200425880 玖、發明說明 (發明說明應敘明：發明所屬之技術領域、先前技術、內容、實施方式及圖式簡單說明） 【發明所屬之技術領域】 本發明的目的係提供一種具醫療效果的人體內支架的製造方法。所謂的支架(stent) 是一種網形的管狀結構，可植入在人體內所有的管狀組織內部，其目的主要是撐開這些 管狀組織阻塞的部位，以疏通之，讓像是血管內的血液，或是膽曩管內的膽汁，或是輸 尿管、輸精管、輸卵管不通的部位，可以暢通。本發明所提供製造人體內用支架的方法 爲，先設計並繪製支架的圖案，然後在以具生物相容性金屬爲原料的薄片上做定位鑽 孔，再根據所設計的圖形利用線切割機切割出支架的網狀圖形，和微放電加工機鑽出線 肋上的孔洞，此時支架半成品是一在每條線肋上有一排孔洞的金屬網片，也就是平面狀 態下的血管支架，接著將其滾圓後，利用顯微焊接的技術將其焊接成爲金屬網管也就是 圓形的血管支架，接著，利用電解拋光的方法，對支架進行清潔與拋光，以去除支架的 毛邊及徑向粗糙面。然後，將生物可降解吸收性材料，使用相關溶液溶解成液體後，在 其中混入已經硏磨成爲微奈米大小顆粒的醫療性藥物，例如一些抗癌、消炎藥物，接著 將此混有醫療效果藥物的生物可吸收性材料溶液，完全霧化噴塗在支架內、外表面上， 因爲支架線肋上具有一整排小孔，所以當帶有藥物溶液噴塗在上面後，因爲液體流動的 原因和因毛細管現象，自動滲入各個小孔內，俟溶解藥劑揮發完畢，生物可降解吸收性 高分子材料會與藥物一起凝固成固體，連同藥物一起包在支架表面上，表面之塗層會像 打上鉚釘一樣，鉚附在支架上不易脫落，藉由生物可降解材料隨著時間慢慢分解，將藥 物漸漸的直接在病灶處釋放出來，防止血管再度阻塞，以達到治療的效果，如此利用台 灣已有的精密機械製造技術，即可製得低廉、具醫療效果之人體內用之支架成品。 【先前技術】 近年來，因大部分工業化國家飲食的高脂化，已使得心血管疾病成爲各國民眾主要 的致命疾病之一，這方面的疾病，以動脈粥狀硬化使血管窄化，甚至產生阻塞的現象， 最爲常見，對於此類疾病，最有效的治療方式是將狹窄的或阻塞的血管直接加以疏通， 也就是利用心血管支架(stent)，植入血管直接加以疏通，因其不需外科手術，幾乎已經 成爲一種最普遍的治療方式，此外，現代社會高度工業化的結果，人類承受相當的社會 200425880 壓力，伴隨而來是人體組織出現不正常的功能障礙’產生很多疾病，造成人體管腔 (intraluminal)的阻塞，例如膽曩管、胰臟管、輸精管、輸尿管、輸卵管等部位的阻塞，或 是癌症末期患者因癌細胞不正常增生所造成的管腔阻塞，身心承受相當大的痛苦，生活 品質非常惡劣，但是又不適合動大型外科手，此時也可以利用此種支架加以疏通，同時， 同一病患的身上，往往不止一處需要安置此種支架，由此可見其廣泛的應用性及需求性。 以血管支架疏通血管的方式而言，是將血管支架放置在血管內的阻塞部位，因支架 本身具有彈性，因此可由血管內部將血管撐開，使血液可以暢通無阻，放置血管支架的 方式大致上有兩種，一種是利用心導管手術，將支架就定位後，把支架外面的套管縮回， 讓支架自行利用本身的彈性張開，另一種方式是利用心導管手術，將血管支架裝置於支 架內未充氣之氣球，順著人體血管運送至定位，然後將支架內的氣球充氣後，利用其擴 張力，使得支架及血管一起撐開，然後將氣球放氣，連同導管一起抽出。根據上述的血 管支架的放置方式可知，因爲血管支架植入定位前需於血管中運行，所以必須小於血管 的直徑，再者當此種支架就定位後，需能將血管內壁撐開，以達到疏通血管的目的，另 外因爲病灶處，通常會有分岔的其他血管，爲了能在支架放置定位後，其他分支血管仍 可以讓血流通過，因此，大部分血管支架的結構爲一根長約20 - 40 mm的網狀管子，且 此支架張開前的直徑約爲1 mm左右，以便能在血管中運行，而張開後的直徑系配合放 置處的血管的管徑大小，一般大約介於2 - 4 mm左右。另外其他例如膽曩管、胰臟管、 輸精管、輸尿管、輸卵管等部位的阻塞，所需要的支架尺寸直徑最大可至10 mm左右， 長度則可根據病灶處的需要而作調整。 目前有多種製造支架的方法，其中一種是利用大功率的雷射將不銹鋼切割成網狀的 支架’切割時係利用雷射熔除不需要的部分，而成爲網形結構，此種方法需要相當精密 的3D機械操作及切割定位，操作不易。而且切割過程中因爲雷射高溫作用，會降低材 質強度，另外切割後可能會留下毛邊及粗糖面，成品邊緣所留下的毛邊及粗縫面，可能 會妨礙血流的流通，甚至可能破壞血球或血液中其他成分，另一種方式是利用微影曝光 的技術，在金屬管上覆上光阻劑，然後經過光罩顯影，將金屬置放在飩刻溶液中，把未 被光阻劑保護之處去除。此種方法製造支架的缺點是，仍舊無法將3D圓管網狀的支架 一體成型，還是必須經過捲管過程，也就是說必須在平面狀態下進行微影蝕刻，而且最 重要的是因爲金屬蝕刻溶液會由側面進入光罩遮蔽處，如此可能造成纟虫刻處不均勻、不 規則’支架的網形結構不易控制，容易失敗。此外上述兩種製程所需的設備較爲昂貴， 200425880 因而提高支架的費用，以台灣而言，一個支架的售價約爲新台幣50,000元左右。若是病 患體內需要裝置多個支架時在經濟上實在是一項重大負擔。 目前已知的支架製造方法中並無法對病灶處施以治療，病人在植入支架之後，仍舊 必須依靠藥物治療控制再發性，無論是吞服藥物或是注射藥物治療，前者容易於經過人 體消化系統腸胃道時遭到吸收分解，而後者也極易爲人體循環系統所吸收，真正用在治 療上的份量極少，因此，這兩種治療方式，都會讓醫生必須增加病人的用藥量’這樣〜 方面浪費寶貴的藥物資源，一方面使用過多的藥物，眾所周知，對人體確有不良的副作 用，並且病人在植入後，一般而言，出現這種栓塞現象的病人在病灶處再發率都很高， 所以在植入後三個月到半年之間都必須做定時的回診追蹤該支架，以確保安全’所以， 若能夠在支架上直接塗佈一層藥物，直接在病灶處治療，將會是病人的一大福音。很可 惜的目前尙無該種支架製造技術。 因此若能利用低廉的設備，並且可以解決習知技術的缺點，將能大幅降低製造成 本。可使產品價格下降，造福廣大的病患。 【發明內容】 本發明的目的係提供一種具醫療效果的人體內用支架的製造方法。本發明係根據先 前發明人已經申請專利的血管支架製造技術，加以應用有限元素分析的方法，探討支架 在植入時的撐開情形，硏究支架線肋內應力數據，然後在支架表面上塗佈一層混有抗細 胞增生、消炎藥物在一起的生物可降解吸收性高分子材料鍍層，藉由生物可降解吸收材 料隨著時間慢慢分解時，會將藥物漸次的釋放出來，直接在病灶處治療抑制細胞增生， 防止血管再度阻塞，並可針對不同阻塞的原因治療阻塞的以達到治療的效果。 本發明所提供製造用於人體內具醫療效果支架的方法爲，先設計並繪製支架的圖 案，然後再以金屬爲原料的薄片上做定位鑽孔，再根據所設計的圖形進行切割，切割出 支架的網狀圖形，之後，再利用本國已經相當成熟的微機械加工技術，在金屬薄片上已 經成形的網狀結構，於網狀線肋上利用微放電加工技術進行鑽孔。然後，將線肋上有一 排孔洞的金屬網片滾圓，並利用顯微焊接的技術將其焊接成爲金屬網管，接著，利用電 解拋光的方法，對支架進行清潔與拋光，以去除支架的毛邊及徑向粗糖面。