Bone fracture healing: cell therapy in delayed unions and nonunions.

Bone fracture healing impairment related to mechanical problems has been largely corrected by advances in fracture management. Better protocols, more strict controls of time and function, and hardware and surgical technique evolution have contributed to better prognosis, even in complex fractures. However, atrophic nonunion persists in clinical cases where, for different reasons, the osteogenic capability is impaired. When this is the case, a better understanding of the basic mechanisms under bone repair and augmentation techniques may put in perspective the current possibilities and future opportunities. Among those, cell therapy particularly aims to correct this insufficient osteogenesis. However, the launching of safe and efficacious cell therapies still requires substantial amount of research, especially clinical trials. This review will envisage the current clinical trials on bone healing augmentation based on cell therapy, with the experience provided by the REBORNE Project, and the insight from investigator-driven clinical trials on advanced therapies towards the future. This article is part of a Special Issue entitled Stem Cells and Bone.

[1]  R Cancedda,et al.  Repair of large bone defects with the use of autologous bone marrow stromal cells. , 2001, The New England journal of medicine.

[2]  P. Giannoudis,et al.  Fracture healing: the diamond concept. , 2007, Injury.

[3]  D. Heymann,et al.  Mechanisms of bone repair and regeneration. , 2009, Trends in molecular medicine.

[4]  J. Caetano-Lopes,et al.  Upregulation of Inflammatory Genes and Downregulation of Sclerostin Gene Expression Are Key Elements in the Early Phase of Fragility Fracture Healing , 2011, PloS one.

[5]  J. Schroeder,et al.  Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[6]  P. Hernigou,et al.  Cancer risk is not increased in patients treated for orthopaedic diseases with autologous bone marrow cell concentrate. , 2013, The Journal of bone and joint surgery. American volume.

[7]  F Beaujean,et al.  Percutaneous autologous bone-marrow grafting for nonunions. Influence of the number and concentration of progenitor cells. , 2005, The Journal of bone and joint surgery. American volume.

[8]  N. Ishiguro,et al.  Differential Effects of Culture-expanded Bone Marrow Cells on the Regeneration of Bone Between the Femoral and the Tibial Lengthenings , 2009, Journal of pediatric orthopedics.

[9]  Yusuf Khan,et al.  Bone graft substitutes , 2006, Expert review of medical devices.

[10]  D. Graves,et al.  Tumor necrosis factor alpha (TNF-alpha) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing. , 2005, Bone.

[11]  Stefan Wolfart,et al.  Man as living bioreactor: fate of an exogenously prepared customized tissue-engineered mandible. , 2006, Biomaterials.

[12]  H. Burchardt Biology of bone transplantation. , 1987, The Orthopedic clinics of North America.

[13]  Cato T Laurencin,et al.  Tissue engineering of bone: material and matrix considerations. , 2008, The Journal of bone and joint surgery. American volume.

[14]  C. Romanò,et al.  Low-intensity pulsed ultrasound for the treatment of bone delayed union or nonunion: a review. , 2009, Ultrasound in medicine & biology.

[15]  Robert E Guldberg,et al.  Mechanical regulation of vascular growth and tissue regeneration in vivo , 2011, Proceedings of the National Academy of Sciences.

[16]  Aaron Schindeler,et al.  Bone remodeling during fracture repair: The cellular picture. , 2008, Seminars in cell & developmental biology.

[17]  Antonios G Mikos,et al.  Strategies for controlled delivery of growth factors and cells for bone regeneration. , 2012, Advanced drug delivery reviews.

[18]  Petros Lenas,et al.  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. , 2009, Tissue engineering. Part B, Reviews.

[19]  J. Vacanti,et al.  Tissue engineering : Frontiers in biotechnology , 1993 .

[20]  D. Graves,et al.  Tumor necrosis factor alpha (TNF-α) coordinately regulates the expression of specific matrix metalloproteinases (MMPS) and angiogenic factors during fracture healing , 2005 .

[21]  Kozo Nakamura,et al.  A local application of recombinant human fibroblast growth factor 2 for tibial shaft fractures: A randomized, placebo‐controlled trial , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  Priyan Mendis,et al.  Role of chemical and mechanical stimuli in mediating bone fracture healing , 2012, Clinical and experimental pharmacology & physiology.

[23]  R. L. Cain,et al.  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 , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[24]  L. Cooper,et al.  Macrophage cell lines produce osteoinductive signals that include bone morphogenetic protein-2. , 2002, Bone.

