生物可分解之溫感性水膠及其生醫應用之研究

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研究生：	陳進富 Chen, Chin-Fu
論文名稱：	生物可分解之溫感性水膠及其生醫應用之研究 The Study of Biodegradable Thermo-Sensitive Hydrogels and their Biomedical Applications
指導教授：	朱一民 Chu, I-Ming
口試委員:
學位類別：	博士 Doctor
系所名稱：	工學院 - 化學工程學系 Department of Chemical Engineering
論文出版年：	2010
畢業學年度：	98
語文別：	英文
論文頁數：	174
中文關鍵詞：	水膠、溫感性、生物可分解性、生醫應用、藥物遞送
外文關鍵詞：	hydrogel, thermosensitive, biodegradable, bioapplication, drug delivery
相關次數：	點閱：5 下載：0
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在過去十年中，有關溫度敏感性水膠於不同生醫領域之應用已被文獻廣泛地報導出來，其中包括藥物遞送、細胞包覆及組織修復。此種溫度敏感性水膠為一種可注射性之液體，可利用微小化之侵入方式進入體內於需求之組織、器官內固化或膠化。此外，溫度敏感性水膠具有下列優點，不需要有機溶劑、可以在特定部位形成膠體。因為具有簡單的溶液混合藥劑型態、與生理系統之生物相容性、方便的投藥方式，所以此種水性之溶液膠體系統於藥物治療及生醫之應用，可作為藥物遞送與控制系統、生物活性物質之遞送及組織工程之應用。當此成形水膠可提供生物相容性及生物降解性及無毒性之降解產物時，其在活體內之應用將可有很大之利基。在本研究中，一系列的生物降解型溫度敏感性水膠藉由甲基化聚乙二醇與不同之聚酯類單體如D,L-乳酸酐(D,L-lactide), 甘醇酸酐(Glycolide), b-丙內酯(b-propiolactone), d-戊內酯(d-valerolactone) 及 e-己內酯(e-caprolactone)進行開環共聚合反應。所製得之產物利用1H質譜儀(1H NMR)分析其結構皆如預期之物質，並利用可見光紫外光光度計分析臨界微胞濃度且使用粒徑分析儀量測微胞之粒徑大小，同時可用可見光紫外光光度計分析此類共聚物水膠之溫度敏感性，而水膠之黏彈性則可用流變儀加以量測，此種溶膠行為是一種奈米微胞隨溫度上升自動聚集為物理性膠體之現象。此類水膠之生物相容性利用瓊脂擴散法(agar diffusion)加以分析判斷。在生醫應用之測試則針對環孢靈及替考普寧作藥物遞送之測試，並作活體外對皮膚之生物黏膠測試，在活體內之測試則對骨組織缺損作修補及骨髓炎之治療測試，並完成複合組織之異體移植耐受性實驗。環孢靈及替考普寧可分別在31及13天持續釋放到約70 %左右。包含替考普寧的mPEG-PLGA水凝膠對骨髓炎治療是一種有效的方法，其結果可由組織切片染色及免疫分析加已證實。對於骨肌皮瓣的複合組織異體移植與抑制免抑反應的環孢靈藥物，mPEG-PVLA水膠系統是一種良好的同種異體移植的藥物遞送系統。

