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研究生： 劉席瑋
Hsia-Wei Liu
論文名稱： 鏈式骨成形蛋白與間葉幹細胞於組織工程骨再生之研究
Tethered Bone Morphogenetic Protein and Mesenchymal Stem Cells Applied for Tissue-Engineered Bone Regeneration
指導教授： 薛敬和
口試委員:
學位類別： 博士
Doctor
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2006
畢業學年度： 94
語文別： 中文
論文頁數： 224
中文關鍵詞： 鄰分泌 、骨成形蛋白 、骨髓間葉幹細胞 、骨原細胞 、支架 、生物反應器 、光聚合包囊 、肌腱-骨癒合 、組織工程骨再生
外文關鍵詞： Juxtacrine, Bone morphogenetic protein, Bone marrow mesenchymal stem cell, Osteoprogenitor cell, Scaffold, Bioreactor, Photoencapsulation, Tendon-Bone healing, Tissue engineered bone regeneration
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    • 本文提出人造鄰分泌訊號生長因子靶向控釋系統模式作為重組人第二型骨成形蛋白控制釋放系統應用於骨再生。「凝膠模塑/鹽瀝濾法」預鑄三維多孔聚乳酸□聚甘醇酸支架。支架材料預浸漬於30 %雙氧水中，採用紫外線照射法進行光氧化反應，支架材料表面層形成過氧化基，接著以丙烯酸為間隔基將I型膠原蛋白分子藉由光誘導接枝聚合反應固定化於三維支架材料表面，重組人第二型骨成形蛋白共價鍵結於I型膠原蛋白接枝□塗佈表面層。另外，亦以具有雙面異功能性之丙烯醯基-聚乙二醇-N-羥基琥珀醯亞胺為間隔基橋聯骨成形蛋白後，再吸附固定於光氧化反應後之多孔支架。
    骨成形蛋白共價鍵結於膠原蛋白接枝□塗佈之表面，支架於體外二十八日內釋放實驗結果表明累積釋放量約為初始劑量之三分之一，且保持生物活性，顯示持續與緩慢雙相釋放，骨成形蛋白固定化支架將會抑制其與受體結合之活化複合物自細胞膜外自由擴散與內質化作用。骨膜細胞與骨髓間葉幹細胞量測生長因子調控細胞增殖與分化訊號之表達。高保留率與緩慢釋放之骨生長因子傳遞系統，運用多孔空間構形的支架，可增進細胞的貼附；骨生長因子鏈式於支架表面，一方面可提高載體內保留率避免在體內溶解流失，另一方面細胞與骨生長因子直接作用，以基質分泌的方式調節細胞的增殖和分化，骨成形蛋白能和跨膜絲/蘇氨酸蛋白激酶型受體結合，可能通過磷酸化介導信號傳遞從而誘導成骨蛋白及骨基質形成，促進骨癒合。為鑑定骨成形蛋白固定化支架上細胞之表型，以掃描式電子顯微鏡、細胞活力、組織學、免疫組化檢測評估細胞活性。骨成形蛋白固定化支架延長細胞內訊號刺激。鄰分泌訊號傳遞的結果促使細胞生長與分化。本研究發展三維多孔性支架結構，在微重力旋轉式生物反應器中動態細胞培養，可促進骨細胞高密度生長與高度分化。紐西蘭白兔股骨內髁及顱骨缺損模式分別建立動物實驗之鬆質骨與皮質骨缺損模型，評估無細胞之合成骨替代物或細胞/支架複合結構物植入體內後之骨再生情形。顯示仿生性結構支架表面共固定細胞識別黏附分子與骨生長因子可引發骨誘導與骨生成作用，應用於骨組織工程與再生醫學研究。
    光能敏感性水膠之快速應答特性，使其在各領域能廣泛地應用，包含了組織工程與再生醫學。具有互穿網絡結構之光能敏感性水膠雙丙烯酸聚乙二醇酯與細胞或組織接觸時，可透過光聚合而形成水膠，且無毒副作用，當用於組織工程時，細胞可懸浮在聚合物水溶液中，光聚合後細胞均勻分散在水膠載體內；本文亦將鏈式骨成形蛋白光能敏感性水膠包囊小鼠骨髓間葉幹細胞後，於體外成骨培養基體系中誘導培養，再植入小鼠背部肌袋並觀察新骨生成。研究證實其包囊骨髓間葉幹細胞後，將所得溶液暴露於365 nm紫外線下即轉變成水膠，可顯著增加載體內細胞分泌基質量，具成骨能力作用。進一步可注射細胞水凝膠溶液後再從體外光聚合固化，作為前十字韌帶重建之肌腱□骨癒合可行性評估。動物實驗，組織學上結果發現，控制組在第三週發現在肌腱及骨頭隧道之間開始有纖維組織生成，隨著膠原纖維連續性沿軸向重建組織；在第六週可見有骨頭長入間隔在肌腱及骨頭隧道之間的纖維層組織。含可溶性骨成形蛋白組在第六週發現肌腱與骨頭介面纖維層的厚度逐漸減少，可見長入的骨頭與骨皮質形成層之間已更趨成熟而組織化且已更進一步長入融合。含鏈式骨成形蛋白組在第六週則可見在骨皮質纖維層已出現纖維軟骨的形成，肌腱與骨頭已逐漸癒合而形成堅固的組織。生物力學測試結果，在介面強度方面，鏈式骨成形蛋白水膠組之最大極限拉出負荷隨著時間而遞增。六週比三週皆呈有意義增加，在第三週之介面強度，鏈式骨成形蛋白水膠組比可溶性骨成形蛋白水膠組大；在第六週，鏈式骨成形蛋白水膠組比無控制組達有意義增加。

    The studies describe a biomimetic mode of juxtacrine insoluble signaling stimulation for target delivery of recombinant human bone morphogenetic protein-2 (rhBMP-2) to prolong its retention for use in bone tissue engineering that would provide localized release in a manner that is triggered by cellular activity. A porous three-dimensional scaffold of poly-(lactide-co-glycolide) was fabricated by means of gel molding and particulate leaching. Collagen immobilization onto the scaffold surface was produced by performing photo-induced graft polymerization of acrylic acid, and rhBMP-2 was tethered to the collagenous surface by covalent conjugation. On pharmacokinetic analysis, in vitro enzyme-linked immunosorbent and alkaline phosphatase assays revealed sustained, slow release of rhBMP-2 over 28 days, with a cumulative release of one third of the initial load diffusing out of the scaffold. Conjugation of rhBMP-2 inhibited the free lateral diffusion and internalization of the activated complex of rhBMP-2 and the bone morphogenetic protein receptor. Osteoprogenitor cells were used as bone precursors to determine the expression of biosignaling growth factor in regulating cell proliferation and differentiation. To identify the phenotype of cells seeded on the rhBMP-2–conjugated scaffold, cellular activity was evaluated with scanning electron microscopy and with viability, histological, and immunohistochemical testing. The rhBMP-2–conjugated scaffold prolonged stimulation of intracellular signal proteins in cells. Enhancement of cell growth and differentiation was considered a consequence of juxtacrine signaling transduction. Animal studies of rhBMP-2–containing filling implants showed evidence of resorption and de novo bone formation.
