镁合金膜引导骨再生修复重度萎缩下颌牙槽骨的实验研究
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摘要
种植义齿作为现在广泛应用的口腔修复治疗方法,因为具有良好的美观效果、咀嚼效能和舒适度,无基牙损伤,及对牙槽骨的保存作用,已逐渐成为医生和患者的首选治疗方案。但由于种植义齿严格的适应症,要求患者有足够的骨质及骨量,使相当一部分缺牙患者无法选择综合评价最好的修复方法。例如糖尿病、骨质疏松、牙槽骨严重吸收的患者。为了解决这部分患者的需求,口腔工作者们致力于扩展种植义齿的适应症,从而提高修复治疗效果并进一步提高患者生活水平。
牙槽骨严重吸收的患者,由于长时间缺牙未修复,局部牙槽骨失去生理刺激,在宽度和高度上会出现进行性的吸收,导致严重骨缺损,使种植修复难以实施。针对这种情况,骨增量是切实可行的解决办法。目前可实现牙槽骨垂直增量的方法主要有骨移植、自体牙材料移植、骨牵引。自体骨移植因为骨供区的损伤,术后并发症多等问题应用受到限制；自体牙移植的材料来源为自体可拔除的健康牙体组织,不仅可选择的病例少,材料数量也很有限,临床难以推广；骨牵引技术要求高,治疗时间长且期间患者有明显不适感,同时也易发感染等并发症；人工骨移植材料来源丰富,且具有良好生物相容性和骨传导性,无上述并发症,配合引导骨再生膜应用可得到良好的修复效果。应用人工骨进行骨增量在上颌牙槽骨和下颌牙槽骨实现的难度有显著不同,由于上颌骨体部内有上颌窦,可以上颌窦底部骨板为依托,通过上颌窦提升术达到垂直骨增量的目的,但在下颌骨,牙槽骨的垂直骨增量则存在如下难点：(1)修复材料的塑形；(2)骨再生空间的建立和维持；(3)血液供应。所以本研究以引导骨再生膜为切入点,配合组织工程骨进行设计创新,以期解决上述难点。
在理想的引导骨再生膜的探索中,可总结出其应符合如下条件：具备良好的生物安全性和生物可降解性,且具有适应的降解速度,良好的机械性能可建立并维持骨再生空间。镁合金是一种可降解的金属,具有金属的力学性能,同时具备生物可吸收性,这就使它有望成为最适宜的引导骨再生膜材料。故本研究将镁合金引入引导骨再生膜的行列,并联合组织工程骨、PRP凝胶作为修复材料,以镁合金引导骨再生膜为内部修复材料解决塑形问题,并建立和维持骨再生空间,以PRP凝胶的促血管生成作用结合周围接触骨面血来源,从内外共同解决血液供应问题,探讨此修复方法对严重吸收下颌牙槽骨的垂直增量效果。
镁合金作为可降解的金属,又因为其物理性质接近骨皮质,成为骨相关研究方向的热点。同时,镁合金在体内降解后,产物主要为MgCO3,Mg(OH)2,CaCO3,呈碱性,与细菌形成口腔主要致病源—菌斑的常规环境相反,是否可达到抑菌作用,成为新研究方向的思考。细菌在口腔内通过局部附着、聚集、增殖,引起局部炎症或者产酸破坏口腔软硬组织。其中,与修复及种植植入体密切相关的为引起种植体周围炎的主要致病菌。镁合金在口腔内持续降解的过程中,释放的碱性产物,会对种植体周围炎致病菌有何影响,局部生物相容性如何,以及对全身的影响,都是镁合金在口腔内应用的关键问题。实验第二部分通过对这些问题的探讨,为镁合金口腔内应用进行初步探索,并为新的研究方向奠定基础。
降解性和力学性能是镁合金的两个重要性质,其降解速度直接关系到降解产物的浓度、体内用量的评估等,也直接影响力学指标的变化,是体内应用的一个重要参数。尤其是应用于引导骨再生膜时,镁合金的用量需在成骨期的降解中,能够经受一定外力维持结构完整,达到维持骨再生空间的目的。口颌面部是一个血运十分丰富的环境,且牙槽骨受到复杂的咬合力。镁合金在此处的降解速度可能与长骨环境中有差别,其在降解过程中,力学参数的改变是否会使它在咬合力的作用下失去结构完整性,将在实验第三部分中给予评价。
第一部分镁合金膜引导骨再生修复重度萎缩下颌牙槽骨的成骨评价
目的：探讨镁合金作为引导骨再生膜,联合组织工程骨垂直增量修复严重吸收下颌牙槽骨的成骨效果。
方法：
1、首先模拟临床,建立犬下颌牙槽骨严重吸收骨缺损模型。
2、通过全骨髓培养法获得骨髓间充质干细胞,进行分化鉴定、培养扩增、矿化诱导10天后与nHA/PLA支架共培养,构建体外三维培养组织工程骨。
3、依据牙槽骨缺损形态设计AZ31BB镁合金GBR膜形态,并通过有限元分析优化。
4、通过不同离心速度设置探讨二次离心法制备PRP的具体方法。
5、动物手术：组织工程骨于术前复合PRP凝胶,实验组联合AZ31BB镁合金GBR膜共同植入骨缺损区,阳性对照组联合钛合金GBR膜,无引导骨再生膜nHA/PLA+PRP为空白对照组。
6、术后分1-10天、10-20天、20-30天三组,分别于每组收尾两天行四环素、钙黄绿素双荧光标记,激光共聚焦显微镜下观察,计算成骨速度。
7、术后4W、8W、12W取材,行影像学、组织学观察,评价成骨。
结果：
1、成功建立犬下颌牙槽骨吸收骨缺损模型,骨缺损形态及骨生理状态贴近临床,缺损区被覆软组织正常,缩短常规建模时间。
2、从骨髓中分离培养,获得骨髓间充质干细胞,并通过分化鉴定,细胞经矿化诱导后成功构建体外三维培养的组织工程骨。
3. AZ31BB镁合金GBR膜外形符合骨缺损形态,固位钉中心至膜中心2.4mm组具有最优抗力形,在最大500N咬合力加载下,仍可维持结构完整性。
4、固定离心机情况下,14ml全血2200r/min离心,弃上清,约6m1余液2400r/min二次离心,制备PRP所得血小板浓度810×109/L,为原血液5-8倍,为有效浓度。
5、镁合金组初期成骨速度显著高于钛合金对照组和空白对照组,阳性对照组与空白对照组间差异无统计意义。
6、镁合金组与钛合金组比较,骨密度、骨小梁体积分析差异无统计学意义,镁合金材料周围成骨活跃,但镁合金组由于降解产气,使成骨体积少于钛合金组,且表面高度不规则。
第二部分ZA31B镁合金口内应用对口腔环境的影响及生物安全性评价
目的：探讨ZA31镁合金口腔内应用对局部环境及全身安全性的影响。方法：
1、于修复材料植入术前、取材术前,用精密PH试纸检测材料植入局部唾液PH值,进行对比分析。
2、于修复材料植入术前、取材术前,取犬下颌第一磨牙近中颊尖龈上、龈下菌斑,提取基因组DNA,测量DNA浓度,初步评价细菌总量；合成引物,以β-actin为内参,通过Q-PCR进行细菌相对定量检测,评价镁合金对细菌数量的影响。
3、于修复材料植入术前、取材术前,取4ml静脉血,检测血生化指标,比较材料植入前后数值变化。
4、修复材料植入后,每天观察软组织愈合情况。取材后,取镁合金被覆软组织,制作组织学切片,亚甲基蓝染色,镜下观察。