In the past ten years, an increasing number of thermo-sensitive hydrogels have been widely reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. These thermo-sensitive hydrogels are injectable fluids that can be introduced into the body in a minimally invasive manner prior to solidifying or gelling with the desired tissue or organ. Additionally, the thermo-sensitive hydrogels own many advantages, such as it does not require organic solvents and can be an in-situ forming gel. Because of the simplicity of pharmaceutical and biomedical uses of the water-based sol–gel transition that can be used as drug delivery-control systems, bioactive compounds delivery, and tissue engineering. When the formed gel is proven to be biocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivo applications where degradation is desired. In this study, a series of the biodegradable thermo-sensitive hydrogels were synthesised by the ring open polymerization of the methoxy polyethylene glycol with various kinds of the ester monomers, such as the D,L-lactide, glycolide, b-propiolactone, d-valerolactone and e-caprolactone. Results of those products defined by 1H n.m.r. spectras indicated that these materials were indeed the compounds expected. The critical micelle concentrations of those copolymers were measured by the UV-VIS Spectrophotometer and the particle sizes of those polymeric micelles were measured by the dynamic light scattering (DLS). The thermo-sensitive properties of those copolymeric hydrogels were measured by the UV-VIS Spectrophotometer. The viscoelastic properties of those copolymers were measured by Rheostress(Haake rheostress 600). The sol-gel transition behavior of diblock copolymers was confirmed by the nano micelle spontaneous aggregating to physical gel with increasing temperature. The biocompatability of those novel thermo-sensitive hydrogels were tested by the agar diffusion. The biomedical applications were tested by the drug delivery of cyclosporine A and teicoplanin, the bioglue for skin in vitro and the bone tissue repair in vivo, the therapy of osteomyelitis in vivo, and the induced tolerance of the composite tissue allotransplanation (CTA). The sustained release of cyclosporine A and teicoplanin was about 70% for 31 and 13 days, respectively. The mPEG-PLGA hydrogel containing teicoplanin was effective for treating osteomyelitis in rabbits as detected by the histological staining and immunoblotting analyses. The results of the osteomyocutaneous flap transfer indicated that the CTA with the immunosuppression drug, CsA, was an excellent allograft with the mPEG-PVLA sol-gel delivery system.

TABLE OF CONTENTS

誌謝................................................................................................................................I
中文摘要.......................................................................................................................II
ABSTRACT.................................................................................................................IV
LIST OF TABLES....................................................................................................XIX
LIST OF FIGURES…………………………………………………………………XX
LIST OF SCHEMES……………………………………………………………..XXVI
LIST OF ABBREVIATIONS……………………………………………………XXVII

CHAPTER 1
General Introduction

1.1 Biomaterials…………………………….........…………………………………….2
1.2 Types of Biomaterials..................……………….………………………………....3
1.3 Biodegradable Polymers.............………………………………………….……….8
1.4 Biodegradable Polymers as Injectable Drug Delivery System…………………….9
1.5 In Situ Gelling hydrogels for Drug Delivery…………………………..………….11
1.6 REFERENCES…………………………….…………………………..………….17

CHAPTER 2
Study on the Novel Biodegradable Thermo-Sensitive Hydrogels of mPEG-b- Polyesters Diblock Copolymers

2.1 INTRODUCTION………………………………………………………………...20
2.2 MATERIALS AND METHODS……………….………………………………...24
2.2.1 Materials………………………………………………………………………...24
2.2.2 Synthesis of diblock copolymers………………………………………………..24
2.2.3 Characterization of diblock copolymers……………………….………………..25
2.2.3.1 Gel permeation chromatography (GPC)………………………………............25
2.2.3.2 Proton nuclear magnetic resonance (1H NMR)…………………….................25
2.2.3.3 Lower critical solution temperature (LCST) measurement…………………...25
2.2.3.4 Critical micelle concentration (CMC) determination........................................26
2.2.3.5 Micelle size determination................................................................................26
2.2.3.6 Sol-to-gel viscosity measurement…………………….………………………27
2.2.4 Degradation of polymers in vitro……………………………………………….27
2.3 RESULTS AND DISCUSSION………………………………………….………30
2.3.1 Synthesis of mPEG-polyester Diblock Copolymers……………………………30
2.3.2 Solution properties…………………………………………………...................31
2.3.3 Sol-to-gel viscosity properties………………………………………………….33
2.3.4 Degradation of polymers in vitro……………………………………………….35
2.4 CONCLUSIONS…………………………………………………………………49
2.5 REFERENCES………………………………………………………..………….50

CHAPTER 3
Studies on the Preparation and Characterization of mPEG-Polyesters Biodegradable Bioglue for Bone Defect Repair

