Bone morphogenetic protein—2 application by a poly(d,l-lactide)—coated interbody cage: in vivo results of a new carrier for growth factors

2002 ◽  
Vol 97 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Frank Kandziora ◽  
Hermann Bail ◽  
Gerhard Schmidmaier ◽  
Georg Schollmeier ◽  
Matti Scholz ◽  
...  

Object. Growth factors such as bone morphogenetic protein—2 (BMP-2) have been proven to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum method to deliver such growth factors remains a matter of discussion. The purpose of this study was to determine the safety and efficacy of a new poly(d,l-lactide) (PDLLA) carrier system for BMP-2 and to compare this carrier system with a collagen sponge carrier in a sheep cervical spine interbody fusion model. Methods. Thirty-two sheep underwent C3–4 discectomy and fusion: Group 1, titanium cage (eight animals); Group 2, titanium cage coated with a PDLLA carrier (eight animals); Group 3, titanium cage coated with a PDLLA carrier including BMP-2 (150 µg) (eight animals); and Group 4, titanium cage combined with a collagen sponge carrier including BMP-2 (150 µg) (eight animals). Blood samples, body weight, and temperature were assessed. Radiographs were obtained pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After the sheep were killed 12 weeks postoperatively, flexion—extension radiography was performed to evaluate fusion sites. Quantitative computerized tomography scans were obtained to assess bone mineral density (BMD), bone mineral content (BMC), and bone callus volume (BCV). Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral, and elastic zone were determined. Histomorphological and -morphometrical analyses were performed, and polychrome sequential labeling was used to determine the timeframe of new bone formation. There were no differences among the groups concerning blood counts, body weight, and temperature. Compared with the noncoated cages, all PDLLA-coated cages showed significantly higher values for BMD of the callus, as well as slightly higher values for BMC, BCV, and the bone volume/total volume ratio. In comparison with the cage-alone group, the BMP-2 groups showed significantly higher values for BMD and biomechanical stiffness. Histomorphological, -morphometrical, and polychrome sequential labeling analyses demonstrated greater progression of callus formation in the BMP-2 groups than in any other group. Compared with BMP-2 delivered using a collagen sponge carrier, BMP-2 application with a PDLLA carrier resulted in a higher BCV and a greater progression of interbody callus formation in the histomorphometrical analysis. Conclusions. The use of cervical spine interbody fusion cages coated with PDLLA as a delivery system for growth factors was effective. In this 12-week follow-up study, the PDLLA coating showed no adverse effects. The slight but not significant positive effect of the PDLLA carrier on interbody fusion might be a result of the degradation process of the biodegradable carrier. Compared with collagen sponge delivery of BMP-2, the PDLLA-coated interbody cages significantly increased the results of interbody bone matrix formation. In this new combination (implant + PDLLA + growth factor) the cage represents a “real fusion” cage, because it not only serves as a mechanical device for spinal fixation but also as a local drug delivery system.

2005 ◽  
Vol 3 (6) ◽  
pp. 436-443 ◽  
Author(s):  
Alan T. Villavicencio ◽  
Sigita Burneikiene ◽  
E. Lee Nelson ◽  
Ketan R. Bulsara ◽  
Mark Favors ◽  
...  

Object. Recombinant human bone morphogenetic protein—2 (rhBMP-2) is being increasingly used for spinal fusion. There are few data regarding its clinical safety, effectiveness, and clinical outcome when applied on an absorbable collagen sponge (ACS) in conjunction with allograft for transforaminal lumbar interbody fusion (TLIF). Methods. Seventy-four consecutive patients undergoing TLIF for degenerative disc disease were divided into five groups depending on whether the patient underwent a minimally invasive or open approach, as well as the number of spinal levels surgically treated. Surgery-related data, fusion results, complications, and clinical outcome were evaluated. The mean follow-up duration was 20.6 months (range 14–28 months). The radiographic fusion rate was 100% at 12 and 24 months after the surgery. No bone overgrowth or other complications related to BMP use were demonstrated. Conclusions. Analysis of the results demonstrated that TLIF combined with a BMP-2—soaked ACS is a feasible, effective, and safe method to promote lumbar fusion. There were no significant intergroup differences in clinical outcome between patients who underwent open compared with minimally invasive procedures. Patient satisfaction rates, however, were higher in the minimally invasive procedure group. The efficacy of BMP-2 was not dependent on which approach was used or the number of spinal levels that were treated.


