Harvinder S. Sandhu

The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report.

Study Design. A prospective randomized controlled human clinical pilot trial. Objectives. To determine the feasibility of using rhBMP-2/collagen as a substitute for autogenous bone graft inside interbody fusion cages to achieve arthrodesis in humans. Summary of Background Data. Preclinical studies have shown rhBMP-2 to be an effective substitute for autogenous bone graft, but there are no studies to date documenting such efficacy for human spine fusion. Methods. Fourteen patients with single-level lumbar degenerative disc disease refractory to nonoperative management were randomized to receive lumbar interbody arthrodesis with a tapered cylindrical threaded fusion cage filled with rhBMP-2/collagen sponge or autogenous iliac crest bone. Patients were evaluated with radiographs, sagittally reformatted computed tomography scans, and Short Form-36 and Oswestry outcome questionnaires. Results. All 11 patients who received rhBMP-2 were judged by three independent radiologists to have solid fusions (at 6, 12, and 24 months postimplantation), whereas only 2 of the 3 control patients, who received the standard treatment of autogenous iliac crest bone, were deemed to be fused. The Oswestry Disability Questionnaire scores of the rhBMP-2 group improved sooner (after 3 months) than those of the autograft group, with both groups demonstrating similar improvement at 6 months. Short Form 36 scores continued to improve up to 24 months. Conclusion. The arthrodesis was found to occur more reliably in patients treated with rhBMP-2–filled fusion cages than in controls treated with autogenous bone graft, although the sample size was limited. There were no adverse events related to the rhBMP-2 treatment. This study is one of the first to show consistent and unequivocal osteoinduction by a recombinant growth factor inhumans.

The biology of bone grafting.

Abstract Many approaches are used to repair skeletal defects in reconstructive orthopaedic surgery, and bone grafting is involved in virtually every procedure. The type of bone graft used depends on the clinical scenario and the anticipated final outcome. Autogenous cancellous bone graft, with its osteogenic, osteoinductive, and osteoconductive properties, remains the standard for grafting. However, the high incidence of morbidity during autogenous graft harvest may make the acquisition of grafts from other sources desirable. The clinical applications for each type of bone graft are dictated by the structure and biochemical properties of the graft. An elegant cellular and molecular cascade follows bone transplantation. Bone graft incorporation within the host, whether autogenous or allogeneic, depends on many factors: type of graft (autogenous versus allogeneic, vascular versus nonvascular), site of transplant, quality of transplanted bone and host bone, host bed preparation, preservation techniques, systemic and local disease, and mechanical properties of the graft.

Incidental Durotomy in Spine Surgery

Study Design. Retrospective review of a large series of patients who underwent spinal surgery at a single institution during a 10-year period. Objectives. To further clarify the frequency of incidental durotomy during spine surgery, its treatment, associated complications, and results of long-term clinical follow-up. Summary of Background Data. Incidental durotomy is a relatively common occurrence during spinal surgery. There remains significant concern about it despite reports of good associated clinical outcomes. There have been few large clinical series on the subject. Methods. A retrospective review was conducted of clinical and surgical records and radiographic data for consecutive patients who underwent spinal surgery performed by the two senior surgeons from January 1989 through December 1998. Results. A total of 2144 patients were reviewed, and 74 were found to have dural tears occurring during or before surgery. Incidental durotomy occurred at the time of surgery in 66 patients (3.1% overall incidence). Incidence varied according to the specific procedure performed but was highest in the group that underwent revision surgery. The incidence of clinically significant durotomies occurring during surgery but not identified at the time was 0.28%. All dural tears that occurred during surgery and were recognized (60 of 66) were repaired primarily. Pseudomeningoceles developed in five of the remaining six patients. All six patients had subsequent surgical repair of dural defects because of failure of conservative therapy. A mean follow-up of 22.4 months was available and showed good long-term clinical results for all patients. Conclusions. Incidental durotomy, if recognized and treated appropriately, does not lead to long-term sequelae.

Laparoscopic anterior spinal arthrodesis with rhBMP-2 in a titanium interbody threaded cage.

