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Biomedical subjects

Scott D Boden

Publications and source records attributed to Scott D Boden.

At least 19 recordsLinked to original sources
PubMed2006

Surgical vs nonoperative treatment for lumbar disk herniation: the Spine Patient Outcomes Research Trial (SPORT): a randomized trial.

CONTEXT: Lumbar diskectomy is the most common surgical procedure performed for back and leg symptoms in US patients, but the efficacy of the procedure relative to nonoperative care remains controversial. OBJECTIVE: To assess the efficacy of surgery for lumbar intervertebral disk herniation. DESIGN, SETTING, AND PATIENTS: The Spine Patient Outcomes Research Trial, a randomized clinical trial enrolling patients between March 2000 and November 2004 from 13 multidisciplinary spine clinics in 11 US states. Patients were 501 surgical candidates (mean age, 42 years; 42% women) with imaging-confirmed lumbar intervertebral disk herniation and persistent signs and symptoms of radiculopathy for at least 6 weeks. INTERVENTIONS: Standard open diskectomy vs nonoperative treatment individualized to the patient. MAIN OUTCOME MEASURES: Primary outcomes were changes from baseline for the Medical Outcomes Study 36-item Short-Form Health Survey bodily pain and physical function scales and the modified Oswestry Disability Index (American Academy of Orthopaedic Surgeons MODEMS version) at 6 weeks, 3 months, 6 months, and 1 and 2 years from enrollment. Secondary outcomes included sciatica severity as measured by the Sciatica Bothersomeness Index, satisfaction with symptoms, self-reported improvement, and employment status. RESULTS: Adherence to assigned treatment was limited: 50% of patients assigned to surgery received surgery within 3 months of enrollment, while 30% of those assigned to nonoperative treatment received surgery in the same period. Intent-to-treat analyses demonstrated substantial improvements for all primary and secondary outcomes in both treatment groups. Between-group differences in improvements were consistently in favor of surgery for all periods but were small and not statistically significant for the primary outcomes. CONCLUSIONS: Patients in both the surgery and the nonoperative treatment groups improved substantially over a 2-year period. Because of the large numbers of patients who crossed over in both directions, conclusions about the superiority or equivalence of the treatments are not warranted based on the intent-to-treat analysis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000410.

Adult↗
PubMed2006

LIM mineralization protein-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads.

Development and repair of the skeletal system and other organs is highly dependent on precise regulation of bone morphogenetic proteins (BMPs), their receptors, and their intracellular signaling proteins known as Smads. The use of BMPs clinically to induce bone formation has been limited in part by the requirement of much higher doses of recombinant proteins in primates than were needed in cell culture or rodents. Therefore, control of cellular responsiveness to BMPs is now a critical area that is poorly understood. We determined that LMP-1, a LIM domain protein capable of inducing de novo bone formation, interacts with Smurf1 (Smad ubiquitin regulatory factor 1) and prevents ubiquitination of Smads. In the region of LMP responsible for bone formation, there is a motif that directly interacts with the Smurf1 WW2 domain and can effectively compete with Smad1 and Smad5 for binding. We have shown that small peptides containing this motif can mimic the ability to block Smurf1 from binding Smads. This novel interaction of LMP-1 with the WW2 domain of Smurf1 to block Smad binding results in increased cellular responsiveness to exogenous BMP and demonstrates a novel regulatory mechanism for the BMP signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2006

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.

Bone Morphogenetic Protein 2↗
PubMed2006

Effect on bone induction of using contrast media to reconstitute recombinant human bone morphogenetic protein-2 in an ectopic model in rats.

OBJECT: In this study the authors tested the osteoinductive potential of recombinant human bone morphogenetic protein-2 (rhBMP-2) when combined with each of three commercially available contrast media (Conray, Omniscan, and Optiray). METHODS: Initial in vitro and cadaver tests verified the feasibility of using contrast media to visualize absorbable collagen sponge implants containing rhBMP-2 on fluoroscopic radiographic images. For the feasibility studies, lyophilized rhBMP-2 was prepared for injection by reconstitution with contrast media instead of sterile water. For the in vivo study, samples of an rhBMP-2 stock solution were diluted to 0.1 mg/ml by using three contrast media. In each sample, the final solution consisted of 97% contrast medium by volume. Recombinant human bone morphogenetic protein-2 diluted with sterile water for injection was used as a positive control. The rhBMP-2 solutions were applied to 0.5-cm3 collagen sponges and implanted subcutaneously on the thoracic cavity of athymic rats. At 4 weeks, the rats were killed, and the implants were removed. The explants were graded for degree of bone formation by using manual palpation and radiographic and histological assessments. CONCLUSIONS: By all methods of evaluation used, rhBMP-2 diluted with Omniscan was equivalent to rhBMP-2 diluted with sterile water in inducing bone formation. Both Conray and Optiray were shown to inhibit the osteoinductive potential of rhBMP-2.

