Joseph D. Smucker

Increased swelling complications associated with off-label usage of rhBMP-2 in the anterior cervical spine

Study Design/Setting. Independent, retrospective clinical record review with a concurrent control. Objective. To identify whether rhBMP-2 is associated with an increased incidence of clinically relevant postoperative prevertebral swelling problems in patients undergoing anterior cervical fusions. Summary of Background Data. Bone Morphogenetic Protein-2 (rhBMP-2) is FDA approved as a bone graft substitute in anterior lumbar interbody fusions. rhBMP-2 has also been used “off-label” in anterior cervical fusions. We suspected that rhBMP-2 might increase the incidence of adverse swelling events. Methods. A total of 234 consecutive patients (ages 12–82 years) undergoing anterior cervical fusion with and without rhBMP-2 over a 2-year period at one institution comprised the study population. The incidence of clinically relevant prevertebral swelling was calculated. The populations were compared and statistical significance was determined. Results. A total of 234 patients met the study criteria, 69 of whom underwent anterior cervical spine fusions using rhBMP-2; 27.5% of those patients in the rhBMP-2 group had a clinically significant swelling event versus only 3.6% of patients in the non-rhBMP-2 group. This difference was statistically significant (P < 0.0001) and remained so after controlling for other significant predictors of swelling. Conclusions. Off-label use of rhBMP-2 in the anterior cervical spine is associated with an increased rate of clinically relevant swelling events.

Clinical outcomes of BRYAN cervical disc arthroplasty: a prospective, randomized, controlled, multicenter trial with 24-month follow-up.

Study Design/Setting Prospective, randomized, 3-center, clinical trial. Objective To prospectively compare the outcomes of cervical arthroplasty with the BRYAN Cervical Disc Prosthesis (Medtronic Sofamor Danek, Inc, Memphis, TN) to anterior cervical discectomy and fusion (ACDF). Summary of Background Data Surgical treatment of cervical disc pathology commonly involves techniques that employ discectomy and fusion (ACDF). This “gold-standard” technique has demonstrated good clinical and radiographic outcomes. Common adverse effects of this procedure are associated with the adjacent level degeneration and bone-graft harvest. Several investigators have independently reported successful short-term outcomes with the BRYAN Cervical Disc Prosthesis. In addition, a significant body of knowledge has been collected regarding the wear patterns and adjacent level effects of this device in human and animal models. Methods As part of an FDA IDE trial, 3 centers collected prospective outcomes data on 115 patients randomized in a 1:1 ratio to ACDF (Control group) or arthroplasty with the BRYAN Cervical Disc Prosthesis (Investigational group). Results Demographic and surgical data were generally similar in the 2 populations. Outcomes data collected at routine postoperative intervals for 24 months demonstrated that the Investigational group had statistically significant (P<0.05) improvements as assessed by the Neck Disability Index, the Neck Pain Score, and SF-36 Physical component scores. The improvement in the Mental Component Subscore values for the BRYAN and control groups was equivalent at 24 months (P=0.055). Arm pain relief was similar in both groups (P=0.152). During the course of the 2-year follow-up, 4 patients in the Control group required surgical intervention and 3 patients in the Investigational group required ACDF for adjacent level disease. Conclusions At 24 months, cervical arthroplasty with the BRYAN Cervical Disc Prosthesis compares favorably with ACDF as defined by standard outcomes scores.

Artificial disc versus fusion: a prospective, randomized study with 2-year follow-up on 99 patients.