Anterior lumbar interbody arthrodesis is commonly performed for conditions involving infection, deformity, and instability. The purpose of this investigation was to determine the effective dose of recombinant human bone morphogenetic protein-2 (rhBMP-2) as a bone graft substitute inside a titanium threaded interbody fusion cage using a nonhuman primate model of laparoscopic anterior lumbar interbody arthrodesis. Eight adult rhesus monkeys underwent laparoscopic exposure of the lumbosacral spine followed by insertion of a hollow titanium threaded cylindrical cage (Sofamor-Danek, Memphis, TN, U.S.A.). Before insertion, the chamber of the cage was filled with a collagen sponge delivery vehicle soaked with either 0 mg/ml (sham, buffer only), 0.75 mg/ml (low dose), or 1.5 mg/ml (high dose) of rhBMP-2 (Genetics Institute, Cambridge, MA, U.S.A.). Fusions were evaluated in a blinded fashion with plain radiographs and computed tomography (CT) scans 12 and 24 weeks after surgery, and by manual palpation and histology after euthanasia 24 weeks after surgery. All five monkeys treated with a cage filled with rhBMP-2 obtained a solid fusion as assessed by manual palpation. The two monkeys that received no growth factor did not achieve solid fusions. Plain radiographs were of limited value, with fusions best assessed on sagittally reconstructed CT scans. Scans from the two animals treated without growth factor showed ingrowth of bone only into the outer edges of the cage, but not through the center. Scans from the rhBMP-2-treated animals demonstrated arthrodesis with continuous bone growth through the cage. Histologic analysis demonstrated normal mature trabecular bone surrounding and growing through the cages, which correlated with the CT scan findings. We conclude that rhBMP-2 delivered in a threaded titanium interbody cage can serve as a bone graft substitute in a nonhuman primate model. Sagittal reconstructed CT may be a better method to assess for fusion with this device.

Use of rhBMP-2 in Combination with Structural Cortical Allografts: Clinical and Radiographic Outcomes in Anterior Lumbar Spinal Surgery

BACKGROUND Recombinant human bone morphogenetic protein-2 soaked into an absorbable collagen sponge (rhBMP-2/ACS) has been shown in a nonhuman primate study and in a pilot study in humans to promote new bone formation and incorporation of an allograft device when implanted in patients undergoing anterior lumbar interbody arthrodesis. However, a larger series with longer follow-up is needed to demonstrate its superiority to autogenous iliac crest bone graft. METHODS Between 1998 and 2001, a two-part, prospective, randomized, multicenter study of 131 patients was conducted to determine the safety and efficacy of the use of rhBMP-2/ACS as a replacement for autogenous iliac crest bone graft in anterior lumbar spinal arthrodesis with threaded cortical allograft dowels. Patients were randomly assigned to a study group that received rhBMP-2/ACS or to a control group that received autograft. The clinical and radiographic outcomes were determined with use of well-established instruments and radiographic assessments. RESULTS The patients in the study group had significantly better outcomes than the control group with regard to the average length of surgery (p < 0.001), blood loss (p < 0.001), and hospital stay (p = 0.020). Fusion rates were significantly better in the study group (p < 0.001). The average Oswestry Disability Index scores, Short-Form-36 physical component summary scores, and low-back and leg-pain scores were significantly better in the study group (p < 0.05). CONCLUSIONS In patients undergoing anterior lumbar interbody arthrodesis with threaded allograft cortical bone dowels, rhBMP-2/ACS was an effective replacement for autogenous bone graft and eliminated the morbidity associated with graft harvesting.

Effective doses of recombinant human bone morphogenetic protein-2 in experimental spinal fusion.

Study Design Nineteen dogs underwent L4‐L5 intertransverse process fusions with either 58 μg, 115 μg, 230 μg, 460 μg, or 920 μg of recombinant human bone morphogenetic protein‐2 carried by a polylactic acid polymer. A previous study (12 dogs) compared 2300 μg of recombinant human bone morphogenetic protein‐2, autogenous iliac bone, and carrier alone in this model. All fusions subsequently were compared. Objectives To characterize the dose‐response relationship of recombinant human bone morphogenetic protein‐2 in a spinal fusion model. Summary of Background Data Recombinant osteoinductive morphogens, such as recombinant human bone morphogenetic protein‐2, are effective in vertebrate diaphyseal defect and spinal fusion models. It is hypothesized that the quality of spinal fusion produced with recombinant human bone morphogenetic protein‐2, above a threshold dose, does not change with increasing amounts of inductive protein. Methods After decortication of the posterior elements, the designated implants were placed along the intertransverse process space bilaterally. The fusion sites were evaluated after 3 months by computed tomography imaging, high‐resolution radiography, manual testing, mechanical testing, and histologic analysis. Results As in the study using 2300 μg of recombinant human bone morphogenetic protein‐2, implantation of 58–920 μg of recombinant human bone morphogenetic protein‐2 successfully resulted in intertransverse process fusion in the dog by 3 months. This had not occurred in animals containing autograft or carrier alone. The cross‐sectional area of the fusion mass and mechanical stiffness of the L4‐L5 intersegment were not dose‐dependent. Histologic findings varied but were not related to rhBMP‐2 dose. Inflammatory reaction to the composite implant was proportional inversely to the volume of the fusion mass. Conclusions No mechanical, radiographic, or histologic differences in the quality of intertransverse process fusion resulted from a 40‐fold variation in dose of recombinant human bone morphogenetic protein‐2.

