A multicenter, prospective, randomized trial evaluating a new hemostatic agent for spinal surgery.

STUDY DESIGN: A prospective, randomized trial comparing Proceed, a gelatin-based hemostatic sealant (treatment), with Gelfoam-thrombin (control) in stopping intraoperative bleeding during spinal surgery. OBJECTIVES: To determine the effectiveness and safety of Proceed. SUMMARY OF BACKGROUND DATA: Proceed has been tested in animal models to determine its safety and effectiveness as a hemostatic agent. The current study was conducted under a Food and Drug Administration-approved Investigational Device Exemption to evaluate the effectiveness and safety of Proceed in humans. METHODS: For this study, 127 patients undergoing spinal surgery were randomized into either the treatment or control group after standard surgical means to control bleeding had failed. The bleeding site was evaluated at 1, 2, 3, 6, and 10 minutes after the hemostatic agent was applied. The application was considered successful if the bleeding stopped within 10 minutes. Follow-up evaluation was performed at 12 to 36 hours, then at 6 to 8 weeks after surgery. RESULTS: Proceed stopped bleeding in 98% of the patients (first bleeding site only) within 10 minutes, as compared with 90% of the control patients (P = 0.001). At 3 minutes, successful hemostasis had been achieved in 97% of the Proceed group, as compared with 71% of the control group (P = 0.0001). There was no difference in the adverse event profile between the two groups. CONCLUSIONS: A significantly larger number of bleeding sites had achieved hemostasis with Proceed than with Gelfoam-thrombin at 1, 2, and 3 minutes after application. Proceed was as safe as Gelfoam-thrombin when used for hemostasis during spinal surgery procedures.

The effect of nicotine on gene expression during spine fusion.

STUDY DESIGN: A rabbit model of posterolateral spine fusion was used to investigate the effect of nicotine on cytokine expression during spine fusion. OBJECTIVES: To determine the effects of nicotine on the known gene expression pattern of bone morphogens and related proteins expressed during spine fusion. SUMMARY OF BACKGROUND DATA: The mechanism by which nicotine increases the pseudarthrosis rate of spine fusion is unknown. Recently, a distinct temporal and spatial pattern of cytokine expression during bone formation has been described. The authors hypothesized that nicotine would alter this known pattern, thereby revealing the mechanism by which nicotine exerts its effect. METHODS: Twenty-eight New Zealand White rabbits underwent posterolateral spine fusion with autogenous bone graft. Fourteen rabbits received systemic nicotine by a miniosmotic pump. Fusions were harvested at 0, 2, 5, and 7 days and 2, 3, and 4 weeks after arthrodesis. Specimens were divided into the outer zones adjacent to the transverse processes and the central zones between the transverse processes. Gene expression of type I and II collagen, bone morphogenic protein-2, -4, and -6 and basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) was then measured at each time point in each of the two zones. RESULTS: Nicotine inhibited expression of all cytokines measured, mainly in the central zone. However, the previously described temporal and spatial patterns of expression were preserved. CONCLUSIONS: Nicotine inhibits expression of a wide range of cytokines, including those associated with neovascularization and osteoblast differentiation. Therefore, the effects of nicotine appear to involve more than just local vasoconstriction.

Management of acute odontoid fractures with single-screw anterior fixation.

OBJECTIVE: Accepted management strategies for odontoid fractures include external immobilization and surgical stabilization using anterior or posterior approaches. Displaced Type II fractures and rostral Type III fractures are at high risk for nonunion. Anterior fixation of odontoid fractures with a single cortical lag screw is a relatively new technique that combines rigid internal stabilization with preservation of intrinsic C1-C2 motion. We retrospectively reviewed our series of 26 consecutive patients who underwent odontoid screw fixation, to further define the safety and efficacy of the technique. METHODS: During a 5-year period, 26 patients presented with acute traumatic Type II odontoid fractures. Ten patients were female and 16 were male, with a mean age of 35 years. All patients underwent anterior odontoid screw fixation by the senior surgeon (RWH), within a mean of 3 days after injury. All patients were postoperatively maintained in external orthoses, for a mean of 7.2 weeks, and were monitored with serial clinical and radiographic examinations. RESULTS: With a mean follow-up period of 30 months, radiographic fusion was documented for 25 of 26 patients (96%). No complications related to the surgical approach were identified, and all patients remained in neurologically stable condition. Two complications (8%) were related to the instrumentation; one patient required external immobilization because of suboptimal screw placement, and one patient required posterior atlantoaxial arthrodesis because of inadequate fracture reduction. CONCLUSION: Single-screw anterior odontoid fixation was associated with a relatively low complication rate and a high fusion rate in this study. We think that this should be the preferred treatment method for acute Type II odontoid fractures.

Posterolateral lumbar intertransverse process spine arthrodesis with recombinant human bone morphogenetic protein 2/hydroxyapatite-tricalcium phosphate after laminectomy in the nonhuman primate.

