Osteogenic protein versus autologous interbody arthrodesis in the sheep thoracic spine. A comparative endoscopic study using the Bagby and Kuslich interbody fusion device

STUDY DESIGN: Using an in vivo interbody arthrodesis model, the efficacy of the Bagby and Kuslich (BAK) device packed with recombinant human osteogenic protein-1 (rhOP-1) was evaluated. OBJECTIVES: To compare the efficacy of osteogenic protein with that of autograft for interbody arthrodesis, with fusion success based on biomechanical, histologic, and radiographic analyses. SUMMARY OF BACKGROUND DATA: The use of recombinant human bone morphogenetic proteins (rhBMPs) as osteoinductive bone graft substitutes or expanders has recently gained considerable research interest, particularly when applied in posterolateral arthrodesis. However, whether these results can be extrapolated to a successful interbody spinal arthrodesis remains uncertain. METHODS: Twelve sheep underwent a multilevel thoracic spinal decompression by thoracoscopic approach. Three noncontiguous destabilization sites (T5-T6, T7-T8, T9-T10) were prepared and randomly treated as follows. Control group treatments were nonsurgical, destabilization alone, and empty BAK. Experimental groups were treated with autograft alone, BAK device packed with autograft, or BAK device packed with rhOP-1. Four months after surgery, interbody fusion status was quantified by biomechanical testing, computed tomography, microradiography, and histomorphometry. RESULTS: Results of biomechanical analysis showed statistically higher segmental stiffness levels when comparing the control and experimental groups with four of the five testing methods (P < 0.05). Computed tomography and microradiography characterized destabilization alone as producing one fusion in six preparations; the empty BAK, two in six;, autograft alone, four in eight; BAK with autograft, five in eight; and BAK with rhOP-1 group, six in eight-all evidenced by woven trabecular bone spanning the fusion sites. Histomorphometry yielded significantly more trabecular bone formation at the fusion sites in the three experimental groups than in the two control groups (P < 0.05). CONCLUSIONS: Interbody spinal fusions showing biomechanical and histomorphometric equivalency to autologous fusions have been achieved with rhOP-1. The functional unit stability and histologic osteointegration evidenced by the BAK/rhOP-1 complex shows this interbody arthrodesis technique to be a viable alternative toconventional autologous iliac crest, thereby obviating the need for an iliac crest donor site and associated patient morbidity.     

Beta tricalcium phosphate: observation of use in 100 posterolateral lumbar instrumented fusions

BackgroundBeta tricalcium phosphate (B-TCP) is increasingly used to supplement lamina autograft to perform posterolateral lumbar-instrumented arthrodesis.PurposeTo determine the radiographic arthrodesis and pseudarthrosis rates after multisegment lumbar laminectomies and one- or two-segment posterolateral instrumented fusion using lamina autograft and an artificial bone graft expander B-TCP (Vitoss; Orthovita, Malvern, PA, USA).Study design/settingTo document radiographic arthrodesis/pseudarthrosis rates using lamina autograft and B-TCP.Patient sampleOne hundred patients with lumbar spinal stenosis underwent multisegment laminectomies (average 3.6 segments) and one- (78 patients) or two- (22 patients) segment posterolateral instrumented arthrodesis.Outcome measuresTwo-year postoperative outcomes were assessed using Short-Form 36 questionnaires.MethodsThe arthrodesis mass consisted of lamina autograft and B-TCP. Two independent neuroradiologists, using both dynamic X-rays and 2D-CT studies performed 3, 4.5, 6, and up to 12 months postoperatively, documented radiographic arthrodesis progression.ResultsOne-segment arthrodesis was performed in 79 patients; 74 (93.7%) were radiographically fused “early” (6.5 postoperative months), 2 (2.5%) fused “late” (6.5–12 months), and 3 (3.8%) exhibited pseudarthrosis. Two-segment arthrodesis was performed in 21 patients; 14 (66.7%) radiographically fused “early,” 5 (23.8%) fused “late,” and 2 (9.5%) exhibited pseudarthrosis. Although chi-square analyses revealed a significant increase in the number of “late” radiographic fusions occurring for patients undergoing two-level arthrodesis, no significant difference in radiographic pseudarthrosis rates was noted between the two patient populations. In both groups, Short-Form 36 questionnaires revealed nearly comparable maximal improvement on seven of eight Health Scales by the second postoperative year.ConclusionsAt 6.5 months after multisegment lumbar laminectomies with posterolateral instrumented lumbar arthrodesis using lamina autograft/B-TCP, more one-segment (93.7%) versus two-segment (66.7%) radiographic arthrodesis occurred. By 1 year after operation, there was no significant difference in fusion rates between one- and two-segment radiographic arthrodeses.     

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.     

The effect of osteogenic protein-1 in instrumented and noninstrumented posterolateral fusion in rabbits.