5、取材时,取心、肝、脾、肺、肾组织,制作组织学切片,HE染色,镜下观察。
结果：
1、材料植入局部术前、术后唾液PH值略有变化,但差异无统计学意义。
2、由DNA浓度可见,镁合金植入后与植入前相比,总菌量显著下降,差异具有统计学意义。Q-PCR结果显示,各个菌种数量在术后均有所下降,差异均具有统计学意义,其中Pg、Pi数量减少显著,可达100倍以上。菌斑中的细菌组成因各个菌数量变化的差异出现改变。
3、血生化指标显示,术前、术后差异无统计学意义,且均在正常值范围内。
4、术后7天,口内观有4例黏膜组织因感染未愈合,局部有红肿表现,其余犬软组织愈合情况良好,未观察到炎症反应。正常愈合组软组织切片镜下观,上皮层、固有层细胞排列正常,未观察到炎症反应。
5、心、肝、脾、肺、肾组织切片镜下观察结果显示,主要脏器的主要结构清晰,无损伤、无病变,未见异常。
第三部分AZ31B镁合金口内应用时降解对力学性能的影响
目的：评价AZ31B镁合金在口腔内应用的降解速率,并测量分析降解程度对力学性能的影响。
方法：
1、AZ31B镁合金引导骨再生膜、固定钉电子天平称重。
2、将矿化诱导2代的骨髓间充质干细胞与nHA/PLA共培养,复合PRP凝胶后,联合AZ31B镁合金引导骨再生膜植入骨缺损区,术后4W、8W、12W取材,取出镁合金材料,清理后充分风干,称重后与术前空白对照组对比分析。
3、扫描电镜下观察AZ31B镁合金材料降解表面形貌,描述其在口腔内植入后降解行为。
4、对降解前后AZ31B镁合金材料表面进行能谱分析,探讨体内降解对表面成分的影响。
5、用牙托粉制作模具,固定AZ31B镁合金材料,用力学加载仪测量最大加载力,分析不同降解组力的变化。
结果：
1、AZ31B镁合金呈层状剥脱式降解。
2、AZ31B镁合金植入体内4W降解1.42%,8W降解4.27%,12W降解11.37%。
3、降解后,镁合金表面组分变化明显,差异具有统计学意义,其中Ca、P、K元素变化最显著。
3、随着降解程度的增加,力学性能成比例下降,但12W组仍可承受最大咬合力。
As a widely used restoration method, dental implant has many advantages including:satisfactory masticatory function; excellent aesthetics; optimal comfort; alveolar bone protection and avoiding abutment tooth injury. However, many patients cannot take those advantages by receiving implant therapy because of its strict indications, such as adequate bone mass and acceptable bone morphology. On this issue, dentists have endeavored to extend the application of implant, for instance, in improving implant survival rate of patients with osteoporosis or diabetes.
Patients with severely absorbed alveolar bone usually suffer from severe bone defect because of lack of physiological stimulation followed by progressive bone absorption. In this situation, bone augmentation is an effective way. Several methods for alveolar bone vertical augmentation exist including bone grafting, autogenous dentin material transplantation, and distraction osteogenesis. However, bone grafting faces the donor site morbidity. Autogenous dentin material transplantation requires extractable healthy teeth as repairing materials thus its application is limited. Distraction osteogenesis requires a longer treat period and increases the discomfortableness and the risk of infection. Bone graft material is widely available and has good biocompatibility and osteoconductive, which promise a better result in bone repairing.unlike maxillary which can gain more bone height by maxillary sinus lifting, vertical bone augmentation in severely absorbed mandible is more difficult to achieve. The key issues are the following:(1)shaping and retention of repairing material;(2) The establishment and maintenance of the bone regeneration space;(3) Blood supply.