1999 ◽  
Vol 90 (2) ◽  
pp. 224-230 ◽  
Author(s):  
Toshiyuki Takahashi ◽  
Teiji Tominaga ◽  
Noriaki Watabe ◽  
A. Toshimitu Yokobori ◽  
Hiroshi Sasada ◽  
...  

Object. The efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) for enhancing anterior cervical spine interbody fusion when added to a porous hydroxyapatite (HA) graft was investigated. Methods. Fourteen mature goats underwent three-level anterior discectomies after induction of endotracheal anesthesia. Porous HA grafts that contained 0, 5, and 50 µg of rhBMP-2 were placed concurrently with anterior cervical spine plates to achieve interbody fusion. The fusion rate, radiological findings, biomechanical stiffness, and histological appearance were evaluated in 42 spinal units immediately and again at 4 and 12 weeks after graft and plate placement. At 12 weeks postsurgery, manual testing showed a 100% fusion rate in the spines with HA grafts containing high-dose rhBMP-2; however, only a 50% fusion rate was shown in spines with grafts that contained no or low-dose rhBMP-2. On radiographic and histological studies the process of solid fusion was seen to be more advanced in relation to the use of larger amounts of rhBMP-2. Biomechanical testing demonstrated significantly higher stiffness values for grafts that contained high-dose rhBMP-2 than those without rhBMP-2 in flexion at 4 weeks, as well as in flexion, extension, and lateral bending tests at 12 weeks. Histological analysis demonstrated that rhBMP-2 increased the amount of bone apposition on the surface of the implants and promoted bone formation in the porous structure without increasing the penetration distance. Conclusions. Through osteogenesis at the fusion site, the addition of rhBMP-2 to a porous HA ceramic graft enhances the rate of anterior cervical fusion.


2002 ◽  
Vol 97 (4) ◽  
pp. 423-432 ◽  
Author(s):  
Jeffrey M. Toth ◽  
Bradley T. Estes ◽  
Mei Wang ◽  
Howard B. Seim ◽  
Jeffrey L. Scifert ◽  
...  

Object. Titanium lumbar interbody spinal fusion devices are reported to be 90% effective in cases requiring single-level lumbar interbody arthrodesis, although radiographic determination of fusion has been debated. Methods. Using blinded radiographic, biomechanical, histological, and statistical measures, researchers in the present study evaluated a radiolucent 70/30 poly(l-lactide-co-d,l-lactide) interbody fusion device packed with autograft or recombinant human bone morphogenetic protein—2 on a collagen sponge in 25 sheep at 3, 6, 12, 18, and 24 months. A trend of increased fusion stiffness, radiographic fusion, and histologically confirmed fusion was demonstrated at 3 months to 24 months postimplantation. Device degradation was associated with a mild to moderate chronic inflammatory response at all postoperative sacrifice times. Conclusions. Use of this material in interbody fusion may be a viable alternative to metals.


2005 ◽  
Vol 3 (1) ◽  
pp. 47-52 ◽  
Author(s):  
Amir Hasharoni ◽  
Yoram Zilberman ◽  
Gadi Turgeman ◽  
Gregory A. Helm ◽  
Meir Liebergall ◽  
...  

