臺灣博碩士論文加值系統

植入式治療在神經疾病中扮演重要的角色，本論文提供了兩種植入式藥物可控制性釋放元件的設計與特性研究。第一部分為利用電沈積法將攜帶藥物的磁性二氧化矽氧化鐵核殼結構奈米粒子沈積在可撓性的導電基板上製作成可撓性的磁控制藥物釋放元件。首先，將導電的塑膠基板以真空膠帶隔成具凹槽圖形的結構當作藥物的閘口，再將導電磁性奈米粒子均勻地沈積在凹槽內形成緻密堆疊的薄層結構；將此整合性的薄膜兩兩合併，可形成厚度在0.5公分以下的可控制性單開口藥物釋放元件。此元件可回應調控外在磁場的大小將所包覆的癲癇藥物乙琥胺(ethosuximide, ESM)以緩慢釋放、持久型釋放、階段式釋放或突放的模式釋放出來，並可呈現不同磁場下的藥物釋放動力學結果。另外，在大鼠的實驗結果也顯示，在磁場開啟下可使元件釋放出ESM並有效地抑制住癲癇鼠腦中的不正常地棘徐波放電，証實此元件有一定的療效。此種植入式可撓性磁敏感型生物晶片式元件不但具生物相容性，並可針對腦內傷口提供目標性且有效又快速藥物釋放治療。
　　另一方面，針對大腦神經疾病一般都以電訊號偵測腦部活動的方式為前提，為了能結合快速偵測病徵並馬上給予藥物的治療以達時效性處理發展出一種可控制性的電敏感型藥物釋放元件。首先利用改質過後具良好親疏水性的雙性幾丁聚醣，加入不同比例的交聯劑Genipin與結構強化劑TEOS以製備成水膠型態，實驗中証實Genipin與TEOS可以改善雙性幾丁聚醣水膠的膨潤性，並擁有良好的藥物釋放行為，並且利用單開口導電的透明塑膠載裝載其水膠，發現在不同外加電場的刺激下會有抑制藥物釋放的效果。其原因在於ESM分子在電場的作用下會呈現較穩定的電子共振態，使得帶負電的藥分子同時經歷反作用方向的電泳運動與電滲透作用，此相反兩力造成藥物分子從水膠擴散出的量減少因而減少了釋放速率。再者，隨著水膠中Genipin的量增加，導致原本帶負電的雙性幾丁聚醣鍊更加負電化，過盛的電滲透作用使水膠收縮力增強，大大將藥量擠出，因此在電場作用下Genipin含愈多，藥物受電場的限制便愈小。而帶負電的TEOS也會造成相同的結果。因此，控制水膠合成的Genipin與TEOS量再配合外加電場，此種可控制藥物釋放的元件應用性便大大提升。

Implanted therapy has played an important role in the field of neurobiology. A flexible magnetically-controllable drug delivery device was designed and fabricated using electrophoretic deposition of drug-carrying magnetic core-shell Fe3O4@SiO2 nanoparticles onto an electrically conductive flexible PET substrate. The PET substrate was first patterned to a desired layout and subjected to deposition. In doing so, a uniform and nanoporous membrane could be produced. After lamination of the patterned membranes, a final chip-like device of thickness less than 0.5 mm is formed that is used for controlled delivery of an anti-epileptic drug, i.e., ethosuximide (ESM). The release of useful drugs can be controlled by directly modulating the magnetic field, and the chip is capable of demonstrating a variety of release profiles (i.e., slow release, sustained release, step-wise release and burst release profiles). These profiles can follow a wide spectrum of patterns ranging from zero to pulsatile release kinetics depending on the mode of magnetic operation. When the magnetic field was removed, the release behavior was instantly ceased, and vice versa. A preliminary in-vivo study using Long-Evans rat model has demonstrated a significant reduction in spike-wave discharge after the ESM was burst released from the chip under the same magnetic induction as in vitro, indicating the potential application of the drug delivery chip. The flexible and membrane-like drug delivery chip utilizes drug-carrying magnetic nanoparticles as the building blocks that ensure a rapid and precise response to magnetic stimulus. Moreover, the flexible chip may offer advantages over conventional drug delivery devices by improvement of dosing precision, ease of operation, wider versatility of elution pattern, and better compliance.
Based on the CNS disease, in order to give a sudden treatment as a response to the signal detected, a flexible electrically-controllable drug delivery device was designed and fabricated by incorporating electrically sensitive CHC (modified chitosan) hydrogels into the electrically-conductive transparent plastic container. Si#CHC hydrogel membrane was first prepared by the addition of genipin and TEOS with different weight ratios. In doing so, the thin and brittle hydrogel membranes with different cross-linked density or interpenetration degree displayed excellent swelling behavior and drug release behavior. Membrane-based device is fabricated by the combination of Si#CHC hydrogels and a transparent plastic container with a single small open hole designed as an outlet for drug elution and two rectangle-shaped platinum plate placed in a constant distance with two parallel sides. Upon the application of an electrical stimulus, the dehygrogenated ESM displayed the electrophoretic movement toward the anode and the electroosmosis toward the cathode. Since the opposite force restricted the net drug release from the hydrogels, the rate of drug release out of the device is decreased. Moreover, the increase of in the degree of which CHC hydrogels crosslinked with genipin leads to the stronger negatively charged polymer. The effect of electroosmotsis, which also facilitates gel shrinkage and force drugs to move out, is enhanced in the presence of the electric voltage. Hence the release profiles under elecltrical stimuli showed the more the contents of genipin, the faster the rate of drug release. Similarly, interpenetration of negatively charged TEOS inside the CHC chains provided more negative charge to the CHC networks. It also give rise to the enhancement of hydrogel shrinkage. So under the induction of the electric field, the rate of ESM release is increased when the content of TEOS is increased.

