| Distraction Osteogenesis(DO), which is a process of new bone formation between the surfaces of bone segments gradually separated by incremental traction, has become a widely accepted method of resolving clinical problems such as bone deformities and defects in craniofacial area. However, the rather long period of bone consolidation time and inferior alveolar nerve (IAN) injury are two concerns in mandibular DO. Nerve growth factor (NGF) is an important growth factor involved in recovery of neurological injuries. On the other hand, NGF is also involved in normal bone metabolism and can enhance bone repair. Our reseach group has found in prior studies that locally applied NGF in distraction gap can enhance bone regeneration and recovery of IAN injury simultaneously in a rabbit model of mandibular DO. Since NGF will be inactivated very soon after being injected directly, the application of delay reslease system is very necessary and can maintain the activity of NGF for a long time, promote the effects, safety and compliance. In situ-forming hydrogels are injectable liquid polymers endowed with an ability to swell in water and induce a liquid–gel transition, which is thus suitable for delayed action preparations. Collagen/nano-Hydroxyapatite(Col/nHA), a new material made by Tsinghua University, has excellent features of natural bone composition and microstructure and can been used in bone defects restoration or drug and growth factors delayed action preparations. The compound of alginate hydrogels and Col/nHA can diminish the swell of hydrogels and promote the delay release effects, and Col/nHA can enhance the new bone formation as the tiny mineralization centers. In addition, on the basis of our prior studies, we deduced that NGF may enhance the new bone formation by inducing peripheral nerve fibers into bone tissues. Therefore we speculate that the sensory nerve fibers play an important role in DO. Consequently, the main aim of this study was to fabricate a novel injectable alginate/Col/nHA hydrogel system with the ability of controlled release of hNGFβand apply it to mandibular DO. Effects of IAN resection on mandibular DO were also studied. Three parts were included in this study:1 Fabrication of a novel injectable alginate/Col/nHA hydrogel system for controlled release of hNGFβObjective: To prepare hNGFβdelay released injectable alginate hydrogels compounded with Col/nHA system and determine its biocompatibility and delay release properties. Methods: Blend the alginate powder and 1% Col/nHA with 0.1mg/ml hNGFβ0.9% normal saline solution, put them standing in 37℃environment after fully ultrasound vibration. The setting time and hNGFβsustaining release were evaluated in vitro, and the degradation was studied in vivo. Results: The initial setting time is 5 min, and the final setting time is 10 min. Release pattern of hNGFβfrom this hydrogels indicated that 40% hNGFβwas released in 48 hours, and 80% hNGFβwas released in 8 days. The release curve levelled off after 72 hours. Hydrogels buried in rabbit muscle degraded after 4 weeks without apparent inflammation. Conclusion: The thermosensitive injective hNGFβdelay released hydrogels system has not only an appropriate setting and injection property, but also a good delay release effect and biocompatibility. It can be used as a good carrier material for hNGFβsustaining release.2 Effects of local injection of hNGFβdelay released hydrogels to mandibular DOObjective: To evaluate the effects of local injection of hNGFβdelay released hydrogels to new bone and IAN function in the rabbit model of mandibular DO. Methods: 16 rabbits underwent bilateral distraction at rates of 0.5 or 1.0 mm/12h. On the 1st day of consolidation, the hydrogels with hNGFβ(20μg) was injected into callus percutaneously. The contralateral side received injections of placebo. At consolidation time of 14d and 28d, regenerate bone specimens were subjected to lateral X-rays examination and histomorphometric analysis including bone volume/total volume (BV/TV) and thickness of new trabeculae(TNT). A simplified sensory nerve test was used for evaluation of IAN function. A paired t test was used for statistical analysis. Results: There was no direct IAN injury caused by the surgery. IAN function of 1.0 mm/12h rate group was elevated at the hydrogels treated side. Hydrogels treated side of 13 rabbits had a higher callus density in X-ray examination than control side on consolidation 14d and 28d. Histomorphometric analysis showed that hydrogels treated side had a significantly increased BV/TV and TNT(P<0.05). Conclusion: Local injection of this hydrogels composite can accelerate callus maturation and IAN injury recovery in the rabbit model of mandibular DO.3 Effects of inferior alveolar nerve resection to rabbit mandibular DO Objectives: To investigate the effects of inferior alveolar nerve resection to new bone formation in rabbit mandibular distraction osteogenesis. Methods: 20 New Zealand White rabbits underwent bilateral distraction osteogenesis with a rate of 1mm/day. The inferior alveolar nerve of one side was resected under the surgical microscope, with great care of protecting the inferior alveolar vessel bundle. The contralateral side received sham operations. The rabbits were sacrificed at consolidation time of 14 and 28 days. The regenerate callus underwent HE staining, histomorphometric analysis and three points bending test. A paired t test was performed using SPSS 12.0 software package. Results: The histological investigation showed that the bone trabeculae were disarrayed containing dispersed cartilage cells in the denervated side, whereas the bone trabeculae were orderly with rich blood vessels and no cartilage cell in the control side. Both new bone volume (NBV) and the thickness of new trabeculae (TNT) were significantly lower in the denervated side than in the control side (P <0.05). Three-point bending test showed that the bending strength on the denervated side were 40.1% and 26.8% lower than the contralateral side at the end of consolidation 14d and 28d selectively(P<0.05). Conclusion: The peripheral nerve plays an important role during the new bone formation in the distraction osteogenesis. |
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