呼吸作用是細胞維持正常生理功能時不可或缺的環節，其反應必須仰賴氧氣的提供才能維持正常機能。在細胞增生、分化、及能量的提供，都扮演著非常關鍵的角色。若細胞處於缺氧狀態的時間過長，呼吸作用無法進行到克氏循環(Kreb’s Cycle)進行有氧呼吸，便無法產生足夠的三磷酸腺苷(adenosine Triphosphate, ATP)維持生理現象。而骨頭在因外力損傷的部位，不只是造成骨頭的斷裂，也會使得原本提供氧氣及養分的哈氏管(Haversian Canal)及血管組織的破壞，使得氧氣以及養分的供應不足，導致骨缺損部位癒合不良。為了加速骨再生及癒合，則需要靠外界來提供氧氣以及養分，使骨修復功能能夠正常運作。根據先前文獻指出，鍶離子的表現對於骨再生前期的蝕骨細胞作用以及中期的成骨細胞分化都有一定程度的影響。本研究欲開發一可產氧之過氧化鍶(strontium peroxide, SrO2)複合式載體，不但能夠長時間提供骨修復所需的氧氣，也能提供適當量的鍶離子來促進骨修復。當PLGA與水接觸並降解之後，會滲透進入載體中和SrO2反應產生過氧化氫(H2O2)， H2O2也會進一步經由MnO2催化並分解出氧氣。本實驗結果顯示，若將含有過氧化鍶的支架(Scaffold)放入低氧環境(Hypoxia)中的磷酸緩衝液(Phosphate Buffer Solution, PBS)中，該支架產生出的氧氣也能夠使該PBS中的溶氧量增加，其天數最長可達四天以上。在細胞實驗，我們證實該支架對於細胞沒有明顯的細胞毒性，並且在最佳化的支架的條件下，不但能促進骨細胞的增生，在細胞的死亡情形也與控制組沒有明顯差異。且在蝕骨細胞的實驗中，利用細胞支架染色、以及蝕骨細胞的染色來看，本實驗的支架確實可以抑制蝕骨細胞的活性。根據以上實驗，我們認為本研究之含有過氧化鍶之產氧支架能夠增強骨再生的能力，利用其產氧之特性改善缺氧環境，並抑制蝕骨細胞的作用以加速骨折修復的速度。

To maintain normal cell physiological function, cellular respiration is an indispensable process. Its reaction requires oxygen, which plays an important role in several processes including cell proliferation, differentiation, and the suppliance of energy, to retain normal cellular functions. If cells are exposed to hypoxia environment for too long, the respiration process cannot continue to Kreb’s cycle to complete the aerobic respiration in order to generate enough ATP for cells to live. At injured bone, not only bone itself fractured but also the Haversian canals, which supply nutrition and oxygen to bone, is destroyed. The injury may lead the insufficient nutrition and hypoxia environment to the fracture and slow down bone regeneration. To accelerate bone regeneration and healing, we need to supply oxygen and nutrition in order to revive bone healing process, which is the most difficult and critical step clinically. According to previous studies, strontium ions have negative effects on osteoclast function and positive effect on osteoblast proliferation. In this study, we developed an oxygen-generating carrier that can slowly release oxygen and strontium ions. After putting the scaffold into water, PLGA degrades and water will then penetrate into the scaffold which further react with SrO2 and generate hydrogen dioxide (H2O2). H2O2 will soon decompose into oxygen and water with the catalytic effect by MnO2. According to this study, by putting or SrO2 scaffold into phosphate buffer solution (PBS) in a closed hypoxia environment, the scaffold can generate oxygen for at least 4 days. In cell experiments, we proved that our scaffold does not have cell toxicity compared to control group, on the opposite hand, it can release oxygen in hypoxia environment for cells to maintain normal function of osteoblasts and suppress osteoclast activity in order to accelerate bone recovery.

