植入型葡萄糖感測系統之動物實驗探討

Performance of implantable glucose sensing system in animal study

林建廷(Jain-Ting Lin)

指導教授 ： 婁世亮

中原大學/工學院/醫學工程研究所/碩士(2011年)

https://doi.org/10.6840/cycu201101102

摘要

定期生理參數檢測對慢性病患者極其重要卻也極具負擔。以糖尿病患者為例，每天的扎針、取血、量測血糖是其賴以保命所必須。本研究之目的為開發植入式無線葡萄糖感測器以期緩和患者身心痛楚。無線感測器包含體外控制子系統及體內感測子系統兩部分，系統的驗證是將無線感測器埋植於約350-克重的Wistar鼠皮下檢測組織液與羅氏Accu-check®血糖儀檢測鼠尾巴靜脈血做血糖測量比較。體外子系統之操作頻率為4 MHz，具有10 mm之垂直位移之容忍度。體內子系統之操作電位輸出範圍為-0.49 ~ +1.02 V，足以提供一般葡萄糖檢測所需之操作電位。於PBS環境中，無線感測器與CH Instruments電化學分析儀在使用相同電極的狀況下檢測葡萄糖濃度變化，二者之間的誤差小於1 %。在導線整合型葡萄糖氧化酶電極的探討，正常鼠與糖尿病鼠的實驗結果都證實此電極能夠於體內分辨葡萄糖濃度且與血糖呈現相同變化趨勢，但由於生物汙化的影響，感測靈敏度下降約25.33~78.98%，靈敏度下降的現象於糖尿病鼠尤甚，下降程度高達92.83~99.01%。無線整合型感測器量測老鼠皮下葡萄糖濃度的實驗結果顯示，所研發之無線感測器亦能於體內分辨葡萄糖濃度的變化且與血糖呈現相同變化趨勢，然而，無線感測器於組織液偵測得葡萄糖濃度變化時間點與尾巴靜脈血糖變化之時間點有11 ~ 19分鐘的延遲，推測這與體內感測子系統阻隔組織液局部循環有關。總言之，本研究已研發完成植入式無線葡萄糖感測雛型系統，它在動物實驗上已見其感測功能，但是生物汙化影響電極靈敏度的問題至為嚴重，是未來亟待解決的重點。

關鍵字

生物汙化 ； 葡萄糖感測器 ； 植入式 ； 糖尿病

並列摘要

Some chronic diseases require periodical measurements of physiological parameters, which could be quite a burden to patients. Taking type I diabetes as an example, a patient may have to use the finger prick method to test his/her blood sugar levels daily. From the patient’s point of view, this is not only physical pain but also mental torture. The ultimate goal of this work is to develop a wireless implantable glucose biosensor to alleviate the physical and mental distress for diabetes patients. The wireless biosensor includes an external control subsystem and internal sensing subsystem. The internal sensing subsystem is to be implanted in the subcutaneous tissues of Wistar rats and feedback glucose response signals to the external control subsystem via a radio frequency wireless technology at 4 MHz. The wireless communications between the two subsystems can tolerate a vertical displacement of 10 mm. To become a functional unit, the internal sensing subsystem is able to provide electrical potential ranging from -0.49 to +1.02 V, which is sufficient for most of amperometric glucose measurements. To evaluate the glucose sensing functionality of the wireless biosensor, a comparison study of measuring glucose in PBS was performed. The biosensor and a CH Instruments (CHI) electrochemical analyzer coupled with a same glucose oxidase (GOx) immobilized mini-electrode set. On average, the variation of the measured response currents by the two systems was less than 1%. There were two in vivo studies performed in this course with each involving six ~350-gram Wistar rats, three normal and three diabetics. First, a Roche Accu-check® device measured glucose concentration by drawing blood from the rats’ tails; and the GOx immobilized mini-electrode sets were subcutaneously implanted into the rats and were connected to the CHI analyzer by wires to measure glucose from the interstitial fluid (ISF). The study results indicated that the mini-electrode sets are capable of differentiating glucose variations from the ISF in all the rats used. In addition, the glucose variations measured from the tail blood with respect to time were analogous to that detected from the ISF. However, the sensitivity of the mini-electrode sets reduced about 25.33 ~ 78.98% for the normal rats. This sensitivity reduction is believed due to the protein absorption on the electrode surface and is commonly referred as biofouling effect. In diabetic rats, this effect is even more severe, about 92.83 ~ 99.01%. The procedures and setups in the second in vivo study were similar to that in the first one except that the completed set of the wireless implantable biosensor was applied in the study. The study results are very like those observed in the first study. A highlight must be noted that there was a time delay of 11 to 19 minutes in comparing the response currents upon glucose or insulin injections between the two systems. It is believed that the delay is associated with the internal subsystem body of the biosensor. Likely it blocked the ISF local mobility. In conclusion, a prototype system of wireless implantable biosensor has been developed and used in the in vivo studies. The biosensor’s glucose detection functionality is confirmed. However, the biofouling effect is an important issue to be resolved in future.

並列關鍵字

implantable-based ； biofouling ； glucose biosensor ； diabetes mellitus

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