聚合物結晶度對引導組織再生膜藥物釋放曲線的影響｜國立臺灣科技大學博碩士論文系統

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研究生：	Jeannete Cindy Claudia Jeannete Cindy Claudia
論文名稱：	聚合物結晶度對引導組織再生膜藥物釋放曲線的影響 The Effect of Polymer Crystallinity to Drug Release Profile for Third Generation of Novel Guided Tissue Regeneration Membrane
指導教授：	何明樺 Ming-Hua Ho 張博鈞 Po-Chun Chang
口試委員:	高震宇 Chen –Yu Kao 謝學真 Hsyue - Jen Hsieh
學位類別：	碩士 Master
系所名稱：	工程學院 - 化學工程系 Department of Chemical Engineering
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	112
中文關鍵詞：	導組織再生、藥物釋放、聚合物結晶度、電紡、甲硝唑、血小板衍生生長因子
外文關鍵詞：	Polymer Crystallinity, Drug Release Profile, Guided Tissue Regeneration, Electrospinning, Metronidazole, PDGF
相關次數：	點閱：225 下載：0
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上一筆

本研究製備了一種用於引導組織再生（Guided Tissue Regeneration, GTR）的新型電紡膜，用來預防感染並促進組織再生。該膜具有夾心狀結構，其中外部兩層是納米纖維，中間是緻密層。夾層的第一層結構由D，L-聚乳酸（poly-DL-lactic acid, PDLLA）納米纖維組成。這些納米纖維裝載甲硝唑（Metronidazole, MNZ）以促進抗菌性並使有害細菌引起的炎症反應最小化。中間層為緻密的L-聚乳酸（poly-L-lactic acid, PLLA）薄膜，其設計用於提供機械強度和細胞吸留性。在第三層中，PLLA奈米纖維在血小板衍生生長因子（platelet-derived growth factor, PDGF）的控制釋放中作為傳送的載體。
首先，我們找出靜電紡絲中高分子濃度、粘度和電場的最佳化參數，並研究MNZ和牛血清白蛋白（Bovine Serum Albumin, BSA）的濃度以獲得均勻的纖維。根據SEM分析，可以獲得均勻且連續化纖維的理想條件為流速為0.15 ml / h，施加電壓為18 kV，工作距離為6 cm，PDLLA和PLLA濃度分別為8％wt和3％wt。PDLLA-MNZ的直徑約為800nm且PLLA-BSA直徑約為600nm。BSA的帶電性使纖維的尺寸略微減小，而極性低MNZ對電紡纖維的直徑並未造成明顯變化。
接著，我們藉由培養7F2骨細胞對奈米纖維進行生物相容性的分析。藉由MTT測定結果，培養在奈米纖維上的7F2細胞活性高過於培養皿上的細胞活性，這是由於奈米纖維具有高比表面積，細胞可附著密度高，且其空隙體積有助於細胞生長和質傳，這也證實了本研究所製備的奈米纖維具有優秀的生物相容性。
為了評估該GTR膜在藥物遞送中的潛力，將MNZ和BSA裝載在PDLLA和PLLA纖維中，然後觀察在水溶液中的釋放曲線。結果證實PDLLA比PLLA更快釋放此兩種藥物，PLLA的釋放較緩慢的原因可能為其高結晶度和低親水性。
體內試驗顯示PDLLA-PDGF層相較於Geistlich Bio-Gide膠原膜，具有較傑出的細胞增生促進效果，細胞實驗也證實了GTR膜對纖維母細胞具有良好的阻擋效果，在未來的臨床應用應具有相當高的潛力。