The ideal GBR membrane should have favorable biosafety and bio-degradability; adaptive degradation rate and adequate mechanical property for establishment and maintenance of the bone regeneration space. Magnesium alloy, as biodegradable metal with both the mechanical property and the bio-degradability, is expected to be an optimal choice for GBR membrane. In this research we introduce magnesium alloy into to the GBR membranes combining with tissue engineered bone as the novel method in restoration. In addition, we add platelet-rich-plasma (PRP) as the osteogenetic factor which can promote angiogenesis in the prosthesis and therefore, resolve the blood supply problem both internally and externally.
As the degradable metal, magnesium alloy's physical property is close to cortical bone. Meanwhile the degradation products are alkaline MgCO3, Mg(OH)2and CaCO3. The alkaline environment is in contrast to the regular bacterial plaque environment and possibly provides the bacteriostatic factors. Intraoral bacteria can incite local inflammation or undermine the hard tissue by attachment, aggregation and proliferation. The main issue is the pathogens cause peri-implantitis. During the degradation process of magnesium alloy, the alkaline products will have effect on the pathogens. Some other issues including local biocompatibility and general influence of magnesium alloy. The second part of this research will focus on these issues and makes a tentative research on intraoral applications of magnesium alloy.
The main properties of magnesium alloy are degradation and mechanical property. The degradation rate is directly related to the concentration of the degradation products and dosage evaluation. When introduce magnesium alloy to the GBR membranes, the dosage should maintain the integral structure in order to resist the external force during Osteogenesis period. Because of the favorable blood supply and complex biting force in oral maxillofacial area, the degradation rate in this environment may differ from that in long bones. During the degradation, the influence of changing mechanics parameters in the structural integrity under biting force will be discussed in the third part of this research.
Part Ⅰ
The evaluation on osteogenetic effect of magnesium alloy membrane in severely absorbed mandibular alveolar bone
Objective:to investigate the osteogenesis effects of magnesium alloy as GBR membrane combined tissue engineered bone in vertical augmentation of severely absorbed alveolar bone。
Methord:
1、Establish the severely absorbed canine alveolar bone defect animal model to simulate the clinical cases.
2、To obtain the BMSCs through whole bone marrow culture. After differentiation and identification, culture and amplification, induced mineralization for10days, the BMSCs are cultured together with nHA/PLA graft to establish tissue engineered bone.
