骨科疾病被認為是全世界第二大的致殘原因。其中，骨缺損是由外傷、感染等因素引起的常見病症之一。儘管骨骼具有獨特的自癒能力，仍有約10%的骨缺損無法正常修復，此情況被稱作延遲癒合或不癒合。因此，目前迫切需要發展新穎的方式以加速骨缺損處的癒合過程。本研究中，我們製備出一摻雜矽奈米顆粒(nSi)之礦化膠原蛋白(MC)支架，他具有引導宿主細胞遷移、促進成骨細胞分化及抗氧化/抗發炎等多重功能，並且能夠促進骨缺損處之骨再生效率。我們以單向凍乾法製備出具有放射狀排列結構之MC-nSi支架（RA-nSi支架），該支架能夠以其結構提供誘導，促進細胞遷移到骨缺損內的支架上。有趣的是，相比於應用生長因子及消炎藥物，支架中摻雜的矽奈米顆粒能夠提供良好的協同作用，即透過矽與水產生的氫氣提供抗發炎效果，以及透過與水反應後於矽表面形成的二氧化矽(SiO2)層的降解而釋放之矽離子達到促進週圍成骨細胞分化的目的。與結構為隨機排列的支架（R支架）相比，RA-nSi支架能夠更明顯的令前驅成骨細胞（MC3T3-E1）沿纖維方向遷移。此外，支架所釋放的氫氣可以透過抑制過度產生的細胞內活性氧物質(ROS)及促炎細胞因子（包含白细胞介素IL-6和IL-1β）以減輕巨噬細胞的氧化壓力及炎症。同時，RA-nSi支架分泌的矽離子可以促進细胞增殖及成骨細胞分化，此結果可從鹼性磷酸酶（ALP）和骨鈣素（OCN）等成骨分化指標物的增加看出。將RA-nSi支架植入小鼠臨界尺寸的顱骨缺損模型中，於8週後顯示最佳的骨再生效果。研究結果表明，RA-nSi支架可被用於加速骨癒合過程，為一種極具發展潛力的策略。

Bone diseases are recognized as the second greatest cause of disability worldwide. Among them, bone defect is one of the most common injuries derived from traumas, infections, and so on. Although bone has the unique ability of self-healing, approximately 10% of the defects will not heal normally, termed non-union or delayed union. Hence, the development of novel modalities for accelerating the healing process at the defect is greatly urgent. In this work, a nanosilicon (nSi) incorporated mineralized collagen (MC) scaffold with radially aligned fibers, which has multifunctions of guiding host-cell recruitment, osteogenic differentiation and anti-oxidative/anti-inflammatory effects that can promote the regeneration process of bone defects is proposed. The unidirectional freezing dry method was used to fabricate a radially aligned MC-nSi scaffold (RA-nSi scaffold) that can provide a topographical cue to promote cell migration into the scaffold on bone defect. Interestingly, instead of using or combining growth factors or anti-inflammatory drugs, the incorporated nSi can effectively provide synergistic effects which are anti-inflammation effects by generated hydrogen gas from the reaction of nSi with water and osteogenic effects of recruited cells by released Si ions through the dissolution of the formed silica (SiO2) layer on nSi surface after reaction with water. The prepared RA-nSi scaffold demonstrates significantly high pre-osteoblasts (MC3T3-E1 cells) recruitment and cells orientation compared with random scaffolds (R scaffold). Additionally, the released hydrogen can attenuate oxidative stress and inflammation in macrophages by the suppression of overproduced intracellular reactive oxygen species (ROS) and pro-inflammatory cytokines including interleukin (IL)-6 and IL-1β. Meanwhile, the secretion of Si ions from RA-nSi scaffolds can enhance the cells proliferation and especially osteogenic differentiation of pre-osteoblasts evidenced by increased osteogenic markers including alkaline phosphatase (ALP) and osteocalcin (OCN). The RA-nSi scaffolds were then implanted into mouse critical-size cranial bone defects, which showed the best bone regeneration outcome at 8 weeks. The findings suggest that RA-nSi scaffolds can be utilized as a promising strategy for enhanced bone healing process.