In this study, a novel electrospun membrane for guided tissue regeneration (GTR) was fabricated to prevent infection and promote tissue regeneration. The membrane had a sandwich-like structure, where the outer two layers were nanofibrous, and the middle was a dense layer. The first layer of sandwich-like structure was composed of poly (D, L-lactide) PDLLA nanofibers. These nanofibers were loaded with metronidazole (MNZ) to promote antibacterial properties and minimize the possible inflammatory reaction caused by harmful bacteria. The second layer in the middle was dense poly (L-lactide) PLLA film, which was designed to provide the mechanical strength and cell occlusivity. In the third layer, PLLA nanofiber played the role as a delivery vehicle for the controlled release of platelet-derived growth factor (PDGF). The released PDGF has been proved to be highly efficient in the promotion of osteogenic differentiation and development.
First, the parameters of electrospinning including polymer concentrations, viscosity, and electric field were optimized. Moreover, the concentrations of metronidazole (MNZ) and bovine serum albumin (BSA) a model protein were also investigated to obtain the uniform fibers. According to SEM analysis, the optimized conditions were in the flow rate of 0.15 ml/h, the applied voltage of 18 kV, and the working distance of 6 cm with the PDLLA and PLLA concentration 8%wt and 3%wt, respectively. The diameters for PDLLA-MNZ nanofibers were about 800nm, and PLLA-BSA nanofibers were approximately 600nm with uniform structures. The sizes of fiber slightly decreased due to BSA loading, while the diameter has not significant changes with MNZ loading.
The analysis of biocompatibility and bioactivity nanofibers were conducted by culturing 7F2 osteoblast. From the cell viability that investigated by MTT assay, tissue culture grade polystyrene (TCPS) that represented the dense form have a lower cell viability than 7F2 that cultured on the nanofibers. With the comparison between dense and fiber, clearly prove that as the larger surface area as the higher density of the cell attachment. As we know that nanofibers have high surface to volume ratio, large void volume to aid cell seeding and penetration.
To evaluate the potential of this GTR membrane in drug delivery, PDLLA and PLLA were loaded with metronidazole and model protein, BSA, and then the releasing profile was observed. Due to their differences in polymer crystallinity, these encapsulated drugs were released with different profiles. Sustained released was observed over 28 days. The releasing profile verified that PDLLA released both drugs faster than PLLA did. In case of MNZ loading, MNZ was released up to 50% and 20% from PDLLA and PLLA, respectively. The slow releasing of PLLA was possibly caused by its high crystallinity and low hydrophilicity.
PDLLA-PDGF and PDLLA-MTZ showed high biocompatibility and facilitated wound healing compared with the conventional membrane. In vivo test showed cell proliferation was especially prominent on the PDLLA-PDGF layer in vivo compared to the Geistlich Bio-Gide collagen membrane. It can be seen on the alveolar ridge, that PDLLA-PDGF promoted osteogenesis significantly. The design represents a beneficial modification, which may be easily adapted for future clinical use.