Factors predicting hospital stay, operative time, blood loss, and transfusion in patients undergoing revision posterior lumbar spine decompression, fusion, and segmental instrumentation.

Study Design. A retrospective chart review was conducted for 112 patients who underwent revision posterior lumbar spine decompression, fusion, and segmental instrumentation. Objective. To ascertain factors predicting hospital stay, operative time, blood loss, and transfusion in patients undergoing revision posterior lumbar spine decompression, fusion, and segmental instrumentation. Summary of Background Data. Posterior lumbar spine decompression and fusion with segmental instrumentation is a common procedure in the treatment of degenerative lumbar spine disorders. Many patients undergoing this procedure have had previous lumbar spine surgery, yet little is known about the factors predicting hospital stay, operative time, blood loss, and transfusion. Methods. The charts of 112 patients (53 men and 59 women) with degenerative lumbar spinal stenosis who underwent revision surgery from March 1992 to June 1999 were reviewed. Their average age was 54 years (range, 27–84 years). All the surgeries included decompression and fusion with segmental instrumentation. The patients’ demographics, comorbid conditions, factors related to previous lumbar spine surgery, diagnosis, number of levels fused, and preoperative hemoglobin and hematocrit were collected and used as the independent variables. Multiple regression analysis was used to ascertain factors predicting length of hospital stay, operative time, intraoperative blood loss, and transfusion. Results. The mean length of hospital stay was 6 ± 2.4 days, the operative time 280 ± 62 minutes, the estimated intraoperative blood loss 1073 ± 716 mL, and the total volume of blood transfused 1.04 ± 1.17 U. For 63% of the patients, a blood transfusion was needed. Increasing age was the significant predictor for hospital stay (P < 0.001). The factors predicting operative time were number of levels fused (P < 0.001), diagnosis of degenerative scoliosis (P < 0.05), and excessive body weight (P < 0.01). The factors predicting intraoperative blood loss were number of levels fused (P < 0.01), body weight (P < 0.001), and high preoperative hemoglobin (P < 0.001). Both logistic and linear regression analysis showed that the factors predicting blood transfusion were number of levels fused (P < 0.01), age (P < 0.05), and low preoperative hemoglobin (P < 0.001). Other factors associated with hospital stay and blood transfusion were unemployment associated with three or more comorbid conditions and compli-cations. The women had less intraoperative blood loss (P < 0.01), but received more transfused blood than the men (P < 0.01). Conclusions. Number of levels fused and age seem to be the most significant factors predicting hospital stay, operative time, intraoperative blood loss, and transfusion in patients undergoing revision posterior lumbar spine decompression, fusion, and segmental instrumentation.

Use of recombinant human bone morphogenetic protein-2 in spinal fusion applications

Bone morphogenetic proteins (BMPs) have been the subject of considerable research for several decades. The academic chronicle began in 1965 with Dr. Marshall Urist’s discovery of osteoinductive activity within demineralized bone protein extracts, and continued with his later identification of the active molecules as bone morphogenetic proteins. This was followed in 1988 by the isolation of an individual protein, BMP-2, from a purified extract and its recombinant production. The long-awaited clinical use and commercial availability of BMPs have only recently approached reality. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is the only BMP for which a prospective randomized pivotal clinical trial for a spine fusion indication has been completed. It has demonstrated equivalence to autogenous iliac bone graft with regard to both fusion rate and clinical outcome. On the basis of this study, the Food and Drug Administration (FDA) has advised that rhBMP-2 be approved for commercialization as the first complete bone graft substitute for spinal fusion indication. At this writing, all other FDA-cleared bone-grafting products are only osteoconductive scaffolds incapable of solely initiating bone formation under the classic definition of osteoinduction: the ability to induce de novo bone formation at a nonbony site. A significant body of data on the use of rhBMP-2 in spinal fusion surgery has been collected. Both the potential uses of rhBMP-2 and its limitations in spinal fusion applications have become clear through this extensive series of preclinical and clinical investigations. It was determined that an application-specific carrier was required to release the rhBMP-2 protein over an adequate period and at a sufficient concentration. Different fusion techniques such as intervertebral arthrodesis and posterolateral intertransverse process arthrodesis presented their own specific challenges, which required specific carrier–rhBMP-2 combinations. The relevant preclinical and clinical research that provided data regarding site-specific product configurations is presented in this article. The first part of the article reviews some of the preclinical efficacy data and lessons learned from these animal studies. The second part describes FDA-approved investigational device exempted (IDE) clinical human trials and their results involving rhBMP-2 for human spinal fusions.

