An Implantable Electrical Stimulation Probe with Bendable Split Anchors via Residual Stress

相關研究文獻顯示，一個人罹患下背痛的機率高達54%至80%，且統計結果指出自1990年起，治療下背痛的經費以每年7%的比例再增加。這些數據顯示下背痛治療的需求近幾年來是一直在增長的，下背痛可經由藥物的途徑達到治療的效果，但是藥物的治療有伴隨著許多副作用的風險，因此，有別於藥物治療的緩解下背痛的方法是一直在尋找並且改良的。 神經探針經由電訊號進行紀錄和刺激某些特定部位的大腦，此種類的治療方法已經被廣泛使用。研究結果顯示，在特定的神經組織進行電刺激會導致不同部位的反應。一般下背痛的臨床治療中，對神經進行一次性電刺激，其療效並非永久性，病人約每隔三到六個月就需再進行電刺激。因此，植入式的電刺激系統已經被開發並且用於不同的長期性的神經電刺激治療，目前有幾種疾病已經通過臨床的研究並廣泛被使用，如帕金森氏症及坐骨神經痛。然而，目前多數的相關植入性手術多為開放性手術，微創手術相對於開放性手術所產生的手術傷口較小，有利於術後恢復，因此，近年來，用於針對微創手術所設計的神經電刺激探針已開始被研究。本研究針對微創手術開發出一款植入性雙極電極電刺激探針，此探針主要包含了一層軟性電路板基板和一層SU-8膜，利用SU-8膜內的殘餘應力，該探針將會變形為似鑷子形狀的機構，以便於夾住目標神經。和先前的研究相比此固定的機制由二為平面演進到三維的固定方法。為了增加殘餘應力的單軸向性使探針具有較大的變形量，SU-8膜被設計有條紋結構，此外，利用靜電紡絲技術製成的明膠纖維薄膜將固定於探針的分岔處當作細胞支架使用，以達到加速傷口癒合，減少免疫反應和確保長期固定的功能。 明膠是由動物體內取得，是一種天然的高分子，材料本身有很好的生物相容性，也很適合某些特定細胞生長，被廣泛使用生醫領域的可植入性材料及細胞養殖上。纖維母細胞被用於細胞培養的實驗中，實驗結果顯示細胞可以很好的貼附在明膠纖維薄膜上，隨著培養天數的增加細胞數量有增加的情況。明膠纖維薄膜的細胞支架被證明有良好的生物相容性和機械性質，有利於細胞生長。此細胞支架被證明可以達到速傷口癒合，減少免疫反應等目的。 為了計算SU-8膜內的殘餘應力，傳統的Stoney’s公式將會被修正為適用於厚膜的情況，使用奈米壓痕技術量測SU-8膜和軟性電路基板的楊氏模數，使用SEM拍攝探針的側面用於量測SU-8膜厚度，而探針的變形量也是使用拍攝的方法進行量測的到。量測的到的SU-8膜和軟性電路板的楊氏模數分別為4.7-5.2 GPa和1.37 GPa。利用修正後的Stoney’s公式，SU-8膜內的殘餘應力可以被計算。實驗結果顯示，薄膜厚度和變形的曲率半徑並沒有一個明顯的關係。但是隨著薄膜厚度的增加，膜內的殘餘應力有上升的趨勢。由於在相同的製程步驟下膜內的殘餘應力會隨著薄膜厚度而改變，因此不能直接利用控制SU-8膜厚來達到控制探針變形量的效果。 探針的固定強度實驗結果中，探針的抗拉強度和其變形程度有一定的關係，和二維的平面探針相比，變形後的三維探針的固定性有明顯的增加。在此拉伸實驗中，將得到的探針的最大的抗拉力進行無因次化，並定義其為探針的抗拉強度。平面探針的最大抗拉力是0.299N，抗拉強度為0.198。變形後高度為10.29 mm 和14.24 mm的探針最大抗拉力分別為0.369 N 和0.398 N，而抗拉強度分別為0.24及0.26，和原平面探針相比抗拉強度分別上升了22.7%和31.3%。但是探針的變形量和抗拉強度並不是單純的正相關，實驗結果顯示，變形高度在13 mm和14 mm之間的探針平均可達到的抗拉強度是最好的，平均的抗拉強度為0.258。 另外，在探針的植入過程中，可以藉由量測探針的阻抗來判定探針是否順利碰觸到目標神經，實驗結果顯示，在低頻域下，探針植入後阻抗的變化比在高頻域明顯。因此，再利用阻抗進行探針偵測時低頻域是較好的選擇。Literature statistics showed that the chance for a person to suffer from low back pain could be up to 54%~80%, and the annual cost on low back pain treatment has 7% annual growth since 1990. These statistics indicate that the needs for low back pain treatment have been increasing. Low back pain can be effectively relieved by pharmacological treatment. However, this type of treatment may cause lots of side effects. Thus, researchers have been seeking other ways for low back pain relief. Neural probes have been widely used for recording and stimulating the specific sites of brains through electrical signal. Studies showed that electrical stimulation on specific neural tissues can evoke different reactions. For clinical low back pain treatment, the target nerve is treated with one-time stimulation, whose therapeutic effect is not permanent. Patients will need the stimulation surgery every 3 to 6 months to suppress the pain. Thus, implantable stimulation systems have been developed for different long-term neural electrical stimulation treatments, such as for Parkinson’s disease and sciatica. However, since implanting surgeries are often invasive, many minimally invasive surgical procedures are conducted nowadays, in order to reduce the size of incisions. This paper presents a bipolar electrode probe used for implantable nerve stimulation treatments in minimally invasive surgeries. The probe is composed of a flexible printed circuit substrate and a fabricated SU-8 layer. This probe features a tweezer-like mechanism caused by residual stress in SU-8 film, which will fix the probe to the target nerve. There are stripes on the SU-8 film so that the residual stress nets in a single direction and forms a curve. In addition, a film of gelatin nanofibers, produced via electrospinning, covers the fixed ends of the probe anchors for cell growth to ensure long-term fixation in the body. In the experiment of the cell culture, the gelatin fibrous membrane is proven to have good biocompatibility and mechanical properties for cell culture. Adhesion and growth of 3T3 fibroblast cells on the membrane is effective. Thus, this cell scaffold attached on the probe should reach expected efficacy. A modified Stoney’s formula is established for estimating residual stress in the SU-8 film. The