Object. The authors hypothesized that spinal fusion can be achieved and monitored by using cell-mediated gene therapy. Mesenchymal stem cells (MSCs) genetically engineered to express recombinant human bone morphogenetic protein—2 (rhBMP-2) conditionally, were implanted into the paraspinal muscles of mice to establish spinal fusion. The goal was to demonstrate an MSC-based gene therapy platform in which controlled gene expression is used to obtain spinal fusion in a murine model. Methods. Mesenchymal stem cells expressing the rhBMP-2 gene were injected into the paravertebral muscle in mice. Bone formation in the paraspinal region was longitudinally followed by performing micro—computerized tomography scanning, histological studies, and an analysis of osteocalcin expression to demonstrate the presence of engrafted engineered MSCs. The minimal period of rhBMP-2 expression by the engineered MSCs required to induce fusion was determined. The results of this study demonstrate that genetically engineered MSCs induce bone formation in areas adjacent to and touching the posterior elements of the spine. This newly formed bone fuses the spine, as demonstrated by radiological and histological studies. The authors demonstrate that injected cells induce active osteogenesis at the site of implantation for up to 4 weeks postinjection. They found that a 7-day induction of rhBMP-2 expression in genetically engineered MSCs was sufficient to form new bone tissue, although the quantity of this bone increased as longer expression periods were implemented. Conclusions. After their injection genetically engineered MSCs can efficiently form new bone in the paraspinal muscle of the mouse to obtain spinal fusion. The extent and quantity of this newly formed bone can be monitored by controlling the duration of rhBMP-2 gene expression.


2000 ◽  
Vol 92 (1) ◽  
pp. 87-92 ◽  
Author(s):  
Annette Kettler ◽  
Hans-Joachim Wilke ◽  
Rupert Dietl ◽  
Matthias Krammer ◽  
Christianto Lumenta ◽  
...  

Object. The function of interbody fusion cages is to stabilize spinal segments primarily by distracting them as well as by allowing bone ingrowth and fusion. An important condition for efficient formation of bone tissue is achieving adequate spinal stability. However, the initial stability may be reduced due to repeated movements of the spine during everyday activity. Therefore, in addition to immediate stability, stability after cyclic loading is of remarkable relevance; however, this has not yet been investigated. The object of this study was to investigate the immediate stabilizing effect of three different posterior lumbar interbody fusion cages and to clarify the effect of cyclic loading on the stabilization. Methods. Before and directly after implantation of a Zientek, Stryker, or Ray posterior lumbar interbody fusion cage, 24 lumbar spine segment specimens were each evaluated in a spine tester. Pure lateral bending, flexion—extension, and axial rotation moments (± 7.5 Nm) were applied continuously. The motion in each specimen was measured simultaneously. The specimens were then loaded cyclically (40,000 cycles, 5 Hz) with an axial compression force ranging from 200 to 1000 N. Finally, they were tested once again in the spine tester. Conclusions. In general, a decrease of movement in all loading directions was noted after insertion of the Zientek and Ray cages and an increase of movement after implantation of a Stryker cage. In all three cage groups greater stability was demonstrated in lateral bending and flexion than in extension and axial rotation. Reduced stability during cyclic loading was observed in all three cage groups; however, loss of stability was most pronounced when the Ray cage was used.


2002 ◽  
Vol 96 (1) ◽  
pp. 17-21 ◽  
Author(s):  
Crispin Wigfield ◽  
Steven Gill ◽  
Richard Nelson ◽  
Ilana Langdon ◽  
Newton Metcalf ◽  
...  

Object. The authors report the preservation of motion at surgically treated and adjacent spinal segments after placing an artificial cervical joint (ACJ) and they describe the influence of interbody fusion on changes in angulation occurring in the sagittal plane at adjacent levels in the treatment of cervical spondylosis. Methods. The authors conducted a prospective nonrandomized study of patients in whom an ACJ was placed or autologous bone graft interbody fusion was performed. Angular measurements at levels adjacent to that surgically treated were calculated using plain flexion—extension radiographs obtained at 6-month intervals. Analyses of qualitative data, such as increase or decrease in adjacent-level motion, and the degree of disc degeneration were performed. Quantitative data were also analyzed. In the fusion group a significant increase in adjacent-level movement was demonstrated at the 12-month follow-up visit compared with the group of patients in whom ACJs were placed (p < 0.001). The increase in movement occurred predominantly at intervertebral discs that were preoperatively regarded as normal (p < 0.02). An overall reduction in adjacent-level movement was observed in patients who underwent joint replacement, although this was compensated for by the movement provided by the ACJ itself. Conclusions. Fusion results in increased motion at adjacent levels. The increase in adjacent-level motion derives from those discs that appear radiologically normal prior to surgery. It remains unknown whether ACJs have a protective influence on adjacent intervertebral discs.