[25]  A. Ateschrang,et al.  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. , 2008, The Journal of bone and joint surgery. British volume.

[26]  L. Claes,et al.  Magnitudes of local stress and strain along bony surfaces predict the course and type of fracture healing. , 1998, Journal of biomechanics.

[27]  Joyce Doorn,et al.  cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo , 2008, Proceedings of the National Academy of Sciences.

[28]  Benjamin A Alman,et al.  Wnt pathway, an essential role in bone regeneration , 2009, Journal of cellular biochemistry.

[29]  Abhay Pandit,et al.  Fabrication methods of porous metals for use in orthopaedic applications. , 2006, Biomaterials.

[30]  T. Miclau,et al.  Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions? , 2007, Injury.

[31]  P. Esbrit,et al.  C-terminal parathyroid hormone-related protein increases vascular endothelial growth factor in human osteoblastic cells. , 2000, Journal of the American Society of Nephrology : JASN.

[32]  H. Petite,et al.  Strategies for improving the efficacy of bioengineered bone constructs: a perspective , 2011, Osteoporosis International.

[33]  Y. Liao,et al.  Stem cell therapy for bone repair: a systematic review and meta‐analysis of preclinical studies with large animal models , 2014, British journal of clinical pharmacology.

[34]  M. Sefton,et al.  Tissue engineering. , 1998, Journal of cutaneous medicine and surgery.

[35]  M. Vallet‐Regí,et al.  Osteostatin improves the osteogenic activity of fibroblast growth factor-2 immobilized in Si-doped hydroxyapatite in osteoblastic cells. , 2012, Acta biomaterialia.

[36]  P. Hernigou,et al.  Percutaneous autologous bone-marrow grafting for nonunions. Surgical technique. , 2006, The Journal of bone and joint surgery. American volume.

[37]  Lutz Claes,et al.  Shear movement at the fracture site delays healing in a diaphyseal fracture model , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[38]  L. Applegate,et al.  Bone regeneration and stem cells , 2011, Journal of cellular and molecular medicine.

[39]  Mark A. Lee,et al.  Managing atrophic nonunion in the geriatric population: incidence, distribution, and causes. , 2013, The Orthopedic clinics of North America.

[40]  J. Macdermid,et al.  Effects of Low-Intensity Pulsed Ultrasound Therapy on Fracture Healing: A Systematic Review and Meta-Analysis , 2012, American journal of physical medicine & rehabilitation.

[41]  K. Sinha,et al.  Genetic and molecular control of osterix in skeletal formation , 2013, Journal of cellular biochemistry.

[42]  A. Buck,et al.  Integrated FDG-PET-CT: its role in the assessment of bone and soft tissue tumors , 2010, Archives of Orthopaedic and Trauma Surgery.

[43]  Petros Lenas,et al.  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. , 2009, Tissue engineering. Part B, Reviews.

[44]  A. Ateschrang,et al.  Fibula and tibia fusion with cancellous allograft vitalised with autologous bone marrow: first results for infected tibial non-union , 2008, Archives of Orthopaedic and Trauma Surgery.

[45]  Seok-Jung Kim,et al.  A multi-center, randomized, clinical study to compare the effect and safety of autologous cultured osteoblast(Ossron™) injection to treat fractures , 2009, BMC Musculoskeletal Disorders.

[46]  B. Hall,et al.  Chondrogenic cell differentiation from membrane bone periostea , 1997, Anatomy and Embryology.

[47]  U. Albisinni,et al.  Enhanced tibial osteotomy healing with use of bone grafts supplemented with platelet gel or platelet gel and bone marrow stromal cells. , 2007, The Journal of bone and joint surgery. American volume.

[48]  Ian Harvey,et al.  Bone morphogenetic protein (BMP) for fracture healing in adults. , 2010, The Cochrane database of systematic reviews.

[49]  Lutz Claes,et al.  Local tissue properties in bone healing: Influence of size and stability of the osteotomy gap , 1998, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[50]  G. Sukhikh,et al.  Mesenchymal Stem Cells , 2002, Bulletin of Experimental Biology and Medicine.

[51]  P. Hernigou,et al.  Supercharging irradiated allografts with mesenchymal stem cells improves acetabular bone grafting in revision arthroplasty , 2014, International Orthopaedics.

[52]  J. Schrooten,et al.  Multi-level factorial analysis of Ca2+/Pi supplementation as bio-instructive media for in vitro biomimetic engineering of three-dimensional osteogenic hybrids. , 2012, Tissue engineering. Part C, Methods.

