Chen S.-D., Yeh K.-H., Huang Y.-H., Shaw F.-Z.* (2010) Effects of intracortical administration of ethosuximide in rats with spontaneous or pentylenetetrazol-induced spike-wave discharges. Epilepsia, in revision. (IF: 4.052) (SCI)
Lee H.-W., Huang H.-Y., Chen S.-D., Shaw F.-Z.* (2010) Chronic lamotrigine treatment on a rat model with spontaneous spike-wave discharges. Epilepsia, in submission. (IF: 4.052) (SCI)
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Liang SF, Chang WL, Liao YC, Chen YJ, Wang HC, Shaw FZ. (2010) On-line real-time seizure detection in rats with spontaneous absence or pentylenetetrazol-induced epilepsy.
Journal of Neural Engineering, in submission. (IF: 3.739) (SCI)
Shaw FZ*, Liao YF, Chen RF, Lin RCS. The zona incerta in spontaneous spike-wave discharges of the rat. Cerebral Cortex, in preparation. (impact factor: 5.907) (SCI) Shaw FZ, Huang CC. “Distortionless powerline interference removal method using S-transform” 中華民國專利 97133429.
Liao YC, Hsieh CH, Liang SF, Young CP, Chang DW, Shaw FZ. A Wireless and Portable Real-time Epilepsy Detection and Control System. Biomedical Engineering Society 2009 Annual Symposium (2009 生物醫學工程年會及科技研討會), Taipei, Taiwan (2009).[學生 口頭論文競賽佳作]
Shaw F.-Z.* (2010) Epileptic rat models for a closed-loop seizure controller. Annual Meeting of Taiwan Epilepsy Society, Taipei, Taiwan.
Shaw F.-Z.* (2010) Epileptic rat models for a closed-loop seizure controller. 4th Asian Epilepsy Surgery Congress, Taipei, Taiwan.
Shaw F.-Z.*, Yeh K.-H. (2010) Lateral somatosensory cortex in spontaneous and PTZ-induced spike-wave discharges of the rat evaluated by ethosuximide. 16th World Congress of Basic and Clinical Pharmacology, Copenhagen, Denmark.
Liang S.-F., Shaw F.-Z., Young C.-P., Chang D.-W., Liao Y.-C. (2010) A closed-loop brain computer interface for real-time seizure detection and control. 32nd Annual International IEEE EMBS conference, Buenos Aires, Argentina.
Lee H.-W., Huang H.-Y., Shaw F.-Z.* (2010) Chronic lamotrigine treatment on seizure and anxiety-/depression-like behaviors of the rat with spontaneous absence epilepsy. 49th Annual Conference of Taiwanese Psychology Association, Chiayi, Taiwan.
Yen-Po Chang, Kun-Ho Liu, Chih-Shin Chao, San-Yuan Chen*, Dean-Mo Liu, Synthesis and characterization of mesoporous Gd2O3 nanotube and its use as a drug-carrying vehicle, Acta Biomaterialia 6 (2010) 3713–3719. (IF=3.98, N/M=5.1%)
Shang-Hsiu Hu, Kuan-Ting Kuo, Wei-Lin Tung, Dean-Mo Liu,and San-Yuan Chen* , A Multifunctional Nanodevice Capable of Imaging, Magnetically Controlling, and In Situ Monitoring Drug Release, Advanced Functional Materials, 19, 3396–3403 (2009) (IF=6.99, N/M=4.21%)
Wei-Chen Huang, Kun-Ho Liu, Shang-Hsiu Hu, San-Yuan Chen* and Dean-Mo Liu, “A Flexible Drug Delivery Chip for Magnetically-Controlled Release of Anti-Epileptic Drug”, Journal of Controlled Release 139 (3), 221-228,NOV (2009) (IF=5.949, N/M=5.90%)
C. P. Young, S. F. Liang, D. W. Chang, Y. C. Liao, F. Z. Shaw and C. H. Hsieh, “A Portable Wireless On-line Closed-loop Seizure Controller in Freely Moving Rats,” IEEE Trans. on Instrumentation & Measurement, vol.59, No. 10, in press, 2010.
