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研究生:謝玠揚
研究生(外文):Chien-Yang Hsieh
論文名稱:聚麩胺酸及幾丁聚醣複合生醫基材之製程探討、性質改良及制放應用
論文名稱(外文):γ-poly(glutamic acid)/chitosan composite tissue engineering scaffolds – investigation of fabrication process, enhancement of cytocompatibility and application in controlled release
指導教授:謝學真
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:化學工程學研究所
學門:工程學門
學類:化學工程學類
論文種類:學術論文
論文出版年:2005
畢業學年度:93
語文別:英文
論文頁數:162
中文關鍵詞:幾丁聚醣聚麩胺酸
外文關鍵詞:chitosanγ-poly(glutamic acid)
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組織工程(tissue engineering)結合生醫基材(scaffolds)、細胞(cells)以及訊息分子(signaling molecules)的應用,使細胞在適合的基材上生長,並接受訊息分子調控,形成人體組織,用於修復或取代體內功能缺損的組織。基於此構想,基材、細胞、訊息分子三者之間必須密切配合。首先,所選用的基材,必須適合細胞生長,且能將訊息分子適當的釋放,以收調控之效。因此,在基材的選擇上,細胞相容性以及控制釋放特性成為主要考量因素。
為了建立適合組織工程應用的基材,本研究選用幾丁聚醣(chitosan)作為主要材料,並且使用冷凍凝膠法(freeze-gelation method)將其製備成多孔狀基材(porous scaffolds)。冷凍凝膠法是一個新的多孔基材製備方法,具有省時、節約能源以及減少溶劑殘留等優點。對於多孔狀基材而言,機械性質(mechanical properties)的表現在其實際應用上有相當大的影響,因此本研究針對機械性質,探討改變冷凍凝膠法的製程(process of fabrication)條件以及添加交聯劑(cross-linking reagent)對其造成的影響。在第三章中,針對冷凍凝膠法,我們選擇三項重要的製程參數(process variables)進行探討,包括:冷凍溫度(freezing temperature)、基材溶液中醋酸濃度(concentration of acetic acid in scaffold solution)、浸洗液中乙醇濃度(ethanol concentration in the rinse buffer)。在交聯處理方面,使用 glutaraldehyde(GTA),N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC)以及tripolyphosphate(TPP)等三種交聯劑對多孔狀基材進行交聯。製程參數實驗的結果顯示,較高的冷凍溫度和醋酸濃度,均可使基材的抗張強度(tensile strength)及伸長量(elongation)上升;乙醇濃度造成的影響比較不明顯,抗張強度微幅上升,而伸長量則是微幅下降。在交聯劑方面,GTA的效果最明顯,抗張強度有顯著提升,EDC 和 TPP的效果則不很顯著。根據以上的實驗數據, 我們可進一步在選定的操作調件範圍內成功地建立了一個數學模式,可定量描述製程參數和基材機械性質之間的關係。
當有效地製備幾丁聚醣多孔狀基材後,下一個目標就是改善它的細胞相容性(cytocompatibility)。雖然幾丁聚醣不具細胞毒性,且具有生物可分解性,但是對於某些細胞而言,它的細胞相容性表現不是很好。聚麩胺酸(γ-poly(glutamic acid),γ-PGA)是一種親水性(hydrophilicity)極佳的生物可分解性高分子,因此在第四章,我們利用聚麩胺酸來修飾幾丁聚醣基材。幾丁聚醣和聚麩胺酸混合後會因為帶電性相反易形成沈澱,為了得到均勻的混合溶液,我們發展了新的混合方式來避免沈澱的產生。由螢光染色的結果,可確認聚麩胺酸和幾丁聚醣在複合基材中均勻度相當良好。掃瞄式電子顯微鏡(SEM)的結果確認其多孔狀結構。膨潤度(swelling ratio)和接觸角(contact angle)的數據,顯示經過聚麩胺酸改質後,基材的親水性質有顯著的改善。機械性質(mechanical property)測定顯示添加聚麩胺酸亦可增加基材的抗張強度。由老鼠骨瘤細胞(rat osteosarcoma cells,ROS)的培養結果,顯示聚麩胺酸亦可顯著的提升基材的細胞相容性。綜上所述,由於良好的親水性、細胞相容性以及機械性質,聚麩胺酸/幾丁聚醣複合基材是一種在組織工程應用上極具潛力的新生醫材料。
在組織再生的科技上,基材、細胞以及訊息分子的恰當配合方能獲致理想的成效。因而在第五章,我們利用聚麩胺酸/幾丁聚醣複合基材作為訊息分子-骨形成蛋白(bone morphogenetic proteins,BMPs)的載體(carrier),探討其控制釋放(controlled release)特性。骨形成蛋白可以促進骨骼生成,被廣泛的應用在骨缺損的治療。另製作幾丁聚醣基材以及以冷凍乾燥法製備聚乳酸(PLLA)基材以為比較。由BMP-2釋放的結果顯示,聚麩胺酸/幾丁聚醣複合基材較其他基材在總釋放量及持續時間上的表現都較為優異,非常適合做為BMP-2的控制釋放載體。此外,在BMP-2的穩定性測試上,我們發現在p-dioxane(聚乳酸的溶劑)中,BMP-2被破壞的情況相當嚴重,而在醋酸(幾丁聚醣的溶劑)中則相對穩定許多。總結第五章的實驗結果,將聚麩胺酸/幾丁聚醣複合基材應用於BMP-2的控制釋放載體的表現相當良好,可以進一步應用在骨缺損及其他相關疾病的治療。
綜觀本研究,首先針對冷凍凝膠法製作多孔狀基材的製程參數加以探討,利用改變製程參數及交聯處理的條件,我們可以對基材的機械性質進行調控,獲致良好的幾丁聚醣基材。接著利用聚麩胺酸對其進行改質,顯著改善其親水性及細胞相容性。最後,利用聚麩胺酸/幾丁聚醣複合基材做為訊息分子BMP-2的載體,探討其控制釋放特性。根據各項實驗結果顯示,聚麩胺酸/幾丁聚醣複合基材是一個相當良好的組織工程基材,在材料強度、細胞相容性,親水性及BMP-2的控制釋放上,都有相當優異的表現。此外,未來它可以進一步應用在骨缺損的治療上,是相當具有應用潛力的生醫材料。