STUDY DESIGN: A nonhuman primate lumbar intertransverse process arthrodesis model was used to evaluate recombinant human bone morphogenetic protein 2 (rhBMP-2) in a hydroxyapatite-tricalcium phosphate (HA-TCP) carrier as a complete bone graft substitute. OBJECTIVES: To assess the ability of a ceramic material to serve as a carrier for various doses of rhBMP-2 as a bone graft substitute in a primate model of posterolateral intertransverse process spinal fusion after laminectomy. SUMMARY OF BACKGROUND DATA: The reported non-union rates for posterolateral lumbar spine fusion with autogenous iliac crest bone range from 5-35%. Recombinant human bone morphogenetic protein 2 has shown potential to serve as a bone graft substitute for posterolateral intertransverse process spine fusion. Although a resorbable collagen sponge was a suitable carrier in rabbits and dogs, it was too compressible for the paraspinal muscles in rhesus monkeys. This failure of the collagen carrier has prompted evaluation of the feasibility of an alternative carrier material and the required dose of rhBMP-2. METHODS: Twenty-one adult rhesus monkeys underwent a laminectomy at L4-L5 followed by bilateral intertransverse process arthrodesis via the same midline incision (n = 16) or a minimally invasive video-assisted posterolateral approach (n = 5). Bone graft implants on each side consisted of either 5 cm3 of autogenous iliac crest bone or 60:40 HA-TCP blocks (1.2 x 0.5 x 3.7 cm) loaded with a solution containing 0, 6, 9, or 12 mg of rhBMP-2 per side. The monkeys were killed 24 weeks after surgery. Inspection, manual palpation, radiography, and histology were used to assess fusion and to detect any bony growth into the laminectomy defect. RESULTS: Fusion was not achieved in any of the monkeys treated with autogenous iliac crest bone graft. Both of the monkeys treated with the HA-TCP blocks with 0 mg rhBMP-2 achieved fusion. All 15 monkeys treated with the HA-TCP blocks and either of the three doses of rhBMP-2 achieved solid fusion. Two animals had extension of the fusion on one side because of malpositioned ceramic block. The results in animals fused via the minimally invasive video-assisted technique were the same as inthose fused with the open technique. Histologic analysis showed some ingrowth of bone into the ends but not-through the ceramic block in the absence of rhBMP-2. When the ceramic blocks were loaded with rhBMP-2 there was a dose-dependent increase in the amount and quality of bone throughout the ceramic carrier based on qualitative assessment. No significant bone encroachment on the exposed thecal sac through the laminectomy defect was observed in any of the monkeys. CONCLUSION: Hydroxyapatite-tricalcium phosphate proved to be a suitable carrier for rhBMP-2 in the posterolateral spine fusion model in rhesus monkeys. Even in the presence of a laminectomy defect, there was no evidence of bone induction outside the confines of the ceramic carrier.

The Marshall R. Urist Young Investigator Award. Gene expression during autograft lumbar spine fusion and the effect of bone morphogenetic protein 2.

A prospective animal study of posterolateral lumbar spine arthrodesis was performed to determine the temporal and spatial pattern of gene expression and to determine the effect of recombinant human bone morphogenetic protein 2 on the gene expression pattern of a healing spine fusion mass. In Group 1, 20 adult New Zealand rabbits underwent L4-L5 posterolateral intertransverse process arthrodesis using autograft alone. Two rabbits were euthanized at each of the following points: 0, 2, and 4 days, and 1, 2, 3, 4, 5, 6, and 10 weeks after surgery. The same surgical technique was used for 16 rabbits in Group II, except that the autograft first was soaked in a solution of recombinant human bone morphogenetic protein 2 before implantation. Ribonucleic acid was extracted from different regions of the fusion mass at each point and analyzed for expression of bone and cartilage related genes using reverse transcription polymerase chain reaction. A reproducible temporal sequence and spatial pattern of gene expression was found in healing spine fusions. In the central portion of the fusion mass a temporal lag in gene expression was observed that parallels the lag in healing within the central zone previously observed in histologic studies. Treatment of bone graft with recombinant human bone morphogenetic protein 2 resulted in an increase in the early expression of bone morphogenetic protein 6 which was associated with expression of higher levels of Type I collagen, osteocalcin, and other bone related genes. These findings suggest that central nonunion may be associated with delayed expression of osteoblast related genes in the central region of the forming fusion mass. The growth factor, recombinant human bone morphogenetic protein 2, increased the level of bone related gene expression throughout the fusion mass, eliminated the delay in healing within the central zone, and may decrease the likelihood of a nonunion.

Experimental posterolateral lumbar spinal fusion with a demineralized bone matrix gel.