3、Design the shape of AZ31B magnesium alloy GBR membrane based on alveolar defect morphology.
4、To investigate the specific method of twice centrifugation to prepare PRP through adjust the centrifugal speed.
5、Animal surgeries:experimental group:AZ31Bmagnesium alloy GBR membrane+PRP gel+tissue engineered bone; control group:titanium alloy GBR membrane+PRP gel+tissue engineered bone; blank group:tissue engineered bone+PRP.
6、Fluorescence label the calcium deposition10days,20days and30days after the operation. Calculate the osteoporosis rate under the laser scanning confocal microscope
7、Harvest after4,8and12weeks and evaluate the osteogenesis effects through Radiological and histological observation
Result:
1、We successfully establish the severely absorbed canine alveolar bone defect animal model. The morphology and physiological status approximate clinical situations.
2、The BMSCs are obtained after induced mineralization to manifact the tissue engineered bone.
3、The shape of AZ31B magnesium alloy GBR membrane is coincidence with that of the bone defect. When the distance from the centre of screw to the centre of the membrane is2.4mm, the resistance reached the maximum, which can maintain the whole structure under500N's biting force.
4、To centrifugate14ml whole blood in speed of2200r/min. To decant the supernatant. The remaining liquid is conducted to the second centrifugation. The concentration of PRP received is810×109/L,(6times of that of original whole blood),which meet the criterion of5-8times.
5、In early stage, the osteogenesis rate in magnesium alloy group is significantly higher than other two groups. No statistical difference founded between the positive control and the blank group.
6、No statistical difference in bone density or Trabecular bone volume is founded between titanium alloy group and the magnesium alloy group. Although the osteogenesis is more active around the magnesium alloy, but the volume of new formed bone is less than that in titanium alloy group and exhibit highly irregular charistic because of the gas generated during magnesium degradation.
Part2the effect of the application of AZ31B magnesium alloy on the oral environment and evaluation of its biological safety
Objective:To investigate the effect of the application of AZ31B magnesium alloy on local environment and the safety throughout the body.
Methods:
1、Test and analysis the PH value of saliva with short range PH paper both before implantation and harvest procedure.
2.To collect the supragingival and subgingival dental plaque of the first mandible molar in canine. Extract the genomic DNA, measure the DNA concentration, estimate the amounts of bacteria. To evaluate the impact of magnesium alloy on the amount of bacteria
3、Draw venous blood4ml both before implantation and harvest procedure. Evaluate the changes in blood biochemical indexes.
4、Observe the Healing characteristics of soft tissues after implantation. The soft tissues adhered to magnesium alloy are observed by using tissue sectioning under microscope.
5、The tissues of heart, liver, spleen, lung and kidney are also observed using tissue sectioning (HE staining) under microscope.
Result:
1、The PH value of saliva with short range PH paper has a slightly change before and after implantation. However the difference is not statistically significant.
2、The result of Q-PCR shows that the amounts in all sorts of bacteria are lower after the procedure. The differences were all statistically significant, especially Pg and Fn, the amount of which reduced more than100times.
3、No statistical difference in blood biochemical indexes was founded before and after the procedure, and both are within the normal range.
4、Mucous failed to heal in4cases7days after the procedure because of infection and presents local swelling. All other tissues healed well without inflammatory reaction. Normal cell arrangement is observed in both epithelial layer and固有层under microscope without inflammatory reaction.
5、No damage, lesion or other abnormal founded in heart, liver, spleen, lung and kidney according to the results of tissue sectioning Part Ⅲ Effect of AZ31B magnesium alloy intraoral degradation on its mechanical property
Objective:To investigate the intraoral degradation rate of the AZ31B magnesium alloy and analyze the effect of degradation level on its mechanical property.
Methods:
1、To weigh the AZ31B magnesium alloy GBR membrane and the screws with the electronic balance.
2、The methods of preparation, implantation and harvest see part Ⅰ. The magnesium alloy materials harvested are weighed after cleaning and air-drying and analyzed compared with the blank control group.
3、To observe the surface degradation morphology of the AZ31B magnesium alloy material and to describe the detail of its intraoral degradation.
4、To conduct the energy spectrum analysis on the surface of AZ31B magnesium alloy and to investigate the effects of intraoral degradation on the surface substances.
5、To manufacture the mould with denture acrylic for AZ31B magnesium alloy material fixation and to measure the maximum loading force.
Result:
1、The degradation process of AZ31B magnesium alloy are proved to be lamellar and exfoliative.