然後，將生 物可降解吸收性材料PLLA或是PGA，使用單種或是兩種不同比率混合，使用相關溶液 洛解後，在其中混入抗細胞增生藥物，例如，五氧化二砷，或是一些抗癌藥物，這些抗 200425880 癌藥物已經經過硏磨成爲微米甚至奈米級大小的顆粒，將此混有抗細胞增生、消炎藥物 的生物可降解性材料溶液，完全霧化噴塗在支架內、外表面上，因爲支架線肋上具有一 整排小孔，所以當帶有藥物溶液噴塗在上面後，除了會吸附在支架表面外，也會因液體 流動或是毛細管現象，自動滲入各個小孔內，俟溶解藥劑揮發完畢，生物可降解高分子 材料會與藥物一起凝固成固體，連同藥物一起包在支架表面上，表面之塗層會像打上鉚 釘一樣，鉚附在支架上不易脫落，如此即可製得具醫療效果之血管支架成品。 【貫施方式一】 本發明一種具醫療效果支架的製造方法，第1圖所示爲本發明之製造支架的方法槪 要流程圖。首先設計並繪製支架的圖形，此步驟係利用電腦輔助設計(Computer Aided Design，CAD)，利用pro-engineering或是Solid-work的軟體將擬製的支架繪製成圖形，如 第2⑻、2(b)圖所示。接著，進行程式撰寫並進行測試，此程式包括後續定位鑽孔時以 及原料金屬薄片切割時，可程式控制精密鑽床以及可程式控制線切割機所使用的程式， 此兩部機器所使用的程式在定位部分必須一致，以免因爲定位不準造成成品不良，之 後，進行鑽模夾具的設計與製作，利用上下兩層厚度約爲1 mm的鋼料，將原料金屬薄 片夾緊，成爲三明治試片，再利用精密鑽床進行定位鑽孔。定位鑽孔完成後，需檢視其 孔位是否正確，若是正確則可利用線切割機進行切割，此處可使用CNC工具機進行切 割加工，藉此切割出所需的網形結構(stent pattern)，接著進行半成品的檢驗，可以利用掃 瞄式電子顯微鏡(scanning electron microscopy, SEM)進行觀察，以確定支架是否有線寬不 一，或是線肋斷線的情形，線切割機切割完成的支架形狀之照片圖示於第3圖。 接著利用微放電加工的技術，在支架各條線肋上鑽出一系列的孔洞，孔洞直徑大小 約爲線肋寬度的三分之一，也可視支架材質的強度作適當的調整，孔洞並不一定要是圓 形，像是三角形或是四方形任何形狀皆可’孔洞間距約爲兩倍孔洞之直徑或是根據需要 作適度調整成幾倍以上皆可，經微放電加工後鑽孔之局部放大圖圖示於第4圖。 然後將此階段之半成品進行滾圓及顯微精密焊接的步驟，此步驟係利用機械夾具將 平面金屬網捲成圓柱形金屬網管，再進行精密顯微焊接，之後再利用SEM檢驗焊接結 果是否適當，而後將此圓柱形金屬網管進行電解拋光’以去除支架之毛邊和徑向粗糙 面，並同時將支架表面進行清潔與鏡面拋光作用’再以SEM檢驗電解拋光結果，支架 邊緣已經變得相當光滑，通過SEM檢驗後，即可製得支架’如第5(a)、5(b)、5(c)圖所 10 200425880 不0 接著進行藥物塗佈的步驟。首先將生物可降解材料具聚左旋乳酸PLLA或是聚羥基 乙酸PGA (poly-glycolie add)以適當之溶劑溶解，例如丙酮或是氯仿，將其溶解成爲溶 液，再加入抗細胞增生之藥物’例如五氧化二砷或是類脂醇抗炎劑(dexamethasone)，將 該類藥物硏磨成爲微米級甚至奈米級大小粉末，倒1入溶液內，經超音波震盪磁石攪拌均 勻，然後將其霧化噴出，噴在上述已經製得之血管支架內外表面上，待溶劑揮發完畢後， 生物可降解性高分子材料會與奈米級藥物一起以固態方式黏附在支架表面上，包括孔洞 內部，這樣會如剛卩釘般固定在支架表面上，如第6圖所示。當具鍍層支架隨心導管輸 入體內時，鍍層不會因摩擦力造成鍍層與支架剝離，讓塗層脫落。 第一種PLLA鍍層是在支架表面鍍上含有類脂醇抗炎劑(dexamethasone)或是使用 包有氧化砷(As2〇5)的PLLA生物可降解性材料(PLLA在此當作結合劑使用，binder) (Medisorb Technologies International)，PLLA 又稱爲聚左旋乳酸，化學式:C3H6〇3，單 體分子量= 90.08，C:H:0= 40:6.71:53.29，沸點392.2 K。顏色爲透明色，基本上爲非 結晶體，或是具有少部分結晶。使用前會用X-ray加以檢驗其結晶性。可用以溶解 的溶劑有三種分別是：氯仿(chloroform)、丙酮、三氯甲院，氯仿中添加l%w/w的 PLLA作成含有2% w/w dexamethasone的懸浮液，所採用的PLLA有兩種’ 一種 是低分子量〜80KD另一種爲高分子量〜320KD的PLLA，然後將所合成的溶液 噴灑在支架上，dexamethasone對PLLA的比率爲2 : 1，每個支架上約噴有0.8 mg的 dexamethasone，0.4 mg的PLLA，鍍層厚度預計約爲1〇帅，在霧狀噴灑的同時’至 於經過乾燥殺菌洗淨之後，dexamethasone之化學穩定度，則將其用高壓液態層析法 (chromatography spectra)來測試。至於類脂醇抗炎劑(dexamethasone)或是氧化砷(As£)5) 使用前會以我們實驗室中已經很成熟的奈米粉製造技術’用來製造奈米級粉末的機 械化合金法來製造(該項技術本發明人已經硏究多年且有論文發表)，也就是用滾磨機 來製造奈米級的殺細胞用藥物。使用前當然會用穿透式電子顯微鏡(TEM)加以檢驗所 硏磨完成的藥物是否已經成爲奈米級，藥物粉末越細小’配合高分子降解材料逐漸 降解慢慢的將藥物釋放出來，這樣釋放出來的藥物量分佈會比較均勻’而且局部濃 度會較小，比較不會刺激血管內璧，引起發炎現象，本項高分子和藥物之混合比率， 重量濃度爲1 %和2%兩種。經過硏磨後的藥物當然會用EDS和x-my檢驗，以確定它 的化學成分和結晶是否已經遭受到破壞。 200425880 PLLA本身無毒性，少量存在於人及動物的血管及肌肉裡，人體在劇烈運動後會 增加體內的含量，也同時存在於肝臟、腎臟、胸腺、或其他身體內的流質當中，因 此他本身是一種生物可吸收性材料。CAS註冊號碼:79-33-4。化學結構式表示如下:200425880 发明 Description of the invention (The description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments, and the drawings) [Technical field to which the invention belongs] The purpose of the present invention is to provide a person with a medical effect Manufacturing method of body stent. The so-called stent is a net-shaped tubular structure that can be implanted inside all the tubular tissues in the human body. The main purpose is to open up the blocked areas of these tubular tissues to clear them and let it look like blood