SU-8 thickness was measured with a scanning electron microscopy (SEM); the radius of curve was computed by trigonometry, and the Young’s moduli of SU-8 and flexible printed circuit (FPC) were determined by a nanoindenter. The thicknesses and radii are variable, while the Young’s moduli for FPC and SU-8 were mostly constant at 1.37 GPa and 4.7-5.2 GPa, respectively. With the revised Stoney’s formula, the residual stress could then be calculated. The results of experiment show that there are no obvious relationship between the thickness of the film and the radius of curvature. The residual stress of the SU-8 film is affected by the film thickness. Thus, the deformation of bendable split anchor in the probe cannot be controlled by SU-8 film thickness, but the residual of the SU-8 film increase with increasing film thickness. In the experiment of holding strength test, the breaking force is dominated by the deformation of the bendable split anchors in the probe. The deformation of the bendable split anchor has an optimum holding strength. The experiment results show that breaking forces of the curved probe are higher than plane probe. Breaking force of the plane probe is 0.299 N, and normalized breaking force is 0.198. The probes with the curvature heights of 10.29 mm and 14.24 mm have the breaking forces of 0.368 N and 0.398 N, respectively; the normalized breaking force is 0.24 and 0.26, which are 22.7% and 31.3% higher than that of the plane probe, respectively. The probes with curvature heights between 13 mm and 14 mm have maximum average breaking force about 0.258. In the implanting process, the impedance of the probe should be measured using low-frequency signal in order to determine whether the probe touches the target nerve.口試委員會審定書 # 致謝 i 中文摘要 ii ABSTRACT iv SYMBOL TABLE vii CONTENTS xii LIST OF FIGURES xv LIST OF TABLES xx Chapter 1 Introduction 1 1.1 Background and Motivation 1 1.1.1 Low back pain and spinal cord stimulation treatment 1 1.1.2 Implantable stimulation system 2 1.2 MEMS stimulation electrode and anchoring 4 1.2.1 Bipolar vs. monopolar configuration 4 1.2.2 Significance and methods of electrode anchoring 5 1.3 Literature review of implantable stimulation electrode/probe 5 1.4 Thesis organization 9 Chapter 2 Probe design and fabrication 11 2.1 Working principle of the probe adhesion 11 2.2 Probe design 14 2.2.1 Probe structure 14 2.2.2 Flexible printed circuit (FPC) substrate design and structure 16 2.3 Probe fabrication 20 Chapter 3 Residual stress in thin films 25 3.1 Introduction of residual stress 25 3.1.1 Overview of residual stress 25 3.1.2 Residual stress in SU-8 film 28 3.2 Modified Stoney’s formula which is applied to thick film 31 3.2.1 Original Stoney’s formula 31 3.2.2 Modified Stoney’s formula 32 3.3 Relationship between residual stress and film thickness 37 Chapter 4 Cell culture of electrospun gelatin fibers 43 4.1 Introduction of electrospinning technique 43 4.1.1 Principle of electrospinning technique 43 4.1.2 Development of electrospinning technique 45 4.2 Application of gelatin fibers in biomedical engineering 48 4.3 Gelatin fibrous membrane 49 4.3.1 Materials 49 4.3.2 Fabrication of gelatin fiberous membrane 49 4.4 Measurement of mechanical strength 53 4.4.1 Mechanical property of polymers 53 4.4.2 Experiment setup and process 55 4.4.3 Test results and discussion 57 Chapter 5 Experiment of Cell culture 59 5.1 Cell culture 59 5.1.1 Materials 59 5.1.2 Solution formula 59 5.1.3 Method 60 5.2 Cell morphology observation by fluorescence staining 61 5.2.1 Materials 61 5.2.2 Fluorescence staining 61 5.3 Cell morphology observation by SEM 63 Chapter 6 Probe test 65 6.1 Structure holding strength test 65 6.1.1 Experiment setup and process 65 6.1.2 Test results and discussion 67 6.2 Impedance test 76 6.2.1 Experimental setup and process 76 6.2.2 Model of equivalent circuit 78 6.2.3 Test results and discussion 82 Chapter 7 Conclusion and future work 87 7.1 Conclusion 87 7.2 Future work 90 REFERENCE 9