S. F. Liang, H. C. Wang, W. L. Chang, “ Combination of EEG Complexity and Spectral Analysis for Epilepsy Diagnosis and Seizure Detection,” EURASIP Journal on Advances
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Signal Processing, vol. 2010, 853434, 15 pages, 2010a.
S. F. Liang, F. Z. Shaw, C. P. Young, D. W. Chang, and Y. C. Liao, “A closed-loop brain computer interface for real-time seizure detection and control,” 32rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 4950-4953, Buenos Aires, Argentina, Aug. 31 – Sep. 4, 2010b
S. F. Liang, W. L. Chang, and H. M. Chiueh, “EEG-based Absence Seizure Detection Methods,” in Proceeding of International Joint Conference on Neural Networks 10, Barcelona, Spain, July, 1725-1728, 2010c.
D. W. Chang, S. F. Liang, C. P. Young, F. Z. Shaw, Y. D. Liu, Y. C. Liu and J. J. Chen, "A Wireless Portable Behavioral State and Physiological Signal Monitoring System for Freely Moving Rats", in Proc. Int. Instrum. Meas. Technol. Conf., Austin, pp. 1353-1357, 2010.
4. Patent:
1. Shaw FZ, Huang CC. “Distortionless powerline interference removal method using S-transform” 中華民國專 利97133429.
2. 應用於慢性疾病的生物自我偵測及回饋誘導藥物釋放系統 申 請 日：民國 99 年 9 月 15 日
申請國家：中華民國、美國 案件類型：發明
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智慧型生物訊號誘導藥物釋放系統前瞻研究:以癲癇症為模式－應用於訊號誘導藥物釋放 系統之智慧型生醫複合材料結構製程與性質研究(子計畫二)
Frontier Research on Smart Biologically-Stimuli Drug Delivery System Based on Epilepsy - Development and characterization of smart responsive biomedical composite structure
for drug delivery system
計畫編號：NSC-98-2627-B-009-001 執行期限：98年8月1日至99年7月31日
主持人：陳三元 國立交通大學材料科學與工程學系
共同主持人：黃國華 國立交通大學奈米科技研究所
一、 中文摘要
本子計畫的最主要目標在於開發一個可應用於癲癇症之智慧型生醫複合材料結構製程，並 與子計畫-1及子計畫-3整合發展成一個具有迴饋偵測及治療。當偵測到癲癇異常放電時，
啟動藥物釋放系統給藥以抑制異常放電的電刺激之藥物載體結構。因此本計畫在第三年度 主要是發展一個以兩性幾丁聚醣和無機二氧化矽為材料的生物相容複合水膠，其組成、熱 穩定性和結構都會被分析與最佳化。以抗痙攣藥物-乙琥胺為模擬藥物，電敏感複合水膠 在體外試驗呈現系統化的釋藥行為。其釋藥行為是由於在直流電場下，藥物分子和複合水 膠電特性被電泳機制和電滲行為影響產生。經由癲癇老鼠模型更進一步的調察發現，被設 計成系統化的眝藥體，複合水膠，能夠自行偵測與傳遞訊號，使老鼠的癲癇發作次數降低。
經由這計畫的整合研究的確已經可以達到當初的目標，希望未可以在實際癲癇療程證明其 自行偵測和系統化藥物傳輸的特性。
關鍵詞：電敏感性、奈米結構混層水膠、藥物載體、藥物釋放傳遞、自我偵測迴饋、癲癇
Abstract
This study reports the development of a biocompatable Nano-structured hybrid hydrogel based on an amphiphilic chitosan and inorganic silica, where the chemical composition, thermal stability and structural integrity of the resulting hybrid were characterized and optimized.
Electrically-responsive drug elution behavior of the hybrid hydrogel was evaluated systematically in-vitro using an anticonvulsant drug, ethosuximide, as model molecule. The release behavior was explained using a combined mechanism of electrophoretic and electro-osmotic actions between drug molecule and electron mobility of the hybrid hydrogel under a given DC electric field. Further integrating the hybrid hydrogel, designed as a chip-like drug reservoir, with an automatic self-detection and signal transmitter system, applying to a rat’s model, the resulting seizure frequency was considerably reduced and has experimentally proved that such a self-detection chip-like drug delivery device holds promising prospective in practical epileptic treatment.
