目錄
1 第一章 緒論 1
1.1 醫療器械市場分析 1
1.2 骨植入物介紹 3
1.2.1 骨植入物種類 3
1.2.2 骨釘螺紋種類 3
1.2.3 骨釘材質 6
1.2.4 骨癒合過程 7
1.3 生醫材料介紹 8
1.3.1 生醫材料種類與介紹 9
1.3.2 理想生物醫療材料所需條件 11
1.3.3 生醫材料發展 12
1.4 磷酸鈣種類與特性 13
1.5 研究動機與目的 15
1.6 論文架構 16
2 第二章 文獻回顧與基礎理論 17
2.1 文獻回顧 17
2.1.1 非結晶磷酸鈣(ACP) 17
2.1.2 非結晶磷酸鈣陶瓷合成 18
2.1.3 非結晶磷酸鈣陶瓷抑制劑添加 19
2.1.4 生醫陶瓷與高分子材料混練 20
2.2 射出成形技術 21
2.3 田口實驗法 23
2.3.1 品質工程三階段 23
2.3.2 品質特性三因子 24
2.3.3 損失函數 25
2.3.4 直交表 26
2.3.5 訊號雜訊比 26
2.3.6 變異數分析 26
3 第三章 實驗步驟 28
3.1 實驗流程 28
3.2 實驗藥品及設備 29
3.2.1 實驗藥品 29
3.2.2 實驗設備 33
3.3 奈米級非結晶磷酸鈣陶瓷粉末合成 43
3.4 材料量測與分析 44
3.4.1 掃描式電子顯微鏡附加能量分散光譜儀 44
3.4.2 X光繞射分析 44
3.5 複合材料製作 45
3.6 模流分析 46
3.6.1 填充參數設定 46
3.6.3保壓時間參數設定 47
3.6.4 冷卻時間設定 47
3.7熱壓成形 48
3.8 骨釘射出成形 48
3.8.1 成形視窗 49
3.8.2骨釘製程參數選定 50
3.8.3 田口品質工程 51
3.8.4 橫切面研究 52
3.9 水中硬度鈣離子濃度檢測 53
3.10 細胞試驗 54
3.10.1 生物相容性試驗(MTT assay) 54
3.10.2 骨分化能力測定(ALP assay) 55
3.10.3 骨礦化能力測定 56
3.11 降解試驗 57
3.12 扭轉試驗 58
4 第四章 結果與討論 59
4.1 材料量測與分析 59
4.1.1 掃描式電子顯微鏡附加能量分散光譜儀 59
4.1.2 X光繞射分析 60
4.2 拉伸試驗 61
4.3 射出成形 63
4.3.1 短射試驗 63
4.3.2 田口試驗 63
4.3.3 橫切面研究 71
4.3.4 射出結果討論 76
4.4 水中硬度鈣離子濃度檢測 77
4.5 細胞試驗 78
4.5.1 生物相容性試驗(MTT assay) 78
4.5.2骨分化/礦化試驗 78
4.6 降解試驗 82
4.7 扭轉測試 84
5 第五章 結論與未來展望 85
5.1 結論 85
5.2 未來展望 85
6 參考文獻 86

6 參考文獻
[1]Fortune Business Insights, “Medical Devices Market Size, Share & COVID-19 Impact Analysis, by Type (Orthopedic Devices, Cardiovascular Devices, Diagnostic Imaging invitro Diagnostics, Minimally Invasive Surgery, Wound Management, Diabetes Care, Ophthalmic Devices, Dental Devices, Nephrology, General Surgery, and Others); By End User (Hospitals & ASCs, Clinics, and Others), and Regional Forecast, 2023-2030”, Maeket(Global) Research Report, (2023).
[2]社團法人國家生技醫療產業策進會，“2022生醫上市櫃營收前20大暨各領域營收表現”，Avaiable at: https://ibmi.taiwan-healthcare.org/zh/bio_highlights_detail.php?REFDOCID=0rod3wss2j6pp3nf, Accesed January 2023.