摘要 I
Abstract II
目錄 III
圖目錄 VII
表目錄 IX
第一章 緒論 1
1-1 骨頭 1
1-1-1骨組織的組成 1
1-1-2骨頭內的細胞組成 2
1-1-3骨折(Bone Fracture) 3
1-2 骨再生作用(Bone Regeneration) 4
1-2-1 骨再生的分子生物作用機制 4
1-2-2 骨再生的步驟 6
1-3 氧氣於骨修復的重要性 8
1-3-1 缺氧與成骨細胞的關係 8
1-3-2 缺氧及蝕骨細胞的關係 9
1-3-3血管新生 9
1-4 免疫與骨分化的關係 10
1-4-1 巨噬細胞與成骨作用 10
1-4-2 巨噬細胞與骨折修復 11
1-5 現行治療法 11
1-5-1石膏固定 11
1-5-2 骨移植 12
1-5-3 高壓氧治療(Hyperbaric Oxygen Treatment, HBOT) 14
1-5-4 人工關節及骨釘、骨板 16
1-5-5 陶瓷材料 18
1-6 鍶在人體內扮演的角色 19
1-6-1 鍶(Strontium, Sr) 19
1-6-2 雷奈酸鍶(Strontium Ranelate) 19
1-6-3 成骨作用(Osteogenesis) 20
1-6-4 血管新生(Angiogenesis) 21
1-6-5 免疫調節作用 22
1-7 產氧材料(Oxygen Generating Materials) 22
1-8 聚乳酸-聚乙醇酸(Poly lactic-co-glycotic acid, PLGA) 25
1-9 明膠海綿(Gelatin Sponge) 25
1-10 研究動機與實驗目的 26
第二章、材料與方法 29
2-1 以PLGA包覆Gelatin Scaffold並包有SrO2及MnO2之複合式支架製備 29
2-2 包覆SrO2及MnO2之產氧支架的特性分析 29
2-2-1產氧支架之型態分析 29
2-2-2 產氧支架之氧氣產生情形 30
2-2-3 SrO2產氧支架於PBS中之離子釋放情形 30
2-2-4產氧支架產生之酸鹼微環境 30
2-3 細胞培養 30
2-3-1小鼠顱頂成骨細胞前體細胞系(MC3T3-E1) 30
2-3-2 小鼠巨噬細胞(RAW264.7) 31
2-4細胞存活率分析(CCK-8 Assay) 31
2-5細胞貼附測試(Cell Adhesion) 32
2-6細胞存活及死亡染色(Live and Dead Staining) 32
2-7 RAW264.7分化蝕骨細胞之檢測 33
2-8 即時聚合酶連鎖反應(Real-time polymerase chain reaction, Real-time PCR) 34
2-9細胞免疫螢光染色 38
第三章、結果與討論 39
3-1 SrO2產氧支架之巨觀及微觀圖 39
3-1-1 SrO2產氧支架之巨觀圖 39
3-1-2 SEM圖 39
3-2 SrO2產氧支架之表面元素分析 42
3-3 SrO2產氧支架之氧氣產生情形 43
3-4 SrO2產氧支架於PBS中之離子釋放情形 44
3-5 SrO2產氧支架產氧後之酸鹼微環境 44
3-6 SrO2產氧支架對於細胞之增生能力 47
3-6-1 鍶離子濃度對於MC3T3-E1增生的影響 47
3-6-2產氧支架內二氧化錳的濃度對於MC3T3-E1增生的影響 48
3-6-3 產氧支架內過氧化鍶的濃度對於MC3T3-E1增生的影響 50
3-6-4 產氧支架對於MC3T3-E1之細胞毒性測試 51
3-7 SrO2產氧支架之細胞貼附情形 51
3-8 SrO2產氧支架調節RAW264.7極化之情形 54
3-9 SrO2產氧支架抑制RAW264.7分化為蝕骨細胞之情形 55
3-9-1 即時聚合酶連鎖反應 55
3-9-2蝕骨細胞免疫螢光染色 56
3-9-3 抗酒石酸酸性磷酸酶染液(TRAP)染色 57
第四章、結論 58
參考文獻 59

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