Animals↗
PubMed2005

The use of cultured bone marrow cells in type I collagen gel and porous hydroxyapatite for posterolateral lumbar spine fusion.

STUDY DESIGN: Posterolateral lumbar transverse process fusion was completed using the cultured bone marrow cells in type I collagen gel and porous hydroxyapatite. OBJECTIVE: To compare the efficacy of cultured bone marrow cells with that of bone morphogenetic protein (BMP) as a graft alternative to autologous bone for posterolateral spine fusion. SUMMARY OF BACKGROUND DATA: The clinical application of BMP for spinal fusion may be limited by high dose and cost. Recently, mesenchymal stem cells have been studied in various fields because of their capability to differentiate into various cells, including those in the osteogenic lineage. METHODS: Thirty adult rabbits were used. Each underwent single-level, bilateral, posterolateral intertransverse process fusions at L4-L5. The animals were divided into 4 groups, each according to the material implanted: (1) autologous bone (autograft, n = 9); (2) porous hydroxyapatite (HA) particles and type I collagen sheet with 100 microg rhBMP-2 (BMP-HA, n = 7); (3) bone marrow cells (1 x 10(6) cells/mL, low-marrow-HA, n = 7); and (4) bone marrow cells (1 x 10(8) cells/mL, high-marrow-HA, n = 7). Before implantation for groups 3 and 4, fresh bone marrow cells from the iliac crest of each animal were cultured in a standard medium for 2 weeks. For one additional week, the marrow cells were cultured in 10(-8) M dexamethasone, type I collagen gel, and HA. Animals were euthanized 6 weeks after surgery. Spinal fusions were evaluated by radiograph, manual palpation, and histology. RESULTS: The fusion rates were 4 of 7 in the autograft group, 7 of 7 in the BMP-HA group, 0 of 7 in the low-marrow-HA group, and 5 of 7 in the high-marrow-HA group. The histology in the BMP-HA and high-marrow-HA groups showed that grafted HA fragments were connected with mature new bone. The pores of HA fragments were filled up with bone matrix. In the low-marrow-HA group, fibrous tissue was predominant in the grafted fragments. CONCLUSIONS: This study shows that the cultured bone marrow cells can act as a substitute for autograft or BMP in spine fusion. The current formulation may yield improved fusion success and better quality of fusion bone as compared to autograft.

Animals↗
PubMed2005

Lower dose of rhBMP-2 achieves spine fusion when combined with an osteoconductive bulking agent in non-human primates.

STUDY DESIGN: A non-human primate lumbar intertransverse process arthrodesis model was used to evaluate the effectiveness of different formulations of recombinant human bone morphogenetic protein-2 (rhBMP-2) to induce consistent bone formation. OBJECTIVE: To determine if the combination of rhBMP-2/absorbable collagen sponge (ACS) wrapped around a bulking agent, consisting of a biphasic calcium phosphate/collagen composite, could achieve posterolateral spine fusion with a dose of rhBMP-2 (3.0 mg/side) that previously failed to induce posterolateral fusion in rhesus monkeys with other carriers. SUMMARY OF BACKGROUND DATA: Successful bone induction in both human and non-human primates has required higher concentrations of BMP than were required in lower order models. The Food and Drug Administration approved concentration of rhBMP-2 for interbody fusion (1.5 mg/mL) when delivered on the ACS alone without a bulking agent (doses 3-9 mg/side) has failed to induce clinically relevant amounts of bone formation in a posterolateral spine fusion model in rhesus monkeys. Previously, a higher concentration of 2.0 mg/mL of rhBMP-2 delivered on stacked sheets of a biphasic calcium phosphate ceramic/collagen compression resistant matrix (CRM) was required to achieve fusion in the rhesus monkey and was the basis for this study (doses of 6-12 mg/side). METHODS: Nine skeletally mature, rhesus macaque monkeys underwent single level posterolateral arthrodesis at L4-L5. Two different rhBMP-2 doses were evaluated in 3 delivery configurations. The first 3 monkeys received 10 mg/side (2.5 mL at 4.0 mg/mL) of rhBMP-2 loadeddirectly onto a CRM carrier (15% hydroxyapatite/85%beta-tricalcium phosphate ceramic/collagen matrix), resulting in a final concentration of 2.0 mg/mL. The second 3 monkeys received 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 loaded directly on the CRM carrier, resulting in a 0.6 mg/mL final concentration. Three additional monkeys also received the 3 mg/side (2.0 mL at 1.5 mg/mL) of rhBMP-2 delivered on an ACS, which was then wrapped around the dry CRM matrix used as a bulking agent, yielding a 1.5 mg/mL final concentration of rhBMP-2 on the sponge wrapped around the bulking agent. The monkeys were euthanized at 24 weeks after surgery. Manual palpation, plain radiographs, computerized tomography, and nondecalcified histology were used to evaluate fusion in a blinded fashion. RESULTS: The 3 monkeys with 10 mg rhBMP-2 placed directly on the CRM carrier (2.0 mg/mL final concentration) achieved solid fusion. The 3 monkeys that underwent fusion with 3 mg of rhBMP-2 placed directly on the CRM carrier (0.6 mg/mL final concentration) failed to achieve fusion. In contrast, the 3 monkeys that underwent fusion with the same 3 mg dose of rhBMP-2 dispensed only on an ACS that was wrapped around the CRM achieved solid bilateral fusion. CONCLUSIONS: This study shows the importance of carrier optimization and final implant protein concentration for the successful delivery of rhBMP-2. By combining the properties of the ACS with the CRM, the required dosage of rhBMP-2 was diminished by more than 3-fold in the non-human primate model. This finding suggests that the currently available concentration of rhBMP-2 (1.5 mg/mL) could be successful for achieving posterolateral spine fusion when combined with an osteoconductive bulking agent that can support the induced new bone formation.