BACKGROUND CONTEXT: The use of rigid instrumentation combined with bone graft makes intuitive sense given the requirements for vascular ingrowth, bone formation and a stable environment for the cellular events of healing to develop. However, with the advances of potent osteoinductive growth factors, the role of internal fixation may come into question. Whether bone morphogenic proteins (BMPs) would benefit from a more "stable" spinal segment for bone production and modeling remains unknown. In addition, it is unknown whether BMP and rigid fixation may have an additive effect on fusion healing. PURPOSE: This study is proposed to test the hypothesis that rigid fixation in the lumbar spine would be advantageous to achieve fusion for autogenous bone grafting, but fusion would occur regardless of fixation with the use of osteogenic protein (OP)-1. STUDY DESIGN/SETTING: A histologic and radiographic analysis of BMP in a rabbit lumbar fusion model. METHODS: Thirty-two rabbits were randomized into four groups: 1) control animals: in situ posterolateral L5-L6 arthrodesis using autogenous iliac crest bone graft; 2) fixation group: posterolateral arthrodesis L5-L6 with autogenous bone graft and interspinous fixation; 3) OP-1 group: in situ posterolateral L5-L6 arthrodesis using OP-1 and 4) combined OP-1 and fixation group. Radiographic fusion analysis was performed with computed tomography scans at 3 and 12 weeks after surgery. Decalcified histology was performed to assess tissue morphology and cellularity. RESULTS: Minimal evidence of fusion was noted at 3 weeks with autograft or OP-1. By 12 weeks, all OP-1-treated animals had solid fusion, whereas no fusion was noted in autograft animals. The addition of fixation slightly increased radiographic fusion at 3 weeks in autograft and OP-1 groups but did not affect OP-1 animals at 12 weeks where all were fused. Decalcified histologic results confirmed the proliferative bone formation noted with OP-1 and the variable cellular response with autograft. CONCLUSIONS: The results of the present study suggest that the osteoinductive effect of OP-1 may be only minimally enhanced early in the bone healing process but does not appear to be affected in the long term by spinal fixation in the rabbit intertransverse fusion model. Fixation appeared to enhance early fusion in the autograft group.     

Lumbar body fusion with a bioresorbable cage in a goat model is delayed by the use of a carboxymethylcellulose-stabilized collagenous rhOP-1 device.

The purpose of this study was to evaluate the efficacy of recombinant human osteogenic protein-1 (rhOP-1) with a carboxymethylcellulose-stabilized collagenous carrier as a bone graft substitute for instrumented lumbar spinal fusion in an established goat model. Twenty goats received a resorbable poly-L-lactic acid (PLLA) interbody cage packed with either rhOP-1 and its carrier or autologous bone graft. The carrier material was bovine collagen type-1 stabilized with carboxymethylcellulose. The fusion segments were retrieved at 3 or 6 months postimplantation and evaluated by radiographic and histologic analyses. The rhOP-1 graft substitute, used in combination with the resorbable PLLA cage, showed inferior results as compared to autologous bone graft in the goat lumbar fusion model. Whereas four out of five segments from the autograft group were fused after 6 months, none of the four segments receiving the rhOP-1 graft substitute were fused at this time point. Bone ingrowth into the cage was delayed or absent in the experimental group, whereas all autograft specimens showed advanced bone ingrowth (3 months) or fusion (6 months). We suggest that the fusion process was inhibited, because cells were unable to penetrate the rhOP-1 graft material. This led to delayed bone formation and in some cases inadequate tissue formation.     

Healing of segmental bone defects with granular porous hydroxyapatite augmented with recombinant human osteogenic protein-1 or autologous bone marrow.

Hydroxyapatite is a synthetic bone graft, which is used for the treatment of bone defects and nonunions. However, it is a rather inert material with no or little intrinsic osteoinductive activity. Recombinant human osteogenic protein-1 (rhOP-1) is a very potent biological agent, that enhances osteogenesis during bone repair. Bone marrow contains mesenchymal stem cells, which are capable of new bone formation. Biosynthetic bone grafts were created by the addition of rhOP-1 or bone marrow to granular porous hydroxyapatite. The performance of these grafts was tested in a sheep model and compared to the results of autograft, which is clinically the standard treatment of bone defects and nonunions. A 3 cm segmental bone defect was made in the tibia and fixed with an interlocking intramedullary nail. There were five treatment groups: no implant (n=6), autograft (n=8), hydroxyapatite alone (n=8), hydroxyapatite loaded with rhOP-1 (n=8), and hydroxyapatite loaded with autologous bone marrow (n=8). At 12 weeks, healing of the defect was evaluated with radiographs, a torsional test to failure, and histological examination of longitudinal sections through the defect. Torsional strength and stiffness of the healing tibiae were about two to three times higher for autograft and hydroxyapatite plus rhOP-1 or bone marrow compared to hydroxyapatite alone and empty defects. The mean values of both combination groups were comparable to those of autograft. There were more unions in defects with hydroxyapatite plus rhOP-1 than in defects with hydroxyapatite alone. Although the differences were not significant, histological examination revealed that there was more often bony bridging of the defect in both combination groups and the autograft group than in the group with hydroxyapatite alone. Healing of bone defects, treated with porous hydroxyapatite, can be enhanced by the addition of rhOP-1 or autologous bone marrow. The results of these composite biosynthetic grafts are equivalent to those of autograft.     