Keywords: Electrically-responsive, Nanostructured Hybrid hydrogel, Controlled drug release, Drug delivery device, Self-detection and Feed-back, Epilepsy
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二、緣由與目的
The average life span of human has been prolonged considerably due to the explosive development of medical science and technology over recent decades, where advanced therapeutic strategies have been extensively explored and collectively employed to various disease treatments. Up to date, efforts to efficiently deliver therapeutic drugs to patients with minimal side effects, enhanced efficacy and improved compliance have received greatest attention worldwide in recent decade. Among the development of drug delivery systems, demands for biological self-detection and response-induced features of drug delivery system has been most interesting and is foreseeing its future market development due to increased amount of aged population [1]. Therefore, combination with an intelligent rapid response drug delivery system is the trend for biotechnology and medical technology. A multi-functionalized drug delivery nanosystem would be required and designed, including targeted mechanism, diagnosis and real-time controlled drug release.
Drug delivery systems can be controlled by applying an external stimulus included electrical field, magnetic field and ultrasonic waves, etc, upon which drug is eluted with a pre-designed pattern from the system to diseased host to minimize life-threatened occurrence [2-5]. However, each part of the therapeutic treatment is operated discretely, with no relevant signal intimately connected separate parts and this renders possible lose of best time of medication. Therefore, it needs to develop a drug delivery system by combination of wireless detector, close-loop automatic detection system and response-induced drug release system [6,7].
Under ideal operation, it is expected that through amplifier and wireless signal transition, the systems can simultaneously diagnose whether the symptom has occurred. Then, the drug-content device elutes drug with therapeutically effective dose based on detection and translation of the corresponding intensity of abnormal signal by the system. Through such an operation, it would reduce the side effects on the patients. Epilepsy, for example, can be detected by analyzing the electroencephalogram (EEG) data, and can be employed as a disease model for study and was used in this work [8-11]. To design a system for analyzing EEG data, the signal induced by the system can feedback to manipulate drug release with a signal-dose dependent manner. Thus a system, consists of signal amplifier, wireless transmitter, and drug delivery device, can be a very useful clinical tool for epilepsy treatment. The former two components have been successfully developed and tested in a number of earlier studies [12-14], and it turns to be more critical to develop a drug delivery system which can be smartly responding to the signal translated from the system, giving a timely and effective medical treatment and this is one of the major research objective of this work, where a smart and mechanically reliable hybrid hydrogel is designed and developed for the purpose.
Use of an environmentally responsive hydrogel as reservoir to deliver therapeutic substances has received widest attention for recent decade [15,16]. However, mechanical fatigue and weakness of polymeric hydrogels renders a long-term application more challenged, for instance, structural collapse or degradation of a given hydrogel under cyclically environmentally-induced (mostly, electric field) mechanical deformation may occur. Relaxation of the deformed hydrogel when removed the induced field may also retard the efficiency of the subsequent release of the drug, reducing therapeutic efficacy to a certain extent, this is especially critical for acute symptom such as epileptic seizure. Increasing addition of chemical cross-linker may achieve better performance, however, deteriorating biocompatibility of the resulting hydrogels. Therefore, to reinforce the conventional hydrogels with improved responsiveness and cyclic service performance to the external stimulus, an attempt of incorporating higher inorganic component together with a minimal concentration of organic cross-linker was made in order to ascertain the biocompatibility of resulting hydrogels and improved stimulus-induced responsiveness. In this work, a modified chitosan was employed, which was characterized with biocompatibility, biodegradability, non-toxic, non-irritable, and moisturized as described in our previous
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publications[17,18]. This modified chitosan was further hybridized with inorganic silica and a cross-linking agent. The resulting hybrid hydrogels were characterized and employed as a drug reservoir for electrically-response drug delivery system in vitro. Further integration to form a biological self-detection and signal conversion system to deliver anti-epileptic drug in vivo was demonstrated where the instantaneous epileptic discharge can be detected through the signal conversion into electric, and these signals will activate the structural change of the hybrid hydrogel to trigger drug elution through wireless transmission.
2. Experimental Procedures