in the blood vessels. , Or the bile in the bile duct, or the ureter, vas deferens, and fallopian tubes can be blocked. The method for manufacturing a stent for human body provided by the present invention is: firstly design and draw a pattern of the stent, then perform positioning drilling on a sheet made of biocompatible metal as a raw material, and then use a wire cutting machine according to the designed figure The mesh pattern of the stent was cut and the holes on the wire ribs were drilled by the micro-discharge processing machine. At this time, the semi-finished product of the stent is a metal mesh with a row of holes in each wire rib, which is a vascular stent in a flat state. After rounding it, it is welded into a metal mesh tube, which is a circular vascular stent, using micro-welding technology. Then, the stent is cleaned and polished by electrolytic polishing to remove the burr and radial roughness of the stent. surface. Then, after dissolving the biodegradable absorbent material into a liquid using the relevant solution, it is mixed with medical drugs that have been honed into micron-sized particles, such as some anti-cancer and anti-inflammatory drugs, and then mixed with medical effects. The bioabsorbable material solution of the drug is completely atomized and sprayed on the inner and outer surfaces of the stent. Because the stent ribs have a whole row of small holes, when the drug solution is sprayed on it, due to the reasons of liquid flow and Due to the capillary phenomenon, it automatically infiltrates into the small holes, and the volatilizing agent is volatilized. The biodegradable absorbent polymer material will solidify with the drug to form a solid, and it will be wrapped on the surface of the stent together with the drug. The surface coating will be like rivets. Similarly, riveting on the stent is not easy to fall off. By slowly decomposing the biodegradable material over time, the drug is gradually released directly at the lesion to prevent the blood vessels from being blocked again to achieve the effect of treatment. Precision machinery manufacturing technology can produce low-cost, medically effective stent products for human body[Previous technology] In recent years, due to the high fat diet in most industrialized countries, cardiovascular disease has become one of the major fatal diseases of people in various countries. In this regard, atherosclerosis narrows blood vessels and even produces them. Obstruction is the most common. For this type of disease, the most effective treatment is to clear the narrowed or blocked blood vessels directly, that is, to use a cardiovascular stent to directly unblock the implanted blood vessels. The need for surgery has almost become one of the most common treatments. In addition, as a result of the high industrialization of modern society, humans are under considerable social pressure of 200425880, which is accompanied by abnormal dysfunction of human tissues, which causes many diseases and causes the human body. Intraluminal obstructions, such