IGF-I and TGF-beta1 application by a poly-(D,L-lactide)-coated cage promotes intervertebral bone matrix formation in the sheep cervical spine.
METHODS
A sheep cervical spine interbody fusion model was used to determine the effect of combined insulin-like growth factor-I (IGF-I) and transforming growth factor-beta-1 (TGF-beta1) applied by a poly-(D,L-lactide) (PDLLA)-coated cage.


OBJECTIVE
The purpose of this study was to determine the effect of a new PDLLA carrier system, and to evaluate the effect of combined IGF-I and TGF-beta1 application in a sheep cervical spine model.


BACKGROUND
Growth factors such as bone morphogenic protein-2 have been shown to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum growth factor for promoting spinal fusion and the optimum method for delivering such growth factors are still a matter of discussion.


METHODS
In this study, 32 sheep underwent C3-C4 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), and Group 4 (titanium cage coated with a PDLLA carrier including IGF-I [5% w/w] and TGF-beta1 [1% w/w; n = 8). Blood samples, body weight, and body temperature were analyzed. Radiographic scans were performed before and after surgery, then at 1, 2, 4, 8, and 12 weeks, respectively. At the same time points, the disc space height, intervertebral angle, and lordosis angle were measured. After 12 weeks, the animals were killed, and fusion sites were evaluated using functional radiographic views of the animals in flexion and extension. Quantitative computed tomographic scans were performed to assess bone mineral density, bone mineral content, and bony callus volume. Biomechanical testing of the motion segment C3-C4 was performed in flexion, extension, axial rotation, and lateral bending. The stiffness, range of motion, neutral zone, and elastic zone were determined. Histomorphologic and histomorphometric 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 in terms of blood counts, body weight, and temperature. Over a 12-week period, cage Groups 2 to 4 showed significantly higher values for the intervertebral angle than for the bone graft. Functional radiographic assessment showed significantly lower residual flexion-extension movement in Group 4 than in any other group. The PDLLA-coated cages with IGF-I and TGF-beta1 showed significantly higher values for bone mineral density, bone mineral content, and bony callus volume. The average stiffness in rotation and bending was significantly higher, and the range of motion, neutral zone, and elastic zone in rotation were significantly lower in Group 4 than in any other group. Although only one animal in Group 4 demonstrated solid bony fusion after 12 weeks, histomorphometric evaluation showed a more progressed bone matrix formation in the group that had PDLLA-coated cages with IGF-I and TGF-beta1 than in any other group. Polychrome sequential labeling showed accelerated intervertebral bone matrix formation in Group 4.


CONCLUSIONS
The findings showed that PDLLA coating of cervical spine interbody fusion cages as a delivery system for growth factors was effective. Although IGF-I and TGF-beta1 application by a PDLLA-coated interbody cage was not able to achieve solid bony fusion during the 12-week follow-up period, these growth factors significantly increased the results of interbody bone matrix formation. Additional longer-term studies are required to determine whether combined IGF-I and TGF-beta1 application leads to a successful spinal fusion.
Unfall und Wiederherstellungschirurgie, Universitätsklinikum Charité der Humboldt, Universität Berlin Campus Virchow, Klinikum, Berlin, Germany.
Frank
F
Kandziora
Gerhard
G
Schmidmaier
Georg
G
Schollmeier
Herman
H
Bail
Robert
R
Pflugmacher
Thomas
T
Görke
Martin
M
Wagner
Michael
M
Raschke
Thomas
T
Mittlmeier
Norber P
NP
Haas
D020341:Absorbable Implants; D000818:Animals; D001672:Biocompatible Materials; D001831:Body Temperature; D001835:Body Weight; D001857:Bone Matrix / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology; D002574:Cervical Vertebrae / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology / Q000601:surgery; D004337:Drug Carriers; D004359:Drug Therapy, Combination; D005260:Female; D006406:Hematoma; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D023421:Models, Animal; D009333:Neck; D011091:Polyesters / Q000008:administration & dosage*; D015203:Reproducibility of Results; D012756:Sheep; D013123:Spinal Fusion / Q000009:adverse effects / Q000295:instrumentation*; D013131:Spine / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology / Q000601:surgery*; D014057:Tomography, X-Ray Computed; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*; D053773:Transforming Growth Factor beta1; D016896:Treatment Outcome
D001672:Biocompatible Materials; D004337:Drug Carriers; D011091:Polyesters; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C033616:poly(lactide); D007334:Insulin-Like Growth Factor I