The time-dependent effect of ibandronate on bone graft remodeling in an ovariectomized rat spinal arthrodesis model

Background contextIn osteoporotic patients undergoing spinal arthrodesis, the use of bisphosphonates (BPs) remains controversial with regard to bone fusion. There is no consensus about the appropriate time to give BPs to patients with osteoporosis undergoing spinal arthrodesis.PurposeWe aimed to study the effect of BPs, given at different times, on the bone response to osteoporotic spinal arthrodesis.Study design/settingRadiological, histologic, and molecular assessments of bone formation after the different administration time of ibandronate in an ovariectomized (OVX) rat spinal fusion model.MethodsFemale Sprague-Dawley rats (n=100) were OVX (n=80) or non-OVX operated (n=20) and randomized into five groups: non-OVX, osteoporosis, and osteoporosis with early, simultaneous, and late BP groups. Eight weeks after ovariectomy, lumbar spinal arthrodesis was performed using autologous tailbones. Animals were killed 4 and 8 weeks after arthrodesis, and bone formation was assessed by measuring bone mineral density (BMD), messenger RNA expression, manual palpation, radiological evaluation, and histomorphometry.ResultsCompared with late administration, early administration of ibandronate increased femur BMD in OVX rats and did not hinder bone fusion. Radiological analysis showed that groups given early ibandronate had increased bone volume in the grafted site 8 weeks after surgery. Histomorphometric analysis showed that ibandronate positively affected endochondral and intramembranous ossification. In the OVX groups, ibandronate increased bone turnover to a level similar to that in the non-OVX group. These findings suggested that early administration of ibandronate did not inhibit osteogenesis, including endochondral and intramembranous ossification and fusion rate.ConclusionsOur results suggest that the early administration of BPs may not hinder the bone fusion of osteoporotic patients undergoing spinal arthrodesis.     

The First Clinical Trial of Beta-Calcium Pyrophosphate as a Novel Bone Graft Extender in Instrumented Posterolateral Lumbar Fusion

Background

Porous β-calcium pyrophosphate (β-CPP) was developed to improve the fusion success of posterolateral lumbar fusion (PLF). The possibility of accomplishing PLF using a mixture of porous β-CPP and iliac bone was studied. This paper reports the radiologic results of PLF using the β-CPP plus autograft for lumbar degenerative disease as a bone graft extender.

Methods

A prospective, case-matched, radiographic study evaluating the results of short segment lumbar fusion using a β-CPP plus autograft was performed to compare the efficacy of β-CPP plus autograft with that of an autograft alone for short segment lumbar fusion. Thirty one consecutive patients (46 levels) underwent posterolateral fusion with pedicle screw fixation and additional posterior lumbar interbody fusion. In all patients, 3 mL of β-CPP plus 3 mL of autogenous bone graft was placed randomly in one side of a posterolateral gutter, and 6 mL of autogenous iliac bone graft was placed on the other. The fusion rates, volumes of fusion masses, and bone absorption percentage were evaluated postoperatively using simple radiographs and 3 dimensional computed tomography (3D-CT) scans.

Results

The control sides treated with an autograft showed significantly better Lenke scores than the study sides treated with β-CPP at 3 and 6 months postoperatively, but there was no difference between the two sides at 12 months. The fusion rates (confirmed by 3D-CT) were 87.0% in the β-CPP group and 89.1% in the autograft group, which were not significantly different. The fusion mass volumes and bone absorption percentage at 12 months postoperatively were 2.49 mL (58.4%) and 1.89 mL (69.5%) for the β-CPP and autograft groups, respectively, and mean fusion mass volume was significantly higher in the β-CPP group.

Conclusions

β-CPP combined with an autograft is as effective as autologous bone for grafting during instrumented posterolateral spinal fusion. These findings suggest that β-CPP bone chips can be used as a novel bone graft extender for short-segment posterolateral spinal fusion.     

The use of coralline hydroxyapatite with bone marrow, autogenous bone graft, or osteoinductive bone protein extract for posterolateral lumbar spine fusion