as bile ducts, pancreatic ducts, vas deferens, ureters, fallopian tubes, etc., or occlusions caused by abnormal growth of cancer cells in end-stage cancer patients. Painful, poor quality of life, but not suitable for large surgical hands This kind of stent can also be used for dredging. At the same time, the same patient often needs to place this kind of stent in more than one place, which shows its wide application and demand. In terms of vascular stents to unblock blood vessels, the vascular stent is placed in the occluded part of the blood vessel. Because the stent itself is elastic, the blood vessel can be opened by the inside of the blood vessel so that the blood can flow unimpeded. The method of placing the vascular stent is roughly There are two types. One is the use of cardiac catheter surgery. After the stent is positioned, the cannula outside the stent is retracted to allow the stent to expand by its own elasticity. The other method is to use the cardiac catheter surgery to install the vascular stent in the The uninflated balloon in the stent is transported to the positioning along the human blood vessel. After the balloon in the stent is inflated, the expansion force is used to expand the stent and the blood vessel together. Then the balloon is deflated and pulled out with the catheter. According to the placement method of the vascular stent described above, because the vascular stent needs to operate in the blood vessel before implantation and positioning, it must be smaller than the diameter of the blood vessel. After the stent is positioned, the inner wall of the blood vessel needs to be opened. To achieve the purpose of dredging blood vessels, and because there are usually branched other blood vessels at the lesion, in order to allow other branch blood vessels to allow blood flow after the stent is positioned, most of the vascular stent structures are long Reticulated tube of about 20-40 mm, and the diameter of this stent before opening is about 1 mm in order to be able to operate in the blood vessel, and the diameter after opening is based on the diameter of the blood vessel in the place where it is placed, which is generally between about About 2-4 mm. In addition, for other obstructions such as the bile duct, pancreatic duct, vas deferens, ureter, fallopian tubes, etc., the required stent size can be up to about 10 mm in diameter, and the length can be adjusted according to the needs of the lesion. At present, there are various methods for manufacturing the stent. One of them is to use high-power laser to cut the stainless steel into a mesh stent. When cutting, the laser is used to remove unnecessary parts and become a mesh structure. This method requires considerable Precise 3D mechanical operation and cutting positioning make operation difficult. In addition, due to the high temperature of the laser during the cutting process, the strength of the material will be reduced. In addition, burrs and rough sugar surfaces may be left after cutting. The burrs and rough seams left on the edges of the