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研究生： 黃思晴
Huang, Szu-Ching
論文名稱： 運用生物可分解高分子與礦物質開發孔洞結構之骨骼替代物
Synthesis of Porous Biodegradable Polymeric Scaffolds with Bone Minerals as Bone Substitute
指導教授： 王潔
Wang, Jane
口試委員: 賴伯亮
陳怡文
學位類別： 碩士
Master
系所名稱： 工學院 - 化學工程學系
Department of Chemical Engineering
論文出版年： 2017
畢業學年度： 105
語文別： 英文
論文頁數： 79
中文關鍵詞： 生物可降解 、高分子 、骨頭再生 、組織工程 、孔洞支架
外文關鍵詞： Biodegradable, Polymer, Bone regeneration, Tissue engineering, Porous scaffold
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    • 骨組織再生對於骨頭受損之病人十分重要，而骨支架移植是骨折及腫瘤手術後常用於刺激骨再生的治療方式；自體、異體與人造支架是最為常見的骨頭移植物，其中人造支架能夠引發較少的排斥免疫反應。在此研究中，利用聚甘油癸二酸酯（PGS）和聚（甘油癸二酸）丙烯酸酯（PGSA）混摻骨組織中常見之礦物質，進一步製成具有孔洞結構的骨頭移植物。
    本研究可分為兩個部分：首先，PGS孔洞支架係經由鹽析法而成，骨頭磷酸鹽類hydroxyapatite（HAP）與whitlockite（WH）也一併加入結構當中增強機械強度及骨傳導性、骨誘導性，並測試孔洞大小及礦物質比例對性質所造成的影響；第二，藉由3D列印技術，製造出PGSA孔洞結構，控制孔洞形狀與分佈進而獲得不同性質的骨頭支架。
    PGS孔洞結構具有高孔隙率（約80%）與高滲透率（1到8 m2），在加入礦物質後明顯提高其壓縮強度；PGS支架的降解性也受孔洞大小、礦物質比例影響。在細胞培養實驗中，可以看出材料的滲透率影響細胞生長；PGS支架在動物實驗當中呈現低排斥性，血管新生的現象也表示此移植物有助於組織再生。不同礦物質對於PGS孔洞支架有不同的影響，在HAP和WH相比之下，WH的高溶解性與低強度影響了PGS/WH材料的機械與降解性質。而細胞培養中，WH的高誘導性並未加強MC3T3-E1分化的基因表現。
    PGSA支架有較PGS高的壓縮強度、較低的降解速度。PGSA孔洞材料不如PGS材料受到滲透率的限制，HAP所具備的骨傳導性能高度展露，並促進細胞在支架上的生長。PGSA支架的性質受孔洞大小、分佈等影響，也因此能藉由設計不同3D結構獲得符合目標組織所需的性質結構。藉由初步的測試，PGS/mineral與PGSA/mineral孔洞支架表現出高生物相容性，而可調控的機械與降解性質，搭配高孔隙率與滲透率，更有利於這兩種材料在組織工程上的應用。