STUDY DESIGN: A posterolateral lumbar arthrodesis animal model using coralline hydroxyapatite as a bone graft substitute. OBJECTIVE: To determine the effectiveness of coralline hydroxyapatite as a bone graft substitute for lumbar spine fusion when used with bone marrow, autogenous bone graft, or an osteoinductive bone protein extract. SUMMARY OF BACKGROUND DATA: Coralline hydroxyapatite is commonly used as a bone graft substitute in metaphysial defects but its use in a more challenging healing environment such as the posterolateral spine remains controversial. There are no published animal studies in which the use of coralline hydroxyapatite has been evaluated in a posterolateral lumbar arthrodesis model. METHODS: Single-level posterolateral lumbar arthrodesis was performed at L5-L6 in 48 adult New Zealand White rabbits. Rabbits were assigned to one of three groups based on the graft material they received: 3.0 mL coralline hydroxyapatite 1.5 mL plus bone marrow; 1.5 mL coralline hydroxyapatite plus 1.5 mL autogenous iliac crest bone; and, 3.0 mL coralline hydroxyapatite plus 500 micrograms bovine-derived osteoinductive bone protein extract on each side. Rabbits were killed after 2, 5, or 10 weeks, and the spines were excised and evaluated by manual palpation, radiographs, tensile biomechanical testing, and nondecalcified histology. RESULTS: Fusions were assessed by manual palpation at 5 weeks for comparisons among the three groups of graft materials. The coralline hydroxyapatite used with bone marrow produced no solid fusions (0/14). When combined with an equal amount of autogenous iliac crest bone, coralline hydroxyapatite resulted in solid fusion in 50% (7/14) of the rabbits (P < 0.05). When combined with the osteoinductive growth factor extract, the coralline hydroxyapatite resulted in solid fusion in 100% (11/11) of the rabbits (P < 0.05). The fusion masses in the growth factor group were significantly stronger (1.8 +/- 0.2 vs. 1.3 +/- 0.1; P = 0.02) and stiffer (1.5 +/- 0.2 vs. 1.2 +/- 0.1, P = 0.04) based on tensile testing to failure when normalized to the adjacent unfused level. CONCLUSION: These data indicate that coralline hydroxyapatite with bone marrow was not an acceptable bone graft substitute for posterolateral spine fusion. When combined with autogenous iliac crest bone graft-coralline hydroxyapatite served as a graft extender yielding results comparable to those obtained with autograft alone. Coralline hydroxyapatite served as an excellent carrier for the bovine osteoinductive bone protein extract yielding superior results to those obtained with autograft or bone marrow.     

The effect of spinal instrumentation particulate wear debris. an in vivo rabbit model and applied clinical study of retrieved instrumentation cases.

STUDY DESIGN: The current study was undertaken to determine if the presence of spinal instrumentation wear particulate debris deleteriously influences early osseointegration of posterolateral bone graft or disrupts an established posterolateral fusion mass.OBJECTIVES: Using an in vivo animal model, the first phase (basic science) of this study was to evaluate the effect(s) of titanium wear particulate on a posterolateral spinal arthrodesis based on serological, histological and immunocytochemical analyses. The second phase (clinical) was to perform the same analysis of soft tissue surrounding spinal instrumentation in 12 symptomatic clinical patients. SUMMARY OF BACKGROUND DATA: The effect of unintended wear particulate resulting from micromotion between the interconnection mechanisms in spinal instrumentation remains a clinical concern. METHODS: Thirty-four New Zealand White rabbits were randomized into two groups based on postoperative time periods of 2 months (Group 1, n=14) and 4 months (Group II, n=20). Group I underwent a posterolateral arthrodesis (PLF) at L5-L6 using tricortical iliac autograft or tricortical iliac autograft plus titanium particulate. Group 2 all received iliac autograft at the initial surgery and were reoperated on after 8 weeks and treated with PLF exposure alone or titanium particulate. Postoperative analysis included serological quantification of systemic cytokines. Postmortem microradiographic, immunocytochemical and histopathological assessment of the intertransverse fusion mass quantified the extent of osteolysis, local proinflammatory cytokines, osteoclasts and inflammatory infiltrates. Clinical aspect of study: Over the last 2 years, 12 patients more than 0.4 years after spinal instrumentation presented with painful paraspinal inflammation. At surgical exploration, the cultures were negative for infection and the surrounding soft tissue was examined for cytokine reactions. There was loosening of implants and osteolysis in the location of the wear debris in 8 of 12 patients. RESULTS: Basic science phase: serological analysis of systemic cytokines indicated no significant differences in cytokine levels (p>.05) between the titanium or autograft treatments. Immunocytochemistry indicated increased levels of local cytokines: TNF-alpha at the titanium-treated PLF sites at both time periods (p<.05). Osteoclast cell counts and regions of osteolytic resorption lacunae were higher in the titanium-treated versus autograft-alone groups (p<.05), and the extent of cellular apoptosis was markedly higher in the titanium-treated sites at both time intervals. Electron microscopy indicated definitive evidence of phagocytized titanium particles and foci of local, chronic inflammatory changes in the titanium-treated sites. Clinical aspect: Eleven of 12 clinical cases demonstrated elevated TNF-alpha levels and an increased osteoclastic response in the vicinity of wear debris caused by dry frictional wear particles of titanium or stainless steel. Osteolysis most commonly involved loose transverse connectors. Resection of the wear debris and surrounding fibroinflammatory glycocalyx resulted in resolution of clinical symptoms in all 12 cases. CONCLUSIONS: Titanium particulate debris introduced at the level of a spinal arthrodesis elicits a cytokine-mediated particulate-induced response favoring proinflammatory infiltrates, increased expression of intracellular TNF-alpha, increased osteoclastic activity and cellular apoptosis. This is the first basic scientific study and the first clinical study demonstrating associations of spinal instrumentation particulates wear debris and increased cytokines and increased osteoclastic activity. Osteolysis is the number one cause of failure of orthopedic implants in the appendicular skeleton. Spinal surgeons need to increase their awareness of this destructive process.     