finished product may hinder the blood flow and may even damage it. Blood cells or other components in blood, another way is to use lithographic exposure technology, cover the metal tube with a photoresist, and then develop through a photomask, place the metal in the engraving solution, and put the unphotoresist Protection is removed. The disadvantage of this method for manufacturing the stent is that the 3D round tube net-shaped stent cannot still be formed into one piece, or it must go through the tube rolling process, that is, it must be lithographically etched in a flat state, and most importantly because of metal etching The solution will enter the mask shelter from the side, which may cause the uneven and irregular stent's mesh structure to be difficult to control and easy to fail. In addition, the equipment required for the above two processes is more expensive. 200425880 Therefore, the cost of the bracket is increased. In Taiwan, the price of a bracket is about NT $ 50,000. If multiple stents are needed in the patient, it is a significant financial burden. The currently known stent manufacturing methods cannot treat the lesion. After the stent is implanted, the patient must still rely on drug therapy to control the recurrence. Whether the drug is swallowed or injected, the former is easier to pass through the human body. The digestive system is absorbed and broken down in the gastrointestinal tract, and the latter is also easily absorbed by the human circulatory system. The actual amount of treatment is very small. Therefore, both of these treatments will require the doctor to increase the amount of medication used by the patient. ~ On the one hand, it wastes valuable drug resources, on the other hand, it uses too many drugs. As we all know, there are indeed adverse side effects on the human body, and after the implantation, in general, the recurrence rate of patients with this type of embolism is at the lesion. It is very high, so the stent must be tracked regularly for three months to six months after implantation to ensure safety. So, if a layer of medicine can be directly coated on the stent and treated directly at the lesion, it will It is a great gospel for patients. Unfortunately, there is currently no such stent manufacturing technology. Therefore, if low-cost equipment can be used and the shortcomings of the conventional technology can be solved, the manufacturing cost can be greatly reduced. It can reduce the price of products and benefit the majority of patients. SUMMARY OF THE INVENTION An object of the present invention is to provide a method for manufacturing a stent for human body with medical effects. The present invention is based on the vascular stent manufacturing technology that the inventor has applied for before. The method of finite element analysis is applied to explore the expansion of the stent during implantation. The internal stress data of the stent is studied, and then the surface of the stent is painted Coating a layer of biodegradable absorbent polymer material mixed with