Contents
中文摘要………………………………………………i
Abstract……………………………………………………………….……………..iii
Acknowledgments…………………………………………………………….. ....vi
Contents…………………………………………………………………………….vii
Figure Captions………….…………………………………………………………x Table Captions…………………………………………………………………....xiv
Chapter 1 Introduction…………………………………………………………....1
1-1 Introduction and Motivation……….………………………………………1
Chapter 2 Literature Reviews………………………………………………..…..4
2-1 Epilspsy……………………………………………………………………..4
2-1-1 Definition………………………………………………………..…..4
2-1-2 Mechanism………………………………………………….………5
2-1-3 Classification………………………..…………………….……..…5
2-1-4 Therapeutic Treatments………………………………...…………7
2-2 Therapeutic Implanted Device for Epilepsy………………….….………8
2-2-1 Physical Implanted Device for Epilepsy…….…………….……..8
2-2-2 Chemical Implanted Device for Epilepsy………..………………9
2-3 Magnetic Sensitive Nanoparticles..………………………….….……...11
2-3-1 Controllable Drug Delivery System……………………..………11
2-3-2 Magnetic Sensitive Drug Delivery System…………………….12
2-3-3 Iron Oxide Hybrid Nanoparticles……………………………......13
2-4 Electrical Sensitive Hydrogels………………………………..…………16
2-5 Three-Dimensional Drug Delivery Device…………..…………………18
2-5-1 Three-Dimensional Biomedical Device………………………...18
2-5-2 Microelectromechanical Systems in Bio-Appications……......18
2-5-3 Drug Delivery Microchip……………………………………..…..20
Chapter 3 Experimental Procedures………………………………………….22
3-1 A Flexible Drug Delivery Chip for the Magnetically-Controlled Release of Anti-Epileptic Drugs…………………………………………………...22
3-1-1 Synthesis of Core-Shell Fe3O4@SiO2 Nanoparticles..............22
3-1-2 Drug Encapsulation………………………………………...….…23
3-1-3 Electrophoretic Deposition of ESM Nanocarriers…………..…23
3-1-4 In-Vitro Drug Release Study………………………………..…...25
3-1-5 In-Vivo Study…………………………………...……...…….……27
3-2 A Flexible Drug Delivery Chip for the Electrically-Controlled Release of Anti-Epileptic Drugs……………………………………………...……….28
3-2-1 Synthesis of CHC………………………………………………...28
3-2-2 Preparation of Si#CHC Hydrogels………………………………29
3-2-3 Characterization…………………………………………… ….…30
3-2-4 Assembly of Membrane-Based Device…………………..…….31
3-2-5 Drug Release under Electrical Stimulation…………………….32
Chapter 4 Results and Discussion………………………………………….…33
4-1 A Flexible Drug Delivery Chip for the Magnetically-Controlled Release of Anti-Epileptic Drugs…………………………………………..………33
4-1-1 Core-Shell Nanoparticle Synthesis………………...…………...33
4-1-2 Drug Release Profile from Fe3O4@SiO2 Nanoparticles……....35
4-1-3 Characterization of the Fe3O4@SiO2 Membrane…………...…37
4-1-4 Magnetic-Driven Drug Release Behavior………………………40
4-1-5 In-Vivo Study………………………………………………………46
4-2 Controlled Anti-Epileptic Drug Release from the Device………….....49
4-2-1 Microstructural Analysis………………………………………….49
4-2-2 Drug Release Behavior from Si#CHC Hydrogels.……….……54
4-2-3 Drug Release Behavior of Chip-like Device under an Applied Electric Field………………………………..……………………..56
Chapter 5 Conclusion……………………………………………………………69
References…………………………………………………………………………72
Curriculum Vitae………………………………………...………………………..81
Publications……………………………………………………………………….81

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