Erythropoietin augments bone formation in a rabbit posterolateral spinal fusion model

We tested the hypothesis that erythropoietin (EPO) enhances bone formation after posterolateral spinal fusion (PLF) in a rabbit model. Thirty-four adult rabbits underwent posterolateral intertransverse arthrodesis at the L5-L6 level using 2.0 g autograft per side. The animals were randomly divided into two groups receiving subcutaneous daily injections of either EPO or saline for 20 days. Treatment commenced 2 days preoperatively. Hemoglobin was monitored at baseline and 2, 4, and 6 weeks after fusion surgery. After euthanasia 6 weeks postoperatively, manual palpation, radiographic, and histomorphometric examinations were performed. Bone volume of the fusion mass was estimated by CT after 6 weeks. EPO increased bone fusion volume to 3.85 ccm (3.66-4.05) compared with 3.26 ccm (2.97-3.55) in the control group (p<0.01). EPO treatment improved vascularization of the fusion mass and increased hemoglobin levels (p<0.01). Fusion rate tended to be higher in the EPO group based on manual palpation, CT, and radiographic examinations. For the first time EPO has shown to augment bone formation after autograft PLF in a rabbit model. Increased vascularization provides a partial explanation for the efficacy of EPO as a bone autograft enhancer.     

Does spinal instrumentation influence the healing process of posterolateral spinal fusion? An in vivo animal model.

STUDY DESIGN: An in vivo sheep model was used to investigate the effect of spinal instrumentation on the healing process of posterolateral spinal fusion. OBJECTIVES: To examine the role of spinal instrumentation during the healing process of posterolateral fusion. SUMMARY OF BACKGROUND DATA: In long bone fractures, internal fixation improves the union rate but does not accelerate the healing process. Spinal instrumentation also improves the fusion rate in spinal arthrodesis. However, it remains unclear whether the use of spinal instrumentation expedites the healing process of spinal fusion. METHODS: Sixteen sheep underwent posterolateral spinal arthrodeses at L2-L3 and L4-L5 using equal amounts of autologous bone. One of those segments was selected randomly to be augmented with transpedicular screw fixation (Texas Scottish Rite Hospital spinal system). The animals were killed at 8 weeks or 16 weeks after surgery. Fusion status was evaluated by biomechanical testing, manual palpation, plain radiography, computed tomography, and histology. RESULTS: Instrumented fusion segments demonstrated significantly higher stiffness than did uninstrumented fusions at 8 weeks after surgery. Radiographic assessment and manual palpation showed that the use of spinal instrumentation improved the fusion rate at 8 weeks (47% versus 38% in radiographs, 86% versus 57% in manual palpation). Histologically, the instrumented fusions consisted of more woven bone than the uninstrumented fusions at 8 weeks after surgery. The 16-week-old fusion mass was diagnosed biomechanically, radiographically, and histologically as solid, regardless of pedicle screw augmentation. CONCLUSION: The current study's results demonstrated that spinal instrumentation creates a stable mechanical environment to enhance the early bone healing of spinal fusion.     

Posterolateral intertransverse process spinal arthrodesis with rhBMP-2 in a nonhuman primate: important lessons learned regarding dose, carrier, and safety.

Recombinant osteoinductive proteins have been used successfully in canine and rabbit models of posterolateral intertransverse process arthrodesis, but little is known about the ability of these compounds to achieve fusion in nonhuman primates. The goals of this investigation were to compare different combinations of recombinant human bone morphogenetic protein-2 (rhBMP-2) dosages and carriers in a nonhuman primate model of posterolateral intertransverse process spinal fusion and to determine the feasibility of using rhBMP-2 in the presence of exposed dura in a laminectomy model. Posterolateral intertransverse process arthrodeses were performed at L4-5 in 29 rhesus monkeys. The most striking findings were as follows: rhBMP-2 could induce bone in a nonhuman primate spine; the presence of a laminectomy defect with exposed dura did not preclude the safe use of rhBMP-2 for posterolateral fusion; soft tissue compression of the collagen sponge carrier prevented bone induction at standard BMP doses, presumably due to squeezing of the protein out of the sponge; and longer rhBMP-2 loading time into the collagen carrier and mechanical protection from the soft tissue compression both allowed more bone induction at a lower dose of rhBMP-2.     