2、The degradation rate of AZ31B magnesium alloy are1.42%in4weeks,4.27%in8weeks,11.37%in12weeks postoperatively
3、The surfacing substances of the magnesium alloy are significantly changed, especially the amount of Calcium phosphorus and kalium
4、The mechanism property of magnesium alloy descends during degradation, yet the maximum biting force can still be withstand12weeks after implantation.
牙槽骨严重吸收的患者,由于长时间缺牙未修复,局部牙槽骨失去生理刺激,在宽度和高度上会出现进行性的吸收,导致严重骨缺损,使种植修复难以实施。针对这种情况,骨增量是切实可行的解决办法。目前可实现牙槽骨垂直增量的方法主要有骨移植、自体牙材料移植、骨牵引。自体骨移植因为骨供区的损伤,术后并发症多等问题应用受到限制；自体牙移植的材料来源为自体可拔除的健康牙体组织,不仅可选择的病例少,材料数量也很有限,临床难以推广；骨牵引技术要求高,治疗时间长且期间患者有明显不适感,同时也易发感染等并发症；人工骨移植材料来源丰富,且具有良好生物相容性和骨传导性,无上述并发症,配合引导骨再生膜应用可得到良好的修复效果。应用人工骨进行骨增量在上颌牙槽骨和下颌牙槽骨实现的难度有显著不同,由于上颌骨体部内有上颌窦,可以上颌窦底部骨板为依托,通过上颌窦提升术达到垂直骨增量的目的,但在下颌骨,牙槽骨的垂直骨增量则存在如下难点：(1)修复材料的塑形；(2)骨再生空间的建立和维持；(3)血液供应。所以本研究以引导骨再生膜为切入点,配合组织工程骨进行设计创新,以期解决上述难点。
在理想的引导骨再生膜的探索中,可总结出其应符合如下条件：具备良好的生物安全性和生物可降解性,且具有适应的降解速度,良好的机械性能可建立并维持骨再生空间。镁合金是一种可降解的金属,具有金属的力学性能,同时具备生物可吸收性,这就使它有望成为最适宜的引导骨再生膜材料。故本研究将镁合金引入引导骨再生膜的行列,并联合组织工程骨、PRP凝胶作为修复材料,以镁合金引导骨再生膜为内部修复材料解决塑形问题,并建立和维持骨再生空间,以PRP凝胶的促血管生成作用结合周围接触骨面血来源,从内外共同解决血液供应问题,探讨此修复方法对严重吸收下颌牙槽骨的垂直增量效果。
镁合金作为可降解的金属,又因为其物理性质接近骨皮质,成为骨相关研究方向的热点。同时,镁合金在体内降解后,产物主要为MgCO3,Mg(OH)2,CaCO3,呈碱性,与细菌形成口腔主要致病源—菌斑的常规环境相反,是否可达到抑菌作用,成为新研究方向的思考。细菌在口腔内通过局部附着、聚集、增殖,引起局部炎症或者产酸破坏口腔软硬组织。其中,与修复及种植植入体密切相关的为引起种植体周围炎的主要致病菌。镁合金在口腔内持续降解的过程中,释放的碱性产物,会对种植体周围炎致病菌有何影响,局部生物相容性如何,以及对全身的影响,都是镁合金在口腔内应用的关键问题。实验第二部分通过对这些问题的探讨,为镁合金口腔内应用进行初步探索,并为新的研究方向奠定基础。
降解性和力学性能是镁合金的两个重要性质,其降解速度直接关系到降解产物的浓度、体内用量的评估等,也直接影响力学指标的变化,是体内应用的一个重要参数。尤其是应用于引导骨再生膜时,镁合金的用量需在成骨期的降解中,能够经受一定外力维持结构完整,达到维持骨再生空间的目的。口颌面部是一个血运十分丰富的环境,且牙槽骨受到复杂的咬合力。镁合金在此处的降解速度可能与长骨环境中有差别,其在降解过程中,力学参数的改变是否会使它在咬合力的作用下失去结构完整性,将在实验第三部分中给予评价。
第一部分镁合金膜引导骨再生修复重度萎缩下颌牙槽骨的成骨评价
目的：探讨镁合金作为引导骨再生膜,联合组织工程骨垂直增量修复严重吸收下颌牙槽骨的成骨效果。
方法：
1、首先模拟临床,建立犬下颌牙槽骨严重吸收骨缺损模型。
2、通过全骨髓培养法获得骨髓间充质干细胞,进行分化鉴定、培养扩增、矿化诱导10天后与nHA/PLA支架共培养,构建体外三维培养组织工程骨。
3、依据牙槽骨缺损形态设计AZ31BB镁合金GBR膜形态,并通过有限元分析优化。
4、通过不同离心速度设置探讨二次离心法制备PRP的具体方法。
5、动物手术：组织工程骨于术前复合PRP凝胶,实验组联合AZ31BB镁合金GBR膜共同植入骨缺损区,阳性对照组联合钛合金GBR膜,无引导骨再生膜nHA/PLA+PRP为空白对照组。
6、术后分1-10天、10-20天、20-30天三组,分别于每组收尾两天行四环素、钙黄绿素双荧光标记,激光共聚焦显微镜下观察,计算成骨速度。
7、术后4W、8W、12W取材,行影像学、组织学观察,评价成骨。
结果：