[53]  Ranieri Cancedda,et al.  Bone Marrow Stromal Cells (BMSCs) in Bone Engineering: Limitations and Recent Advances , 2004, Annals of Biomedical Engineering.

[54]  K. Pande,et al.  Nonunion of the Diaphysis of Long Bones , 2005, Clinical orthopaedics and related research.

[55]  A. M. Phillips Overview of the fracture healing cascade. , 2005, Injury.

[56]  F. Luyten,et al.  Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology , 2011, Journal of cellular and molecular medicine.

[57]  M. Swiontkowski Parathyroid Hormone 1-84 Accelerates Fracture-Healing in Pubic Bones of Elderly Osteoporotic Women , 2012 .

[58]  M. Vallet‐Regí,et al.  A tissue engineering approach based on the use of bioceramics for bone repair. , 2013, Biomaterials science.

[59]  A. Meunier,et al.  Tissue-engineered bone regeneration , 2000, Nature Biotechnology.

[60]  T A Einhorn,et al.  The cell and molecular biology of fracture healing. , 1998, Clinical orthopaedics and related research.

[61]  P. Esbrit,et al.  C-Terminal Parathyroid Hormone-Related Protein (PTHrP) (107-139) Stimulates Intracellular Ca2+ through a Receptor Different from the Type 1 PTH/PTHrP Receptor in Osteoblastic Osteosarcoma UMR 106 Cells. , 2001, Endocrinology.

[62]  J. Goulet,et al.  Autogenous Iliac Crest Bone Graft: Complications and Functional Assessment , 1997, Clinical orthopaedics and related research.

[63]  M. Perez-Basterrechea,et al.  Repair of long-bone pseudoarthrosis with autologous bone marrow mononuclear cells combined with allogenic bone graft. , 2013, Cytotherapy.

[64]  D Kaspar,et al.  Effects of Mechanical Factors on the Fracture Healing Process , 1998, Clinical orthopaedics and related research.

[65]  Hélène Rouard,et al.  Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation. , 2010, Blood.

[66]  T A Einhorn,et al.  Expression of Osteoprotegerin, Receptor Activator of NF‐κB Ligand (Osteoprotegerin Ligand) and Related Proinflammatory Cytokines During Fracture Healing , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[67]  J. Bishop,et al.  Assessment of Compromised Fracture Healing , 2012, The Journal of the American Academy of Orthopaedic Surgeons.

[68]  R. Higgs,et al.  Changes in Osteoblast, Chondrocyte, and Adipocyte Lineages Mediate the Bone Anabolic Actions of PTH and Small Molecule GSK‐3 Inhibitor , 2007, Journal of cellular biochemistry.

[69]  J. Wysolmerski Parathyroid hormone-related protein: an update. , 2012, The Journal of clinical endocrinology and metabolism.

[70]  A. Jain,et al.  Infected Nonunion of the Long Bones , 2005, Clinical orthopaedics and related research.

[71]  Maurilio Marcacci,et al.  Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study. , 2007, Tissue engineering.

[72]  G S Beaupré,et al.  Correlations between mechanical stress history and tissue differentiation in initial fracture healing , 1988, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[73]  D. Marsh,et al.  The biology of fracture healing: optimising outcome. , 1999, British medical bulletin.

[74]  Andrew Buchanan,et al.  Clinical development of advanced therapy medicinal products in Europe: evidence that regulators must be proactive. , 2012, Molecular therapy : the journal of the American Society of Gene Therapy.

[75]  D. Hak Management of Aseptic Tibial Nonunion , 2011, The Journal of the American Academy of Orthopaedic Surgeons.

[76]  J. Vacanti,et al.  Tissue engineering. , 1993, Science.

[77]  Mohit Bhandari,et al.  Predictors of nonunion and reoperation in patients with fractures of the tibia: an observational study , 2013, BMC Musculoskeletal Disorders.

[78]  M. Elsalanty,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. , 2012, Archives of oral biology.

[79]  P. Esbrit,et al.  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. , 2001, Endocrinology.

[80]  H. Genant,et al.  Teriparatide for acceleration of fracture repair in humans: A prospective, randomized, double‐blind study of 102 postmenopausal women with distal radial fractures , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[81]  Tadashi Kokubo,et al.  Mechanical properties and osteoconductivity of porous bioactive titanium. , 2005, Biomaterials.

[82]  J. Shaughnessy,et al.  Inhibiting Dickkopf‐1 (Dkk1) Removes Suppression of Bone Formation and Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.