Tissue engineering provides a new way to recover physiological function by seeding cells onto scaffolds, together with the use of signaling molecules, to modulate cell growth. Hence, the cooperation between scaffolds, cells, and signaling molecules is becoming the major theme in tissue engineering. The scaffolds themselves must be biocompatible. Further, in many cases in which signaling molecules play an important role, a satisfactory release profile for signaling molecules is required. Thus, the biocompatibility of scaffolds and the release profile of signaling molecules are two important factors which should be considered.
To establish a tissue-engineered prosthesis, the first task is to fabricate suitable scaffolds. In this research, we attempted to fabricate various chitosan-based porous scaffolds using a newly developed “freeze-gelation” method. This method saves time and energy, and there is less residual solvent. For porous scaffolds, the mechanical properties are very important characteristics. The fabrication processes and cross-linking treatments significantly affect these characteristics. In Chapter 3, we investigate the influence of three process variables (freezing temperature, concentration of acetic acid, and ethanol concentration in the rinse buffer) on the freeze-gelation method and also the effect of adding the cross-linking reagents of glutaraldehyde (GTA), N-(3-dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride (EDC), and tripolyphosphate (TPP). For the three process variables, both the tensile strength and the elongation at tensile strength of the porous chitosan scaffolds increased with the freezing temperature and the concentration of acetic acid, whereas increasing the ethanol concentration in the rinse buffer only slightly increased the tensile strength but decreased the elongation. For cross-linking reagents, the data showed that both the tensile strength and elongation increased with the addition of GTA, while the effects of EDC and TPP were not obvious. Further, we successfully established a correlation to describe and predict the mechanical properties of scaffolds within our operating ranges of these three process variables.
After obtaining porous chitosan scaffolds, we tried to enhance their cytocompatibility. Although chitosan is non-toxic and biodegradable, it is not compatible with certain types of cells. In Chapter 4, we chose γ-poly(glutamic acid) (γ-PGA), a hydrophilic and biodegradable polymer, and blended it with the chitosan to prepare composite scaffolds. We developed a new method to obtain a homogeneous solution of chitosan and γ-PGA without the formation of polyion complexes. Both dense and porous γ-PGA/chitosan composite scaffolds were fabricated using the freeze-gelation method. The photographs of fluorescence staining confirmed the homogeneity of the γ-PGA/chitosan composite porous scaffolds. SEM micrographs showed that an interconnected porous microstructure was present in the porous scaffolds. The data of swelling ratio and contact angles both indicated that the hydrophilicity was obviously improved by γ-PGA. Additionally, the tensile strength of the porous γ-PGA/chitosan scaffolds was higher than that of the unmodified chitosan scaffolds. In the cytocompatibility test, the density of rat osteosarcoma (ROS) cells] on the 20% γ-PGA-modified surfaces was almost triple that on the unmodified chitosan surfaces on day 5. Therefore, the γ-PGA/chitosan composite scaffolds, due to their better hydrophilicity, cytocompatibility, and mechanical properties, are very promising biomaterials for tissue engineering applications.