New formulations of demineralized bone matrix as a more effective graft alternative in experimental posterolateral lumbar spine arthrodesis

STUDY DESIGN: A rabbit model of posterolateral intertransverse process spine arthrodesis was used. OBJECTIVE: To determine the efficacy of two new formulations of demineralized bone matrix. SUMMARY OF BACKGROUND DATA: The flowable gel form of Grafton (Osteotech, Eatontown, NJ) demineralized bone matrix has been shown to have osteoinductive properties in various models and currently is used clinically as bone graft material in posterolateral lumbar spine arthrodesis. Two new formulations of Grafton, one made of flexible sheets (Flex) and the other made in a malleable consistency (Putty), have improved handling characteristics compared with the gel form. METHODS: In this study, 108 New Zealand white rabbits underwent bilateral posterolateral intertransverse spine arthrodesis at L5-L6 using autogenous iliac crest bone graft alone (control), one of the new forms of demineralized bone matrix (DBM; made from rabbit bone) alone or in combination with autogenous iliac crest bone. Rabbits were killed 6 weeks after surgery. The lumbar spines were excised, and fusion success or failure was determined by manual palpation and radiography. Specimens also were processed for undecalcified histologic analysis. RESULTS: Manual palpation of the harvested lumbar spines revealed that the fusion rates of the Flex-DBM/Auto group (9/9, 100%) and Putty-DBM/Auto group (10/10, 100%) were superior (P < 0.01) to those of the Auto/control group (3/9, 33%). As a stand-alone graft substitute, Flex-DBM performed superiorly with a fusion rate of 11/11 (100%) compared with that of Putty-DBM (10/12, 83%) and Gel-DBM (7/12, 58%). The devitalized version of Flex-DBM had a fusion rate of 4/11 (36%), which was comparable with the devitalized Putty-DBM rate of 4/12 (33%). Both were superior (P < 0.05) to the devitalized Gel-DBM rate of 0/12 (0%). More mature fusions with greater amounts of trabecular bone were present radiographically and histologically in rabbits that received all forms of demineralized bone matrix than in those in which autograft was used. CONCLUSIONS: The new flexible sheet and malleable putty forms of demineralized bone matrix were effective as graft extender and graft enhancer in a model of posterolateral lumbar spine fusion. These newer formulations of Grafton appear to have a greater capacity to form bone than the gel form or autogenous bone graft alone in this model.     

The efficacy of a nanosynthetic bone graft substitute as a bone graft extender in rabbit posterolateral fusion

BACKGROUND CONTEXTSynthetic bone graft substitutes are commonly used in spinal fusion surgery. Preclinical data in a model of spinal fusion to support their efficacy is an important component in clinical adoption to understand how these materials provide a biological and mechanical role in spinal fusion.PURPOSETo evaluate the in vivo response of a nanosynthetic silicated calcium phosphate putty (OstP) combined with autograft compared to autograft alone or a collagen-biphasic calcium phosphate putty (MasP) combined with autograft in a rabbit spinal fusion model.STUDY DESIGNEfficacy of a nanosynthetic silicated calcium phosphate putty as an extender to autograft was studied in an experimental animal model of posterolateral spinal fusion at 6, 9, 12 and 26 weeks, compared to a predicate device.METHODSSkeletally mature female New Zealand White rabbits (70) underwent single level bilateral posterolateral intertransverse process lumbar fusion, using either autograft alone (AG), a nanosynthetic silicated calcium phosphate putty (OstP) combined with autograft (1:1), or a collagen-biphasic calcium phosphate putty (MasP) combined with autograft (1:1). Iliac crest autograft was harvested for each group, and a total of 2 cc of graft material was implanted in the posterolateral gutters per side. Fusion success was assessed at all time points by manual palpation, radiographic assessment, micro-CT and at 12 weeks only using non-destructive range of motion testing. Tissue response, bone formation and graft resorption were assessed by decalcified paraffin histology and by histomorphometry of PMMA embedded sections.RESULTSAssessment of fusion by manual palpation at the 12 week endpoint showed 7 out of 8 (87.5%) bilateral fusions in the OstP extender group, 4 out of 8 (50%) fusions in the MasP extender group, and 6 out of 8 (75%) fusions in the autograft alone group. Similar trends were observed with fusion scores of radiographic and micro-CT data. Histology showed a normal healing response in all groups, and increased bone formation in the OstP extender group at all timepoints compared to the MasP extender group. New bone formed directly on the OstP granule surface within the fusion mass while this was not a feature of the Collagen-Biphasic CaP material. After 26 weeks the OstP extender group exhibited 100% fusions (5 out of 5) by all measures, whereas the MasP extender group resulted in bilateral fusions in 3 out of 5 (60%), assessed by manual palpation, and fusion of only 20 and 0% by radiograph and micro-CT scoring, respectively. Histology at 26 weeks showed consistent bridging of bone between the transverse processes in the Ost P extender group, but this was not observed in the MasP extender group.CONCLUSIONSThe nanosynthetic bone graft substituted studied here, used as an extender to autograft, showed a progression to fusion between 6 and 12 weeks that was similar to that observed with autograft alone, and showed excellent fusion outcomes, bone formation and graft resorption at 26 weeks.CLINICAL SIGNIFICANCEThis preclinical study showed that the novel nanosynthetic silicated CaP putty, when combined with autograft, achieved equivalent fusion outcomes to autograft. The development of synthetic bone grafts that demonstrate efficacy in such models can eliminate the need for excessive autograft harvest and results from this preclinical study supports their effective use in spinal fusion surgery.     

rhBMP-2 enhancement of posterolateral spinal fusion in a rabbit model in the presence of concurrently administered doxorubicin.