    A novel localization process utilizes acrylate-N-hydroxysuccinimide poly (ethylene glycol) (PEG) as a spacer arm to tether rhBMP-2 on a scaffold surface. Bone marrow–derived mesenchymal stem cells were used as osteogenic precursors to evaluate cellular morphology and phenotypic expression of the scaffolds, which were seeded with the cells in a rotating bioreactor. Bilateral, full-thickness cranial defects in rabbits were selected to investigate the osteogenic effect of in vitro cultured mesenchymal stem cells for in vivo bone tissue engineering. Three-dimensional computed tomography and histology demonstrated that de novo bone formation was enhanced after surgery when PEG-tethered rhBMP-2 conjugate was introduced. Our work revealed the potential for biomimetic surface engineering by entrapping signaling growth factor–stimulated osteogenesis. It would create a new platform for bone-engineered stem cell therapies.
    Photopolymerized hydrogel based on poly (ethylene glycol) diacrylate (PEGDA) was applied to periosteum□derived osteoprogenitor cells encapsulation and orthopaedic tissue engineering. A need was recognized to incorporate rhBMP-2 in binding form into a PEG-tethering network to prevent its rapid, uncontrolled diffusion out of the matrix vehicle. Cell growth and differentiation are controlled by matrix-bound, insoluble signals. In vitro studies demonstrated that covalent conjugation of PEG-tethered rhBMP-2 can be utilized to mimic the extracellular matrix composition when generating engineered bone tissues. Fixation and incorporation of a tendon graft within the bone tunnel is a primary concern when employing tendon graft for ligament reconstruction. This study presents a novel technique for fabricating injectable PEGDA hydrogel photoencapsulated osteoprogenitor cells. A total of 28 adult New Zealand white rabbits were used. The long digitorum extensor tendon was transplanted into a bone tunnel of the proximal tibia. The tendon was pulled through a drill-hole in the proximal tibia and attached to the medial aspect of the tibia. Hydrogel suspension containing osteoprogenitor cells at a concentration of 20 million/ml was injected in the bone tunnel. Histological examination of the tendon-bone interface and biomechanical test for maximal pull-out load were evaluated at postoperative weeks 3 and 6. Histological analysis of tendon-bone interface showed an interface fibrous layer formed by photoencapsulation of periosteal cells between the tendon and the bone. This layer became progressive integrated with tendon and bone surface during the healing process. Biomechanical testing revealed higher maximal pull-out strength in the rhBMP-2 tethering group at all time points with a statistically significant difference at 3 and 6 weeks. The rhBMP-2 tethering group had a higher interface strength-to-length ratio and significant increase at 3 weeks and 6 weeks.