[3]太平洋醫材股份有限公司，“太平洋醫材股份有限公司2Q2022公司簡報”， Avaiable at: https://www.pahsco.com.tw/tw/investors/information-download/0/229/, Accesed September 2022.
[4]M. Majewski, H. Susanne, S. Klaus, “Epidemiology of Athletic Knee Injuries: A 10-year Study”, The Knee, vol. 13, pp. 184-188, (2006).
[5]Am730，“十字韌帶斷裂｜搶籃板致斷十字韌帶 微創重建重返賽場”， Avaiable at: https://www.am730.com.hk/ /健康/十字韌帶斷裂-搶籃板致斷十字韌帶-微創重建重返賽場/337662?fbclid=IwAR0BFvGRL0mtTrHYZNK2A35W2YDns3zL02pOLlssxhSoeiitoKR9vS8d0NA, Accesed September 2022.
[6]日商環球訊息有限公司(GII)，“2023 年全球創傷固定設備和設備市場報告”， Available at: https://www.gii.tw/report/tbrc1210008-trauma-fixation-devices-equipment-global-market.html, Accessed June 2023.
[7]陳謀法，“以有限元素法分析直接骨骼植入型下肢義肢螺釘設計”，國立陽明大學醫學工程研究所碩士論文，(2010)。
[8]高常有，馬列，“醫用高分子材料”，北京：化學工業出版社，(2016)。
[9]J. Wang, J. Xu, W. Liu, Y. Li, L. Qin, “Biodegradable Magnesium (Mg) Implantation Does Not Impose Related Metabolic Disorders in Rats with Chronic Renal Failure”, Scientific Reports 6, Article number: 26341, (2016).
[10]Y. Luo, C. Zhang, J. Wang, F. Liu, K.W. Chau, L. Qin, J. Wang, “Clinical Translation and Challenges of Biodegradable Magnesium-based Interference Screws in ACL Reconstruction”, Bioactive Materials, Vol. 6, Isu. 10, pp. 3231-3243, (2021).
[11]X.N. Gu, X.H. Xie, N. Li, Y.F. Zheng, L. Qin, “In Vitro and in Vivo Studies on a Mg–Sr Binary Alloy System Developed as a New Kind of Biodegradable Metal”, Acta Biomaterialia, Vol. 8, Isu.6, pp. 2360-2374, (2012).
[12]A. Dhawan, N. Ghodadra, V. Karas, M.J. Salata, B.J. Cole, “Complications of Bioabsorbable Suture Anchors in the Shoulder”, The American Journal of Sports Medicine, Vol. 40, No. 6, pp. 1424-1430, (2011).
[13]K.E. Webster, J.A. Feller, A.J. Kimp, T.S. Whitehead, “Revision Anterior Cruciate Ligament Reconstruction Outcomes in Younger Patients: Medial Meniscal Pathology and High Rates of Return to Sport Are Associated with Third ACL Injuries”, The American Journal of Sports Medicine, Vol. 46, No. 5, pp. 1137-1142, (2018).
[14]A. Persson, T. Gifstad, M. Lind, L. Engebretsen, K. Fjeldsgaard, J.O. Drogset, M. Forssblad, B. Espehaug, A.B. Kjellsen, J.M. Fevang, “Graft Fixation Influences Revision Risk after ACL Reconstruction with Hamstring Tendon Autografts: A Study of 38,666 Patients from the Scandinavian Knee Ligament Registries”, 2004–2011. Acta Orthopaedica, Vol. 89, No. 2, pp. 204-210, (2018).
[15]S. Hassanajili, A. Karami-Pour, A. Oryan, T. Talaei-Khozani, “Preparation and characterization of PLA/PCL/HA composite scaffolds using indirect 3D printing for bone tissue engineering”, Materials Science and Engineering: C, Vol. 104, Article 109960, (2019).