BACKGROUND CONTEXT: Spinal fusions can be necessary in patients undergoing chemotherapy with doxorubicin. In a previous study, doxorubicin was shown to decrease spinal fusion rates in a rabbit model of lumbar intertransverse process spinal fusion with autograft iliac crest bone. In the current study, we determine whether spinal fusion with recombinant human bone morphogenetic protein-2 (rhBMP-2) can overcome the inhibitory effect of doxorubicin in spinal fusion. PURPOSE: To determine if rhBMP-2 can overcome the inhibitory effects of doxorubicin (adriamycin) in an animal model of posterolateral spinal fusion. STUDY DESIGN/SETTING: Prospective, controlled, rabbit model of posterolateral lumbar fusion. OUTCOME MEASURES: Spine fusion was assessed by manual palpation (by observers blinded to the treatment group) at the level of arthrodesis. Fusion was graded according to a five-tiered classification (0-4). Posteroanterior radiographs of the excised spines were also graded in a blinded fashion using a six-point scoring system (0-5) devised to describe the amount of bone observed between the L5-L6 transverse processes. METHODS: Thirty-two New Zealand White rabbits underwent posterolateral fusion at L5-L6 with either autograft (iliac crest autograft bone) or rhBMP-2 (rhBMP-2/absorbable collagen sponge (0.86 mg/level). All animals received a dose of doxorubicin (2.5 mg/kg) known to inhibit spine fusion via the central vein of the ear immediately postoperatively. Five weeks postoperatively the rabbits were euthanized. Spine fusion was assessed by manual palpation, and graft quality was assessed with posteroanterior radiographs. RESULTS: Four of the 16 spines (25%) in the autograft group and 16 of the 16 spines (100%) in the rhBMP-2 group fused in the presence of doxorubicin administration (p<.05). There was significantly increased bone formation in the rhBMP-2 group (p<.05). One unilateral, subclinical wound infection was observed in each group at the time of euthanization (autograft [n=1, 6%] and rhBMP-2 [n=1, 6%]). CONCLUSIONS: We confirm that when autograft is used, doxorubicin decreases spinal fusion rate (25%) compared with historical controls (60-75%). More importantly, using rhBMP-2 overcomes the inhibitory effect of doxorubicin, resulting in 100% fusion in our animal model. This study suggests that rhBMP-2 has the potential to improve fusion rates in human patients undergoing chemotherapy with doxorubicin.     

A preliminary comparative study of radiographic results using mineralized collagen and bone marrow aspirate versus autologous bone in the same patients undergoing posterior lumbar interbody fusion with instrumented posterolateral lumbar fusion.

BACKGROUND CONTEXT: Multiple bone graft substitutes for spinal fusion have been studied with varying results. PURPOSE: The purpose of this study was to assess the effectiveness of a mineralized collagen matrix combined with bone marrow, versus autologous bone, in the same patients undergoing a posterior lumbar interbody fusion and an instrumented posterolateral lumbar fusion. STUDY DESIGN/SETTING: A prospective, comparative study. PATIENT SAMPLE: Patients indicated for one-level posterior lumbar interbody fusion and instrumented posterolateral lumbar fusion, serving as self-controls. OUTCOME MEASURES: Thin-cut computed tomographic scans with sagittal reconstruction and plain radiographs, including lateral flexion/extension views were performed and assessed at 12 and 24 months after surgery. Oswestry Disability Index and Visual Analog Scale questionnaires were completed by all patients preoperatively and at 12 and 24 months after surgery. METHODS: After informed consent and failure of nonoperative treatment, 25 consecutive patients requiring one-level instrumented posterolateral fusion combined with posterior interbody fusion were enrolled in the study. Mineralized collagen bone graft substitute combined with bone marrow aspirate was used on one side of the posterolateral fusion, with iliac crest autograft on the contralateral side. RESULTS: A fusion rate of 84% (21/25) was achieved for the autologous bone grafts and 80% (20/25) for the bone graft substitute. The interbody fusion rate was 92% (23/25). Mean Oswestry Disability Index (ODI) scores decreased 57.2% at 12 months and 55.6% at 24 months, compared with baseline. CONCLUSIONS: Mineralized collagen bone graft substitute exhibited similar radiographic results compared with autograft in this model. Further trials incorporating bilateral fusion, as well as posterolateral fusion alone without interbody fusion are warranted to confirm the results of this study.     

