79. Anterior cervical spine fusion using bioresorbable interbody spacers and rhBMP-2

Proceedings of the NASS 19th Annual Meeting / The Spine Journal 4 (2004) 3S–119S element area with increasing alendronate dose (16%, 8%, 6% respectively, p⬍0.001) and corresponding increases in bone area (43%, 52%, 55% respectively, p⬍0.001). Radiographic fusion mass area was 86–111% higher in the alendronate groups compared to controls (p⬍0.001). CONCLUSIONS: Alendronate inhibits spine fusion in rats. Higher percentages of bone area in fusion masses in alendronate-treated animals did not correlate with fusion and likely resulted from unincorporated bone graft. Increased marrow elements in animals not treated with alendronate probably represent new bone formation and remodeling. Alendronate’s beneficial effect in osteoporosis is primarily exerted by osteoclast inhibition but in spine fusion the incorporation and remodeling processes, mediated by osteoclasts and osteoblasts, are disrupted. Osteoblast inhibition may result from direct pharmacologic effects or from disruption of osteoblast-osteoclast paracrine signaling. Based on these data, we recommend that patients undergoing fusion should not take alendronate. DISCLOSURES: Device or drug: ALENDRONATE SODIUM. Status: Approved for this indication. CONFLICT OF INTEREST: No Conflicts. doi: 10.1016/j.spinee.2004.05.078

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OP-1 group (13 biopsies): Histologically viable bone was identified in each of the specimens from the OP-1 group. The viable bone is histologically unremarkable and, based on its microscopic appearance, is expected to have normal mechanical properties. Two of the OP-1 specimens contained areas of hyaline cartilage surrounded by bone in a pattern that suggests a late stage of remodeling of bone of endochondral origin. Residual OP-1 device was recognized in two cases. These residual pieces of collagen carrier were associated with prominent chronic inflammation in one case, and very mild inflammation in another case. Other pieces of collagen carrier were in the process of undergoing phagocytosis by giant cells. In the other 5 cases neither OP-1 device nor active inflammation was recognized. CONCLUSIONS: To our knowledge, the current investigation serves as the first report of surgical exploration and histologic assessment of a human instrumented posterolateral lumbar fusion using bone morphogenetic protein. This study showed that the OP-1 alone can induce new bone formation in human posterolateral fusion. DISCLOSURES: Device or drug: OP-1 device, Stryker Biotech Corp., Hopkington, MA. Status: Investigational/Not approved. CONFLICT OF INTEREST: No Conflicts. doi: 10.1016/j.spinee.2004.05.079

4:09 78. Histology of biopsies obtained from fusion mass in a human instrumented posterolateral fusion osteogenic protein 1 versus hydroxyapatite tricalcium phosphate mixed with local autograft Daisuke Togawa1, Thomas W. Bauer1*, Masahiro Kanayama2, Tomoyuki Hashimoto2, Keiichi Shigenobu2, Shigeru Yamane2; 1 Cleveland Clinic Foundation, Cleveland, OH, USA; 2Hakodate Central General Hospital, Hakodate, Hokkaido, Japan BACKGROUND CONTEXT: A number of pre-clinical investigations have demonstrated efficacy of osteoinductive proteins in spinal fusion, but the safety and efficacy of the proteins in human clinical studies are not yet completely determined. PURPOSE: The purpose of this study was to describe histologic findings of biopsies obtained from bone induced by the Osteogenic Protein-1 (OP1) device during human posterolateral spinal fusion compared to the HA/ TCP mixed with local autograft. STUDY DESIGN/SETTING: Prospective, randomized and controlled clinical study. PATIENT SAMPLE: Nineteen patients having an L3/4 or L4/5 spondylolisthesis with spinal stenosis were included in this Institutional Review Board approved study. OUTCOME MEASURES: Qualitative histologic evaluation. METHODS: Each patient underwent single level posterolateral fusion using pedicle screw instrumentation and was randomized to receive either OP-1 putty alone or a combination of local autograft with hydroxyapatite/ tricalcium phosphate granules. After radiographic confirmation of fusion, a total of 16 patients underwent removal of pedicle screws and a small biopsy was obtained from the fusion mass. RESULTS: A total of 23 biopsies were obtained from 16 patients. There were 9 males and 7 females with an average age of 65 years (44–77). Although the study was randomized, mean age was significantly higher in the OP-1 group (mean 70, range 51–77) than the control group (mean 58, range 43–71, p⫽0.02). At least one year postoperatively (12–32 months), 9 patients (90%) of the control group and 7 patients (78%) of OP-1 group showed radiographic evidence of fusion. Surgical exploration showed that a solid arthrodesis was achieved in 7 patients of the control group and in 5 patients of the OP-1 group. HA/TCP control group (10 biopsies): Residual biomaterial was identified in each of the cases treated with HA/TCP mixed with autograft. The pieces of HA range up to 1 mm in diameter, while the individual crystals of HA appear to have ranged up to approximately 10 um in diameter. In some areas the residual HA showed extensive bone apposition, but in other areas the granules of HA were surrounded by fibrous tissue, not bone. Giant cells were also present around the HA granules in some areas. There were 2 cases in which the specimen showed an area of inflammation associated with the calcium phosphate granules.