[16]J.R. Sheen and V.V. Garla, “Fracture Healing Overview”, StatPearls, StatPearls Publishing, Treasure Island (FL), (2020).
[17]B. Beamer, C. Hettrich, J. Lane, “Vascular Endothelial Growth Factor: An Essential Component of Angiogenesis and Fracture Healing”, Journal of Hospital for Special Surgery, Vol. 6, No. 1, pp. 85-94, (2010).
[18]S.D. Bruck, “Properties of Biomaterials in the Physiological Environment”, CRC Press. Inc., Boca Raton, Florida, (1980).
[19]L.L. Hench, “Bioceramics: From Concept to Clinic”, Journal of the American Ceramic Society, Vol. 74, Isu. 7, pp. 1487-1510, (1991).
[20]STOCKFEEL股感知識庫，Available at: https://www.stockfeel.com.tw/生物醫用材料/，Accessed January 2021。
[21]黃世偉，2010，“高分子材料與醫療器材”，科學發展月刊，455期，頁14-19
[22]American Academy of Orthopedic Surgeons, “2022 Annual Report”, (2022).
[23]PR Newswire, “Global Regenerative Medicines Bone and Joints Research Report 2023: Increasing Product Approvals and Launches & R&D for Stem and Gene Therapies Bodes well for the Sector”, Regenerative Medicines: Bone and Joint Applications, (2023).
[24]C. Vyas, G. Poologasundarampillai, J. Hoyland, P. Bartolo, “3D Printing of Biocomposites for Osteochondral Tissue Engineering”, Biomedical Composites, pp. 261-302 (2017).
[25]L.L. Hench, J.W. Wilson, G. Heimke, “Bioceramics: From Concept to Clinic”, Journal of the American Ceramic Society, Vol. 74, Isu. 7, p.p. 1487-1510, (1991).
[26]M. Canillas, P. Pena, A.H. de Aza, M. A. Rodríguez, “Calcium Phosphates for Biomedical Applications”, Boletín de la Sociedad Española de Cerámica y Vidrio, Vol. 56, Isu.3, pp. 91-112, (2017).
[27]N. Eliaz and N. Metoki “Calcium Phosphate Bioceramics: A Review of Their History, Structure, Properties, Coating Technologies and Biomedical Applications” MDPI, Vol. 10, p.p. 334, (2017).
[28]U.G. K. Wegst, H. Bai, E. Saiz, A. P. Tomsia, R.O. Ritchie, “Bioinspired Structural Materials”, Nature Materials, Vol. 14, pp. 23-36, (2015).
[29]R. Murugan, S. Ramakrishna, “Development of nanocomposites for bone grafting” Composites Science and Technology, Vol. 65, pp. 2385-2406, (2005).
[30]施威任，“奈米級氫氧基磷灰石之合成及燒結”，國立成功大學材料科學與工程學系，博士論文，(2007)。
[31]G. Balasundaram, M. Sato, T.J. Webster, “Using Hydroxyapatite Nanoparticles and Decreased Crystallinity to Promote Osteoblast Adhesion Similar to Functionalizing with RGD”, Biomaterials, Vol. 27, pp. 2798–2805, (2006).
[32]W. Yu, T.W. Sun, C. Qi, Z. Ding, H. Zhao, F. Chen, D. Chen, Y.J. Zhu, Z. Shi, Y. He, “Strontium-doped Amorphous Calcium Phosphate Porous Microspheres Synthesized Through a Microwave-hydrothermal Method Using Fructose 1, 6-Bisphosphate as an Organic Phosphorus Source: Application in Drug Delivery and Enhanced Bone Regeneration”, ACS Applied Materials & Interfaces, Vol. 9, No. 4, pp. 3306-3317, (2017).
[33]M. Nagano, T. Nakamura, T. Kokubo, M. Tanahashi, M. Ogawa, “Differences of Bone Bonding Ability and Degradation Behaviour in Vivo Between Amorphous Calcium Phosphate and Highly Crystalline”, Biomaterials, Vol. 17, No. 18, pp. 1771–1777, (1996).
