臺灣博碩士論文加值系統

此研究中，我們將合成出不同PEO/氨基酸類嵌段共聚物，並探討其微胞以及成膠性質與生物相容性。發現此共聚物在低濃度環境下皆可成膠，而改變其分子量可造成水膠具有不同機械強度與成膠性質。造成水膠不同物理性質之原因，推測為胺基酸鏈段形成之二級結構所致。在體外生物相容性測試方面，將軟骨細胞包埋於水膠內進行培養。由結果中發現軟骨細胞基因表現量增加，細胞明顯增生，並且在培養過程中不會產生局部酸性造成pH值下降，可作為良好之軟骨細胞培養載體。在掃描式電子顯微鏡檢測下，可看出水膠結構型態為膠原纖維狀，並且可看出軟骨細胞分泌細胞外間質附著於纖維之中，顯示水膠材料對於軟骨細胞生物相容性極佳。在glycosaminoglycans細胞染色檢測下，可看出良好軟骨細胞之基因表現。由以上實驗結果可得知，mPEG-alanine水膠在軟骨組織工程有極大應用潛力，未來將朝生物體應用更深入研究探討。

In the recent decades, polymer scientists have begun to look into the remarkable achievements of nature to extract particular knowledge for the design of improved biomaterials. This has led to an increase in hybrid polymers that use biological concepts to control the structures and properties of these hybrids. Combining synthetic materials with peptides, the basic building block of the body, into a single macromolecule offers many possibilities previously unachievable with a single material.
Peptides have the tendency to arrange into a variety of secondary structures that may be exploited in copolymer systems for their stabilizing and self-assembling character through hydrogen bonding. This dissertation sets out to study a collection of poly(ethylene oxide)-peptide materials and discusses their synthesis method, chemical and physical characteristics, and potentials as nanoscale carrier and hydrogel for use in drug and cell delivery.
This study uses amine-terminated PEO-based polymers to initiate ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) form of different amino acids to provide peptide hybrid materials. These materials exhibit the propensity for secondary structure formation in both solid and solubilized forms to provide stability and formation of distinct microarchitectures. Two different PEO-based polymers were used, including poly(ethylene oxide) – poly(propylene oxide) – poly(ethylene oxide) (PEO-PPO-PEO, Pluronic®) and methoxy poly(ethylene glycol) (mPEG).
In the first section, amine-terminated Pluronic was used to synthesize a series of Pluronic-oligo(alanine) and Pluronic-oligo(phenylalanine) copolymers. These copolymers were characterized and evaluated for their ability to carry a model hydrophobic drug, curcumin. The encapsulation efficiency of curcumin increased drastically after the addition of peptides. Furthermore, increased cytotoxicity against HeLa cells and cellular uptake were observed with alanine-contianing nanoparticle formulations. These copolymers were also prepared as thermosensitive hydrogels and exhibited decreased gelation concentration, extended in vitro and in vivo residence time, increased cell compatibility, and change in microarchitecture when compared to native Pluronic. Taken together, results suggest that this material may be suitable for various bio-applications
In the second half of the study, amine-terminated mPEG was used to synthesize a series of neutral, positively charged, and negatively charged copolymers using alanine-NCA, lysine-NCA, and aspartic acid-NCA respectively. The microarchitecture of mPEG-poly(alanine) differed significantly from those of other synthetic thermosensitive hydrogels in its strand-like appearance. Chondrocytes cultured within these hydrogels formed homogenous cell clusters with prolonged incubation. Biochemical analysis and real time polymerase chain reaction (real time RT-PCR) were used to evaluate the relationship between hydrogel characteristics and chondrogenic potential of encapsulated chondrocytes. In the final section, oligo(lysine) and oligo(aspartic acid) were added to the peptide end of mPEG-poly(alanine) to increase solubility, helical stability, and confer pH sensitivity.
In summary, these studies demonstrated that peptide hybrid materials are a feasible option for various bio-applications ranging from drug delivery to tissue engineering in both nanoparticle and hydrogel forms. These structures showed excellent stability and potential degradability in vivo as well as biomimetic character. Further in vivo evaluations are underway to examine the ability of hydrogels to support extended drug release and tissue generation. These materials clearly hold promise as an interesting class of biomaterial with a wide range of application.