1、成功建立犬下颌牙槽骨吸收骨缺损模型,骨缺损形态及骨生理状态贴近临床,缺损区被覆软组织正常,缩短常规建模时间。
2、从骨髓中分离培养,获得骨髓间充质干细胞,并通过分化鉴定,细胞经矿化诱导后成功构建体外三维培养的组织工程骨。
3. AZ31BB镁合金GBR膜外形符合骨缺损形态,固位钉中心至膜中心2.4mm组具有最优抗力形,在最大500N咬合力加载下,仍可维持结构完整性。
4、固定离心机情况下,14ml全血2200r/min离心,弃上清,约6m1余液2400r/min二次离心,制备PRP所得血小板浓度810×109/L,为原血液5-8倍,为有效浓度。
5、镁合金组初期成骨速度显著高于钛合金对照组和空白对照组,阳性对照组与空白对照组间差异无统计意义。
6、镁合金组与钛合金组比较,骨密度、骨小梁体积分析差异无统计学意义,镁合金材料周围成骨活跃,但镁合金组由于降解产气,使成骨体积少于钛合金组,且表面高度不规则。
第二部分ZA31B镁合金口内应用对口腔环境的影响及生物安全性评价
目的：探讨ZA31镁合金口腔内应用对局部环境及全身安全性的影响。方法：
1、于修复材料植入术前、取材术前,用精密PH试纸检测材料植入局部唾液PH值,进行对比分析。
2、于修复材料植入术前、取材术前,取犬下颌第一磨牙近中颊尖龈上、龈下菌斑,提取基因组DNA,测量DNA浓度,初步评价细菌总量；合成引物,以β-actin为内参,通过Q-PCR进行细菌相对定量检测,评价镁合金对细菌数量的影响。
3、于修复材料植入术前、取材术前,取4ml静脉血,检测血生化指标,比较材料植入前后数值变化。
4、修复材料植入后,每天观察软组织愈合情况。取材后,取镁合金被覆软组织,制作组织学切片,亚甲基蓝染色,镜下观察。
5、取材时,取心、肝、脾、肺、肾组织,制作组织学切片,HE染色,镜下观察。
结果：
1、材料植入局部术前、术后唾液PH值略有变化,但差异无统计学意义。
2、由DNA浓度可见,镁合金植入后与植入前相比,总菌量显著下降,差异具有统计学意义。Q-PCR结果显示,各个菌种数量在术后均有所下降,差异均具有统计学意义,其中Pg、Pi数量减少显著,可达100倍以上。菌斑中的细菌组成因各个菌数量变化的差异出现改变。
3、血生化指标显示,术前、术后差异无统计学意义,且均在正常值范围内。
4、术后7天,口内观有4例黏膜组织因感染未愈合,局部有红肿表现,其余犬软组织愈合情况良好,未观察到炎症反应。正常愈合组软组织切片镜下观,上皮层、固有层细胞排列正常,未观察到炎症反应。
5、心、肝、脾、肺、肾组织切片镜下观察结果显示,主要脏器的主要结构清晰,无损伤、无病变,未见异常。
第三部分AZ31B镁合金口内应用时降解对力学性能的影响
目的：评价AZ31B镁合金在口腔内应用的降解速率,并测量分析降解程度对力学性能的影响。
方法：
1、AZ31B镁合金引导骨再生膜、固定钉电子天平称重。
2、将矿化诱导2代的骨髓间充质干细胞与nHA/PLA共培养,复合PRP凝胶后,联合AZ31B镁合金引导骨再生膜植入骨缺损区,术后4W、8W、12W取材,取出镁合金材料,清理后充分风干,称重后与术前空白对照组对比分析。
3、扫描电镜下观察AZ31B镁合金材料降解表面形貌,描述其在口腔内植入后降解行为。
4、对降解前后AZ31B镁合金材料表面进行能谱分析,探讨体内降解对表面成分的影响。
5、用牙托粉制作模具,固定AZ31B镁合金材料,用力学加载仪测量最大加载力,分析不同降解组力的变化。
结果：
1、AZ31B镁合金呈层状剥脱式降解。
2、AZ31B镁合金植入体内4W降解1.42%,8W降解4.27%,12W降解11.37%。
3、降解后,镁合金表面组分变化明显,差异具有统计学意义,其中Ca、P、K元素变化最显著。
3、随着降解程度的增加,力学性能成比例下降,但12W组仍可承受最大咬合力。
As a widely used restoration method, dental implant has many advantages including:satisfactory masticatory function; excellent aesthetics; optimal comfort; alveolar bone protection and avoiding abutment tooth injury. However, many patients cannot take those advantages by receiving implant therapy because of its strict indications, such as adequate bone mass and acceptable bone morphology. On this issue, dentists have endeavored to extend the application of implant, for instance, in improving implant survival rate of patients with osteoporosis or diabetes.