anti-cell proliferation and anti-inflammatory drugs. When the biodegradable absorbent material slowly decomposes over time, the drug will be gradually released and directly at the lesion. The treatment inhibits cell proliferation, prevents revascularization of blood vessels, and can treat the obstructions for different causes of obstruction to achieve the effect of treatment. The method provided by the present invention for manufacturing a stent with a medical effect in the human body is to first design and draw a pattern of the stent, and then perform positioning drilling on a sheet made of metal, and then cut according to the designed figure to cut out After the mesh pattern of the stent is used, the micromechanical processing technology that is quite mature in the country is used, and the mesh structure that has been formed on the metal foil is drilled on the mesh ribs using micro-discharge machining technology. Then, the metal mesh with a row of holes on the wire ribs is rounded and welded into a metal mesh tube using micro-welding technology. Then, the bracket is cleaned and polished by electrolytic polishing to remove the burr and Radial coarse sugar noodles. Then, the biodegradable absorbent material PLLA or PGA is mixed with a single or two different ratios. After the solution is digested with the relevant solution, an antiproliferative drug, such as arsenic pentoxide, or some Anti-cancer drugs. These anti-200425880 cancer drugs have been honed into micron- or nano-sized particles. This solution of biodegradable materials mixed with anti-cell proliferation and anti-inflammatory drugs is completely atomized and sprayed inside and outside the stent. On the surface, because there is a whole row of small holes in the ribs of the stent, when the drug solution is sprayed on it, it will not only adsorb on the surface of the stent, but also automatically penetrate into the small holes due to liquid flow or capillary phenomenon. After the volatilizing agent is volatilized, the biodegradable polymer material will solidify with the drug to form a solid, and it will be wrapped on the surface of the stent with the drug. The coating on the surface will be like a rivet, and it will not easily fall off the stent. Finished vascular stents with medical effects can be made. [Implementation Mode 1] A method for manufacturing a stent with medical effects according to the present invention. FIG. 1 shows a flowchart of a method for manufacturing a stent according to the present invention. First design and draw the graphics of the stent. This step is to use Computer Aided Design (CAD), and use the software of pro-engineering or Solid-work to draw the prepared stent into a graphic, such as 2⑻, 2 (b) As shown. Then, write and test the program. This program includes the programs that can be used to program the precision drilling machine and the program-controlled wire cutting machine during subsequent positioning and drilling and cutting of the raw metal sheet. The programs used by these two machines are The positioning parts