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研究生:葉梓賢
研究生(外文):Tzu-Hsien Yeh
論文名稱: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
論文名稱(外文):Effects of Dicalcium Phosphate Dihydrate(DCPD) with CollagenType I in Bone Regeneration for Peri-implant Bony Defects:Animal Study
指導教授:章浩宏章浩宏引用關係林俊彬林俊彬引用關係
指導教授(外文):Hao-Hueng ChangChun-Pin Lin
口試委員:林弘萍
口試委員(外文):Hong-Ping Lin
口試日期:2016-05-26
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:臨床牙醫學研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:中文
論文頁數:55
中文關鍵詞:磷酸鈣鹽類膠原蛋白植體周圍骨缺損
外文關鍵詞:Calcium phosphateCollagenPeri-implant bony defects
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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。

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.

誌謝............................ 1
中文摘要........................ 2
英文摘要........................ 3
目錄 .......................... 5
圖目錄.......................... 7
表目錄.......................... 8
第一章 序論...................... 9
1.1 前言........................ 9
1.2 研究動機.................... 10
1.3 論文架構.................... 10
第二章 文獻回顧.................. 11
2.1 骨移植材料的種類............. 11
2.2 磷酸鈣鹽類................... 13
2.2.1 歷史沿革................... 13
2.2.2 分類....................... 14
2.2.3 生物降解與骨生成機制..........14
2.3 磷酸鈣骨水泥(CALCIUM PHOSPHATE CEMENT).......................... 16
2.3.1 Apatite CPC ................16
2.3.2Brushite CPC ............... 16
2.4 膠原蛋白...................... 16
第三章 實驗設計和方法...............18
3.1 實驗動物的選擇................. 18
3.2 實驗材料與實驗設計............. 18
3.2.1 實驗植體種類................. 18
3.2.2 實驗骨材種類................. 18
3.2.3 實驗設計..................... 20
3.3 手術過程與術後照顧.............. 21
3.3.1 實驗動物的麻醉................ 21
3.3.2 第一階段的手術步驟............ 21
3.3.3 第二階段的手術步驟............. 21
3.4 非侵入性臨床實驗觀察............. 24
3.4.1 臨床觀察及照顧................ 24
3.4.2 Periotest value (PTV) .......24
3.5物犧牲與標本取得................. 25
3.5.1 福馬林藥水的製備.............. 25
3.5.2 動物的犧牲.................... 25
3.5.3 標本的取得.................... 25
3.6 放射線影像分析與斷層掃描...........27
3.6.1 放射線影像分析................. 27
3.6.2 斷層掃描...................... 27
3.7 標本製作與染色................... 28
3.7.1 標本標本的初步切割.............. 28
3.7.2 含植體磨片標本製備.............. 28
3.7.3 不含植體的脫鈣標本製備........... 30
3.8 骨頭螢光標定...................... 32
3.8.1 標定方法........................ 32
3.8.2 本實驗所使用的螢光染劑........... 32
3.8.3 螢光顯微鏡觀察................... 33
3.9 植體周圍骨頭覆蓋率.................. 34
3.10 本實驗所使用的統計方法............. 35
第四章 實驗結果........................ 36
4.1 植體存活率......................... 36
4.2 植體 PERIOTEST VALUE ............. 36
4.3 放射線影像分析..................... 38
4.4 斷層掃描分析....................... 39
4.5 植體周圍齒槽骨再生率................ 41
4.6 骨螢光標定影像與染色影像............. 43
第五章 討論............................. 47
5.1 實驗結果概論........................ 47
5.2 現有文獻結果討論.................... 48
5.3 實驗設計限制之探討.................. 49
第六章 結論............................ 50
參考文獻............................... 51

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