[34]M. Iafisco, L.D. Esposti, G.B. Ramírez-Rodríguez, F. Carella, J. Gómez-Morales, A.C. Ionescu, E. Brambilla, A. Tampieri, J.M. Delgado-López, “Fluoride-doped Amorphous Calcium Phosphate Nanoparticles as a Promising Biomimetic Material for Dental Remineralization”, Scientific Reports, Vol. 8, pp. 17016, (2018).
[35]Lj. Brečević and H. Füredi-Milhofer, “Precipitation of Calcium Phosphates from Electrolyte Solutions”, Calcified Tissue Research, Vol. 10, p.p. 82-90, (1972).
[36]X. Yin ang M.J. Stott, “Biological Calcium Phosphates and Posner’s Cluster”, The Journal of Chemical Physics, Vol. 118, pp. 3717-3723, (2003).
[37]A.S. Posner and Foster Betts, “Synthetic Amorphous Calcium Phosphate and Its Relation to Bone Mineral Structure”, Accounts of Chemical Research, Vol. 8, pp. 273-281, (1975).
[38]Á. Millán, P. Lanzer, V. Sorribas, “The Thermodynamics of Medial Vascular Calcification”, Frontiers in Cell and Developmental Biology, Vol. 9, Article 633465, (2011).
[39]M.S. Tung and W.E. Brown, “An Intermediate State in Hydrolysis of Amorphous Calcium Phosphate”, Calcified Tissue International, Vol. 35, pp. 783-790, (1983).
[40]X. Niu, S. Chen, F. Tian, L. Wang, Q. Feng, Y. Fan, “Hydrolytic Conversion of Amorphous Calcium Phosphate into Apatite Accompanied by Sustained Calcium and Orthophosphate Ions Release”, Materials Science and Engineering: C, Vol. 70, Part. 2, pp. 1120-1124, (2017).
[41]A. Lotsari, A.K. Rajasekharan, M. Halvarsson, M. Andersson, N. Communications, “Transformation of Amorphous Calcium Phosphate to Bone-like Apatite”, Nature Communications, Vol. 7, Article 4170, (2018).
[42]R. Xavier, “Development and Characterisation of Apatite Plasma Sprayed Coatings on Orthopaedic Prostheses”, Toulouse INP, Ph.D. thesis, (1996).
[43]T. Yu, J. Ye, Y. Wang, “Synthesis and Property of a Novel Calcium Phosphate Cement”, Journal of Biomedical Materials Research Part B: Applied Biomaterials, Vol. 90, pp. 745–51, (2009).
[44]S. Loher, W. Stark, M. Maciejewski, A. Baiker, S.E. Pratsinis, D. Reichardt, F. Maspero, D. Gunther, “Fluoro-apatite and Calcium Phosphate Nanoparticles by Flame Synthesis” Chemistry Material, Vol.17, pp. 36-42, (2005).
[45]P. Layrolle and A. Lebugle, “Characterization and Reactivity of Nanosized Calcium Phosphates Prepared in Anhydrous Ethanol”, Chemistry Material, Vol. 6, No. 11, pp. 1996–2004, (1994).
[46]S. Somrania, M. Banub, M. Jemalc, C. Reyb, “Physico-chemical and Thermochemical Studies of the Hydrolytic Conversion of Amorphous Tricalcium Phosphate into Apatite”, Journal of Solid State Chemistry, Vol. 178, pp. 1337-1348 (2005).
[47]N.C. Blumenthal, V. Cosma, S. Levine, “Effect of Gallium on Thein Vitro Formation, Growth, and Solubility of Hydroxyapatite”, Calcified Tissue International, Vol. 45, pp. 81-87, (1989).