Patients with severely absorbed alveolar bone usually suffer from severe bone defect because of lack of physiological stimulation followed by progressive bone absorption. In this situation, bone augmentation is an effective way. Several methods for alveolar bone vertical augmentation exist including bone grafting, autogenous dentin material transplantation, and distraction osteogenesis. However, bone grafting faces the donor site morbidity. Autogenous dentin material transplantation requires extractable healthy teeth as repairing materials thus its application is limited. Distraction osteogenesis requires a longer treat period and increases the discomfortableness and the risk of infection. Bone graft material is widely available and has good biocompatibility and osteoconductive, which promise a better result in bone repairing.unlike maxillary which can gain more bone height by maxillary sinus lifting, vertical bone augmentation in severely absorbed mandible is more difficult to achieve. The key issues are the following:(1)shaping and retention of repairing material;(2) The establishment and maintenance of the bone regeneration space;(3) Blood supply.
The ideal GBR membrane should have favorable biosafety and bio-degradability; adaptive degradation rate and adequate mechanical property for establishment and maintenance of the bone regeneration space. Magnesium alloy, as biodegradable metal with both the mechanical property and the bio-degradability, is expected to be an optimal choice for GBR membrane. In this research we introduce magnesium alloy into to the GBR membranes combining with tissue engineered bone as the novel method in restoration. In addition, we add platelet-rich-plasma (PRP) as the osteogenetic factor which can promote angiogenesis in the prosthesis and therefore, resolve the blood supply problem both internally and externally.
As the degradable metal, magnesium alloy's physical property is close to cortical bone. Meanwhile the degradation products are alkaline MgCO3, Mg(OH)2and CaCO3. The alkaline environment is in contrast to the regular bacterial plaque environment and possibly provides the bacteriostatic factors. Intraoral bacteria can incite local inflammation or undermine the hard tissue by attachment, aggregation and proliferation. The main issue is the pathogens cause peri-implantitis. During the degradation process of magnesium alloy, the alkaline products will have effect on the pathogens. Some other issues including local biocompatibility and general influence of magnesium alloy. The second part of this research will focus on these issues and makes a tentative research on intraoral applications of magnesium alloy.
The main properties of magnesium alloy are degradation and mechanical property. The degradation rate is directly related to the concentration of the degradation products and dosage evaluation. When introduce magnesium alloy to the GBR membranes, the dosage should maintain the integral structure in order to resist the external force during Osteogenesis period. Because of the favorable blood supply and complex biting force in oral maxillofacial area, the degradation rate in this environment may differ from that in long bones. During the degradation, the influence of changing mechanics parameters in the structural integrity under biting force will be discussed in the third part of this research.
Part Ⅰ
The evaluation on osteogenetic effect of magnesium alloy membrane in severely absorbed mandibular alveolar bone
Objective:to investigate the osteogenesis effects of magnesium alloy as GBR membrane combined tissue engineered bone in vertical augmentation of severely absorbed alveolar bone。
Methord:
1、Establish the severely absorbed canine alveolar bone defect animal model to simulate the clinical cases.
2、To obtain the BMSCs through whole bone marrow culture. After differentiation and identification, culture and amplification, induced mineralization for10days, the BMSCs are cultured together with nHA/PLA graft to establish tissue engineered bone.
3、Design the shape of AZ31B magnesium alloy GBR membrane based on alveolar defect morphology.
4、To investigate the specific method of twice centrifugation to prepare PRP through adjust the centrifugal speed.