    第一章 緒論 1 1.1 前言 1 1.2 骨組織 3 1.2.1 骨骼結構與功能 3 1.2.2 骨骼的組成 6 1.2.3 硬骨形成 8 1.2.4 骨組織修復 9 1.3 骨移植材料 11 1.3.1 天然骨移植材料 12 1.3.2 人工骨移植替代材料 14 1.4 組織工程與再生醫學 18 1.4.1 概述 18 1.4.2 骨組織工程與再生研究文獻綜述 19 1.5 骨組織工程研究的挑戰 27 1.5.1 第三代生醫材料 27 1.5.2 生醫材料仿生化 29 1.5.3 生物大分子表面固定化研究文獻綜述 32 1.6 生長因子控制釋放與組織重建 35 1.6.1 生長因子控釋載體 35 1.6.2 生長因子控制釋放研究文獻綜述 39 1.7 研究動機與目的 46 第二章 理論基礎 48 2.1 骨組織工程支架 48 2.1.1 骨組織工程支架的基本要求 48 2.1.2 骨組織工程支架的設計與製備技術 50 2.2 生醫材料仿生表面工程 56 2.2.1 固定化技術的定義與分類 56 2.2.2 生物大分子固定化方法 59 2.2.3 生醫材料表面改質 63 2.3 生長因子靶向細胞生長的調控 67 2.3.1 概述 67 2.3.2 骨成形蛋白 69 2.3.3 骨成形蛋白誘骨活性 71 2.3.4 骨成形蛋白的受體與訊號傳遞機轉 72 2.3.5 骨成形蛋白的靶細胞 74 第三章 實驗材料與方法 80 3.1 人造鄰分泌訊號生長因子靶向控釋系統 80 3.1.1 實驗藥品 80 3.1.1.1 多孔支架製備與分析 80 3.1.1.2 細胞培養 81 3.1.1.3 動物實驗 82 3.1.2 實驗儀器與裝置 83 3.1.2.1 多孔支架製備與分析 83 3.1.2.2 細胞培養 83 3.1.2.3 動物實驗 84 3.1.3 多孔支架製備與表面改質 86 3.1.4 骨成形蛋白固定於含膠原蛋白載體之多孔支架 86 3.1.5 多孔支架材料特性分析 88 3.1.5.1 孔隙率和壓縮模數測定 88 3.1.5.2 多孔支架含水率和降解率測定 88 3.1.5.3 過氧化基和聚丙烯酸接枝量測定 89 3.1.5.4 膠原蛋白接枝量測定 89 3.1.5.5 骨成形蛋白保留率和釋放動力學定量分析 90 3.1.5.6 表面元素分析 91 3.1.5.7 表面形態分析 91 3.1.6 骨膜幹細胞分離與培養 91 3.1.7 體外釋放骨成形蛋白之生物活性測定 93 3.1.8 種子細胞植入多孔支架 93 3.1.9 細胞形態觀察 94 3.1.10 細胞增殖和細胞存活力檢測 94 3.1.11 細胞分化檢測 94 3.1.12 組織化學和免疫組織化學檢測 95 3.1.13 動物實驗 95 3.1.14 組織切片分析 96 3.2 多孔支架表面鏈式骨成形蛋白刺激骨髓間葉幹細胞分化與骨生成 98 3.2.1 實驗藥品 98 3.2.1.1 多孔支架表面鏈式骨成形蛋白製備與分析 98 3.2.1.2 細胞培養 98 3.2.1.3 動物實驗 100 3.2.2 實驗儀器與裝置 101 3.2.2.1 多孔支架表面鏈式骨成形蛋白製備與分析 101 3.2.2.2 細胞培養 102 3.2.2.3 動物實驗 103 3.2.3 鏈式骨成形蛋白偶聯物製備 104 3.2.4 多孔支架製備與鏈式骨成形蛋白 104 3.2.5 鏈式骨成形蛋白可行性檢測 104 3.2.6 鏈式骨成形蛋白支架特性分析 105 3.2.7 兔骨髓間葉幹細胞分離和成骨誘導 105 3.2.7.1 骨髓間葉幹細胞的分離和培養 105 3.2.7.2 骨髓間葉幹細胞成骨誘導培養與表型鑑定 107 3.2.8 鏈式骨成形蛋白偶聯物生物活性檢測和免疫螢光分析 108 3.2.9 生物反應器成骨誘導分化 109 3.2.10 細胞形態觀察 110 3.2.11 細胞增殖檢測 110 3.2.12 鹼性磷酸酶活性和去氧核糖核酸檢測 110 3.2.13 細胞分泌膠原蛋白基質檢測 111 3.2.14 鈣沉積定量分析 112 