Evaluation of rhBMP-2 with an OPLA carrier in a canine posterolateral (transverse process) spinal fusion model.

Study Design Posterolateral L4-L5 transverse process fusions were done on 14 adult beagles. Six were implanted with recombinant human bone morphogenetic protein-2 carried by open-cell polylactic acid polymer delivery vehicle. Six received autogenous iliac bone graft. Two received carrier alone. Eleven were killed 3 months after implantation. One in each group was maintained for 8 months. Objectives. To compare recombinant human bone morphogenetic protein-2 and open-cell polylactic acid polymer with autogenous iliac bone for inducing transverse process fusion in the canine by 3 months and to determine whether transverse process decortication and implantation of carrier alone causes spontaneous transverse process fusion in the canine. Summary of Background Data Recombinant human bone morphogenetic proteins have healed segmental long bone defects in several models. They have induced interlaminar and facet fusions in canines. Interlaminar and facet fusions have occurred after sham decortications in canines. Recombinant human bone morphogenetic protein-2 has not been evaluated for transverse process fusion in canines. Transverse process fusion is a preferred clinical method for achieving posterior lumbar fusion. Methods Fusion sites were evaluated by serial computed tomography scans. After the dogs were killed, explanted spines were subjected to manual testing, mechanical testing, high resolution radiography, and histologic analysis. Results One hundred percent of recombinant human bone morphogenetic protein-2-implanted sites had solid transverse process fusion by 3 months according to all measures. No autografted sites were fused at this interval. Osseous bridging of posterolateral gutters occurred in the recombinant human bone morphogenetic protein-2-implanted sites after 2 months, the earliest radiographic measure. None of the carrier-only sites showed bone formation. Conclusions Recombinant bone morphogenetic protein-2 carried by open-cell polylactic acid polymer is superior to autogenous iliac bone for producing radiographically and mechanically solid transverse process fusions in canines by 3 months. Spontaneous transverse process fusion does not occur in canines after decortication and open-cell polylactic acid polymer implantation.

Major vascular injury during anterior lumbar spinal surgery: incidence, risk factors, and management.

Study Design. Retrospective chart review. Objective. To examine the incidence of major vascular injury during anterior lumbar spinal surgery, attempt to identify predisposing risk factors, and to discuss management techniques. Summary of Background Data. Major vascular injury can be a catastrophic complication of anterior lumbar spinal surgery. Methods. Current procedural terminology codes were used to identify the occurrence of major vascular injury, defined as injury to the iliac vessels, vena cava, and aorta. Once identified, the office record, hospital chart, operative note, and diagnostic test results were reviewed in detail. Results. Three hundred forty-five operations were performed on 338 patients. Incidence of major vascular complication was 2.9% (10 of 345). There were 9 injuries of the common iliac vein and a single aortic injury. Risk factors identified in patients with major vascular injury were current or previous osteomyelitis or discogenic infection (n = 3), previous anterior spinal surgery (n = 2), spondylolisthesis (n = 2; 1 isthmic Grade II, 1 iatrogenic Grade II), large anterior osteophyte (n = 2), transitional lumbosacral vertebra (n = 1), and anterior migration of interbody device (n = 1). Lateral venorrhaphy by suture (n = 6) and hemoclip application (n = 2) was augmented by topical agents, which constituted the sole method of repair on 1 occasion. Magnetic resonance venography demonstrated iliac vein thrombosis in 1 patient. Conclusion. Current or previous osteomyelitis or discogenic infection, previous anterior spinal surgery, spondylolisthesis, osteophyte formation, transitional lumbosacral vertebra and anterior migration of interbody device point to an increased risk of vascular injury during anterior lumbar spinal surgery. Careful handling of the vascular structures and liberal use of topical hemostatic agents can lead to control of hemorrhage and preservation of vascular patency. Routine postoperative surveillance for proximal deep vein thrombosis, by magnetic resonance venography of the pelvic veins and inferior vena cava, should be performed after venorrhaphy.