複合式雙鈣磷酸鹽類合併第一型膠原蛋白應用於植體周圍骨
缺損之骨再生能力評估:動物試驗

近年來，使用磷酸鈣鹽類作為生物合成的骨材在臨床上已經相當普遍，但此類骨移植材多為顆粒型式，顆粒大小自數十毫米到一毫米都有。雖然顆粒型的骨材比較容易填充縫隙，但是對於移植材料要能夠堅固撐出所需維持的空間以及要能穩定不動這兩點而言，顆粒型的骨材比較不適當。當應用在比較大之齒槽骨缺損時，可能會因為缺損空間而擠壓顆粒型材料而未能撐出空間，無法達到預期性和穩定良好的齒槽骨修復。因此，目前有許多種形式的磷酸鈣鹽類被發展出來，如預製型骨塊，克服其強度不足的部分。在這些材料中，為了達到空間維持和理想地增加新生骨的量與質，骨材吸收的速率需和新骨生成的速率相當，近來有一種主要由雙鈣磷酸鹽合併氫氧基磷灰石組成的新式骨塊被研發出來，這種材料除了具有足夠的機械強度之外，同時也具備了適當的降解率，在骨生成量有不錯的效果，目前已在市面上使用，為了克服該合成骨塊在植入初期容易崩解和吸引更多成骨細胞的聚集，加入第一型膠原蛋白來改善。本實驗的目的主要在研究此種膠原蛋白複合代用骨塊用於植體周圍大範圍齒槽骨缺損重建之效能。本實驗使用了3 隻米格魯一歲成犬，體重介於7 公斤到10 公斤。主要分成3 組，實驗組(n=9)，使用的骨材為複合雙鈣磷酸鹽與氫氧基磷灰石，商品名為MaxiboneR ，合併第一型膠原蛋白之代用骨塊( MaxiboneR + collagen type I, MC)；對照組(n=6)，使用的骨材複合雙鈣磷酸鹽與氫氧基磷灰石之代用骨塊( MaxiboneR , M)；空白組(n= 3)，沒有使用任何骨材 (Empty, E)。將3 隻米格魯獵犬的下顎左右4 顆小臼齒與第一大臼齒拔除，在等待傷口癒合 12 週之後，會將本實驗3 組不同材料合併植體依照不同的時間點隨機種植於3 隻米格魯獵犬的下顎骨左右兩側，手術的方式主要是先在實驗動物的無牙齒槽脊上製備好一定大小的骨缺損，隨即利用預先準備好的骨材進行引導骨生成手術合併植牙手術。手術的時間點主要分成3 個，分別是第0 週、第4 週與第8 週，手術同時也會使用PeriotestR 測試植體動搖度和經皮下注射骨標定染劑以供日後使用螢光顯微鏡觀察植體周圍新生骨質沉積的速率與部位。最後，3 隻米格魯獵犬統一於實驗的第12 週犧牲，接著利用植體穩定度分析、放射線影像分析、斷層掃描分析與組織切片判讀和骨頭螢光標定觀察等方式分析人工植體周圍的骨生成與骨整合程度。在結果的部分，各組植體的存活率是100%，但是卻伴隨程度不一的植體周圍炎；在植體穩定度上，無論在材料上或是觀察時間上，雖然均無顯著差異，但是皆有達到臨床上可以接受的穩定度；在放射線影像中硬組織的覆蓋率，斷層掃描中骨塊新生的體積與骨礦化密度，雖然沒有達到統計上的差異，但是MC 組有高於M 組的趨勢；在螢光標定觀察下，MC 組和 M 組的骨生成的時序性類似；而在組織切片中，M 組在八週時還可以在植體旁靠近齒槽嵴觀察到部分的不成熟骨頭(woven bone)，不過MC 組在骨膜內側或是齒槽嵴大多已為成熟的骨頭 (mature bone)，顯示MC 組在骨頭成熟速率略高於M 組。雖然兩者在統計上並沒有顯著性的差異。不過加入膠原蛋白的DPCD 在臨床的應用上，不會造成局部酸化產生劇烈的發炎反應，也有一定的機械強度，但是材料吸收與新骨生成的速率稍快，影響新生骨材的穩定度和空間維持的能力，經過些許的調整，本研發材料是具有良好生物相容性的人工合成骨材。