Study Design. A total of 115 patients were randomized in a 1:1 ratio to a Bryan artificial disc replacement (56) or an anterior cervical fusion with allograft and a plate (59). Objective. The purpose of this study is to examine the functional outcome and radiographic results of this prospective, randomized trial to determine the role of the Bryan artificial cervical disc replacement for patients with 1-level cervical disc disease. Summary of Background Data. Artificial cervical disc replacement has become an option for cervical radiculopathy. Previous studies have evaluated the efficacy of this alternative without the scientific rigor of a concurrent control population. This study is a pooled data set from 3 centers involved in the U.S. FDA Investigational Device Exemption trial evaluating the Bryan artificial cervical disc. Methods. The purpose of this study is to examine the functional outcome and radiographic results of this prospective, randomized trial to determine the role of the Bryan artificial cervical disc replacement for patients with 1-level cervical disc disease; 12-month follow-up is available for 110 patients and 24 month follow-up complete for 99 patients. There are 30 males and 26 females in the Bryan group and 32 males and 27 females in the fusion group. The average age was 43 years (Bryan) and 46 years (fusion). Disability and pain were assessed using the Neck Disability Index (NDI) and the Visual Analog Scale (VAS) of the neck and of the arm pain. SF-36 outcome measures were obtained including the physical component as well as the mental component scores. Range of motion was determined by independent radiologic assessment of flexion-extension radiographs. We report a prospective, randomized study comparing the functional outcome of cervical disc replacement to an anterior cervical fusion with results of 99 patients at 2 years. Prospective data were collected before surgery and at 6 weeks, 3, 6, 12, and 24 months after surgery. Results. The average operative time for the control group was 1.1 hours and the Bryan Group 1.7 hours.Average blood loss was 49 mL (control) and 64 mL (Bryan). Average hospital stay was 0.6 days (control) and 0.9 days (Bryan). The mean NDI before surgery was not statistically different between groups: 47 (Bryan) and 49 (control). Twelve-month follow-up NDI is 10 (Bryan) and 18 (control) (P = 0.013). At 2-year follow-up, NDI for the Bryan group is 11 and the control group is 20 (P = 0.005). The mean arm pain VAS before surgery was 70 (Bryan) and 71 (control). At 1-year follow-up, Bryan arm pain VAS was 12 and control 23 (P = 0.031). At 2-year follow-up, the average arm pain VAS for the Bryan group was 14 and control 28 (P = 0.014). The mean neck pain VAS before surgery was 72 (Bryan) and 73 (control). One-year follow-up scores were 17 (Bryan) and 28 (control) (P = 0.05). At 2 years: 16 (Bryan) and 32 (control) (P = 0.005). SF-36 scores: Physical component- Before surgery Bryan 34 and control 32. At 24 months: Bryan 51 and control 46 (P = 0.009). More motion was retained after surgery in the disc replacement group than the plated group at the index level (P < 0.006 at 3, 6, 12, and 24 months). The disc replacement group retained an average of 7.9° of flexion-extension at 24 months. In contrast, the average range of motion in the fusion group was 0.6° at 24 months. There were 6 additional operations in this series: 4 in the control group and 2 in the investigational group. There were no intraoperative complications, no vascular or neurologic complications, no spontaneous fusions, and no device failures or explantations in the Bryan cohort. Conclusion. The Bryan artificial disc replacement compares favorably to anterior cervical discectomy and fusion for the treatment of patients with 1-level cervical disc disease. At the 2-year follow-up, there are statistically significant differences between the groups with improvements in the NDI, the neck pain and arm pain VAS scores, and the SF-36 physical component score in the Bryan disc population.

Use of recombinant human bone morphogenetic protein-2 as an adjunct in posterolateral lumbar spine fusion: a prospective CT-scan analysis at one and two years.

Introduction This study determines whether recombinant human bone morphogenetic protein-2 (rhBMP-2) (12 mg at the rate of 1.5 mg/mL) delivered on an absorbable collagen sponge with an added bulking agent can increase posterolateral lumbar spine fusion success rates and decrease time for fusion with autogenous bone grafts. Method A prospective, single institution, clinical case-matched, radiographic, cohort study was undertaken. A total of 52 patients underwent posterolateral lumbar arthrodesis with pedicle screw instrumentation. The experimental group (n=41) underwent placement of Iliac crest bone graft (ICBG) with InFUSE (12 mg/level at the rate of 1.5 mg/mL). The control group (n=11) consisted of sex-matched patients, consecutively collected over the same time period with an instrumented posterolateral arthrodesis and ICBG placed in the intertransverse space. Outcome Measures Thin-cut (2 mm) axial, coronal, and sagittal reconstructions were blindly evaluated for evidence of bridging bone and cortication of the fusion mass by 3 separate reviewers. Fusions were graded and an overall score was given to the quality of the fusion mass. Results Fifty patients (ICBG alone n=11; ICBG/rhBMP-2 n=39) were available for CT evaluation at 2-year follow-up. An overall 97% (68/70 levels; Definite+Probably Fused) fusion rate in the rhBMP-2 group was achieved as compared to the 77% fusion rate (17/22 levels) in the ICBG alone group (P<0.05). In the rhBMP-2 group, 92% of the patients (36/39 patients) received an overall excellent subjective fusion rating as compared to 27% (3/11) in the control group (P<0.05). There was no computed tomographic evidence of soft-tissue ossification, dural ossification, or laminar bone regrowth in any patient. Conclusions The adjunctive use of rhBMP-2 and ICBG seems to be safe and results in significantly larger and more consistent posterolateral fusion masses.