2003 ◽  
Vol 98 (1) ◽  
pp. 125-130 ◽  
Author(s):  
Jason P. Sheehan ◽  
Jonas M. Sheehan ◽  
Howard Seeherman ◽  
Mark Quigg ◽  
Gregory A. Helm

Object. The goal of this study was to evaluate the safety and efficacy of recombinant human bone morphogenetic protein 2 (rhBMP-2) in cranial applications. Methods. Critical-sized calvarial defects were created bilaterally in four rhesus monkeys, and bilateral rectangular bone flaps were created in six others. Control and rhBMP-2—treated sides were randomly chosen for each animal, and an absorbable collagen sponge was used to deliver the growth factor. Over a 6-month period postoperatively, the animals were serially evaluated for bone healing and adverse BMP-related consequences by using the following methods: computerized tomography (CT) scanning, magnetic resonance (MR) imaging, electroencephalography, histological investigations, and cerebrospinal fluid (CSF) analysis. The critical-sized defects for the rhBMP-2—treated and control sides attained 71 ± 12% and 28 ± 11% closure, respectively (four animals; p = 0.04). The CT scans demonstrated that the bone flaps treated with rhBMP-2 had complete osteointegration in five of six animals, whereas scans of the untreated bone flaps demonstrated uniformly poor osteointegration with the intact skull. Histological analysis confirmed well-formed bridges of bone on the rhBMP-2—treated sides. No epileptogenic activity was detected in any of the animals, and MR imaging revealed no evidence of adverse effects on the brain parenchyma. Meningitic irritation was not found on postoperative CSF sample analysis. Conclusions. Treatment of bone flaps and critical-sized cranial defects with rhBMP-2 leads to improved bone formation and osteointegration in nonhuman primates. Initial evaluation of rhBMP-2 appears to indicate a good safety profile for use in cranial procedures in primates.


2002 ◽  
Vol 96 (3) ◽  
pp. 321-332 ◽  
Author(s):  
Frank Kandziora ◽  
Georg Schollmeier ◽  
Matti Scholz ◽  
Jan Schaefer ◽  
Alexandra Scholz ◽  
...  

Object. The purpose of this study was to compare the characteristics of interbody fusion achieved using an autologous tricortical iliac crest bone graft with those of a cylinder- and a box-design cage in a sheep cervical spine model. This study was designed to determine whether there are differences between three interbody fusion procedures in: 1) ability to preserve postoperative distraction; 2) biomechanical stability; and 3) histological characteristics of intervertebral bone matrix formation. Methods. Twenty-four sheep underwent C3–4 discectomy and fusion in which the following were used: Group 1, autologous tricortical iliac crest bone graft (eight sheep); Group 2, titanium cylinder-design cage filled with autologous iliac crest bone graft (eight sheep); and Group 3, titanium box-design cage filled with autologous iliac crest graft (eight sheep). Radiography was performed pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After 12 weeks, the sheep were killed, and fusion sites were evaluated by obtaining functional radiographs in flexion and extension. Quantitative computerized tomography scans were acquired to assess bone mineral density, bone mineral content, and bone callus volume. Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral zone, and elastic zone were determined. Histomorphological and histomorphometric analyses were performed, and polychrome sequential labeling was used to determine the time frame of new bone formation. Over a 12-week period significantly higher values for disc space height and intervertebral angle were shown in cage-treated sheep than in those that received bone graft. Functional radiographic assessment revealed significantly lower residual flexion—extension movement in sheep with the cylinder cage-fixed spines than in those that received bone graft group. The cylinder—design cages showed significantly higher values for bone mineral content, bone callus content, and stiffness in axial rotation and lateral bending than the other cages or grafts. Histomorphometric evaluation and polychrome sequential labeling showed a more progressed bone matrix formation in the cylindrical cage group than in both other groups. Conclusions. Compared with the tricortical bone graft, both cages showed significantly better distractive properties. The cylindrical cage demonstrated a significantly higher biomechanical stiffness and an accelerated interbody fusion compared with the box-design cage and the tricortical bone graft. The differences in bone matrix formation within both cages were the result of the significantly lower stress shielding on the bone graft by the cylinder-design cage.