Animals↗
PubMed2005

Comparison of Healos/bone marrow to INFUSE(rhBMP-2/ACS) with a collagen-ceramic sponge bulking agent as graft substitutes for lumbar spine fusion.

STUDY DESIGN: A rabbit lumbar intertransverse process arthrodesis model was used to evaluate the efficacy of two different bone substitute materials: 1) collagen-hydroxyapatite sponge (Healos bone void filler) combined with heparinized bone marrow; and 2) recombinant human bone morphogenetic protein-2 delivered in a collagen sponge (INFUSE Bone Graft) wrapped around an additional collagen-ceramic sponge (Mastergraft Matrix) as a "bulking agent." OBJECTIVES: To compare the relative efficacy of two different bone graft substitutes to achieve posterolateral lumbar spine fusion in rabbits. SUMMARY OF BACKGROUND DATA: Autogenous bone graft is considered the gold standard graft material for spine fusion. Complications with its use, however, may occur in as many as 30% of patients. A variety of bone substitutes have been used for spine fusion, but there are few direct comparison experiments to determine the relative efficacy of any two alternatives. METHODS: Adult New Zealand white rabbits (n = 24) were divided into two groups and underwent bilateral posterolateral intertransverse process spine arthrodesis at L5-L6. The fusions were augmented by different bone substitute materials as follows: Group 1 (n = 12) received 3 mL of collagen-hydroxyapatite sponge (Healos bone void filler) (10 x 30 x 5 mm, two per side) with 3.0 mL of heparinized bone marrow on each side of the spine. (ratio 1:1); Group 2 (n = 12) received 1.5 mL of rhBMP-2 (0.43 mg/mL solution) on a Type 1 collagen sponge (INFUSE Bone Graft) wrapped around an additional 1.5 mL collagen-ceramic (15%HA/85%TCP) sponge (Mastergraft Matrix) as a bulking agent to provide 3 mL of graft on each side of the spine. Bone marrow was aspirated from posterior iliac crest, and 1 mL of bone marrow was sent to count number of nucleated cells. The rabbits were killed after 8 weeks; the spines were evaluated by manual palpation, radiographs (plain radiograph and CT scan), tensile mechanical testing, and nondecalcified histology. RESULTS: The bone marrow had average of total nucleated cell count 9 x 10 cells. All rabbits (100%) in Group 2 (INFUSE/Mastergraft Matrix) achieved solid spinal fusions by manual palpation and radiographs, whereas solid spinal fusion was not achieved by manual palpation and radiographs in any of the rabbits treated with Healos combined with heparinized bone marrow (Group 1). The plain radiograph and CT scans of Group 1 showed some minimal new bone formation near the transverse processes, but none of these rabbits formed a continuous fusion mass. In contrast, all of plain radiographs and CT scans in Group 2 showed continuous fusion mass and complete graft incorporation between transverse processes bilaterally. Biomechanically, the relative strength and relative stiffness values of L5-L6 (fusion segment) in Group 2 were statistically significant greater than L5-L6 in Group 1 (P < 0.001). Histologic sections confirmed the palpation and radiographic results. CONCLUSION: From the manual palpation, radiographic and biomechanical assessment of fusion, the results in this study showed that INFUSE (rhBMP-2/collagen sponge) consistently produced spine fusion when wrapped around a collagen-ceramic sponge bulking agent (Mastergraft Matrix). Meanwhile, Healos was ineffective as a bone graft material when combined with heparinized autogenous bone marrow.