TABLE OF CONTENT
ABSTRACT        iii
ACKNOWLEGEMENT    v
TABLE OF CONTENT    vii
LIST OF FIGURE        xi
LIST OF TABLE        xv
CHAPTER 1    INTRODUCTON    1
CHAPTER 2    LITERATURE REVIEW    3
2.1    Periodontitis    3
2.2    The Evolvement of Guided Tissue Regeneration Membrane    5
2.2.1    The First Generation of GTR Membrane    5
2.2.2    The Second Generation of GTR Membrane    6
2.2.3    The Third Generation of GTR Membrane    7
2.3    PLLA and PDLLA    9
2.4    Electrospun Membrane    10
2.4.1    The Illustration of Electrospinning Technique    11
2.4.2    Electrospinning Parameters    12
2.5    Metronidazole    15
2.6    Growth Factor Functionalized Electrospun Membrane    18
CHAPTER 3    MATERIAL AND EXPERIMENTAL PROCEDURE    19
3.1    Chemical and Material    19
3.2    Experimental Apparatus    21
3.3    Experimental Procedure    24
3.3.1    Preparation of Polymer Solution    24
3.3.2    Electrospinning of Third-generation of GTR Membrane    25
3.3.3    Dense Membrane Fabrication    26
3.3.4    Sterilization    26
3.4    Characterization of the Third Generation of GTR Membrane    26
3.4.1    Surface Morphology by Scanning Electron Microscopy (SEM)    26
3.4.2    Metronidazole Release Profile    26
3.4.3    BSA Release Profile    27
3.4.4    Water Contact Angle    27
3.4.5    Crystallinity Structure by D2 Phaser    28
3.5    Cell Experiment    28
3.5.1    Cell Type    28
3.5.2    Cell Culture    29
3.5.3    Preparation of Hemoflagellate-Minimum Essential (HO-MEM) Medium    30
3.5.4    Defreezing Cell    31
3.5.5    Cell Counting    31
3.6    Biocompatibility and Cytotoxicity Analysis    32
3.6.1    Cell Attachment    32
3.6.2    SEM Analysis for Cell Attachment    33
3.6.3    Immunochemical Staining    33
3.6.4    MTT Assay    34
3.6.5    Alkaline Phosphatase (ALPase) Assay    36
3.6.6    Occlusion Test    39
3.7    In Vivo Model for Therapeutic Efficiency    40
3.7.1    Micro-Computed Tomography Assessment    41
3.8    Statistical Analysis    42
CHAPTER 4    RESULT AND DISCUSSION    43
4.1    The Effect of Electrospinning Parameters    43
4.1.1    Concentration and Viscosity of Polymer    43
4.1.2    Electrical Field    46
4.1.3    Metronidazole Loading Concentration    49
4.1.4    Bovine Serum Albumin (BSA) Loading Concentration    52
4.2    Crystallinity Structure of PDLLA and PLLA    56
4.3    Drug Release Profile from PDLLA and PLLA Nanofiber    57
4.3.1    Metronidazole Release Profile    57
4.3.2    BSA Release Profile    59
4.3.3    MNZ-BSA Release Profile    61
4.4    Static Water Contact Angle    63
4.5    Biocompatibility and Cytotoxicity of PDLLA and PLLA Nanofiber    66
4.5.1    Cell Attachment and Its Morphology    66
4.5.2    Cell Viability on PDLLA/PLLA Electrospun Fiber    69
4.6    ALP Activity on PDLLA/PLLA Nanofiber    71
4.7    In Vivo Study (Done by Prof. Po-Chun Chang and NTU Dentistry lab member)    73
4.8    Occlusion Test    74
CHAPTER 5    CONCLUSION    77
REFERENCE        79
APPENDIX        91