關鍵字

磷酸鈣鹽類；膠原蛋白；植體周圍骨缺損

並列摘要

Using particulate form calcium phosphates as the biosynthetic materials has become popular in clinical practice. Although the particulate form calcium phosphates are easily to fill small bony defect, they are not stable and rigid enough to maintain the space of bony defect properly. For large bony defect, the particulate form wound be compressed by themselves and flap not to keep the space we want ideally, which result compromised efficacy in alveolar bone regeneration. Thus many combinations of different forms of calcium phosphates have been proposed to overcome insufficiency of strength in grafts. To achieve the goal of space maintenance and bone regeneration, the ratio of material biodegradation and new bone formation has to be identical. Recently, a new bone block constitutes with mainly dicalcium phosphates and partially hydroxyapatites with sufficient strength and adequate resorption rate has been developed and applied clinically. That has not only adequate mechanical strength but also proper ratio of biodegradation and new bone formation. To correct initial collapse of implanted block and attract more cells to aggregate, collagen type I is added. The purpose of this study is to evaluate efficacy of new bone formation of such new developed bone block with collagen type I in large peri-implant alveolar bony defect in animal model. In this study, we use three beagle dogs, weighing between 7 kg to 10 kg, distribute to three groups as following: 1. experimental group (n = 9) which using the bone block containing dicalcium phosphates and hydroxyapatite (DCPD+ HA) as graft in defect, MaxiboneR ,with collagen type I(MaxiboneR +collagen type I, MC group); 2.control group (n = 6) which using the bone block containing dicalcium phosphates and hydroxyapatite (DCPD+ HA) as graft in defect(MaxiboneR , M group); 3.empty group (n = 3) which without any bone graft (blood clot only) in defect(Empty, E). In this experiment, the extraction of four mandibular premolars and one first molar at bilateral mandible was done in the beginning. Following twelve weeks healing, the implantation over the mandible with bony defect preparation and guide bone regeneration would be preceded with test bone grafts or without any grafts randomly. The operations are performed at different time points (0-week, 4-week and 8-week). During operation, the implantation was performed simultaneously with the measurements of implant stability by PeriotestR . Meanwhile, We also injected the bone labeling fluorescence subcutaneously for evaluation of the area and amounts of new bone deposition with fluorescence microscope. After sacrificing at 12-week, the use of implant stability analysis, radiographic analysis, Micro-CT scan analysis, histological analysis and bone labeling technique were performed to evaluate the new bone formation and osseointegration at the bony defect around the eighteen implants. In the results, the dental implant survival rate among these groups was 100% with varying degree of peri-implantitis. To dental implant stability, there was no significant difference regardless of different groups or observed time, but came up to clinically acceptable level. To hard tissue cover ratio radiographically, the volume of new bone formation and bone mineral density by Micro-CT, there was no significant difference, but evinced MC group tended to be better than M group. The bone labeling images displayed the same pattern of mineralized timing about MC and M groups. Histologically, woven bone was partially discovered around dental implant near crestal region in 8-week M group, but there was mature bone under periosteum and crestal region, indicating new bone formation in MC groups is slightly faster than M groups. There is no clear difference between the experimental group and control group. But in clinical application, DCPD with collagen type I does not produce localized acidification leading to severe inflammation and has proper mechanical strength. But the ratio of biodegradation and new bone formation is too slightly fast to impact the stability of new bone and the capability of space maintenance. After properly adjusted, this would be a potentially biocompatible synthetic bone block.

並列關鍵字

Calcium phosphate ； Collagen ； Peri-implant bony defects

參考文獻

1. Al-Sanabani, J. S., et al. (2013). "Application of calcium phosphate materials in dentistry."

International journal of biomaterials 2013.

2. Alkhraisat, M. H., et al. (2008). "Beta-tricalcium phosphate release from brushite cement

surface." J Biomed Mater Res A 84(3): 710-717.

3. Alkhraisat, M. H., et al. (2008). "Beta‐tricalcium phosphate release from brushite cement

國際替代計量

複合式雙鈣磷酸鹽類合併第一型膠原蛋白應用於植體周圍骨缺損之骨再生能力評估:動物試驗

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