自主式精準投藥系統之開發研究與驗證

Abstract

受現代化飲食生活習慣與人口結構老年化之影響，全球慢性疾病如糖尿病與青光眼之盛行率不斷逐年攀升且有年輕化之趨勢，而大部分之慢性疾病除了需透過自我生活習慣的根本調適外，仍需仰賴長期的投藥積極治療。在現行各種的投藥途徑中，以直接針對病灶處進行局部注射為最有效之投藥治療方式，但各式直接注射所帶來的疼痛恐懼與潛在風險，卻常使病患順從性降低而造成治療之效果不彰。為解決此一窘境，本研究之目的即開發一全自主式的微投藥系統，其主要概念為患者隨身配戴或植入此一所開發的裝填藥物之微流體技術投藥系統，透過升級精準投藥劑量之控制與即時異常狀況之偵測，保證投藥之安全無虞。此一系統之開發有助於降低患者原先之被注射次數與手術風險，使得病患的治療順從性與生活品質皆獲得大幅提升與改善；此系統之關鍵技術包括以下三大部分： I. 具自我感測的高效能彈性體微幫浦系統之開發 此研究首先在壓電無閥式微幫浦振動腔體之前後串接彈性結構體，利用此複合結構體所產生之多共振(Multi-resonance)特性以大幅提升其效率達一個數量級以上，並探討多種不同剛性的彈性結構體及其串接順序對系統動態響應之影響。此外，也提出了一個可適用於多彈性體之電路類比集總模型用來快速預估系統之特性，並以流量與彈性體振動之實驗量測來驗證此一模型的有效性。最後，透過在進、出口彈性結構體表面上個別安置一壓電式微壓力感測器以監測進、出口之即時壓力變化，並以此作為回饋訊號來實現閉迴路控制(Closed-loop control)，而達成此一高效穩定輸送之微幫浦系統。 II. 分頻多工之匯/分流控制技術之開發 基於第一部分彈性體結構影響微幫浦輸送效能之特性，本研究進一步提出一多頻分工(Frequency Division Multiplexing, FDM)的匯/分流控制技術與設計驗證；其原理為利用微幫浦在進、出口處平行連接多個剛性大小不等之彈性結構體，設計出各分支相對應之特徵共振頻率，透過合成多頻之振幅調變(Amplitude modulation)或相位調變(Phase modulation)驅動訊號將可實現獨立控制每一分支流，此僅需單一致動器無需外加其他硬體設備就能同時操控多個分支流之控制，其不僅有助於簡化多藥物複合投遞系統之設計與成本，更可應用在各式複雜程序操控流體系統之實驗室晶片(Lab-on-a-chip)而進行反應與檢測。此外，由進一步探討剛性大小排序對樹狀多層彈性結構體分支流之影響，結果發現：在以幫浦為中心下，只有在上層彈性體之剛性大於其下層彈性體才能用分頻多工之技術來實現獨立控制每一分支流，此與心血管循環系統之分支流特性相吻合；反之，在上層彈性體之剛性大於下層彈性體時，將使得各個分支流無法獨立控制。 III. 自主式微投藥統系統之開發 本研究以前述自我感測之微幫浦系統為基礎，透過整合一電容式感測毛細儲藥槽，並以微處器與藍芽通訊模組來自行編程開發手機遠端控制之功能，成功實現了一可用於糖尿病治療的可攜式胰島素皮下注射(transcutaneous injection)系統。此一系統與商售幫浦比較，在相同儲藥槽之容量(300單位)下，體積約僅四分之一而重量為一半，故可提升系統之微小化及患者配戴之舒適性；且其即時對於各種異常狀況之感測，可由目前商售幫浦所需的數分鐘縮短至小於數十毫秒，故能大幅提升安全性；此外，在相同之流量解析度(100 nl/min)下，其並無商售幫浦先天因導螺桿驅動所造成流量不穩定與難以微型化之缺點，更可在不更動主要驅動元件之情況下，透過系統內流阻之調整輕易達成小於一個數量級的流量解析度；進一步，配合商售之連續血糖監測儀(Continuous Glucose Monitoring System, CGMS)已初步成功證實此一微投藥系統可控制糖尿病大鼠之血糖回復至正常值範圍內。而為因應青光眼治療之所需，本研究更進一步微型化上述系統之設計而製作一可植入式(Implantable)眼內注射(Intravitreal injection)微投藥系統，並進行此系統可行性的初步性能測試，此能解決未來微投藥系無法或不便安裝在體外之困擾。