3.1 INTRODUCTION……………………………………………………………..…53
3.2 MATERIALS AND METHODS.………………………………………………..56
3.2.1 Materials………………………………………………………………………..56
3.2.2 Synthesis of diblock copolymers……………………………………………….56
3.2.3 Characterization of diblock copolymers………………………………………..57
3.2.3.1 Gel permeation chromatography (GPC)……………………………………...57
3.2.4 Biocompatibility test-agar diffusion……………………………………………57
3.2.5 Bone defect repair test………………………………………………………….58
3.2.6 Histology and histomorphometry………………………………………………59
3.3 RESULTS AND DISCUSSION…………………………………………………63
3.3.1 Bonding Strength of mPEG-polyester Diblock Copolymers……….………….63
3.3.2 Biocompatibility of mPEG-polyester Diblock Copolymers.………..................63
3.3.3 Bioglue for Bone Defect Repair………………………………………..............64
3.3.4 Compare to Commercial Bioglues……………………………………..............65
3.4 CONCLUSIONS……………………………………………………....................71
3.5 REFERENCES…………………………………………………………………...72

CHAPTER 4
Treatment of Osteomyelitis with Teicoplanin-Encapsulated Biodegradable Thermosensitive Hydrogel

4.1 INTRODUCTION………………………………………………….………..……74
4.2 MATERIALS AND METHODS…………………………………………………76
4.2.1 Materials………….……………………………………………………………..76
4.2.2 Synthesis of mPEG-PLGA diblock copolymers……………….……………….76
4.2.3 Characterization of diblock copolymers……………………………………......77
4.2.3.1 Proton nuclear magnetic resonance (1H NMR)…………………………........77
4.2.3.2 Gel permeation chromatography (GPC)………………………………….......77
4.2.3.3 Critical micelle concentration (CMC) determination.......................................78
4.2.3.4 Micelle size determination...............................................................................78
4.2.3.5 Determination of sol-gel phase transition.........................................................78
4.2.3.6 Sol-to-gel viscosity measurement…………………………………………….79
4.2.4 In vitro Degradation of the mPEG-PLGA polymers……………………………79
4.2.5 Teicoplanin release experiment in vitro ……………………..………………....80
4.2.6 Teicoplanin analysis…………………………………………………………….80
4.2.7 In vivo study…………………………………………………………………….81
4.2.7.1 Production of osteomyelitis in a rabbit model………………………..............81
4.2.7.2 Histological study……………………………………………………………..82
4.2.7.3 Western blot analysis………………………………………………………….83
4.2.7.4 Statistic analysis………………………………………………………………84
4.3 RESULTS AND DISCUSSION…………………………………………………..87
4.3.1 Characterization of the mPEG-PLGA hydrogel…………………….…………..87
4.3.2 In vitro drug release.……….................................................................................90
4.3.3 In vivo evaluation…………………..……………………………………………90
4.4 CONCLUSIONS……………………………………………………....................104
4.5 REFERENCES……………………………………………………………………105

CHAPTER 5
Controlled Release of Cyclosporine A from Biodegradable Amphiphilic Diblock Copolymer Sol-gel Drug Delivery System

5.1 INTRODUCTION………………………….……………………………………109
5.2 MATERIALS AND METHODS…………………………………………..…….113
5.2.1 Materials………………………………………………………………………..113
5.2.2 Synthesis of diblock copolymers………………………………………………113
5.2.3 Characterization of diblock copolymers……………………………………….114
5.2.3.1 Gel permeation chromatography (GPC)……………………………………..114
5.2.3.2 Proton nuclear magnetic resonance (1H NMR)……………………..……….114
5.2.3.3 Critical micelle concentration (CMC) determination......................................115
5.2.3.4 Micelle size determination..............................................................................115
5.2.3.5 Determination of sol-gel phase transition.......................................................115
5.2.3.6 Viscosity of sol-gel transition………………………………………..............116
5.2.4 Degradation of polymers in vitro……………………………………………....116
5.2.5 Drug release in vitro……………………..………………………..…………...117
5.2.6 CsA Analysis……..……………………………………………………………117
5.3 RESULTS AND DISCUSSION………………………………………………..121
5.3.1 Synthesis of mPEG-polyester Diblock Copolymers………………………….121
5.3.2 Sol-gel phase transition…….............................................................................122
5.3.3 Viscosity of sol-gel transition……………..………………………………….124
5.3.4 Degradation of diblock hydrogels in vitro……………………………………125
5.3.5 CsA Drug release from diblock hydrogels in vitro………………..………….126
5.4 CONCLUSIONS………………………………………………………………..133
5.5 REFERENCES………………………………………………………………….134