4:16 79. Anterior cervical spine fusion using bioresorbable interbody spacers and rhBMP-2 Todd Lanman, MD1, Theodore Goldstein, MD2, Thomas Hopkins, PhD, MD3; 1Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Beverly Hills, CA, USA; 3Encino, CA, USA BACKGROUND CONTEXT: Anterior cervical discectomy and interbody fusion (ACDF) is an accepted treatment option for degenerative spondylosis/instability of the cervical spine that is unresponsive to conservative treatment. An animal model study, reported in 1998, concluded that the use of titanium cervical interbody cages with and without the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) resulted in accelerated arthrodesis. Successful cervical fusions have been reported at 6 months in humans using an allograft ring filled with rhBMP-2. Bioresorbable interbody spacers have emerged as an alternative to both autograft and cadaver allograft with the attendant advantage of obviating donor site morbidity and allograft-associated complications. The bioresorbable implant provides immediate motion segment stability, radiolucency, and time dependant stress transfer to host bone with the graft breakdown products not being mutagenic or immunogenic. PURPOSE: The purpose of this evaluation was to determine the feasibility of using a bioresorbable spacer in conjunction with rhBMP-2 for ACDF. STUDY DESIGN/SETTING: From our practice we selected patients who required cervical spine fusion for inclusion into an evaluation of a bioresorbable interbody spacer using rhBMP-2 as an osteoinductive substrate. Followup visits were scheduled for 6 weeks, 3 months, 6 months, 12 months and 24 months. Preoperatively and at all visits, patients completed SF36 Questionnaires as well as high resolution CT scans of the cervical spine. PATIENT SAMPLE: A total of 27 patients have at least 12 months followup (12–18). The patient population was 74% male with a mean age of 46.2 years (22–62). OUTCOME MEASURES: Fusion was defined as bridging bone in the interbody space from the vertebra through the graft to the adjacent vertebra observed on CT scan. Clinical outcomes were assessed by the SF-36 Health Survey. METHODS: All patients had an ACDF with anterior instrumentation. A poly (L-lactide-co-D, L-lactide) (PLA) bioresorbable implant, filled with rhBMP-2 on a collagen sponge, was inserted at each level to be fused. Patients were not required to use a brace or collar of any kind after surgery. RESULTS: One level fusion was performed in 59%, two-level in 26% and three-level in 15% for a total of 42 levels. At 3 months 100% of patients had successful interbody fusion which was maintained at 12 months. No device related complications were seen. SF-36 scores demonstrated

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improvement between time points, except in one patient who required the addition of an adjacent segment fusion following an MVA at 3 months. CONCLUSIONS: In our practice we have noted that the use of bioresorbable spacers filled with rhBMP-2 gave us faster fusion rates (100% at 3 months), which were easier to assess than what we have seen historically with the combination of allograft and rhBMP-2. These initial results suggest that the combination of bioresorbable interbody spacers with rhBMP-2 may provide an alternative treatment for anterior cervical fusion. DISCLOSURES: Device or drug: Infuse. Status: Not approved for this indication. Device or drug: Cornerstone-HSR. Status: Not approved for this indication. CONFLICT OF INTEREST: Author (TL) Consultant: Consultant for Medtronic Sofamor Danek, manufacturer of Infuse and Cornerstone-HSR. doi: 10.1016/j.spinee.2004.05.080

Friday, October 29, 2004 4:35–5:15 PM Concurrent Sessions 4A: Spinal Cord Injury

All 4 SCI individuals developed anemia within the first post-SCI week and survived from 5 weeks to 6 mos. (mean⫽3.9mos.). Both SCI and control groups were comparable regarding age (p⫽0.167). There were significant differences between both groups with respect to the number of preserved axons within DVPs (p⬍0.001) and within CST (p⫽0.013), but not within DC (p⫽0.821). Mean blood hemoglobin concentration was inversely correlated with the number of preserved axons within the DVPs (R=828; p⫽0.028) and there was a trend for an association of larger area of demyelination with lower mean blood hemoglobin concentration (p⫽0.077). CONCLUSIONS: Anemia is a frequent hematological finding in the first week after SCI and correlates with the extent of injury. While post-traumatic anemia is likely multifactorial in etiology, the impact of acute autonomic dysfunction with dysregulation of hematopoietic tissues has to date not received attention. Our data suggest that destruction of DVPs may play important role in the pathobiology of anemia after acute cervical SCI. Given the adverse impact of anemia on tissue healing, this postinjury event merits further attention and study by clinicians. DISCLOSURES: No disclosures. CONFLICT OF INTEREST: Author (JF) Grant Research Support: Supported by the Krembil Neuroscience Centre. doi: 10.1016/j.spinee.2004.05.081

4:35 80. Mechanisms underlying anemia after acute cervical spinal cord injury: clinical neuroanatomical and molecular evidence for autonomic dysfunction Julio Furlan, MD, PhD, Michael Fehlings, MD, PhD, FRCSC; Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

