可用於心臟藥物篩檢之心肌–壓電耦合系統之研發

Abstract

在藥物開發的過程中，藥物篩檢是一段非常重要的流程。其中，在心臟藥物篩檢中，又以心肌的收縮表現、跳動頻率，以及其施力曲線為最重要的特徵指標。因此，在藥物篩檢的過程中，監控心肌產生的力量曲線，成為了最必要的課題。為了能夠量化量測到心肌的施力曲線，現行之量測系統大多選擇以光學系統與高解析度相機，監控測細胞肌節的收縮或柔性基材的形變量，然後以影像分析與模擬估算的方式，將形變量換算為力。然而，此一方法有數個無法避免之重大限制：首先，由影像形變量推算力有其間接性，推算出的結果不能準確代表心肌真正的收縮力；其次，影像處理與運算需要由專業人員操作，無法達成全自動化。最後，受限於光學系統之視野，同一時間能監測之裝置數量亦有限，難以同時間大量地觀測。 為了避開光學系統之若干限制，同時為了達成自動化、即時性的、施力曲線之量測，本研究開發一可應用於心臟藥物篩檢之心肌–壓電耦合系統。以聚偏二氟乙烯(PVDF)柔性薄膜作為壓電材料，製成圓形的壓電換能器，表面以最佳化的細胞外基質(extracellular matrix)促進心肌細胞的附著。此外，本研究亦開發了一介面電路系統，用以處理壓電訊號之放大與濾波。最後，此耦合系統之正確性由兩種已商業化之藥物測試：isoproterenol與metoprolol。實驗結果證實此一心肌–壓電耦合系統可成功進行心肌細胞施力曲線之即時量測，並且能夠量測到在藥物作用下，心肌施力之變化，有望實現自動化、直接性檢測心肌細胞施力訊號及進行初步藥物篩檢的計畫目標。

The drug screening process has been an essential factor in the drug development process. To study the cardiac behavior under drug treatment, the cardiac systolic and diastolic forces, beating frequency, and contractile profile are the most concerned parameters. Hence, monitoring the force is necessary in cardiac drug screening. To acquire quantitative force profiles, most of the current monitoring systems choose to monitor the contractions of sarcomeres or the deformation of flexible substrates by an optical system and high-resolution cameras. Then, the cardiac force profiles are obtained by estimations and calculations on the captured images. However, there are some inevitable limitations of these optical systems: First, since the optical images are the projections of the deformed structure, the detected force profile is an indirect estimation. In addition, the images captured need to be processed by a specialist, which is difficult to convert into a fully automatic process. Finally, the number of devices can be processed is limited by the image field of the optical system. To bypass the limitation of the optical systems, and to achieve an automatic, real-time and direct measurement of cardiac force profile, a cardiac–and–piezoelectric hybrid system for cardiac drug screening was developed in this project. The polyvinylidene fluoride (PVDF) thin film was used to implement the circular piezoelectric transducer in this study. Substrates with different extracellular matrices (ECM) coated were tested to optimize the best cardiomyocyte adhesion promoter. Furthermore, an interface system and electromagnetic (EMI) shielding were built, which can directly convert the mechanical stress of cardiomyocyte into electrical signals, and to reduce the noise from the environment. Finally, this cardiac-and-piezoelectric system was verified by treatment of two commercialized drugs: Isoproterenol and Metoprolol. It was demonstrated that the developed cardiac-and-piezoelectric hybrid platform could detect the real-time contraction profile of cardiac tissue, and the platform could monitor the cardiac behavior under drug treatment based on the measured force profile. In summary, an automatic and real-time hybrid system for cardiac drug screening was developed. This system could potentially become a fully automatic and massive screening platform for the cardiac drug discovery process.