The effects of axial displacement on fracture callus morphology and MSC homing depend on the timing of application.

The local mechanical environment and the availability of mesenchymal stem cells (MSC) have both been shown to be important factors in bone fracture healing. This study was designed to investigate how the timing of an applied axial displacement across a healing fracture affects callus properties as well as the migration of systemically introduced MSC. Bilateral osteotomies were created in male, Sprague-Dawley rats. Exogenous MSC were injected via the tail vein, and a controlled micro-motion was applied to one defect starting 0, 3, 10, or 24 days after surgery. The results showed that fractures stimulated 10 days after surgery had more mineral, less cartilage, and greater mechanical properties at 48 days than other groups. Populations of MSC were found in osteotomies 48 days after surgery, with the exception of the group that was stimulated 10 days after surgery. These results demonstrate that the timing of mechanical stimulation affects the physical properties of the callus and the migration of MSC to the fracture site.

[1]  P Augat,et al.  Effect of dynamization on gap healing of diaphyseal fractures under external fixation. , 1995, Clinical biomechanics.

[2]  K. Kraus,et al.  Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. , 2003, The Journal of bone and joint surgery. American volume.

[3]  P. Algenstaedt,et al.  Bilaterally increased VEGF‐levels in muscles during experimental unilateral callus distraction , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[4]  K. Kraus,et al.  Mesenchymal stem cells and bone regeneration. , 2006, Veterinary surgery : VS.

[5]  J. Aubin Osteoprogenitor cell frequency in rat bone marrow stromal populations: Role for heterotypic cell–cell interactions in osteoblast differentiation , 1999, Journal of cellular biochemistry.

[6]  T. A. Hewett,et al.  Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. , 2001, Experimental hematology.

[7]  H. Frost,et al.  The biology of fracture healing. An overview for clinicians. Part I. , 1989, Clinical orthopaedics and related research.

[8]  L. Claes,et al.  The effect of mechanical stability on local vascularization and tissue differentiation in callus healing , 2002, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[9]  A. White,et al.  Comparison of cyclic loading versus constant compression in the treatment of long-bone fractures in rabbits. , 1981, The Journal of bone and joint surgery. American volume.

[10]  Qiwei Sun,et al.  Knee Loading Accelerates Bone Healing in Mice , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[11]  M. Chopp,et al.  Adult bone marrow stromal cells administered intravenously to rats after traumatic brain injury migrate into brain and improve neurological outcome , 2001, Neuroreport.

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

[13]  Darwin J. Prockop,et al.  Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta , 1999, Nature Medicine.

[14]  A Boyde,et al.  Autologous bone marrow stromal cells loaded onto porous hydroxyapatite ceramic accelerate bone repair in critical-size defects of sheep long bones. , 2000, Journal of biomedical materials research.

[15]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[16]  V. Vigorita,et al.  The osteogenic response to distant skeletal injury. , 1990, The Journal of bone and joint surgery. American volume.

[17]  M. Bidlingmaier,et al.  Systemic Regulation of Distraction Osteogenesis: A Cascade of Biochemical Factors , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[18]  L. Claes,et al.  The effect of micromovement on callus formation , 2001, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[19]  W. Richter,et al.  TGF-β1 as a marker of delayed fracture healing , 2005 .

[20]  M. Chopp,et al.  Treatment of Traumatic Brain Injury in Adult Rats with Intravenous Administration of Human Bone Marrow Stromal Cells , 2001, Neurosurgery.

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

[22]  J Kenwright,et al.  The influence of induced micromovement upon the healing of experimental tibial fractures. , 1985, The Journal of bone and joint surgery. British volume.

[23]  F. W. Rhinelander,et al.  Tibial blood supply in relation to fracture healing. , 1974, Clinical orthopaedics and related research.

[24]  Lutz Claes,et al.  Mitogens are increased in the systemic circulation during bone callus healing , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[25]  E R Draper,et al.  The vascular response to fracture micromovement. , 1994, Clinical orthopaedics and related research.

[26]  L. Muul,et al.  Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Chopp,et al.  Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats , 2001, Journal of the Neurological Sciences.

[28]  A. Ratcliffe,et al.  Bone formation on tissue-engineered cartilage constructs in vivo: effects of chondrocyte viability and mechanical loading. , 2003, Tissue engineering.

[29]  B. Mckibbin,et al.  The biology of fracture healing in long bones. , 1978, The Journal of bone and joint surgery. British volume.

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

[31]  L. Claes,et al.  Ilizarov callus distraction produces systemic bone cell mitogens , 1995, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[32]  M. Chopp,et al.  Ischemic cerebral tissue and MCP-1 enhance rat bone marrow stromal cell migration in interface culture. , 2002, Experimental hematology.

[33]  O. Bagasra,et al.  Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[34]  G. Stein,et al.  Stimulation of Systemic Bone Formation Induced by Experimental Blood Loss , 1997, Clinical orthopaedics and related research.

[35]  Joseph A. Buckwalter,et al.  Orthopaedic Basic Science , 2006 .

[36]  Michael J Gardner,et al.  In vivo cyclic axial compression affects bone healing in the mouse tibia , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[37]  A I Caplan,et al.  A chemically defined medium supports in vitro proliferation and maintains the osteochondral potential of rat marrow-derived mesenchymal stem cells. , 1995, Experimental cell research.

[38]  M. Chopp,et al.  Treatment of Traumatic Brain Injury in Female Rats with Intravenous Administration of Bone Marrow Stromal Cells , 2001 .