must be consistent to avoid defective products due to inaccurate positioning. After that, the design and production of the drilling jig are carried out. The upper and lower layers of steel with a thickness of about 1 mm are used to clamp the raw metal sheet into a sandwich test piece. Then use precision drilling machine for positioning drilling. After the positioning drilling is completed, you need to check whether the hole position is correct. If it is correct, you can use a wire cutter to cut. Here, you can use a CNC tool to perform the cutting process to cut the required stent pattern. Then, the semi-finished product is inspected. Scanning electron microscopy (SEM) can be used to observe whether the stent has different wire widths or the ribs are broken. The shape of the stent cut by the wire cutter The photo icon is shown in Figure 3. Next, a series of holes were drilled in each wire rib of the stent by using micro-discharge machining technology. The diameter of the hole is about one-third of the width of the wire rib. The strength of the material of the stent can be adjusted appropriately. The holes are not It must be round. Any shape like triangle or square can be used. The hole spacing is about twice the diameter of the holes, or it can be adjusted to several times as needed. The micro-discharge machining will enlarge the part of the hole. The figure is shown in Figure 4. Then, the semi-finished products at this stage are subjected to the steps of spheronization and micro-precision welding. This step is to use a mechanical fixture to roll the flat metal mesh into a cylindrical metal mesh tube, and then perform precision micro-welding, and then use SEM to check whether the welding result is appropriate. Then the cylindrical metal mesh tube was electrolytically polished 'to remove the burr and radial rough surface of the bracket, and at the same time to clean and mirror polish the surface of the bracket'. Then the electrolytic polishing results were checked by SEM, and the edge of the bracket had become quite smooth. After passing the SEM inspection, a stent can be prepared, as shown in Figures 5 (a), 5 (b), and 5 (c). 10 200425880 No 0 Then the drug coating step is performed. First dissolve the biodegradable material with poly-L-lactic acid PLLA or poly-glycolic acid add PGA (poly-glycolie add) with an appropriate solvent, such as acetone or chloroform, dissolve it into a solution, and then add an anti-proliferative drug. Arsenic pentoxide or dexamethasone, honed the drug into micron or even nanometer-sized powder, pour 1 into the solution, stir it evenly with ultrasonic vibration magnet, and then mist it It is sprayed and sprayed on the inner and outer surfaces of the vascular stent that has been prepared. After the solvent is evaporated, the biodegradable polymer material and the nano-grade drug will adhere to the surface of the stent, including the inside of the hole, in a solid state. It will be fixed on the surface of the bracket like a stud, as shown in Figure 6. When the coated stent is inserted