Owing to the modern diet and aged society, the prevalence and morbidity of chronic diseases, including diabetes and glaucoma, have been gradually increasing and becoming younger every year. In addition to self-management of lifestyle, most of chronic diseases still rely on a long-term medication therapy. For the present drug delivery pathways, the local injection at lesion site is the most effective treatment. However, the frequent drug application and potential risks of injection may result in low compliance of patients and thus decrease the therapeutic effectiveness. Therefore, to deal with this awkward situation, an autonomous drug-delivery microsystem was developed in the work. The system was designed as a portable or implantable device for the convenience of patient, and the precise dose control and real-time monitoring of malfunctions by microfluidic techniques can ensure its efficacy and safety. This newly developed system brings the benefit in eliminating the low compliance of drug application and fear of regular and frequent direct injections, and thus could greatly enhance the therapeutic quality. The key techniques of the system can be divided into three parts as follows, I. The development of self-sensing and high-efficiency elastomer micropump The piezoelectric valveless micropump is equipped with elastomer to create the character of multi-resonance. Based on the resonance of elastomers, the pumping efficiency can be enhanced one order of magnitude larger than rigid one. The different stiffness and connection order of elastomers were further studied for their effect on frequency response of system. Besides, the electric analogy lumped model was proposed to predict the behavior of multiple elastomers system, and the measurement of flow rate and elastomer dynamics were conducted in experiments to validate the model. Furthermore, piezoelectric micro-pressure sensors were attached to the outer surface of inlet and outlet elastomers for real-time pressure monitoring, respectively, and such feedback pressure signals can be used to realize the closed-loop control for fulfilling a stable drug-delivery micropump. II. The development of branch flow control by Frequency Division Multiplexing Based on the multi-resonance elastomer micropump, the branch flow control technique was realized by the concept of Frequency Division Multiplexing (FDM). The branching system was intentionally connected with different stiffness of elastomers in parallel. Each branch has its own resonant frequency (fr) determined by its elastomer. Without any additional valve(s) or pump(s), the independent flow control at each branch can be realized by the method of amplitude or phase modulation of multiple-fr synthesized signal. This could not only benefit in simplifying the multiple drugs compound delivery system, but also dealing with the complicated flow control on Lab-on-a-chip. Furthermore, a tree-liked branch flow system with multiple layers of elastomers was studied for different connection orders. The results showed that by taking the vibration chamber as the center, if and only if the stiffness of top-layer elastomer is lower than its bottom-layer one, the independent flow control at each branch would be realizable by FDM, which is similar to the cardiovascular circulation branch system. On the contrary, as the stiffness of top-layer elastomer is higher than bottom-layer one, the independent flow control is impossible to be realized due to uncontrollable crosstalk effect. III. The development of autonomous micro-dose drug delivery system Based on the self-sensing micropump system, a capillary reservoir with capacitance sensor was further integrated to successfully realize the insulin-delivery microsystem for diabetes therapy. Besides, the remote control of system was realized by self-programming the micro-processor and Bluetooth module, and its corresponding application software of mobile device was also written to realize a portable drug-delivery microsystem. For the same capacity of drug reservoir, the present system volume and weight are respectively designed as one fourth and half of commercial insulin pump to enhance the wear comfort of patient. Besides, its micro-pressure sensor can detect malfunctions within tens of millisecond to ensure the higher safety of patient. Although the present resolution of flow rate has only achieved 100 nl/min, which is the same as commercial one, the proposed system can be easily miniaturized to have higher resolution of stable flow rate by adjusting its flow resistance due to the absence of inherent drawbacks of screw-based insulin punp, such as unavoidable flow instability and difficulty in miniaturization. With the aid of commercial CGMS, the insulin meditation to diabetic rat by the developed system was further proved its feasibility of blood glucose control. In order to meet the requirement of intravitreal injection of glaucoma, an implantable drug-delivery microsystem was further designed. The above-mentioned portable system was further miniaturized and fabricated to conduct its reliability and performance test in vitro. Such an implantable drug-delivery microsystem can be expected to be utilized for direct injection to inaccessible parts of human body in future.