傳統上以生化實驗探討生物分子性質是巨量分子統計上的結果，相當程度上掩蓋了實際生理現象。直接研究單分子的物理性質可以提供更多基礎的力學資訊，與古典的生化實驗相互結合將更能幫助我們對生命科學的瞭解。生物奈米科技則提供一個新的方法來研究單生物分子。“由上而下”的方法是指使用微機電製程技術來製作一個微米尺度的工具，此微型裝置可以操控奈米尺度的單一DNA分子。另一方面，利用“由下而上”的方式可使分子自我組裝，主要的概念是利用生化技術合成與修飾DNA分子，使DNA分子具有功能性與專一性。本研究整合這兩種方式，巧妙地設計一種新型磁箝以研究奈米DNA分子之性質。

　　本研究利用微機電製程技術發展出2-D與3-D微型磁箝來操縱單DNA分子。必須的平台技術包含（1）DNA局部區域固定技術，（2）微磁力產生裝置之製作與（3）微流體技術，均可以整合成一個DNA操縱平台。為了操縱單DNA分子，本研究發展出高效率、高專一性、高鍵結強度且與微機電製程相容的DNA固定技術。

　　在2-D磁箝系統中，單DNA分子一端固定在金表面，另一端固定在微磁珠。然後對磁箝上的微線圈施加電流，可以產生所需要的磁場來移動微磁珠，藉以操縱單DNA分子。本研究成功地在六個正六角形排列的微線圈中，依序施予圓形排序之電流，使固定在金區域中連結磁珠之DNA拉伸與旋轉。為了量測微磁珠所受的拉力，利用重力、計算與校正磁力，並以單分子力學模型驗證實驗結果。實驗結果指出DNA拉力與模型預測值相當符合。此2-D磁箝對單DNA分子之作用力只在sub-pN範圍，應用僅侷限於DNA之熵響應區域。

　　為了增強磁力，本研究提出了一個新型3-D微型磁箝，此磁箝含有微型電磁鐵與環形捕捉器。配合此環形捕捉器，本研究提出一個配套的DNA局部固定技術。首先，DNA兩端分別鍵結上含有硫醇基的磁珠與未含有硫醇基的磁珠。經硫醇基修飾的磁珠被環形捕捉器吸引至金表面，然後藉著金與硫醇基共價鍵結在金表面上。未經硫醇基修飾之另一端磁珠則懸浮在溶液中，受到微電磁鐵所產生的磁場之操控。為了量測DNA的彈性力，其所受磁力可先藉由微磁珠受到的流體黏滯阻力計算而得。而DNA之力位移曲線進一步以單分子力學模型驗證。實驗量得在10 mM鈉離子濃度下DNA之彈性模數為453 pN。此結果顯示出DNA在低離子濃度下受到靜電排斥力之影響而變得更容易伸長。除了操縱單個DNA分子外，利用3-D磁箝亦成功地拉伸兩條單DNA分子，結果指出DNA呈現高度地非線性行為。此裝置可產生20-pN以上的磁力將DNA分子拉伸至它整個全長以上，而不會伴隨明顯的焦耳熱。此裝置可研究單DNA分子從熵響應到彈性響應的機械性質。

　　為了使磁珠從大型流體輸送裝置流暢地輸送到微型磁箝平台，本研究提出一種極小滯留體積微型連接器。利用PDMS材料以一體成型之灌模方式，以金屬線做為連接管道。直接連接微流管道與毛細管，達到消除微流管道與毛細管間滯留體積的目的，並使樣品在微流管道順暢度大為提高。該微型連接器不需任何的黏著劑、機械鑽孔與精密對位，更沒有傳統連接器使用黏著劑時可能阻斷微流管道的缺點。根據測漏實驗，此微型連接器可以承受150 psi的壓力與50 μL/min的流速。拉伸實驗顯示出它的機械性質足以承受實際的應用。此外，連接器上的毛細管可以進行抽換。此微型連接器不僅可以減少滯留體積，當與傳統的鐵氟龍管連接器比較樣品進樣實驗結果時，使用微型連接器可減少50%的稀釋效應。此極小滯留體積新型連接器明顯改善傳統連接器的缺陷及弊端。更重要的是，它可以應用於任何基材的微流體晶片。

　　微型磁箝操縱平台具有原大型系統才應有的量測性與功能性，並具有以下優點：(1) 非破壞性 (2) 適當的作用力範圍 (3) 易操控 (4) 力學量測性佳 (5) 製作便宜且微機電製程相容。相信此創新之微型磁箝操縱平台將可推廣至其它生物有基線材之研究，如蛋白質與細胞，應用於生命科學與奈米科技領域。