Validation of a C2–C7 cervical spine finite element model using specimen-specific flexibility data

This study presents a specimen-specific C2-C7 cervical spine finite element model that was developed using multiblock meshing techniques. The model was validated using in-house experimental flexibility data obtained from the cadaveric specimen used for mesh development. The C2-C7 specimen was subjected to pure continuous moments up to +/-1.0 N m in flexion, extension, lateral bending, and axial rotation, and the motions at each level were obtained. Additionally, the specimen was divided into C2-C3, C4-C5, and C6-C7 functional spinal units (FSUs) which were tested in the intact state as well as after sequential removal of the interspinous, ligamentum flavum, and capsular ligaments. The finite element model was initially assigned baseline material properties based on the literature, but was calibrated using the experimental motion data which was obtained in-house, while utlizing the ranges of material property values as reported in the literature. The calibrated model provided good agreement with the nonlinear experimental loading curves, and can be used to further study the response of the cervical spine to various biomechanical investigations.

Effects of direct current electrical stimulation on gene expression of osteopromotive factors in a posterolateral spinal fusion model.

Study Design. An in vivo model was used to determine levels of mRNA expression in response to direct current (DC) electrical stimulation in a rabbit posterolateral fusion model. Objectives. This study tested the possibility that DC stimulation at the surgery site would increase expression of genes related to bone formation relative to expression in autograft alone. Summary of Background Data. DC electrical stimulation as an adjunct treatment in spinal surgery has shown increased fusion rates when compared with autograft alone, yet the biology of such treatment is not fully understood. Methods. Thirty New Zealand White rabbits were entered into the study. A posterolateral, intertransverse process fusion was performed bilaterally at L4–L5, with autogenous bone graft. An implantable DC stimulator was placed across the decorticated transverse processes before placement of autograft. Animals were killed at 3, 7, 14, 21, and 28 days. mRNA levels of BMP-2, 4, 6, 7, VEGF, FGF-2, TGF-β, ALK-2, and ALK-3 were evaluated with real-time RT-PCR. Results. mRNA expression was significantly higher in the DC stimulated animals versus the control animals for several of the genes studied. In particular, levels of mRNA were elevated for BMP-2, BMP-6, and BMP-7. Conclusions. This study shows for the first time that DC stimulation results in a sustained increase of multiple osteogenic genes, suggesting that the biologic mechanism for the DC-induced increase in the rate and extent of bone formation observed clinically may be mediated by the up-regulation of these osteoinductive factors.

Crankshaft effect after posterior spinal fusion and unit rod instrumentation in children with cerebral palsy.

Radiographs and charts were reviewed for all children with cerebral palsy who underwent posterior-only spinal fusion with the unit rod for neuromuscular scoliosis by the senior author from 1989 through 1996. Fifty patients were found to have an open triradiate cartilage at the time of fusion. A single observer obtained measurements of the preoperative, postoperative, and most recent spine films using the standard Cobb angle. Amount of change was calculated over the respective periods. Forty-three patients had at least 2 years of clinical follow-up. Twenty-nine patients had more than 2 years of both radiographic (mean, 4.6 years) and clinical follow-up (mean, 4.8 years) with a closed triradiate cartilage on their most recent films. In this group, the mean absolute curve change over the length of radiographic follow-up was 0.6 degrees (range, −9–14). None of the 43 patients with at least 2 years of clinical follow-up (mean, 4.5 years) had any radiographic change that was clinically significant on chart review. Therefore posterior spinal fusion alone with unit rod instrumentation is adequate treatment to control crankshaft deformity in skeletally immature children with neuromuscular scoliosis due to cerebral palsy.

B2A Peptide on Ceramic Granules Enhance Posterolateral Spinal Fusion in Rabbits Compared With Autograft