Animals↗
PubMed2004

ISSLS prize winner: LMP-1 upregulates intervertebral disc cell production of proteoglycans and BMPs in vitro and in vivo.

STUDY DESIGN: Experiments using both in vitro tissue culture and in vivo rabbit methods were used to study the effect of Lim Mineralization Protein-1 (LMP-1) on intervertebral disc (IVD) cell production of proteoglycans and bone morphogenetic proteins (BMPs). OBJECTIVES: To determine the effect of LMP-1 overexpression in IVD cells on the production of proteoglycans and BMPs both in vitro and in vivo and to show that LMP-1 mediates the control of proteoglycan production through its action on BMPs. SUMMARY OF BACKGROUND DATA: Because BMPs are known to increase proteoglycan synthesis and LMP-1 is known to upregulate BMPs in certain cells, it was hypothesized that LMP-1 may increase proteoglycan production in IVD cells. METHODS: DMMB, real-time polymerase chain reaction, and ELISA methods were used to quantitate proteoglycan, mRNA, and protein levels, respectively. Noggin was used to block the effect of the adenovirus carrying LMP-1 (AdLMP-1) on proteoglycan synthesis. In vivo experiments using intradiscal AdLMP-1 injection were performed with New Zealand White rabbits. Three weeks later, the mRNA levels of LMP-1, aggrecan, BMP-2, and BMP-7 were measured. RESULTS: In vitro experiments revealed that the sulfated glycosaminoglycan (sGAG) and aggrecan mRNA levels were significantly increased with AdLMP-1 treatment. Similarly, BMP-2 and BMP-7 mRNA and protein levels increased significantly, but BMP-4 and BMP-6 levels were unchanged. Noggin blocked the upregulation of proteoglycan by AdLMP-1. In vivo discs injected with AdLMP-1 had significantly elevated levels of LMP-1, BMP-2, and BMP-7 mRNA. CONCLUSIONS: LMP-1 overexpression increases disc cell production of proteoglycan, BMP-2, and BMP-7. LMP-1 mediates the control of proteoglycan production through its action on BMP.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Ne-Osteo bone growth factor for posterolateral lumbar spine fusion: results from a nonhuman primate study and a prospective human clinical pilot study.

STUDY DESIGN: Prospective animal and human clinical pilot trial. OBJECTIVES: The purpose of this study was to determine and test the dose of Ne-Osteo growth factor extract and carrier required for consistent radiographic bone induction in humans. SUMMARY OF BACKGROUND DATA: Preclinical studies have demonstrated that Ne-Osteo, an extract-containing bone morphogenetic proteins, was successful at generating spine fusion in rabbits and rhesus monkeys. Consistent fusions have yet to be achieved in nonhuman primates and humans. METHODS: Adult rhesus monkeys underwent single-level posterolateral intertransverse lumbar arthrodesis with either 3.0 mg (N = 4), 5.0 mg (N = 4), 12.5 mg (N = 4), or 25 mg (N = 4) of Ne-Osteo per side. Animals were killed after 24 weeks. In the human clinical trial, 22 patients (18 females, 4 males) had lumbar spinal stenosis and/or spondylolisthesis requiring spine arthrodesis. To minimize patient risk of nonunion, patients received autogenous bone graft from the posterior iliac crest on one side and Ne-Osteo growth factor on the other. The dose was 12.5 mg, 25 or 50 mg, or 25 mg Ne-Osteo per side performed in the three phases, respectively. RESULTS: Three of four monkeys that received 12.5 mg Ne-Osteo per side and four of four that received 25 mg per side achieved solid fusions. In phase I of the human clinical trial, two of six patients showed radiographic bone induction (plain radiograph, CT scans-blindly evaluated) on the Ne-Osteo side (12.5-mg dose). In phase II, both sides were graded as fused in five of six patients. Although graded as fused, the 6-month scans demonstrated a ring of new bone with the center filling in slower (12-24 mo) than was predicted by nonhuman primate studies. As a result, phase III carrier was designed to have a more porous/open early fusion mass than with the dense DBM paste (used in phase I and II) by mixing in local bone or cancellous allograft chips. Results using the 25- and 50-mg doses were the same, so 25 mg was used in phase III. In phase III, 9 of 10 autograft were fused by 12 months. Five of five patients with Ne-Osteo plus local bone and four of five with allograft chips were fused by 6 months. The one patient in this group that did not heal on either the autograft or the Ne-Osteo side was a smoker. CONCLUSIONS: A graft composite of Ne-Osteo bone growth factor with human DBM with or without cancellous allograft or local bone autograft was capable of achieving a contiguous spine fusion mass in 15 of 16 patients at a dose of at least 25 mg per side. This result was comparable with the results using iliac crest autograft (94%) in this side-by-side model. These results warrant confirmation in a definitive trial using Ne-Osteo on both sides of the spine and thus avoiding the need for iliac crest bone graft harvest.