[48]N.C. Blumenthal, V. Cosma, D. Skyler, J. LeGeros, M. Walters, “The Effect of Cadmium on the Formation and Properties of Hydroxyapatite in Vitro and its Relation to Cadmium Toxicity in the Skeletal System”, Calcified Tissue International, Vol. 56, No. 4, pp. 316-322, (1995).
[49]T. Uchino and K. Toda, “Synthesis of Zinc-Containing Amorphous Calcium Phosphate”, Key Engineering Materials, Vol. 529-530, pp. 119-122, (2013).
[50]T.A. Fuierer, M. LoRe, S.A. Puckett, G.H. Nancollas, “A Mineralization Adsorption and Mobility Study of Hydroxyapatite Surfaces in the Presence of Zinc and Magnesium Ions”, American Chemical Society, Vol. 10, No. 2, pp. 4721–4725, (1994).
[51]M.J. Root, “Inhibition of the Amorphous Calcium Phosphate Phase Transformation Reaction by Polyphosphates and Metal Ions”, Calcified Tissue International, Vol. 47, pp. 112-116, (1990).
[52]M. Wang and W. Bonfield, “Chemically Coupled Hydroxyapatite-polyethylene Composites: Structure and Properties”, Biomaterials, Vol. 22, No.11, pp. 1311-1320, (2001).
[53]M.S. Abu Bakar, P. Chang, K.A. Khor, “Mechanical Properties of Injection Molded Hydroxyapatite Polyetheretherketone Biocomposites”, Composites Science and Technology, Vol. 63, No. 3, pp. 421-425, (2003).
[54]林紀穎，“生物可分解PCL骨釘微射出成形研究”，國立高雄科技大學機械工程系碩士論文，台灣 (2018)。
[55]劉睿佳, “生分解中空骨釘微成形最佳化研究”, 國立高雄科技大學機械工程系碩士論文，台灣 (2021)。
[56]A.M. Ambrosio, J. S. Sahota, Y. Khan, C.T. Laurencin, “A Novel Amorphous Calcium Phosphate Polymer Ceramic for Bone Repair: I. Synthesis and Characterization”, Journal of Biomedical Materials Research, Vol. 58, pp. 295-301, (2001).
[57]Y. Gao, W. Weng, K. Cheng, P. Du, G. Shen, G. Han, B. Guan, W. Yan, “Preparation, Characterization and Cytocompatibility of Porous ACP/PLLA Composites”, Journal of Biomedical Materials Research Part A, Vol. 79A, Isu. 1, pp. 193-200, (2006).
[58]黃俊欽，2013，塑膠模具設計分析講義，國立高雄應用科技大學模具工程系碩士課程。
[59]李輝煌，2008，田口方法品質設計的原理與實務，高立圖書公司。
[60]https://www.merckmillipore.com/TW/zh/product/di-Ammonium-hydrogen-phosphate,MDA_CHEM-101207, Accessed January 2023.
[61]https://www.merckmillipore.com/TW/zh/product/msds/MDA_CHEM-102120, Accessed January 2023.
[62]https://www.tri-iso.com/documents/Perstorp_CAPA_6800_PDS.pdf, Accessed January 2023.
[63]https://www.totalenergies-corbion.com/media/eushodia/pds-luminy-l175-190507.pdf, Accessed January 2023.
[64]林麗娟，1994，“X 光繞射原理及其應用”，工業材料，86 期，100-109 頁。
[65]American Society for Testing and Materials, “The Definitive Guide to Plastic Tensile Testing”, ASTM-D638-14, (2017).
[66]M. Yuasa, T. Yamada, T. Taniyama, T. Masaoka, W. Xuetao, T. Yoshii, M. Horie, H. Yasuda, T. Uemura, A. Okawa, S. Sotome, “Dexamethasone Enhances Osteogenic Differentiation of Bone Marrow- and Muscle-Derived Stromal Cells and Augments Ectopic Bone Formation Induced by Bone Morphogenetic Protein-2”, POLS ONE, Vol.10, No. 2, Article. e91584, (2015).