CHAPTER 6
Encapsulation of Cyclosporine A in Biodegradable Polymers for Tolerance Induction in the Composite Tissue Allotransplantation

6.1 INTRODUCTION………………………………………………………….......137
6.2 MATERIALS AND METHODS.……………………………………….……...141
6.2.1 Materials………………………………………………………………............141
6.2.2 Synthesis of mPEG-PVLA diblock copolymers……………………………...141
6.2.3 Determination of the sol-gel-sol transition……………….…………………..142
6.2.4 Sol-to-gel viscosity measurement……………..……………………………...142
6.2.5 Physical loading of CsA in diblock copolymer……………………..………...143
6.2.6 In Vivo Study……..……………………………………………………...……143
6.2.6.1 Evaluation In Vivo release of Cyclosporine A from the polymers and osmotic pump………………………………………………………………………..143
6.2.6.2 Aminal……………………..…….................................................................144
6.2.6.3 Grouping.......................................................................................................144
6.2.6.4 Immunosuppression protocol and non-myeloablative conditioning.............145
6.2.6.5 Allotransplantation procedure………….......................................................145
6.2.6.6 Assessment of Graft-versus-Host Disease (GVHD)…..................................147
6.2.6.7 Chimerism analysis........................................................................................147
6.3 RESULTS AND DISCUSSION………………………………………………..151
6.3.1 Synthesis of mPEG-PVLA Diblock Copolymers………………….…………151
6.3.2 Sol-gel-sol phase transition…….......................................................................151
6.3.3 In Vivo release of Cyclosporine A………..…………………………………..154
6.3.4 Chimerism analysis……………………………………………………….......155
6.3.5 Allotransplantation of osteomyocutaneous flap…….……………..………….156
6.4 CONCLUSIONS……………………………………………………………….165
6.5 REFERENCES…………………………………………………………………166

CHAPTER 7
Summary of this Thesis

7 Summary of this Thesis…………………………………………………….........169




LIST OF TABLES

Table 1.1 The advantages and disadvantages of traditional biomaterials for medical uses…………………………………………………….……………………7
Table 1.2 Polymers showing a LCST in water.………………………………………13
Table 2.1 The stoichiometry and molecular weight of mPEG-polyesters diblock copolymers…………………………………………….……………………29
Table 2.2 The solution properties of the mPEG-polyesters diblock copolymers……..29
Table 3.1 The stoichiometry and molecular weight of mPEG-polyesters diblock copolymers………………………………………………………………….61
Table 3.2 The Definition of Zone and Lysis Index in ASTM 895 Cytotoxicity Test…62
Table 4.1 The molecular weight and solution properties of the mPEG-PLGA diblock Copolymers………………………………………………………………....86
Table 5.1 The physical properties of the mPEG-polyesters diblock copolymers……120
Table 6.1 experimental design table…………………………………………………150