Use of biphasic calcium phosphate versus demineralized bone matrix: retrospective clinical and CT analysis of posterolateral fusion results

Purpose

Bone graft extenders have been developed to prevent donor site morbidity associated with iliac crest bone graft, but few studies compared the efficacy of various substitutes. Our purpose was to determine fusion rate and clinical outcome in patients undergoing lumbar arthrodesis using demineralized bone matrix (DBM) and biphasic calcium phosphate (BCP).

Methods

Patients with degenerative spondylolisthesis undergoing one-level or two-level arthrodesis of lumbar spine were retrospectively reviewed. Two treatment groups placed either BCP or DBM, in addition to local autograft in lumbar posterolateral space. Three-dimensional CT exam and dynamic flexion–extension radiographs at postoperative 2-year were assessed for posterolateral fusion status and pain scale and Oswestry Disability Index (ODI) for clinical outcome.

Results

Of the 148 patients reviewed (including 23 in one- and 58 patients in two-level in BCP group, and 47 in one- and 20 patients in two-level in DBM group), no significant differences were found in terms of age, sex, BMI, smoking, diabetes, steroids, number of level fused, non-union rate or revision surgery between BCP and DBM groups. Significantly improved pain scale of back and leg and ODI were found in both groups postoperatively without group difference. We found a comparable fusion rate in one-level surgery (100% versus 93.6%) and a superior fusion rate of BCP group in two-level surgery (98.3% versus 80.0%, p = 0.01).

Conclusion

Being a bone graft extender without osteoinductive property, with local autograft, BCP is comparable to DBM for one- and superior for two-level fusion. No significant difference was found in clinical outcomes.

     

Factors influencing arthrodesis rates in a rabbit posterolateral spine model with iliac crest autograft

Purpose

The rabbit posterolateral intertransverse spine arthrodesis model has been widely used to evaluate spinal biologics. However, to date, the validity and reproducibility of performance of iliac crest bone graft, the most common and critical control group, has not been firmly established. We evaluated original research publications that utilized this model, identified which experimental conditions affected fusion rates, and developed an algorithm to predict fusion rates for future study designs.

Methods

A MEDLINE search was performed for publications through December, 2011 that utilized this model to evaluate fusion rates elicited by iliac crest autograft. All study parameters were recorded, and logistic regression analyses were performed to determine the effects of these variables on fusion rates as determined by either manual palpation or radiographs.

Results

Seventy studies with 959 rabbits in 102 groups met the inclusion criteria. Excluding studies that measured fusion at 4 or fewer weeks or intentionally tried to decrease the fusion rate, the overall fusion rate for autograft was 58.3 ± 16.3 % (mean ± SD) as determined by manual palpation and 66.4 ± 17.8 % by plain radiographs. Regression analysis demonstrated a difference between these outcome measures with a trend towards significance (p = 0.09). Longer time points and larger volumes of autograft resulted in significantly greater reported fusion rates (p < 0.0001 and p < 0.05, respectively). Neither strain, age, weight, nor vertebral level significantly affected fusion rates.

Conclusions

Although experimental conditions varied across studies, time point evaluation and autograft volume significantly affected fusion rates. Despite some variability demonstrated across certain studies, we demonstrated that when the time point and volume of autograft were controlled for, the iliac crest control group of the rabbit posterolateral spinal arthrodesis model is both reliable and predictably affected by different experimental conditions.     

Cost Comparison of Crossed Screws versus Dorsal Plate Construct for First Metatarsophalangeal Joint Arthrodesis

Expensive surgical implants can significantly add to the cost of a procedure. We performed a crude cost analysis to evaluate and compare the crossed screw technique versus dorsal plating for first metatarsophalangeal arthrodesis. First metatarsophalangeal arthrodeses performed over a 20-month period were selected. Exclusion criteria included diabetes, neuroarthropathy, revision surgery, or alternate fixation. Hospital records were reviewed for each case to determine implant charges. Patient charts and radiographs were also reviewed to determine time to fusion, delayed union/nonunion, revision surgery, or hardware removal. Fifty-five first metatarsophalangeal arthrodeses were performed during the study period. Ten fusions were excluded, leaving 45 fusions for review. The overall fusion rate was 91.1%. The average time to fusion in crossed screw versus plating technique was 73.2 +/- 32.5 days (range, 43 to 162) and 69.3 +/- 37.3 days (range, 44 to 238), respectively, and not statistically significant. The mean implant cost in the crossed screw versus dorsal plating technique was $374.05 +/- 76.3 (range, 278.72 to 530.00) and $603.57 +/- 234.7 (range, 543.40 to 1677.00) respectively and was strongly significant (P = .0002). Complications included 2 delayed unions (1 screw, 1 plate), 4 nonunions (1 screw, 3 plate), 2 revisions (1 screw, 1 plate), and 2 hardware removals (1 screw, 1 plate). SUMMARY: A cost comparison of crossed screws versus dorsal plate construct for first metatarsophalangeal arthrodesis is performed. No statistical difference was found in the time to fusion between the 2 constructs but there was strong statistical difference in hardware cost. This information may aid in the cost management of this procedure without compromising clinical results. ACFAS Level of Clinical Evidence: 2c.