title: Improved healing of large segmental defects in the rat femur by reverse dynamization in the presence of bone morphogenetic protein-2.
abstract: BACKGROUND
  Large segmental defects in bone do not heal well and present clinical challenges. This study investigated modulation of the mechanical environment as a means of improving bone healing in the presence of bone morphogenetic protein (BMP)-2. Although the influence of mechanical forces on the healing of fractures is well established, no previous studies, to our knowledge, have described their influence on the healing of large segmental defects. We hypothesized that bone-healing would be improved by initial, low-stiffness fixation of the defect, followed by high-stiffness fixation during the healing process. We call this reverse dynamization.
  
  
  METHODS
  A rat model of a critical-sized femoral defect was used. External fixators were constructed to provide different degrees of stiffness and, importantly, the ability to change stiffness during the healing process in vivo. Healing of the critical-sized defects was initiated by the implantation of 11 μg of recombinant human BMP (rhBMP)-2 on a collagen sponge. Groups of rats receiving BMP-2 were allowed to heal with low, medium, and high-stiffness fixators, as well as under conditions of reverse dynamization, in which the stiffness was changed from low to high at two weeks. Healing was assessed at eight weeks with use of radiographs, histological analysis, microcomputed tomography, dual x-ray absorptiometry, and mechanical testing.
  
  
  RESULTS
  Under constant stiffness, the low-stiffness fixator produced the best healing after eight weeks. However, reverse dynamization provided considerable improvement, resulting in a marked acceleration of the healing process by all of the criteria of this study. The histological data suggest that this was the result of intramembranous, rather than endochondral, ossification.
  
  
  CONCLUSIONS
  Reverse dynamization accelerated healing in the presence of BMP-2 in the rat femur and is worthy of further investigation as a means of improving the healing of large segmental bone defects.
  
  
  CONCLUSIONS
  These data provide the basis of a novel, simple, and inexpensive way to improve the healing of critical-sized defects in long bones. Reverse dynamization may also be applicable to other circumstances in which bone-healing is problematic.
authors.affiliation: Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, 330, Brookline Avenue, RN-115, Boston, MA 02215, USA. V. Glatt: vglatt@bidmc.harvard.edu
authors.forename: Vaida
authors.initials: V
authors.lastname: Glatt
authors.forename: Micah
authors.initials: M
authors.lastname: Miller
authors.forename: Alan
authors.initials: A
authors.lastname: Ivkovic
authors.forename: Fangjun
authors.initials: F
authors.lastname: Liu
authors.forename: Nicola
authors.initials: N
authors.lastname: Parry
authors.forename: Damian
authors.initials: D
authors.lastname: Griffin
authors.forename: Mark
authors.initials: M
authors.lastname: Vrahas
authors.forename: Christopher
authors.initials: C
authors.lastname: Evans
mesh_terms: D015502:Absorptiometry, Photon / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001861:Bone Regeneration / Q000187:drug effects; D004195:Disease Models, Animal; D016267:External Fixators; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000473:pathology* / Q000628:therapy*; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D005592:Fracture Fixation / Q000295:instrumentation / Q000379:methods; D017102:Fracture Healing / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010865:Pilot Projects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013718:Tensile Strength; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D055114:X-Ray Microtomography / Q000379:methods
chemical_list: D055396:Bone Morphogenetic Protein 2; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2