4:42 81. Tempol, an antioxidant, improves locomotor function and decreases tissue loss after spinal cord injury in the rat Virany Hillard1, Richard Zeman2, Kaushik Das2, Yan Zhang2, Hong Peng2, Joseph Etlinger2; 1New York Medical College, Valhalla, NY, USA; 2New York Medical College, NY, USA

BACKGROUND CONTEXT: Spinal cord injury (SCI) is a devastating event that may cause motor, sensory, and autonomic dysfunction, which can affect autonomic innervation of the kidneys, spleen, bone marrow and surrounding tissues. PURPOSE: This study was undertaken (1) to evaluate the incidence of anemia within the first post-SCI week; (2) to verify the influence of age, gender, level and severity of SCI on post-SCI anemia; and (3) to the association of destruction of descending vasomotor pathways (DVPs) with blood hemoglobin concentration after SCI. STUDY DESIGN/SETTING: This study included: (a) clinical data review of individuals with acute traumatic SCI admitted to a university-teaching hospital, and (b) histopathological examination of postmortem spinal cord tissue. PATIENT SAMPLE: We selected all consecutive individuals with acute, isolated SCI who were admitted to our hospital from 1998–2000. Also, postmortem spinal cord from 4 men with acute cervical SCI and 3 control cases (males) without SCI were examined. OUTCOME MEASURES: Mean blood hemoglobin concentration within the first week after acute traumatic SCI as well as area of demyelination and number of preserved axons within the DVPs, dorsal column (DC), and corticospinal tracts (CST) in sections caudal to the SCI site. METHODS: Severity of SCI was classified based on the ASIA scale. Individuals with polytrauma or chronic systemic diseases and individuals with ASIA E after spine trauma were excluded. Postmortem spinal cord tissues were examined using histochemical staining (LFB) for myelin preservation and immunocytochemical staining (NF 200) for axonal preservation. Measurements and counts were carried out using Image-Pro software. Data were analyzed using Student’s t-test and multiple linear regression. RESULTS: There were 24 individuals with acute, isolated SCI (17M, 7F; ages 17–83 years, mean=56) in our Spinal Cord Database. Most individuals had mild (ASIA C10, D7) cervical SCI (21/24). Reduced hemoglobin concentration occurred in 83.3%. There was no correlation between hemoglobin concentration and age or level of SCI, but individuals with more severe SCI (R⫽0.971; p⫽0.003) and females (p⬍0.001) showed lower hemoglobin concentration. From our Spinal Cord Tissue Bank, we selected 4 individuals with severe (ASIA A2, B2) cervical SCI (4M, age 66–82 years, mean⫽70.2) and 3 control cases (3M, age 30–73 years, mean⫽52).

BACKGROUND CONTEXT: Current treatment for paralyis caused by spinal cord injury (SCI) remains limited. The amount of recovery of locomotor function following incomplete SCI is thought to depend, in part, on the extent of inflammation occurring in the injured spinal cord tissue. The increased production of reactive oxygen species (ROS) after SCI results in tissue damage. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is an antioxidant that can act as a superoxide dismutase mimic that scavenges free radicals. Therefore, an approcah toward enhancing recovery from SCI is to optimize the capacity fo the spinal cord to oppose ROS-mediated tissue damage. PURPOSE: The ability of Tempol, a ROS-scavenger, to promote recovery of locomotor function and spare spinal cord tissue was investigated in an animal model of SCI. STUDY DESIGN/SETTING: All animals were housed in a temperatureregulated (23⬚C) animal facility. All procedures were reviewed and approved by the Use and Care of Animals Committee at the New York Medical College. Because urinary tract infection is common in animals with SCI, antibiotics (Amoxicillin PO) were added prophylactically to the drinking water and the animals’ bladder were emptied frequently by manual expression until urinary function returned. No animal died during the experiment, and all recovered bladder function by the 4th week. PATIENT SAMPLE: Ninety-one female Wistar rats (250 g) obtained from Charles Rivers laboratories were used in the study. OUTCOME MEASURES: Locomotor function was determined for 6 weeks post-injury with the 21 point Basso, Beattie, and Bresnahan (BBB) scale followed by histological analysis of sparred tissue at the contusion site and statistical significance by repeated measures ANOVA, least significant difference post hoc and t test at the P⬍0.05 level. METHODS: Female Wistar rats were anesthetized, a laminectomy was performed at T10, and a contusion injury was induced with a weight-drop device. To study locomotor and histologic outcomes, the experimental group (n⫽20) received injections of Tempol (275 mg/kg, IP) 20 minutes post-injury, and the control group (n⫽21), saline-vehicle. To examine doseresponsiveness, experimental groups (n⫽10) received Tempol at 68.75– 550 mg/kg. Other groups (n⫽10) received Tempol (275 mg/kg) at 4 hours, or 2 days post-injury. Locomotor function was determined with the 21point BBB scale for 6 weeks post-injury. Spinal cords were harvested at 6 weeks for histologic analysis.