3.2.15 動物實驗 113 3.2.16 電腦斷層掃瞄檢測 114 3.2.17 組織切片分析和組織形態測量 115 3.3 鏈式骨成形蛋白光敏感性水膠用於前十字韌帶重建之肌腱-骨癒合 116 3.3.1 實驗藥品 116 3.3.1.1 鏈式骨成形蛋白偶聯物和光敏感性水膠製備 116 3.3.1.2 細胞培養 116 3.3.1.3 動物實驗和反轉錄聚合酶連鎖反應 118 3.3.2 實驗儀器與裝置 120 3.3.2.1 鏈式骨成形蛋白偶聯物和光敏感性水膠製備 120 3.3.2.2 細胞培養 120 3.3.2.3 動物實驗和反轉錄聚合酶連鎖反應 121 3.3.3 小鼠骨髓間葉幹細胞分離和培養 123 3.3.4 流式細胞分析儀檢測細胞免疫表型 123 3.3.5 成骨誘導分化和特異性指標檢測 124 3.3.6 鏈式骨成形蛋白偶聯物製備 125 3.3.7 鏈式骨成形蛋白偶聯物生物活性檢測 125 3.3.8 光敏感性水膠製備與骨髓間葉幹細胞包囊 126 3.3.9 細胞存活力分析 126 3.3.10 細胞分泌膠原蛋白基質和去氧核糖核酸檢測 127 3.3.11 鈣沉積定量分析 127 3.3.12 小鼠皮下植入實驗 128 3.3.13 組織切片和免疫螢光分析 128 3.3.14 反轉錄聚合酶連鎖反應(RT-PCR) 129 3.3.15 骨膜幹細胞分離與培養 130 3.3.16 動物實驗 131 3.3.17 組織切片分析 133 3.3.18 反轉錄聚合酶鏈鎖反應(RT-PCR) 133 3.3.19 生物力學試驗 134 第四章 結果與討論 136 4.1 人造鄰分泌訊號生長因子靶向控釋系統 136 4.1.1 多孔支架材料特性分析 136 4.1.1.1 孔隙率和壓縮模數測定 136 4.1.1.2 多孔支架含水率和降解率測定 136 4.1.1.3 過氧化基和聚丙烯酸接枝量測定 138 4.1.1.4 膠原蛋白接枝量測定 139 4.1.1.5 骨成形蛋白保留率和釋放動力學定量分析 140 4.1.1.6 表面元素分析 143 4.1.1.7 表面形態分析 145 4.1.2 體外釋放骨成形蛋白之生物活性測定 146 4.1.3 細胞形態觀察 147 4.1.4 細胞增殖和細胞存活力檢測 148 4.1.5 細胞分化檢測 149 4.1.6 免疫螢光分析 150 4.1.7 組織切片分析 152 4.1.8 討論 153 4.2 多孔支架表面鏈式骨成形蛋白刺激骨髓間葉幹細胞分化與骨生成 160 4.2.1 鏈式骨成形蛋白可行性與鏈式骨成形蛋白支架特性分析 160 4.2.2 兔骨髓間葉幹細胞分離和成骨誘導 163 4.2.3 鏈式骨成形蛋白偶聯物生物活性檢測和免疫螢光分析 165 4.2.4 細胞形態觀察 167 4.2.5 細胞增殖檢測 168 4.2.6 鹼性磷酸酶活性檢測 168 4.2.7 細胞分泌膠原蛋白基質檢測 170 4.2.8 鈣沉積定量分析 170 4.2.9 電腦斷層掃瞄檢測 172 4.2.10 組織切片分析和組織形態測量 174 4.2.11 討論 177 4.3 鏈式骨成形蛋白光敏感性水膠用於前十字韌帶重建之肌腱□骨癒合 180 4.3.1 流式細胞分析檢測陽性細胞表達率 180 4.3.2 成骨誘導分化和特異性指標檢測 180 4.3.3 鏈式骨成形蛋白偶聯物生物活性檢測 181 4.3.4 光敏感性水膠製備與骨髓間葉幹細胞包囊 183 4.3.5 細胞存活力分析 184 4.3.6 細胞分泌膠原蛋白基質與鈣沈積量檢測 184 4.3.7 小鼠皮下植入組織切片和免疫螢光分析 186 4.3.8 反轉錄聚合酶連鎖反應(小鼠) 186 4.3.9 兔肌腱□骨介面組織切片分析 190 4.3.10 反轉錄聚合酶鏈鎖反應(兔) 191 4.3.11 生物力學試驗 192 4.3.12 討論 192 第五章 結論與展望 197 參考文獻 201

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