LIST OF FIGURES

Figure 1.1 Schematic illustration of TBH………………………….…………………10
Figure 1.2 Possible mechanism of drug release from biodegradable polymers.……..10
Figure 1.3 The chemical structure of poly(N-isopropylacrylamide).………………...13
Figure 1.4 The chemical structure of poly(ethylene glycol-b-propylene glycol-b-ethylene glycol) (Poloxamer) and its derivatives.……………....14
Figure 1.5 The chemical structure of poly(ethylene glycol)/poly(D,L-lactic acid-co-glycolic acid) block copolymers……..………………………….14
Figure 2.1a 1H NMR spectra of mPEG-PLGA diblock copolymers………………….37
Figure 2.1b 1H NMR spectra of mPEG-PPLA diblock copolymers………………….38
Figure 2.1c 1H NMR spectra of mPEG-PVLA diblock copolymers…………………39
Figure 2.1d 1H NMR spectra of mPEG-PCLA diblock copolymers…………………40
Figure 2.2a Critical micelle concentration of the aqueous solution of mPEG-PLGA diblock copolymers measured at 25 ℃. CMC was determined by the two extrapolated lines of the absorbance at 356 nm………………………….41
Figure 2.2b Critical micelle concentration of the aqueous solution of mPEG-PPLA diblock copolymers measured at 25 ℃. CMC was determined by the two extrapolated lines of the absorbance at 356 nm………………………….42
Figure 2.2c Critical micelle concentration of the aqueous solution of mPEG-PVLA diblock copolymers measured at 25 ℃. CMC was determined by the two extrapolated lines of the absorbance at 356 nm………………………….43
Figure 2.2d Critical micelle concentration of the aqueous solution of mPEG-PCLA diblock copolymers measured at 25 ℃. CMC was determined by the two extrapolated lines of the absorbance at 356 nm………………………….44
Figure 2.3 Temperature dependence of absorption of diblock copolymers with various compositions; polymer conc. 1 wt%..........................................................45
Figure 2.4 The viscosity versus temperature curves for mPEG-PLGA diblock copolymer aqueous solution at different concentrations (10-30 wt%)……...…………46
Figure 2.5 The viscosity versus temperature curves for various diblock copolymers aqueous solutions at same concentration (30 wt% )……………………….47
Figure 2.6 The degradation behavior of mPEG-polyester diblock copolymers determined by the weight lost method……………………………………..48
Figure 3.1 Bonding strength of the mPEG-polyesters bioglues compare with fibrin glue……………………………………………………………..………….67
Figure 3.2 The X-ray spectroscopy of the bone defect in the survival rabbit, A: for 1week, B: for 3 weeks……………………………………………………..68
Figure 3.3 The healing sample of bone tissue from the sacrificed rabbit after 4 weeks………………………...…………………………………………….69
Figure 3.4 The cross-section of healing bone tissue with HE Stain compared to the normal bone tissue. (normal bone: X100)…………………………………70
Figure 4.1 1H NMR spectra of mPEG-PLGA (550-1405) diblock copolymer……….94
Figure 4.2 Phase diagrams of the Gel I (550-1030), Gel II (550-1105) and Gel III (550-1405) diblock copolymers………………...…………………………95
Figure 4.3 Temperature-viscosity diagram for the Gel I (550-1030), Gel II (550-1105)  and Gel III (550-1405) copolymer solutions (20 wt%)………………...…96
Figure 4.4 In vitro degradation of the Gel III (550-1405). The mass loss (A) and molecular weight reduction (B) of Gel III at different concentrations (15, 20 and 25 wt%) were measured in a 31-day period…………………………..97
Figure 4.5 The release profiles of teicoplanin from Gel III (15, 20 and 25 wt%)…….98
Figure 4.6 Treatment of the S. aureus-induced osteomyelitis in rabbits with the teicoplanin-impregnated PMMA cement beads. (A) Induction of osteomyelitis by inoculation of S. aureus in the rabbit femur. Infection was subsided after 4-week (B) and 8-week treatment (C) with the teicoplanin-impregnated PMMA cement beads. (D) The PMMA cement beads created physical barriers that prevented new bone from growing into the defect……………………………………………………………..…....99
Figure 4.7 Treatment of the S. aureus-induced osteomyelitis in rabbits with the teicoplanin-loaded mPEG-PLGA hydrogel. (A) Inoculum of S. aureus and induction of the osteomyelitis. (B) and (C) Four and eight weeks after the teicoplanin-encapsulated mPEG-PLGA treatment, osteomyelitis was subsided and bony defect healed progressively. (D) Normal bone control..100
Figure 4.8 Histological analyses of the untreated and teicoplanin-treated osteomyelitic tissues. (A) H & E stain (200X) of the osteomyelitis samples. Arrows indicate the neutrophilic polymorphonuclear leukocytes and small lymphocytes aggregation in marrow abscess of osteomyelitis. After 4-week treatment with teicoplanin-impregnated PMMA or mPEG-PLGA, mixed inflammatory cell filtration was still observed in marrow. An almost thorough recovery from the bone infection was shown after 8-week treatment. (B) Pathological evaluation of the untreated and teicoplanin-treated osteomyelitis. Compared to the untreated group, treatment with teicoplanin carried by PMMA or by mPEG-PLGA significantly displayed a reduced histological grading scale after 4- and 8- weeks. *, P<0.05…………………………….101
Figure 4.9 Expression of the COL1A1 protein in the untreated and teicoplanin-treated osteomyelitic tissues. (A) After 4-week treatments, the indicated samples were subjected to analyze the COL1A1 expression by Western blot analysis. The expression of□□β-actin was served as a reference gene for loading control. The relative expression of the COL1A1 to □β-actin was calculated and shown in the right upper panel. #, P > 0.05. (B) Expression of the COL1A1 protein after 8-week treatment. *, P < 0.05; Control, normal bone; OM, osteomyelitis, PMMA, the teicoplanin-impregnated PMMA; mPEG-PLGA, the teicoplanin-encapsulated mPEG-PLGA hydrogel…….102
Figure 4.10 Abundance of the inflammation-dependent immunoglobulin G (IgG) in osteomyelitis. (A) Expression of IgG was detected in control, osteomyelitis (OM), and osteomyelitis received teicoplanin treatment for 4 weeks. The untreated osteomyelitic sample exhibited abundant expression of both heavy chains and light chains of IgG. The shorter exposure image was shown in the right panel. Treatment of osteomyelitis with the teicoplanin-loaded mPEG-PLGA hydrogel displayed a much lower IgG expression when compared to the treatment with the teicoplanin-impregnated PMMA. (B) Expression of IgG in osteomyelitis after 8-week treatment. The inflammation-dependent IgG was completely removed when the osteomyelitis was treated with either teicoplanin-impregnated PMMA or mPEG-PLGA for 8 weeks. Control, normal bone; OM, osteomyelitis, PMMA, the teicoplanin-impregnated PMMA; mPEG-PLGA, the teicoplanin-encapsulated mPEG-PLGA hydrogel…………………………103