5、Animal surgeries:experimental group:AZ31Bmagnesium alloy GBR membrane+PRP gel+tissue engineered bone; control group:titanium alloy GBR membrane+PRP gel+tissue engineered bone; blank group:tissue engineered bone+PRP.
6、Fluorescence label the calcium deposition10days,20days and30days after the operation. Calculate the osteoporosis rate under the laser scanning confocal microscope
7、Harvest after4,8and12weeks and evaluate the osteogenesis effects through Radiological and histological observation
Result:
1、We successfully establish the severely absorbed canine alveolar bone defect animal model. The morphology and physiological status approximate clinical situations.
2、The BMSCs are obtained after induced mineralization to manifact the tissue engineered bone.
3、The shape of AZ31B magnesium alloy GBR membrane is coincidence with that of the bone defect. When the distance from the centre of screw to the centre of the membrane is2.4mm, the resistance reached the maximum, which can maintain the whole structure under500N's biting force.
4、To centrifugate14ml whole blood in speed of2200r/min. To decant the supernatant. The remaining liquid is conducted to the second centrifugation. The concentration of PRP received is810×109/L,(6times of that of original whole blood),which meet the criterion of5-8times.
5、In early stage, the osteogenesis rate in magnesium alloy group is significantly higher than other two groups. No statistical difference founded between the positive control and the blank group.
6、No statistical difference in bone density or Trabecular bone volume is founded between titanium alloy group and the magnesium alloy group. Although the osteogenesis is more active around the magnesium alloy, but the volume of new formed bone is less than that in titanium alloy group and exhibit highly irregular charistic because of the gas generated during magnesium degradation.
Part2the effect of the application of AZ31B magnesium alloy on the oral environment and evaluation of its biological safety
Objective:To investigate the effect of the application of AZ31B magnesium alloy on local environment and the safety throughout the body.
Methods:
1、Test and analysis the PH value of saliva with short range PH paper both before implantation and harvest procedure.
2.To collect the supragingival and subgingival dental plaque of the first mandible molar in canine. Extract the genomic DNA, measure the DNA concentration, estimate the amounts of bacteria. To evaluate the impact of magnesium alloy on the amount of bacteria
3、Draw venous blood4ml both before implantation and harvest procedure. Evaluate the changes in blood biochemical indexes.
4、Observe the Healing characteristics of soft tissues after implantation. The soft tissues adhered to magnesium alloy are observed by using tissue sectioning under microscope.
5、The tissues of heart, liver, spleen, lung and kidney are also observed using tissue sectioning (HE staining) under microscope.
Result:
1、The PH value of saliva with short range PH paper has a slightly change before and after implantation. However the difference is not statistically significant.
2、The result of Q-PCR shows that the amounts in all sorts of bacteria are lower after the procedure. The differences were all statistically significant, especially Pg and Fn, the amount of which reduced more than100times.
3、No statistical difference in blood biochemical indexes was founded before and after the procedure, and both are within the normal range.
4、Mucous failed to heal in4cases7days after the procedure because of infection and presents local swelling. All other tissues healed well without inflammatory reaction. Normal cell arrangement is observed in both epithelial layer and固有层under microscope without inflammatory reaction.
5、No damage, lesion or other abnormal founded in heart, liver, spleen, lung and kidney according to the results of tissue sectioning Part Ⅲ Effect of AZ31B magnesium alloy intraoral degradation on its mechanical property
Objective:To investigate the intraoral degradation rate of the AZ31B magnesium alloy and analyze the effect of degradation level on its mechanical property.
Methods:
1、To weigh the AZ31B magnesium alloy GBR membrane and the screws with the electronic balance.
2、The methods of preparation, implantation and harvest see part Ⅰ. The magnesium alloy materials harvested are weighed after cleaning and air-drying and analyzed compared with the blank control group.
3、To observe the surface degradation morphology of the AZ31B magnesium alloy material and to describe the detail of its intraoral degradation.
4、To conduct the energy spectrum analysis on the surface of AZ31B magnesium alloy and to investigate the effects of intraoral degradation on the surface substances.
5、To manufacture the mould with denture acrylic for AZ31B magnesium alloy material fixation and to measure the maximum loading force.
Result:
1、The degradation process of AZ31B magnesium alloy are proved to be lamellar and exfoliative.
2、The degradation rate of AZ31B magnesium alloy are1.42%in4weeks,4.27%in8weeks,11.37%in12weeks postoperatively
3、The surfacing substances of the magnesium alloy are significantly changed, especially the amount of Calcium phosphorus and kalium
4、The mechanism property of magnesium alloy descends during degradation, yet the maximum biting force can still be withstand12weeks after implantation.
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