　Directly studying the physical properties of biopolymers at the single-molecule level is often more informative than classical bulk experiments which average over several molecules. Bio-nanotechnology enables new methods of directly observing and manipulating individual biological molecules. The top-down approach can adopt MEMS (micro-electro-mechanical-systems) fabrication technologies to produce a micro-scale device, which can manipulate a single DNA molecule with a 2-nm diameter. The bottom-up process focuses on the molecular self-assembly, which operates using human-made synthesis to modify and address a single DNA molecule. This study develops a micro-magnetic platform using the synergy strategies of a top-down approach with a bottom-up process to investigate single DNA molecule properties.

　This study develops 2-D and 3-D micromachined magnetic tweezers for DNA manipulation using MEMS technologies. Essential platform technologies, including localized DNA immobilization, micro-magnetic device fabrication and microfluidics, can be integrated to form the micromachine-based DNA manipulation platform. For specific end anchoring, this study developed highly effective and strong binding methods, which are compatible with MEMS technologies, for constructing DNA molecules with two sticky ends.

　In the 2-D magnetic tweezers system, one end of a single DNA molecule was specifically bonded with a magnetic bead, and the other end was bonded with a gold surface. The molecule was then manipulated under a magnetic field generated by built-in hexagonally-aligned microcoils. This study successfully demonstrated the stretching and rotation of a single DNA molecule. To quantify the magnitude of magnetic forces acting on the DNA molecule, force calculation based on the gravity balance was performed and further verified by the Worm-Like chain (WLC) model. The measured DNA stretching forces were found to agree reasonably with the fitting values. The magnitude of forces acting on a DNA molecule is within the sub-pN range, enabling the study of DNA in an entropic region.

　To enhance magnetic forces, a new 3-D magnetic tweezers consisting of micro-electromagnets and a ling-trap structure was proposed. To improve the localized DAN immobilization efficiency, a novel ring-trapper structure was used to handle the vertical movement of magnetic beads which adhered to the DNA molecules. One extremity of the DNA molecule, which was bound to the thiol-modified magnetic bead, could be immobilized covalently on a gold surface. The other extremity, which was bound to another unmodified magnetic bead, could be manipulated under a magnetic field generated by micro-electromagnets. To measure the DNA stretching force, the magnetic force acting on the magnetic bead was calibrated by using the modified Stoke’s law. The force-extension curve was further fitted by the WLC model, Odijk’s model and Hooke’s law. A value of 453 pN for elastic modulus of DNA was obtained at an ionic strength of 10 mM Na+. This result reveals that DNA becomes more susceptible to elastic elongation at a low ionic strength due to electrostatic repulsion. In addition to a single DNA stretching, this study also successfully demonstrated the stretching of two DNA molecules using the 3-D magnetic tweezers. The experimental data reveals that DNA presents a highly nonlinear behavior. The apparatus can exert over 20-pN magnetic forces with less heating to extend the DNA molecule over the whole contour length to investigate its entropic and elastic regions.

　To connect the magnetic tweezers with the external large-scale fluid equipment efficiently, this study presented a simple and versatile micro-connector manufactured using PDMS casting. To eliminate the dead volume, a capillary was bridged to a micro-channel via a connection channel, which was formed by removing a metal wire after PDMS casting. The proposed method does not require any adhesive, precise drilling, delicate alignment procedure or micromachining processes. Additionally, the proposed method could prevent blocking of the capillaries, a phenomenon which was commonly observed when using adhesives. The proposed method can achieve detachable and reusable micro-connectors with a minimal dead volume. According to leakage tests, the micro-connector could withstand pressures up to 150 psi and a maximum flow rate of 50 μL/min. The pull-out tests show that the PDMS fitting could provide sufficient mechanical strength for practical applications. Not only does the novel micro-connector significantly eliminate the dead volume but it also raises the detection signal. Compared with the traditional Teflon tubing fitting, the micro-connector can reduce at least 50% the dilution effect for sample loading analysis because the dead volume is substantially eliminated. Most significantly, the proposed micro-connector couples capillaries to microfluidic chips more flexibly than other micro-connectors.

　With these methods, the size of the apparatus can be reduced markedly, allowing the magnetic tweezers platform to be mass-produced at low cost. Most significantly, the microfabricated system can be simplified without losing sensitivity and functionality, unlike in other methods such as the use of large-scale magnetic tweezers and optical tweezers.

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