Figure 5.1 1H NMR spectra of (a) mPEG-PLGA (b) mPEG-PVLA diblock copolymers………………………………………………………………..128
Figure 5.2 Sol-gel transition diagram of the mPEG-polyesters diblock copolymers....129
Figure 5.3 The viscosity versus temperature curves for various diblock copolymers aqueous solutions at same concentration (30 wt%)………………………130
Figure 5.4 The degradation behavior of mPEG-polyesters diblock copolymers determined by the weight lost method……………………………………131
Figure 5.5 The CsA release profiles of mPEG-polyesters diblock copolymers hydrogels with various concentrations in vitro……………………………………….132
Figure 6.1 The sol-gel-sol phase transition of mPEG-PVLA diblock copolymer aqueous solution…………………………………………………………………….158
Figure 6.2 The viscosity of sol-gel-sol phase transition of various concentrations for the mPEG-PVLA diblock copolymer aqueous solution……………………….159
Figure 6.3 The cyclosporine A released profiles for the single dose and the mPEG-PVLA sol-gel drug delivery system in vivo……………………….160
Figure 6.4 The chimerism level measured by the flow cytometry analysis of immunosuppression drug released from mPEG-PVLA sol-gel drug delivery system……………………………………………………………………..161
Figure 6.5 The chimerism level analysis of the CTA allograft with differential immunosuppression condition (a)multiple injection (b)mPEG-PVLA sol-gel drug delivery system………………………………………………………162
Figure 6.6 The survival rate of osteomyocutaneous flap CTA with various experimental model: (1) group I (2) group II (3) group III (4) group IV………………..163
Figure 6.7 The images for the osteomyocutaneous flap CTA surgery within 150days: (a) donor (b) osteomyocutaneous flap (c) recipient (d) recipient at day 20 (e) recipient at day 50 (f) recipient at day 150………………………………..164




