IGF-I and TGF-1 application by a poly-(D,L-lactide)–coated cage promotes fusion in the sheep cervical spine

Abstract

Frank Kandziora, MD, N.P. Hass, Gerhard Schmidmaier, Georg Schollmeier, Herman Bail, Robert Pflugmacher, MD, Thomas Gorke, Martin Wagner, Thomas Mittlmeier, PhD, Michael Raschke, Berlin, GermanyStudy design: Growth factors such as bone morphogenetic protein (BMP)-2 have proven to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum growth factor to promote spinal fusion, as well as the optimum method to deliver such growth factors, is still a matter of discussion. A sheep cervical spine interbody fusion model was used to determine the effect of IGF-I and TGF-1 application by a biodegradable poly-(D,L-lactide) (PDLLA)–coated cage. The purpose of this study was to determine the safety and efficacy of a new PDLLA carrier system and to evaluate the safety and efficacy of combined IGF-I and TGF-1 application in a sheep cervical spine model.Methods: Thirty-two sheep underwent C3–4 discectomy and fusion: Group 1: autologous tricortical iliac crest bone graft (n=8); Group 2: titanium cage (n=8); Group 3: titanium cage coated with a PDLLA carrier (n=8); Group 4: titanium cage coated with a PDLLA carrier including IGF-I (5% w/w) and TGF-1 (1% w/w) (n=8). Blood samples, body weight and temperature were analyzed. Radiographic scans were performed pre- and postoperatively and after 1, 2, 4, 8 and 12 weeks, respectively. At the same time points, disc space height, intervertebral angle and lordosis angle were measured. After 12 weeks, animals were killed and fusion sites were evaluated using functional radiographic views in flexion and extension. Quantitative computed tomographic scans were performed to assess bone mineral density, bone mineral content and bony callus volume. Biomechanical testing was performed in flexion, extension, axial rotation and lateral bending. Stiffness, ranges of motion, neutral and elastic zone were determined. Histomorphological and histomorphometrical analysis was performed, and polychrome sequential labeling was used to determine the time frame of new bone formation.Results: There were no differences between the groups concerning blood counts, body weight and temperature. Over a 12-week period, the cage Groups 2, 3 and 4 showed significantly higher values for intervertebral angle compared with the bone graft. Functional radiographic assessment revealed significantly lower residual flexion/extension movement in Group 4 than in any other group. The PDLLA-coated cages with IGF-I and TGF-1 showed significantly highest values for bone mineral density, bone mineral content and bony callus volume. Average stiffness in rotation and bending was significantly higher, and range of motion, neutral and elastic zone in rotation were significantly lower in Group 4 than in any other group. Histomorphometrical evaluation showed a more progressed bone matrix formation in PDLLA-coated cages with IGF-I and TGF-1 than in any other group. Polychrome sequential labeling showed accelerated intervertebral fusion in Group 4.Conclusion: PDLLA coating of cervical spine interbody fusion cages as a delivery system for growth factors was effective and safe. The PDLLA coating showed no adverse effects. IGF-I and TGF-1 application by a PDLLA-coated interbody cage significantly increased results of interbody fusion in a sheep cervical spine model without adverse side effects. In this new combination (implant plus PDLLA plus growth factors) the cage represents a “real fusion” cage, because it does not only serve as a mechanical device for spine fixation but also as a local drug delivery system.