Combining scaffolds, cells, and signaling molecules to induce the regeneration of tissues has become the central theme of tissue engineering. In Chapter 5, we demonstrate the use of signaling molecules in tissue-engineered scaffolds. Bone morphogenetic proteins (BMPs) can promote the formation of bone and cartilage tissues, and are utilized to cure bone defects. In order to provide for the stable and sustained release of BMPs, we used freeze-gelled γ-PGA/chitosan composite porous scaffolds as carriers for delivering BMP-2. For comparison, scaffolds made of freeze-dried chitosan, freeze-dried PLLA, and freeze-gelled chitosan were also prepared. From the controlled release data of BMP-2, the freeze-gelled γ-PGA/chitosan composite scaffolds provided the most-satisfactory release curve, followed by the freeze-gelled chitosan, freeze-dried chitosan, and freeze-dried PLLA scaffolds. In the stability test of BMP-2 in various solvents, p-dioxane (the solvent for PLLA) seriously deteriorated BMP-2, whereas acetic acid (the solvent for chitosan) did not. In brief, our results indicated that the freeze-gelled γ-PGA/chitosan composite scaffold is very promising as a carrier system for BMP-2. This novel biomaterial can be further developed and potentially applied to the therapy of bone defects and other related diseases.
This research investigated in detail the effects of process variables on the mechanical properties of the scaffolds. The chitosan scaffolds fabricated by the freeze-gelation method were further modified by γ-PGA, and the cytocompatibility of γ-PGA/chitosan scaffolds was examined using ROS cells. Finally, the scaffolds were used as carriers for a signaling molecule, BMP-2. Our results clearly indicated that the γ-PGA/chitosan scaffold is a very promising tissue engineering material. It has good biodegradability, cytocompatibility, and hydrophilicity. The microstructure and mechanical properties of this scaffold can easily be adjusted and enhanced by changing the conditions of the freeze-gelation and cross-linking processes. It can also be a good carrier for the delivery of BMP-2. In summary, the freeze-gelled γ-PGA/chitosan scaffold developed in this research is a very promising tissue engineering biomaterial, and can be applied to the therapy of bone defects and other diseases.
Acknowledgements..........................................i
Abstract..................................................v
中文摘要.................................................ix
Contents...............................................xiii
List of figures ......................................xix
List of tables ....................................xxiii
List of symbols and abbreviations.......................xxv

