2012, 97:2947-2956.
60. Valin A., Guillen C., Esbrit P. C-terminal parathyroid hormone-related protein (PTHrP) (107-139) stimulates intracellular Ca(2+) through a receptor different from the type 1 PTH/PTHrP receptor in osteoblastic osteosarcoma UMR 106 cells. Endocrinology 2001, 142:2752-2759.
61. Takemoto M., Fujibayashi S., Neo M., Suzuki J., Kokubo T., Nakamura T. Mechanical properties and osteoconductivity of porous bioactive titanium. Biomaterials 2005, 26:6014-6023.
62. Stewart A.F., Cain R.L., Burr D.B., Jacob D., Turner C.H., Hock J.M. Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1-34, parathyroid hormone-related protein 1-36, and SDZ-parathyroid hormone 893. J Bone Miner Res 2000, 15:1517-1525.
63. Langer R., Vacanti J.P. Tissue engineering. Science 1993, 260:920-926.
64. Hernigou P., Mathieu G., Poignard A., Manicom O., Beaujean F., Rouard H. Percutaneous autologous bone-marrow grafting for nonunions. Surgical technique. J Bone Joint Surg Am 2006, 88(Suppl. 1):322-327. Pt 2:.
65. Hernigou P., Poignard A., Beaujean F., Rouard H. Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 2005, 87:1430-1437.
66. Ateschrang A., Ochs B.G., Ludemann M., Weise K., Albrecht D. Fibula and tibia fusion with cancellous allograft vitalised with autologous bone marrow: first results for infected tibial non-union. Arch Orthop Trauma Surg 2009, 129:97-104.
67. Dallari D., Savarino L., Stagni C., Cenni E., Cenacchi A., Fornasari P.M., et al. 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 2007, 89:2413-2420.
68. Ochs B.G., Schmid U., Rieth J., Ateschrang A., Weise K., Ochs U. Acetabular bone reconstruction in revision arthroplasty: a comparison of freeze-dried, irradiated and chemically-treated allograft vitalised with autologous marrow versus frozen non-irradiated allograft. J Bone Joint Surg (Br) 2008, 90:1164-1171.
69. Quarto R., Mastrogiacomo M., Cancedda R., Kutepov S.M., Mukhachev V., Lavroukov A., et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 2001, 344:385-386.
70. Marcacci M., Kon E., Moukhachev V., Lavroukov A., Kutepov S., Quarto R., et al. Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study. Tissue Eng 2007, 13:947-955.
71. Kitoh H., Kawasumi M., Kaneko H., Ishiguro N. Differential effects of culture-expanded bone marrow cells on the regeneration of bone between the femoral and the tibial lengthenings. J Pediatr Orthop 2009, 29:643-649.
72. Kim S.J., Shin Y.W., Yang K.H., Kim S.B., Yoo M.J., Han S.K., et al. A multi-center, randomized, clinical study to compare the effect and safety of autologous cultured osteoblast(Ossron) injection to treat fractures. BMC Musculoskelet Disord 2009, 10:20.
73. Petite H., Viateau V., Bensaid W., Meunier A., de Pollak C., Bourguignon M., et al. Tissue-engineered bone regeneration. Nat Biotechnol 2000, 18:959-963.
74. Derubeis A.R., Cancedda R. Bone marrow stromal cells (BMSCs) in bone engineering: limitations and recent advances. Ann Biomed Eng 2004, 32:160-165.
75. Khan Y., Yaszemski M.J., Mikos A.G., Laurencin C.T. Tissue engineering of bone: material and matrix considerations. J Bone Joint Surg Am 2008, 90(Suppl. 1):36-42.
76. Warnke P.H., Wiltfang J., Springer I., Acil Y., Bolte H., Kosmahl M., et al. Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible. Biomaterials 2006, 27:3163-3167.
77. Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Retrieved 12/03/2014, from. http://ec.europa.eu/health/documents/eudralex/vol-1/index_en.htm#reg.
78. Hernigou P., Homma Y., Flouzat-Lachaniette C.H., Poignard A., Chevallier N., Rouard H. Cancer risk is not increased in patients treated for orthopaedic diseases with autologous bone marrow cell concentrate. J Bone Joint Surg Am 2013, 95:2215-2221.
79. Tarte K., Gaillard J., Lataillade J.J., Fouillard L., Becker M., Mossafa H., et al. Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. Blood 2010, 115:1549-1553.
80. WHO International Clinical Trials Registry Platform - ICTRP. Retrieved 12.03.2014, from. http://www.who.int/ictrp/en/.
81. European Clinical Trials Database-EudraCT. Retrieved 12.03.2014, from. https://www.clinicaltrialsregister.eu.
82. ClinicalTrials.gov. Retrieved 12.03.2014, from. https://www.clinicaltrials.gov.
83. Maciulaitis R., D'Apote L., Buchanan A., Pioppo L., Schneider C.K. Clinical development of advanced therapy medicinal products in Europe: evidence that regulators must be proactive. Mol Ther 2012, 20:479-482.
84. ESF Forward look on investigator-driven clinical trials 2009, European Science Foundation, Strasbourg.
85. Liebergall M., Schroeder J., Mosheiff R., Gazit Z., Yoram Z., Rasooly L., et al. Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther 2013, 21:1631-1638.
86. Petite H., Vandamme K., Monfoulet L., Logeart-Avramoglou D. Strategies for improving the efficacy of bioengineered bone constructs: a perspective. Osteoporos Int 2011, 22:2017-2021.