[67]A. Martins, A.R. Duarte, S. Faria, A.P. Marques, R.L. Reis, N.M. Neves, “Osteogenic Induction of hBMSCs by Electrospun Scaffolds with Dexamethasone Release Functionality”, Biomaterials, Vol. 31, Isu. 22, pp. 5875-5885, (2010).
[68]American Society for Testing and Materials, “In Vitro Degradation Testing of Hydrolytically Degradable Polymer Resins and Fabricated Forms for Surgical Implants”, ASTM-F1635-11, (2020).
[69]A. Oyane, H.M. Kim, T. Furuya, T. Kokubo, T. Miyazaki, T. Nakamura, “Preparation and Assessment of Revised Simulated Body Fluids”, Journal of Biomedical Materials Research Part A, Vol. 65A, Isu. 2, pp. 188-195, (2003).
[70]American Society for Testing and Materials, “Standard Specification and Test Methods for Absorbable Plates and Screws for Internal Fixation Implants”, ASTM-F2502-17, (2017).
[71]https://www.turtle.com/1335039/Product/sawbones-1522-01, Accessed January 2023.
[72]J. Li, X.L. Lu, Y.F. Zheng, “Effect of Surface Modified Hydroxyapatite on the Tensile Property Improvement of HA/PLA Composite”, Applied Surface Science, Vol. 255, Isu. 2, pp. 494-497, (2008).
[73]L. Aliotta, V. Gigante, R. Geerinck, M.B. Coltelli, A. Lazzeri, “Micromechanical Analysis and Fracture Mechanics of Poly(lactic acid) (PLA)/Polycaprolactone (PCL) Binary Blends”, Polymer Testing, Vol. 121, Article. 107984, (2023).
[74]A. Visco, D. Nocita, A. Giamporcaro, S. Ronca, G. Forte, A. Pistone, C. Espro, “Effect of Ethyl Ester L-Lysine Triisocyanate Addition to Produce Reactive PLA/PCL Bio-polyester Blends for Biomedical Applications”, Journal of the Mechanical Behavior of Biomedical Materials, Vol. 68, pp. 308-317, (2017).
[75]C.M. Lin, Y.T. Hung, C.M. Tan, “Hybrid Taguchi–Gray Relation Analysis Method for Design of Metal Powder Injection-Molded Artificial Knee Joints with Optimal Powder Concentration and Volume Shrinkage”, Polymers, Vol. 13, No. 6, pp. 865, (2021).
[76]H.M. Kim, T. Himeno, T. Kokubo, T. Nakamura, “Process and Kinetics of Bonelike Apatite Formation on Sintered Hydroxyapatite in a Simulated Body Fluid”, Biomaterials, Vol. 26, Isu. 21, pp. 4366-4373, (2005).
[77]Q. Ma, K. Rubenis, Ó.E. Sigurjónsson, T. Hildebrand, T. Standal, S. Zemjane, J. Locs, D. Loca, H.J. Haugen, “Eggshell-derived Amorphous Calcium Phosphate: Synthesis, Characterization and Bio-functions as Bone Graft Materials in Novel 3D Osteoblastic Spheroids Model”, Smart Materials in Medicine, Vol. 4, pp. 522-537, (2023).
[78]J.Y. Choi, B.H. Lee, K.B. Song, R.W. Park, I.S. Kim, K.Y. Sohn, J.S. Jo, H.M. Ryoo, “Expression Patterns of Bone-related Proteins During Osteoblastic Differentiation in MC3T3-E1 Cells”, Journal of Cellular Biochemistry, Vol. 61, Isu. 4, pp. 609-618, (1996).
[79]Y. Ahmadzadeh, A. Babaei, A. Goudarzi, “Assessment of Localization and Degradation of ZnO Nano-particles in the PLA/PCL Biocompatible Blend Through a Comprehensive Rheological Characterization”, Polymer Degradation and Stability, Vol. 158, pp. 136-147, (2018).