Abstract....................................................................................................................ii
Contents...................................................................................................................iii
List of Figures..........................................................................................................vi
Chapter 1: Introduction........................................................................................1
1.1. Bone healing and bone tissue engineering.............................................1
1.2. Cell migration and its effects on bone healing process........................2
1.3. The effects of radially aligned structure on bone healing....................3
1.4. Methods to fabricate radially aligned substrate.....................................4
1.5. Inflammation and bone regeneration.......................................................5
1.6. Hydrogen therapy and hydrogen generation from nanosilicon particles .....................................................................................................................6
1.7. Degradation of silica layer on silicon surface and further osteogenic
differentiation effect...............................................................................................7
1.8. Introduction of mineralized collagen (collagen and hydroxyapatite)8
1.9. Our design and purpose of the research....................................................9
1.10. Tree chart of experiment design................................................................11
Chapter 2: Materials and methods......................................................................12
2.1. Synthesis and characterization of MC and MC-nSi..................................12
2.1.1. Materials..........................................................................................................12
2.1.2. The preparation of MC................................................................................12
2.1.3. Characterization of MC................................................................................12
2.1.4. The preparation of MC-nSi.........................................................................13
2.2. Fabrication of MC/MC-nSi with random/radially aligned structure.....13
2.3. Optimization of RA-nSi scaffolds..................................................................14
2.3.1. Compressive test............................................................................................14
2.3.2. Porosity.............................................................................................................14
2.3.3. SEM and elemental mapping.....................................................................14
2.3.4. Live/Dead Staining........................................................................................15
2.4. Hydrogen release profile................................................................................15
2.5. Si ions release profile.......................................................................................15
2.6. Cell Migration Studies.....................................................................................16
2.6.1. MC3T3-E1 cells culture.................................................................................16
2.6.2. Cell migration test and cell alignment......................................................16
2.7. Anti-inflammation studies ...............................................................................17
2.7.1. RAW 264.7 cells culture................................................................................17
2.7.2. Cell viability.....................................................................................................17
2.7.3. Cellular ROS scavenging test......................................................................17
2.7.4. Determination of cytokine production.....................................................17
2.8. Osteogenic differentiation studies................................................................18
2.8.1. Cell proliferation............................................................................................18
2.8.2. Evaluation of ALP activity and OCN protein levels................................18
2.9. In vivo studies.....................................................................................................19
2.9.1. Animal experiments.......................................................................................19
2.9.2. Micro-CT analysis...........................................................................................19
2.9.3. Histological analysis......................................................................................19
2.10. Statistical Analysis...........................................................................................19
Chapter 3: Results and discussion........................................................................20
3.1. Characterization of MC...................................................................................20
3.2. Optimization of RA-nSi scaffolds.................................................................21
3.2.1. Morphology of RA scaffolds with different concentration of MC.....21
3.2.2. Porosity of RA scaffolds with different concentration of MC..............22
3.2.1. Mechanical properties of RA scaffolds with different concentration of MC and different amounts of nSi.........................................................................23
3.3. SEM images of RA scaffolds incorporated with different amounts of nSi................................................................................................................................23
3.4. Live/Dead staining...........................................................................................24
3.5. Elemental mapping (EDS) and the whole SEM images of optimized RA-40nSi scaffolds.................................................................................................25
3.6. Cell migration and alignment.......................................................................26
3.7. Hydrogen release profile...............................................................................29
3.8. Si ions release profile......................................................................................30
3.9. In vitro anti-inflammatory and anti-oxidative effects by hydrogen gas ......................................................................................................................................31
3.9.1. RAW cells viability.........................................................................................31
3.9.2. Cellular ROS scavenging test.....................................................................31
3.9.3. Pro-inflammatory cytokines suppression................................................32
3.10. In vitro osteogenic differentiation effects by Si ions.............................33
3.10.1. MC3T3-E1 cells proliferation...................................................................33
3.10.2. ALP activity and OCN protein levels.......................................................33
3.11. In vivo studies..................................................................................................34
3.11.1. Micro-CT analysis........................................................................................34
3.11.2. Histological analysis...................................................................................35
Chapter 4: Conclusion.............................................................................................37
References.................................................................................................................38

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