LIST OF FIGURE

Figure 2.1 The observation of periodontitis from (a) surgical exposure of bone loss (arrow) resulting from periodontitis adjacent to maxillary anterior tooth (b) radiograph showing loss of bone support [1]    3
Figure 2.2 The illustration of the placement of GTR membrane treatment in the periodontitis treatment [15]    5
Figure 2.3 The commercial non-resorbable e-PTFE GTR membrane and its application [21]    6
Figure 2.4 Chemical structure of (a)poly(L-lactide) PLLA;    10
Figure 2.5 The schematic of electrospinning setup    12
Figure 2.6 Metronidazole structure    15
Figure 3.1 Mouse Bone Marrow Cells - 7F2    29
Figure 3.2 Schematic Diagram of Hemocytometer    32
Figure 3.3 Schematic Diagram of Hemocytometer’s Grid    32
Figure 3.4 The reaction of the dye MTT (yellow) into purple product formazan [90]    35
Figure 3.5 Micro BCA Assay Reaction [91]    38
Figure 3.6 Cell inserted with 0.8 µm membrane pore size    40
Figure 3.7 Schematic setup barrier function of GTR membrane [78, 92]    40
Figure 4.1 The effect of PDLLA concentration (%wt) to morphology of electrospun nanofiber membrane (a) 6% (b) 7% (c) 7.5% (d) 8%    43
Figure 4.2 The effect of PLLA concentration (%wt) to morphology of electrospun nanofiber membrane (a) 2% (b) 2.5% (c) 3% (d) 3.5%    44
Figure 4.3 Relationship between different polymer concentration corresponding with the viscosity    45
Figure 4.4 The SEM images of 3% PLLA and 8% PDLLA with the same electrical field of 3kV/cm    46
Figure 4.5 The fiber diameter with different polymer concentration with the same electric field of 3kV/cm    47
Figure 4.6. Bar diagram diameter PLLA and PDLLA in varied electrical field.    48
Figure 4.7 The SEM images of 3% PLLA and 8% PDLLA    49
Figure 4.8 SEM images of PDLLA loaded with (a) 0wt%, (b) 5wt%, (c ) 10wt% and (d) 20wt% Metronidazole    51
Figure 4.0.9 SEM images of PLLA loaded with (a) 0wt%, (b) 5wt%, (c ) 10wt% and (d) 20wt% Metronidazole    51
Figure 4.10 Fiber Diameter of PLLA and PDLLA loaded with various concentration of metronidazole    52
Figure 4.11. SEM images of PDLLA and PLLA fiber morphology with varied water content: 20µl, 60 µl and 100µl in 2ml polymer solution    53
Figure 4.12 Fiber diameter of PDLLA and PLLA loaded with BSA.    54
Figure 4.13 SEM Images of the BSA loading in 8%PDLLA and 3%PLLAwith BSA concentration of 0, 2, 4, and 8mg/200µl water in 2 ml polymer solution    55
Figure 4.14 XRD spectra of PLLA and PDLLA electrospun nanofiber    56
Figure 4.15 Cumulative release of MNZ-PDLLA    58
Figure 4.16 Cumulative release of MNZ from    58
Figure 4.17 The schematic diagram of the drug delivery systems in    59
Figure 4.18 Cumulative release of BSA-PLLA    61
Figure 4.19 Cumulative release of BSA from PLLA    61
Figure 4.20 Cumulative release of MNZ from    63
Figure 4.21 Water contact angle of fibrous membrane    64
Figure 4.22 Water droplet on (a) PDLLA, (b) PLLA, (c) PLLA+BSA, (d) PDLLA+MNZ fibrous membrane    64
Figure 4.23 Water contact angle of dense membrane    65
Figure 4.24 Water droplet on (a) PDLLA, (b) PLLA, (c) PLLA+BSA, (d) PDLLA+MNZ dense membrane    65
Figure 4.25 SEM Images of 7F2 osteoblast cell after cultivation for 1 day on (a) PLLA, (b) PDLLA, (c ) PLLA-BSA, (d) PDLLA-MNZ fibrous membrane    66
Figure 4.26 SEM Images of 7F2 osteoblast cell after cultivation for 5 day on (a) PLLA, (b) PDLLA, (c ) PLLA-BSA, (d) PDLLA-MNZ nanofiber    67
Figure 4.27 SEM Images of 7F2 osteoblast cell after cultivation for 7 day on (a) PLLA, (b) PDLLA, (c ) PLLA-BSA, (d) PDLLA-MNZ nanofiber    68
Figure 4.28 Fluorescent microscopic images of 7F2 seeded on the control and PDLLA nanofiber. F-actin was labeled by rhodamine-conjugated phalloidin (red), and nuclei was labeled by DAPI (blue) at day 1.    69
Figure 4.29 Cell Viability of Osteoblast Cell 7F2 on PLLA with and without MNZ.    70
Figure 4.30 Cell Viability of Osteoblast Cell 7F2 on PLLA with and without BSA.    71
Figure 4.31 ALP Expression of Osteoblast Cell 7F2 in PDLLA With or Without MNZ.    72
Figure 4.32 ALP Expression of Osteoblast Cell 7F2 in and PLLA With or Without BSA.    72
Figure 4.33 The micro-CT assessments of the FGM on the alveolar ridge on days 14 and 28. The representative sagittal sections from each group on days 14 and 28. Dash boxes indicate the osseous defects.    74
Figure 4.34 The viability of penetrated cells on bottom layer with GTR membrane and just supporting membrane.    76

LIST OF TABLE

Table 2.1 Metronidazole loaded into various polymeric blends for GTR membrane    17
Table 3. 1 The Electrospinning parameters used to obtain    25
Table 3.2 Mouse bone marrow cell 7F2 information    28
Table 3. 3 Cell passage number count    30


                                

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