Animals↗
PubMed2004

Evidence of osteoinduction by Grafton demineralized bone matrix in nonhuman primate spinal fusion.

STUDY DESIGN: A nonhuman primate posterolateral lumbar intertransverse process arthrodesis model was used to evaluate osteoinductive bone graft materials. OBJECTIVES: To test two new formulations of Grafton demineralized bone matrix (Flex and Matrix) for evidence of osteoinduction and their potential efficacy as an extender or enhancer for autogenous bone in a previously validated nonhuman primate posterolateral lumbar fusion model. SUMMARY OF BACKGROUND DATA: Whereas several demineralized bone matrix formulations have been shown to be variably osteoinductive in rodent ectopic bone assays and rabbit spine applications, few have demonstrated efficacy in higher species and in more challenging applications such as posterolateral spine fusion. The authors are not aware of any published studies describing any demineralized bone matrix that has been tested in a nonhuman primate posterolateral spine fusion model. METHODS: After approval by the institutional animal care and use committee, eight skeletally mature rhesus macaques underwent single-level posterolateral arthrodesis. In four animals, autograft (4 g/side) was implanted with a piece of human Grafton Flex demineralized bone matrix. In the other four animals, rhesus Grafton Matrix demineralized bone matrix, a new and more porous formulation of Flex, was implanted with autograft (4 g) on one side of the spine, and Matrix with half the amount of autograft (2 g) was implanted on the opposite side. Radiographs were taken at intervals until the animals were killed at 24 weeks. Spinal fusion was evaluated by manual palpation (status was fused or not fused), and computed tomography was done to visualize the amount of bone formation. RESULTS: Fusion was ascertained by palpation in two of four monkeys receiving Flex with autograft and in three of four monkeys receiving Matrix with autograft. Evidence of osteoinduction was seen in all four monkeys on the Matrix with 4 g autograft side, which had larger fusion masses than in the other treatments. Histologic examination showed that the bone formed was normal. CONCLUSIONS: The rhesus Matrix formulation performed better than the human Flex. Evidence of osteoinduction was seen in all four monkeys that received Matrix, which improved the fusion success of autograft. This alone suggested that it might play a role as a graft enhancer, not merely as a graft extender. Human studies are warranted.

Animals↗
PubMed2004

Glucocorticoid regulation of human BMP-6 transcription.

Addition of dexamethasone (Dex) to human mesenchymal stem cells (hMSCs) resulted in a 16-fold increase in human bone morphogenetic protein-6 (hBMP-6) mRNA levels 24 h after treatment. Evaluation of luciferase expression after transfection of HeLa cells with hBMP-6 promoter/luciferase reporter constructs indicated that the hBMP-6 promoter activity was contained in a 268-bp region (-1051 to -784 where +1 is the translation start site) over 600 bases 5' to that previously published. It further showed that the promoter activity is regulated by glucocorticoid treatment. Analysis of RNA from hMSCs and HeLa cells by primer extension, RNase protection, and 5' RACE further narrowed the location of the transcription start site to an 84-bp region (-940 to -857). To determine whether this start site was regulated in hMSCs, hBMP-6 mRNA levels in control and Dex-treated cells were quantitated by RT-PCR using one primer set in the translated region of the gene and one located just 3' of the 84-bp region. Both primer sets showed hBMP-6 mRNA levels approximately 16- to 22-fold higher in the Dex-treated cells, demonstrating that hBMP-6 transcription is being regulated by glucocorticoids in the pluripotent hMSCs at the upstream transcription start site.

Base Sequence↗
PubMed2003

Summary statement: emerging techniques for treatment of degenerative lumbar disc disease.

Emerging techniques for management of degenerative disc disease include modern fusion interbody cage devices, intradiscal electrothermal therapy, and disc prostheses among others. The management of discogenic low back pain is controversial: its accurate diagnosis is difficult, and treatment is inconsistent. Before wide application, the advantages and disadvantages of each procedure must be considered in lieu of inadequate study design and the lack of sufficient long-term outcome studies.

Electrocoagulation↗