LIST OF SCHEMES

Scheme 2.1 Schematic diagram of the synthesis routes of mPEG-polyester diblock copolymers……………………………………………………………......28
Scheme 3.1 Schematic diagram of the synthesis routes of mPEG-polyester diblock copolymers………………………………………………………………..60
Scheme 4.1 Schematic diagram of the synthesis routes of mPEG-PLGA diblock copolymers……………………….……………………………………….85
Scheme 5.1 Schematic diagram of the synthesis routes of mPEG-polyesters diblock copolymers……………………………………………………………….119
Scheme 6.1 Schematic diagram of the synthesis routes of mPEG-PVLA diblock copolymers……………………………………………………………….149

                                

1.6 REFERENCES

1. Clemson Advisory Board for Biomaterials “Definition of the word biomaterial”, The 6th Annnal Intermalionel Biomaterial Symposium, April 20-24, 1974
2. Middleton JC, Tipton AJ. Biomaterials 21: 2335, (2000).
3. Jeong B, Choi YK, Bae JH, Zentner G, Kim SW. J. Control. Release 62: 109, (1999).
4. Lewis DH. Drug Pharm. Sci. 45: 1, (1990).
5. Leong KW, Blott BC, Langer R, J. Biomed. Mater. Res. 19: 941, (1985).
6. Wuthrich P, Ng SY, Roskos RV, Heller J. J. Control. Release 21: 191, (1992).
7. Bennet DB, Li X, Adams N, Hoes CJT, Feijen J, Kim SW. J. Control. Release 16: 43, (1991).
8. Couvreur P, Puisieux F. Adv. Drug Del. Rev. 10: 141, (1992).
9. Cohen S, Bano MC, Visscher KB, Chow M, Allcock HR, Langer R. J. Am. Chem. Soc. 112: 783, (1990).
10. Kwon GS, Yokoyama M, Okano T, Sakurai Y, Kataoka K, Inoue S. J. Control. Release 11: 269 (1990).
11. Youxin L, Kissel T. J. Control. Release 27: 243, (1993).
12. Winzenburg G, Schmidt C, Fuchs S, Kissel T. Adv. Drug Del. Rev. 56: 1453, (2004).
13. Jeong B, Kim SW, Bae YH. Adv. Drug Del. Rev. 54: 37, (2002).
14. Stile RA, Burghardt WR, Healy KE. Macromolecules 32: 7370, (1999).
15. Bae YH, Okano T, Kim SW. J. Polym. Sci. B Polym. Phys. 28: 923, (1990).
16. Alexandridis P, Hatton TA. Colloids Surface A: PHysicochem. Eng. Aspects 96: 1, (1995).
17. Jeong B, Bae YH, Kim SW. J. Biomed. Mater. Res. 50: 171, (2000).
18. Schild HG. Prog. Polym. Sci. 17: 163, (1992).
19. Miyazaki S, Ohkawa Y, Takada M, Attwood D. Chem. Pharm. Bull. 40: 2224, (1992).
20. Jeong B, Bae YH, Kim SW. Colloids Surf. B 16: 185, (1999).
21. Lee DS, Shim MS, Kim SW, Lee H, Park I, Chang T. Macromol. Rapid Commun. 22: 587, (2001).
22. Kim MS, Seo KS, Khang G, Cho SH, Lee HB. J. Polym. Sci. A Polym. Chem. 42: 5784, (2004).
23. Kim MS, Hyun H, Khang G, Lee HB. Macromolecules 39: 3099, (2006).

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