1999 ◽  
Vol 90 (1) ◽  
pp. 109-114 ◽  
Author(s):  
Tord D. Alden ◽  
Debra D. Pittman ◽  
Elisa J. Beres ◽  
Gerald R. Hankins ◽  
David F. Kallmes ◽  
...  

Object. Gene therapy has many potential applications in neurosurgery. One application involves bone morphogenetic protein-2 (BMP-2), a low-molecular-weight glycoprotein that induces bone formation in vivo. Numerous studies have demonstrated that the BMP-2 protein can enhance spinal fusion. This study was undertaken to determine whether direct injection of an adenoviral construct containing the BMP-2 gene can be used for spinal fusion. Methods. Twelve athymic nude rats were used in this study. Recombinant, replication-defective type 5 adenovirus with the cytomegalovirus (CMV) promoter and BMP-2 gene (Ad-BMP-2) was used. A second adenovirus constructed with the CMV promoter and β-galactosidase (β-gal) gene (Ad-β-gal) was used as a control. In three groups (four rats each) 7.5 µl of virus (5 × 108 particles/µl) was injected percutaneously and paraspinally at the lumbosacral junction: Group 1 received Ad-BMP-2 bilaterally; Group 2 received Ad-BMP-2 on the right, Ad-β-gal on the left; and Group 3 received Ad-β-gal bilaterally. Computerized tomography (CT) scans of the lumbosacral spine were obtained at 3, 5, 8, and 12 weeks. At 12 weeks, the animals were killed and underwent histological inspection. Ectopic bone formation was observed both on three-dimensionally reconstructed CT scans and histological examination in all rats at sites treated with Ad-BMP-2. Histological analysis demonstrated bone at different stages of maturity adjacent to the spinous processes, laminae, and transverse processes. Conclusions. Results of this study clearly demonstrated that it is possible to produce in vivo endochondral bone formation by using direct adenoviral construct injection into the paraspinal musculature, which suggests that gene therapy may be useful for spinal fusion in the future.


2005 ◽  
Vol 2 (5) ◽  
pp. 521-525 ◽  
Author(s):  
Maxwell Boakye ◽  
Praveen V. Mummaneni ◽  
Mark Garrett ◽  
Gerald Rodts ◽  
Regis Haid

Object. The authors reviewed clinical and radiographic outcomes in patients who had undergone anterior cervical discectomy and fusion (ACDF) involving the placement of polyetheretherketone (PEEK) spacers filled with recombinant human bone morphogenetic protein (rhBMP)—2. Methods. Data obtained in 24 cases were retrospectively evaluated. The follow-up period ranged from 12 to 16 months (mean 13 months). Fifteen patients presented with radiculopathy, eight with myeloradiculopathy, and one with quadriparesis. Single-level ACDF was performed in 12 patients, two-level ACDF in nine, and three-level ACDF in three. Clinical outcomes were assessed using Odom criteria, and fusion was assessed by examining flexion—extension radiographs and computerized tomography scans in cases in which arthrodesis was questionable. Follow-up data were available for 23 patients. One patient died of medical complications unrelated to surgery 4 weeks after ACDF. Clinical outcomes were rated as good/excellent in 22 patients (95%) and fair in one (5%). Solid radiographically documented fusion, with evidence of solid bridging bone and no instability on flexion—extension x-ray films, was present in all cases. Complications included transient recurrent laryngeal nerve injury in one case, transient C-5 paresis in one, cerebrospinal fluid leakage in one, and transient dysphagia in two. Conclusions. Analysis of the results indicated that ACDF involving an rhBMP-2—filled PEEK spacer leads to good clinical outcomes (by Odum criteria) and solid fusion (even in multilevel cases) while avoiding the complications associated with harvesting iliac crest bone grafts.


Sign in / Sign up

Export Citation Format

Share Document