BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) induce bone formation but are difficult to localize, and subsequent diffusion from the site of interest and short half-life reduce the efficacy of the protein. Currently, spine fusion requires stripping, decortications of the transverse processes, and an autograft harvest procedure. Even in combination with BMPs, clinical spinal fusion has a high failure rate, presumably because of difficulties in localizing sufficient levels of BMP. PURPOSE: The goal was to achieve reliable spine fusion through a single injection of a cell-based gene therapy system without the need for any surgical intervention. STUDY DESIGN: Eighty-seven immunodeficient (n=44) and immune-competent (n=43) mice were injected along the paraspinous musculature to achieve rapid induction of heterotopic ossification (HO) and ultimately spinal arthrodesis. METHODS: Immunodeficient and immune-competent mice were injected with fibroblasts, transduced with an adenoviral vector to express BMP2, along the paraspinous musculature. Bone formation was evaluated via radiographs, microcomputed tomography, and biomechanical analysis. RESULTS: ew bridging bone between the vertebrae and the fusion to adjacent skeletal bone was obtained as early as 2 weeks. Reduction in spine flexion-extension also occurred as early as 2 weeks after injection of the gene therapy system, with greater than 90% fusion by 4 weeks in all animals regardless of their genetic background. CONCLUSIONS: Injection of our cell-based system into the paraspinous musculature induces spinal fusion that is dependent neither on the cell type nor on the immune status. These studies are the first to harness HO in an immune-competent model as a noninvasive injectable system for clinically relevant spinal fusion and may one day impact human spinal arthrodesis.
BACKGROUND CONTEXT: Bone morphogenetic proteins (BMPs) induce bone formation but are difficult to localize, and subsequent diffusion from the site of interest and short half-life reduce the efficacy of the protein. Currently, spine fusion requires stripping, decortications of the transverse processes, and an autograft harvest procedure. Even in combination with BMPs, clinical spinal fusion has a high failure rate, presumably because of difficulties in localizing sufficient levels of BMP. PURPOSE: The goal was to achieve reliable spine fusion through a single injection of a cell-based gene therapy system without the need for any surgical intervention. STUDY DESIGN: Eighty-seven immunodeficient (n=44) and immune-competent (n=43) mice were injected along the paraspinous musculature to achieve rapid induction of heterotopic ossification (HO) and ultimately spinal arthrodesis. METHODS:Immunodeficient and immune-competent mice were injected with fibroblasts, transduced with an adenoviral vector to express BMP2, along the paraspinous musculature. Bone formation was evaluated via radiographs, microcomputed tomography, and biomechanical analysis. RESULTS: ew bridging bone between the vertebrae and the fusion to adjacent skeletal bone was obtained as early as 2 weeks. Reduction in spine flexion-extension also occurred as early as 2 weeks after injection of the gene therapy system, with greater than 90% fusion by 4 weeks in all animals regardless of their genetic background. CONCLUSIONS: Injection of our cell-based system into the paraspinous musculature induces spinal fusion that is dependent neither on the cell type nor on the immune status. These studies are the first to harness HO in an immune-competent model as a noninvasive injectable system for clinically relevant spinal fusion and may one day impact humanspinal arthrodesis.
Authors: Christine M Fouletier-Dilling; Pablo Bosch; Alan R Davis; Jessica A Shafer; Steven L Stice; Zbigniew Gugala; Francis H Gannon; Elizabeth A Olmsted-Davis Journal: Hum Gene Ther Date: 2005-11 Impact factor: 5.695
Authors: B P Hecht; J S Fischgrund; H N Herkowitz; L Penman; J M Toth; A Shirkhoda Journal: Spine (Phila Pa 1976) Date: 1999-04-01 Impact factor: 3.468
Authors: T D Alden; D D Pittman; E J Beres; G R Hankins; D F Kallmes; B M Wisotsky; K M Kerns; G A Helm Journal: J Neurosurg Date: 1999-01 Impact factor: 5.115
Authors: Elizabeth A Olmsted-Davis; Zbigniew Gugala; Francis H Gannon; Patricia Yotnda; Robert E McAlhany; Ronald W Lindsey; Alan R Davis Journal: Hum Gene Ther Date: 2002-07-20 Impact factor: 5.695
Authors: Ashvin K Dewan; Rahul A Dewan; Nathan Calderon; Angie Fuentes; Zawaunyka Lazard; Alan R Davis; Michael Heggeness; John A Hipp; Elizabeth A Olmsted-Davis Journal: J Orthop Surg Res Date: 2010-08-21 Impact factor: 2.359
Authors: Jeffrey C Wang; Linda E A Kanim; Stephen Yoo; Patricia A Campbell; Arnold J Berk; Jay R Lieberman Journal: J Bone Joint Surg Am Date: 2003-05 Impact factor: 5.284
Authors: Yujie Lu; Chinmay D Darne; I-Chih Tan; Banghe Zhu; Mary A Hall; Zawaunyka W Lazard; Alan R Davis; Lashan Simpson; Eva M Sevick-Muraca; Elizabeth A Olmsted-Davis Journal: Opt Express Date: 2013-10-07 Impact factor: 3.894
Authors: Pedro Alvarez-Urena; Eleanor Davis; Corinne Sonnet; Gabrielle Henslee; Zbigniew Gugala; Edward V Strecker; Laura J Linscheid; Maude Cuchiara; Jennifer West; Alan Davis; Elizabeth Olmsted-Davis Journal: Tissue Eng Part A Date: 2017-01-25 Impact factor: 3.845
Authors: Eleanor L Davis; Corinne Sonnet; ZaWaunyka W Lazard; Gabrielle Henslee; Zbigniew Gugala; Elizabeth A Salisbury; Edward V Strecker; Thomas A Davis; Jonathan A Forsberg; Alan R Davis; Elizabeth A Olmsted-Davis Journal: J Orthop Res Date: 2016-03-14 Impact factor: 3.494