STUDY DESIGN: A controlled rabbit model of lumbar posterolateral intertransverse process arthrodesis was used to evaluate a bone graft substitute. OBJECTIVE: To determine the efficacy of demineralized bone matrix gel as an autograft extender, using different ratios of demineralized bone matrix to autograft and to determine the efficacy of demineralized bone matrix as an autogenous bone graft enhancer by adding it to the usual quantity of autograft. SUMMARY OF BACKGROUND DATA: Autogenous bone is considered the most effective bone graft material for posterolateral lumbar arthrodesis, yet nonunions occur in up to 30% of patients. In addition, donor site complications may occur in 25-30% of patients. This has prompted the search for and investigation of bone graft extenders, enhancers, and substitutes. Commercially available demineralized bone matrix gel is one possible graft extender and enhancer, which, unlike mineralized allografts, has osteoinductive properties. Although the gel is in common use, the efficacy of demineralized bone matrix when used for posterolateral spine arthrodesis has not been examined in prospective clinical studies. Furthermore, no known animal studies have tested demineralized bone matrix gel in a posterolateral arthrodesis model. METHODS: Forty-seven New Zealand white rabbits underwent bilateral posterolateral spine arthrodesis at L5-L6 using autogenous iliac crest bone graft alone or in combination with demineralized bone matrix. Four groups were formed on the basis of the ratio of autograft to demineralized bone matrix: autograft alone (3 mL), 100:0 group; autograft (3 mL) and demineralized bone matrix (1.5 mL), 100:50 group; autograft (1.5 mL) and demineralized bone matrix (1.5 mL), 50:50 group; and autograft (0.75 mL) and demineralized bone matrix (2.25 mL), 25:75 group. Rabbits were killed 6 weeks after surgery. Inspection, manual palpation, radiographic film, and histologic evaluation were used to assess fusion. RESULTS: All groups had similar fusion rates (66-73%) based on manual palpation. Rabbits implanted with demineralized bone matrix had more mature fusion masses, evidenced by the greater trabecular bone formation seen on radiographic film and histologic study. CONCLUSIONS: Demineralized bone matrix was effective as a graft extender when used in up to a 3:1 ratio with autograft in a rabbit posterolateral spine fusion model. When less than the standard volume of autograft was used, the addition of demineralized bone matrix gel lead to fusion success rates comparable to those of the standard amount of autograft alone. However, demineralized bone matrix did not increase the frequency of successful fusion when added to the standard amount of autograft.

Video-assisted lateral intertransverse process arthrodesis. Validation of a new minimally invasive lumbar spinal fusion technique in the rabbit and nonhuman primate (rhesus) models.

STUDY DESIGN: Cadaveric anatomic and in vivo survival animal studies were performed to develop a new arthrodesis technique for the lumbar spine. OBJECTIVES: To examine the feasibility, efficacy, and safety of a minimally invasive lumbar intertransverse process arthrodesis technique using an osteoinductive growth factor (rhBMP-2) delivered in a collagen sponge carrier. The technique was first developed using a rabbit model and modified for the nonhuman primate (rhesus monkey), a larger animal with the most similar bone biology to humans. SUMMARY OF BACKGROUND DATA: The morbidity of conventional posterolateral lumbar intertransverse process arthrodesis includes graft donor site morbidity; paraspinal muscle devascularization, denervation, and scarring and nonunion in up to 36% of patients. Minimally invasive anterior lumbar interbody arthrodesis techniques have been developed, but these often require a metal implant and carry risks to major vessels and development of retrograde ejaculation. A minimally invasive technique for posterolateral intertransverse process arthrodesis has not been described previously. METHODS: In Part 1, we examined seven New Zealand white rabbits and five rhesus monkeys at necropsy and during nonsurvival surgeries to determine the best access routes and to develop special instruments for video-assisted lateral intertransverse process arthrodesis. In Part 2, 38 New Zealand white rabbits underwent L4-L5 intertransverse process arthrodesis: the "OPEN" group (n = 16) underwent a standard open muscle-splitting approach using rhBMP-2 (bone morphogenetic protein) and collagen as a bone graft substitute; the "video-assisted control" group (n = 6) underwent video-assisted lateral intertransverse process arthrodesis with the collagen implant only (no growth factor); and the "video-assisted-BMP" group (n = 16) underwent video-assisted lateral intertransverse process arthrodesis with rhBMP-2 and collagen as the graft material. In Part 3, rhesus monkeys (n = 4) underwent video-assisted lateral intertransverse process arthrodesis using rhBMP-2 and collagen after laminectomy of L4-L5. RESULTS: In Part 1, we identified expedient, minimally invasive routes to the intertransverse process interval appropriate for each species: an intermuscular approach for the rabbit and a lateral, extramuscular approach for the rhesus monkey. In Part 2, all rabbits in the OPEN and video-assisted-BMP groups achieved solid intertransverse process lumbar fusions when assessed at 10 weeks. There were no neurologic impairments nor any difference between the two groups in the frequency of postoperative infection or other complications. None of the animals in the video-assisted control group showed evidence of fusion. In Part 3, exposure, decortication and grafting with rh-BMP-2 and collagen was accomplished successfully in all four monkeys through the video-assisted minimally invasive approach without complications. CONCLUSION: Video-assisted lateral intertransverse process arthrodesis is a feasible, effective, and safe method of lumbar spinal fusion in the rabbit and rhesus monkey. Use of this arthrodesis procedure will minimize the morbidity of paraspinal muscle denervation and devascularization seen with open intertransverse process fusion techniques, and the use of an osteoinductive growth factor will eliminate the problem of graft donor site morbidity and possibly increase the chances for successful fusion.