Study Design. Six groups of 10 animals underwent single level, uninstrumented posterolateral lumbar fusions. Graft sites were implanted with autologous bone, autologous bone plus B2A coated granules with concentrations of 0-, 50-, 100-, or 300 &mgr;g/mL, or no graft material. Explanted motion segments were analyzed by Faxitron radiographs, computerized tomography (CT), manual palpation, and histology. Objective. The synthetic peptide B2A2-K-NS (B2A) was evaluated as a novel agent for augmenting spinal fusion in a posterolateral, noninstrumented rabbit lumbar spine fusion model. Summary of Background Data. There have been many efforts to increase the rate of posterolateral spinal fusion while, at the same time minimizing, use of autologous bone with its inherent harvest morbidity. Methods. B2A coated ceramic granules (0-, 50-, 100-, and 300 &mgr;g/mL) were mixed 1:1 with autogenous iliac crest bone and implanted. Autogenous bone alone was used as a positive control. Fusion was assessed at 6 weeks via radiographs and manual palpation. These results were confirmed with histology and CT. Results. Fusion results from palpation and radiographic evaluations were similar. CT and histology confirmed bridging bone across the transverse processes for fused spines. The highest fusion rates were observed in the 100 &mgr;g B2A/mL group—89% in comparison to 33% for uncoated granules (0 &mgr;g B2A/mL) and 63% for autograft alone. These differences were statistically significant. Conclusion. All investigated B2A concentrations demonstrated increased fusion rates. Fusion masses resulting from the implantation of 100 &mgr;g B2A/mL granules demonstrated new woven bone: fused to the transverse processes, within granule pores, bridging bone across the transverse processes, and bridging residual bone graft and granules. It was concluded that each investigated concentration of B2A coated granules in a 1:1 mixture with autograft increased fusion rates in comparison to controls in this rabbit model.

Biomechanical Analysis of Cervical Disc Replacement and Fusion Using Single Level, Two Level, and Hybrid Constructs

Study Design. A biomechanical study comparing arthroplasty with fusion using human cadaveric C2–T1 spines. Objective. To compare the kinematics of the cervical spine after arthroplasty and fusion using single level, 2 level and hybrid constructs. Summary of Background Data. Previous studies have shown that spinal levels adjacent to a fusion experience increased motion and higher stress which may lead to adjacent segment disc degeneration. Cervical arthroplasty achieves similar decompression but preserves the motion at the operated level, potentially decreasing the occurrence of adjacent segment disc degeneration. Methods. 11 specimens (C2–T1) were divided into 2 groups (BRYAN and PRESTIGE LP). The specimens were tested in the following order; intact, single level total disc replacement (TDR) at C5–C6, 2-level TDR at C5–C6–C7, fusion at C5–C6 and TDR at C6–C7 (Hybrid construct), and lastly a 2-level fusion. The intact specimens were tested up to a moment of 2.0 Nm. After each surgical intervention, the specimens were loaded until the primary motion (C2–T1) matched the motion of the respective intact state (hybrid control). Results. An arthroplasty preserved motion at the implanted level and maintained normal motion at the nonoperative levels. Arthrodesis resulted in a significant decrease in motion at the fused level and an increase in motion at the unfused levels. In the hybrid construct, the TDR adjacent to fusion preserved motion at the arthroplasty level, thereby reducing the demand on the other levels. Conclusion. Cervical disc arthroplasty with both the BRYAN and PRESTIGE LP discs not only preserved the motion at the operated level, but also maintained the normal motion at the adjacent levels. Under simulated physiologic loading, the motion patterns of the spine with the BRYAN or PRESTIGE LP disc were very similar and were closer than fusion to the intact motion pattern. An adjacent segment disc replacement is biomechanically favorable to a fusion in the presence of a pre-existing fusion. Level of Evidence: N/A

The effect of transdermal nicotine on fracture healing in a rabbit model.

Objective: Cigarette smoking inhibits fracture healing and places the patient at a higher risk of delayed union and nonunion. Nicotine has been implicated as the primary ingredient responsible for these effects. However, an analysis of current published investigations reveals conflicting data, with some evidence that nicotine alone does not significantly affect healing. We undertook an animal study of the effects of transdermal nicotine on fracture healing. Methods: Twenty-two adult male New Zealand white rabbits were randomly assigned to the nicotine group or the control group. A midshaft tibial osteotomy was performed on the left tibiae of all 22 rabbits. The nicotine rabbits were exposed using a 10.5-mg transdermal patch applied daily to the ear. Radiographs were obtained, and the area of fracture callus was assessed. Rabbits were euthanized at 21 days. Fractures were stressed to failure, and load/deformation curves were recorded. Results: The average area of callus formation was greater in the control group (Control: 0.158 cm2, Nicotine: 0.124 cm2), but the difference was not statistically significant (P = 0.30). There was a significant difference between the 2 groups for mean normalized torque to failure (Nicotine: 36% of nonfractured side, Control: 69% of nonfractured side, P = 0.028). The control group mean normalized stiffness was significantly greater than that for the nicotine rabbits (Control: 87%, Nicotine: 43%, P = 0.036). There were 3 nonunions in the nicotine group (27%) compared with none in the control group (P = 0.062). Conclusions: In a rabbit model of fracture healing, transdermal nicotine exposure resulted in decreased mechanical strength of healing fractures at 21 days and a higher rate of nonunion at 21 days compared with that of controls.