    Bone grafting is a common treatment for bone fracture and tumor by facilitating the regeneration of bone tissue. Autologous, allologous or synthetic grafts are often used in bone grafting, and implantation of synthetic scaffold causes less rejection and inflammation compared to ordinary bone graft. In this project, synthesis of biodegradable porous scaffold for orthopedic implant was developed. Poly(glycerol sebacate) (PGS) and poly(glycerol sebacate) acrylate (PGSA) were fabricated into porous scaffolds with the supplement of bone minerals.
    First, PGS porous structure was manufactured by salt-leaching method. Hydroxyapatite (HAP) or whitlockite (WH) was added to increase mechanical strength and osteoconduction. Effects of different pore sizes and mineral ratio were studied. Second, PGSA porous structure was manufactured by 3D printing technique. Mechanical and physiological properties were obtained by designing different pore structure.
    Porosity and permeability tests showed that porosity of PGS scaffolds remained 80% between different batches, with relatively high hydraulic conductivity compared to other common bone scaffolds. The compression strength was also enhanced by adding HAP or WH. Enzymatic degradation test showed that polymer erosion rate was effect by total surface area and permeability. In cell culture test, cell viability was affected by permeability of scaffolds. Minimum inflammation and angiogenesis were observed after 3 months implantation.
    Compared between HAP and WH scaffolds, PGS/WH scaffolds had higher degradation rate but lower compressive strength, due to the relatively high solubility and low mechanical strength of WH mineral. On the other hand, it showed that WH scaffolds were less osteoinductive than HAP scaffolds in MC3T3-E1 cell differentiation.
    PGSA porous scaffolds had higher compressive strength and lower degradation rate than PGS scaffolds. With similar permeability of PGSA and PGSA/HAP scaffolds, viability of MC3T3-E1 cells was higher on osteoconductive PGSA/HAP scaffolds. Properties of PGSA porous scaffolds were affected by controllable pore sizes and arrangements. Therefore, with various pore construction, PGSA scaffolds with desirable characteristics could be fabricated.
    PGS/HAP and PGSA/HAP porous scaffolds with good biocompatibility were successfully fabricated. Biodegradability and mechanical strength could be modified for medical applications by changing the pore size and mineral ratio. From these results, it is believed these biodegradable porous substitutes are worth for further investigation and utilization of the porous scaffolds in clinical practice is promising.

    Abstract 3 List of Figures 8 List of Tables 11 1 Research Background 12 1.1 Introduction to Tissue Engineering 12 1.1.1 Overview of Tissue Engineering 13 1.1.2 Bone Tissue Regeneration 15 1.2 Criteria of Tissue Engineering Scaffolds 16 1.2.1 Material Selection 17 1.2.2 Ideal Physical Features of Medical Scaffolds 18 1.2.3 Common Scaffold Fabrication Methods 20 1.3 Biomaterials in Bone Tissue Engineering 23 1.3.1 Overview of Biomaterial Science 24 1.3.2 Biodegradable Polymeric Biomaterials 24 1.3.2.1 Poly(Glycerol Sebacate) 24 1.3.2.2 Poly(Glycerol Sebacate) Acrylate 26 1.3.3 Minerals in Bone Tissue Engineering Scaffolds 28 1.3.3.1 Calcium Phosphate 28 1.3.3.2 Whitlockite 30 1.3.3.3 Calcium Phosphate and Bone Remodeling 30 1.3.3.4 Bone Healing Process Induced by Magnesium Releasing Whitlockite 31 1.4 Motivation and Purpose 34 2 Experimental Design 35 2.1 Materials and Equipment 35 2.2 Porous PGS/Mineral Scaffold 37 2.2.1 Synthesis of PGS 37 2.2.2 Salt Leaching Method 37 2.3 Porous PGSA/HAP Scaffold 38 2.3.1 Synthesis of PGSA 38 2.3.2 Porous PGSA Scaffold Design 38 2.3.3 3D Printed Porous Scaffold 39 2.4 Characterization of Porous Scaffolds 40 2.4.1 Porosity Measurement 40 2.4.2 Permeability Test 40 2.4.3 Compression Test 41 2.4.4 Enzymatic Degradation Test 41 3 Result and Discussion 42 3.1 Porous PGS/Mineral Scaffolds 42 3.1.1 Scaffold Morphology 42 3.1.2 Porosity 44 3.1.3 Permeability 45 3.1.4 Compressive Strength 46 3.1.5 Enzymatic Degradation Rate 49 3.1.6 Cell Culture 53 3.1.7 Rat Calvarial Defect Experiment 57 3.2 Porous PGSA/HAP Scaffolds 60 3.2.1 Morphology of Scaffold Structure 60 3.2.2 Porosity 63 3.2.3 Compression Strength 64 3.2.4 Enzymatic Degradation Rate 66 3.2.5 Cell Culture 68 4 Conclusion 69 5 Future Work 71 6 References 72

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