Abstract of the Dissertation i
Table of Contents v
Vita xii

Chapter I: 1
General introduction and literature review
1.1 General Introduction 2
1.2 Amphiphilic block copolymers 3
1.2.1 Block copolymer assembly 4
1.2.2 Stimuli-responsive block copolymers 6
1.2.3 Bio-related applications of amphiphilic block copolymers 9
1.3 Peptides for peptide hybrid polymers 10
1.3.1 Amino acids 11
1.3.2 The amide bond and primary structure 11
1.3.3 Secondary structures 12
1.3.4 Tertiary structure 13
1.4 Peptide hybrid polymers 15
1.5 PEO-PPO-PEO (Pluronic) 17
1.5.1 Behavior in aqueous solution 17
1.5.2 Improving Pluronic 20
1.6 Cartilage tissue engineering 22
1.6.1 The extracellular matrix 22
1.6.2 Mimicking the ECM 24
1.7 Aims of the study 26
1.8 References 26

Chapter II: 35
Oligo(alanine)- modified PEO-PPO-PEO: synthesis and characterization

2.1 Introduction 36
2.2 Materials and methods 38
2.2.1 Materials 38
2.2.2 End group modification of PEO-PPO-PEO 38
2.2.3 Ninhydrin assay for verification of amination 39
2.2.4 Preparation of N-carboxyanhydride form of amino acids 39
2.2.5 Ring opening polymerization 40
2.2.6 Characterization of the copolymers 41
2.3 Results and discussion 41
2.3.1 Synthesis of the copolymer 41
2.3.2 Effect of peptide addition on physical characters 47
2.4 Conclusion 49
2.5 References 49

Chapter III: 52
Oligo(alanine)-modified PEO-PPO-PEO: encapsulation of curcumin and in vitro evaluations
3.1 Introduction 53
3.2 Materials and methods 54
3.2.1 Materials 54
3.2.2 Preparation of empty and curcumin-loaded nanocarriers 55
3.2.3 Characterization of micelles 55
3.2.4 Entrapment and drug release 56
3.2.5 Cytotoxicity 56
3.2.6 Internalization of curcumin by cells 57
3.3 Results and discussion 57
3.3.1 Characterization of nanoparticles 57
3.3.2 Preparation of free and drug-loaded carriers 58
3.3.3 Characterization of free and drug-loaded carriers 59
3.3.4 Cytotoxicity against HeLa 64
3.4 Conclusion 69
3.5 References 70

Chapter IV: 73
Oligo(alanine)-modified PEO-PPO-PEO: enhanced gelation properties and their potential as cell carrier
4.1 Introduction 74
4.2 Materials and methods 74
4.2.1 Materials 74
4.2.2 Probing secondary structures 74
4.2.3 Molecular chain movements 75
4.2.4 Gelation characteristics of hydrogels 75
4.2.5 In Vitro disintegration of hydrogels 76
4.2.6 Scanning electron microscopy 76
4.2.7 Release of a model dye 76
4.2.8 In vitro and in vivo evaluation of cell compatibility 77
4.3 Results 77
4.3.1 Presence of secondary structures 78
4.3.2 1H NMR and 13C NMR 82
4.3.3 Gelation profile 87
4.3.4 SEM and disintegration 89
4.3.5 Release of a model dye 92
4.3.6 In vitro and in vivo evaluations 93
4.4 Discussion 99
4.4.1 Secondary structures and microscale arrangements 99
4.4.2 Gelation character 104
4.4.3 Cellular compatibility 105
4.5 Conclusion 106
4.6 References 106

Chapter V: 110
mPEG-poly(peptide) hydrogels: distinct microarchitecture and promotion of chondrogenic cell clusters
5.1 Introduction 111
5.2 Materials and methods 113
5.2.1 Materials 113
5.2.2 Synthesis of mPEG-poly(alanine) 114
5.2.3 Solution and gelation properties 115
5.2.4 Incorporation of chondrocytes 115
5.2.5 Biochemical analysis 116
5.2.6 Gene expression of encapsulated chondrocytes 116
5.2.7 LIVE/DEAD and alcian blue staining 117
5.2.8 Scanning electron microscopy evaluation 117
5.2.9 Statistical analysis 117
5.3 Results and discussion 117
5.3.1. Synthesis of a series of mPEG-PA copolymers 117
5.3.2 Sol-gel profile and rheology measurements 120
5.3.3 Studies of secondary structures in copolymer solutions 122
5.3.4 Hydrogel microstructure 125
5.3.5 Biochemical analysis and real time-PCR 127
5.3.6 LIVE/DEAD and alcian blue staining 130
5.3.7 Hydrogel morphology after prolonged culture 133
5.4 Conclusion 135
5.5 References 135



Chapter VI: 141
Charged mPEG-poly(peptide) materials: Synthesis and characterization

6.1 Introduction 142
6.2 Materials and methods 143
6.2.1 Materials 143
6.2.2 Preparation of NCA form of charged amino acids 143
6.2.3 Preparation of charged mPEG-oligo(peptide) materials 144
6.2.4 Characterization of copolymers 145
6.2.5 Characterization of micelles and hydrogels 145
6.2.6 Biocompatibility 145
6.3 Results and discussion 146
6.3.1 Characterization of copolymers 146
6.3.2 Secondary structures 149
6.3.3 pH sensitivity character 150
6.3.4 Hydrogel microarchitecture 159
6.3.5 Biocompatibility 160
6.4 Conclusion 160
6.5 References 161

Afterword 164

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