研發新式含鍶骨水泥應用於口腔顎面缺損之重建：動物實驗

Abstract

骨材無論是在骨科或是牙科的應用上均十分廣泛且重要，對於骨質疏鬆治療、脊髓骨手術需求、顏顎面骨腫瘤切除患者、齒槽骨量不足需植牙者、牙周缺 損需修補等等，骨材的出現可以有效達到缺損修補的效果，又不需造成自體爲取得移植骨所造成的二次傷害，也可大幅降低異種骨產生排斥現象的機率，對患者 和醫師而言為一大福音。目前市面上常見骨材為磷酸鈣鹽類和硫酸鈣鹽類，通常會於此兩種主材料內混合不同添加物或是改變其結構以改良材料吸收情況、性質 或是引導骨再生功能，但仍有吸收期過長、操作性不佳等缺點，含鍶骨水泥目前 主要應用於骨科手術，成效良好且引導骨再生能力佳，但尚未應用於口腔及顎面 區域，此區域需考量到可能接觸到唾液或是需承受咬合重力等因素，所以本研究團隊期望開發適合口腔顎面且操作性、塑形性均佳的含鍶骨水泥。 本實驗選用三隻一歲左右，約十公斤的米格魯及一隻土狗，但實驗過程中不 幸土狗逝世，數據無法納入討論，因此實際上的實驗分組為九組含 5% Sr-HA 的 硫酸鈣骨水泥實驗組(n=9)、六組含 5%HA 硫酸鈣骨水泥的對照組(n=6)和三組完 全不填補材料的空白組(n=3)。每隻犬隻下顎雙側的第一小臼齒至第一大臼齒拔 除後等待一個月以上至骨缺損初步癒合後，每側設計三個 10x4 mm 的骨缺損區域，雙側共計六個，分配於距離犧牲前四周、八周和十二周三個時間點製造缺損 及放入材料並植入植體，術後均會施打螢光針劑，材料置放前後以及犬隻犧牲前均測試植體穩定商數(ISQ)，待犧牲後分別拍攝電腦斷層影像，量測其植體周圍骨量、植體和骨交接面積和骨礦化密度，並製作未脫鈣磨片和脫鈣磨片，拍攝螢 光影像及染色厚進行組織細部觀察。 結果部份，含鍶骨水泥在生物相容性上表現十分優異，置入後不會對周遭軟 組織造成嚴重的發炎反應，也無材料暴露的情況，傷口癒合狀況良好，植體骨整合成功率為 100%；在材料植體穩定性部分則可看到材料初期穩定性佳有顯著差異(P=0.024)，但各時間點數據經統計和對照組以及空白組無顯著差異。電腦斷層分析部分，實驗組的植體和骨接觸面積、骨礦化密度和骨量純以數據來看，似有比另外兩組略佳，但因樣本數的影響，統計後仍屬無顯著差異；骨螢光標定和染色影像觀察的結果則可以看到實驗組缺損區域活躍的骨生成情況，可知含鍶骨水泥於口腔顎面應用上有其發展性，若進一步將成分和性質做調整，可更有利其未來的發展。

Bone substitute materials are already widely used in orthopedic and oral maxillofacial surgery such as treatment of osteoporosis, vertebroplasty, bone tumor excision, implant-related bone augmentation, and periodontal defect for a long while. The advantages of synthetic bone substitute materials, which are no need to have another wound of donor site for bone graft to restore defect and can decrease the possibility of rejection caused by xenografts, make the patients be safer and comfortable. Either calcium phosphate or calcium sulfate are the common materials for bone substitute materials used to combine other additives to improve the material characters, change structure or function of osteoconduction and osteoinduction, but there’re still some disadvantages such as long resorption time, bad operability. Strontium-containing bone cement with excellent capability of guiding bone regeneration is only applied to orthopedic surgery so far. Therefore, we try to develop the ideal strontium-containing bone substitute material with good operability, functional efficacy and suitable for oral maxillofacial defect where is affected by salivary and occlusion force. Four dogs, including three a-year-old beagles and a Taiwanese hybrid dog weighing about 10 kg, were enrolled in our research. However, the Taiwanese hybrid dog passed away during research to that the data related was excluded. Research groups were classified as experiment group (n=9) composed of 5% Sr-HA bone cement, control group (n=6) composed of 5% HA bone cement, and empty group (n=3) without any bone material filling. Bilateral mandibular teeth form premolar to first molar were extracted and the 10x4 mm defects designed at mandibular edentulous ridge after 6 weeks, followed with bone cement filling, implantation and fluorescent agent injection. There were three experiment groups, two control groups, and an empty group were set each time at 4 weeks, 8 weeks and 12 weeks before sacrifice. We had implant stability quotient (ISQ) at three particular time: before bone cement filling, after bone cement filling, and before sacrifice. Otherwise, we also did a variety of analysis for bone cement such as tomography for bone volume, intersection surface of implant and alveolar bone, and bone mineral density analysis, fabricating decalcified bone section and undecalcified bone section for histology analysis, radiography, and fluorescent labeling analysis. The result of strontium-containing bone cement showed that the wound healing is ideal, it also shows the bone cement neither irritates periodontal soft tissue causing severe inflammation nor leads the material or bone exposure, and the success rate implant osseointegration showed 100%, which proves the great biocompatibility of bone cement. As we can see, initial stability of timing (before and after) placing material are significantly different (P=0.024), but there are no significant difference between three time points. Otherwise, there are also no significant difference when comparing intersection surface of implant and surrounding bone, bone mineral density, and bone volume between three groups by tomography, which may affected by the number of samples although experiment group’s data seems better than the others. Good result of regenerated bone volume and biocompatibility were noted in experiment group during research, strontium-containing bone cement was expected to contribute to oral and maxillofacial surgery in the future.