Chapter 1 Introduction..............................1
1.1 Background.......................................1
1.2 Objectives.......................................3
1.3 The scheme of this research......................5
1.3.1 Overview.........................................5
1.3.2 Part I : Optimization of the freeze-gelation and
cross-linking processes for preparing porous
chitosan scaffolds (chapter 3)....................6
1.3.3 Part II : Preparation of γ-PGA/chitosan composite
tissue engineering scaffolds (chapter 4)..........6
1.3.4 Part III : Fabrication and release behavior of a
novel freeze-gelled γ-PGA/chitosan scaffold as
a carrier for BMP-2 (chapter 5)...................6

Chapter 2 Literature survey........................9
2.1 Tissue engineering...............................9
2.1.1 History and origins of tissue engineering........9
2.1.2 Definition and development of tissue
engineering......................................13
2.1.3 Perspectives for the future.....................18
2.2 Chitosan........................................20
2.2.1 Introduction of chitosan........................20
2.2.2 Biomedical applications of chitosan.............22
2.2.3 Other applications of chitosan..................24
2.3 Freeze-gelation method..........................26
2.4 γ-poly(glutamic acid)...........................28
2.5 Bone morphogenetic protein-2....................30
2.6 Rat osteosarcoma cells..........................32

Chapter 3 Optimization of freeze-gelation and
cross-linking processes for preparing
porous chitosan scaffolds................35
Concept..................................................35
Abstract.................................................36
3.1 Introduction....................................37
3.2 Materials and methods...........................41
3.2.1 Materials.......................................41
3.2.2 Preparation of porous scaffolds by freeze-
gelation method..................................41
3.2.3 Preparation of cross-linked porous scaffolds....43
3.2.4 The influence of freezing temperature...........43
3.2.5 The influence of concentration of acetic acid in
chitosan solution................................43
3.2.6 The influence of the ethanol concentration in
the rinse buffer.................................44
3.2.7 Establishment of a predictive correlation.......44
3.2.8 Use of the two-level factorial design method
to check the correlation.........................45
3.2.9 Analysis of the mechanical properties of the
scaffolds........................................45
3.2.10 Analysis of scaffold structure by SEM...........46
3.3 Results and Discussion..........................48
3.3.1 Effects of cross-linking reagents...............48
3.3.2 The influence of freezing temperatures..........53
3.3.3 The influence of concentration of acetic acid
in chitosan solution.............................55
3.3.4 The influence of ethanol concentration in the
rinse buffer.....................................59
3.3.5 Establishing a predictive correlation...........61
3.3.6 Use the two-level factorial design to check
the correlation..................................63
3.3.7 Analysis of scaffold structure by SEM...........65
3.4 Conclusion......................................67

Chapter 4 Preparation of γ-pga/chitosan composite
tissue engineering scaffolds.............69
Concept..................................................69
Abstract.................................................70
4.1 Introduction....................................71
4.2 Materials and Methods...........................75
4.2.1 Materials.......................................75
4.2.2 Preparation of scaffolds........................75
4.2.3 Loss of γ-PGA in the fabrication process........78
4.2.4 SEM analysis for porous scaffolds...............78
4.2.5 Fluorescence microscopic observation of
porous scaffolds.................................79
4.2.6 DSC analysis....................................79
4.2.7 FT-IR analysis..................................79
4.2.8 Contact angles of dense films...................80
4.2.9 Swelling behavior of dense films................80
4.2.10 Analysis of mechanical properties...............80
4.2.11 Adsorption of protein onto scaffold surfaces....81
4.2.12 Determination of cytocompatibility..............81
4.2.13 Determination of cell activity by MTT assay.....82
4.3 Results and Discussion..........................83
4.3.1 The loss of γ-PGA in the fabrication process....83
4.3.2 SEM analysis of porous scaffolds................84
4.3.3 Fluorescence staining of chitosan and γ-PGA
in the porous scaffolds..........................86
4.3.4 DSC analysis....................................88
4.3.5 FT-IR analysis..................................90
4.3.6 Swelling behavior of dense films................92
4.3.7 Contact angles of dense films...................94
4.3.8 Mechanical properties of the porous scaffolds...96
4.3.9 Mechanical properties of the dense films........98
4.3.10 Adsorption of serum proteins onto scaffold
surfaces........................................100
4.3.11 Cytocompatibility of the scaffolds.............101
4.3.12 Determination of cell activity by MTT assay.....104
4.4 Conclusions....................................106

Chapter 5 Fabrication and release behavior of
a novel freeze- gelled γ-pga/chitosan
scaffold as a carrier for BMP-2.........109
Concept.................................................109
Abstract................................................110
5.1 Introduction...................................111
5.2 Materials and Methods..........................116
5.2.1 Materials......................................116
5.2.2 Preparation of the freeze-gelled chitosan
scaffolds and freeze-gelled γ-PGA/chitosan
scaffolds.......................................116
5.2.3 Preparation of the freeze-dried chitosan
scaffolds and freeze-dried PLLA scaffolds.......117
5.2.4 Analysis of the scaffold structure by SEM......117
5.2.5 Loading of BMP-2 on scaffolds..................117
5.2.6 Controlled release of BMP-2 from scaffolds.....119
5.2.7 Analysis of the release behavior of BMP-2......119
5.2.8 Stability test of BMP-2 in various solvents....121
5.3 Results and discussion.........................122
5.3.1 SEM analysis for porous scaffolds..............122
5.3.2 Controlled release of BMP-2 from scaffolds.....124
5.3.3 Stability test of BMP-2 in solvents............128
5.4 Conclusions....................................131

Chapter 6 Conclusions and future works............133
6.1 Conclusions....................................133
6.2 Future works...................................135

References..............................................139
Publications............................................159
Journal Papers..........................................159
Conference Papers.......................................159
Master Thesis...........................................161
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