into the body with the catheter, the coating will not peel off the coating and the stent due to friction, and the coating will fall off. The first PLLA coating is coated on the surface of the stent with a lipid-based anti-inflammatory agent (dexamethasone) or a PLLA biodegradable material coated with arsenic oxide (As205) (PLLA is used here as a binding agent, binder) (Medisorb Technologies International), PLLA is also known as poly-L-lactic acid, chemical formula: C3H6O3, monomer molecular weight = 90.08, C: H: 0 = 40: 6.71: 53.29, boiling point 392.2 K. The color is transparent, is basically amorphous, or has a small amount of crystals. X-ray is used to check its crystallinity before use. There are three kinds of solvents that can be dissolved: chloroform, acetone, and trichloromethane. Chloroform is added with 1% w / w PLLA to make a suspension containing 2% w / w dexamethasone. There are two types of PLLA used. Species' One is low molecular weight ~ 80KD and the other is high molecular weight ~ 320KD PLLA, and then the synthesized solution is sprayed on the stent. The ratio of dexamethasone to PLLA is 2: 1, and about 0.8 mg of dexamethasone is sprayed on each stent. , 0.4 mg of PLLA, the thickness of the coating is expected to be about 10 mm. When spraying in mist form, as for the chemical stability of dexamethasone after drying and sterilizing and washing, it is subjected to high-pressure liquid chromatography (chromatography spectra). test. As for the lipid alcohol anti-inflammatory agent (dexamethasone) or arsenic oxide (As £) 5), it will be manufactured using the well-established nano-powder manufacturing technology in our laboratory. (This technology has been studied by the present inventors for many years and has been published in papers), that is, nanometer-level cytocidal drugs are manufactured by using a roller mill. Before use, of course, a transmission electron microscope (TEM) will be used to check whether the finished drug has become nano-grade. The smaller the powder of the drug, the more the polymer degradation material will gradually degrade the drug and release it slowly. The distribution of the amount of the drug will be more uniform, and the local concentration will be smaller, which will not stimulate the intravascular vessels and cause inflammation. The mixing ratio of this polymer and the drug is 1% and 2% by weight. The honing drug is of course tested with EDS and x-my to determine if its chemical composition and crystals have been damaged. 200425880 PLLA itself is non-toxic. It is found in small amounts in the blood vessels and muscles of humans and animals. The human body increases its content after strenuous exercise. It also exists in the liver, kidney, thymus, or other body fluids. Therefore, he himself Is a bio-absorbable material. CAS registration number: 79-33-4. The chemical structural formula is expressed as follows:
其他名字：Lactic acid; L-(+)-Lactic acid; Propanoic acid，2-hydroxy-, (S)-; Lactic acid, L-; Espiritin; (S)-2-Hydroxypropionic acid; (+)-Lactic acid; d-Lactic acid; L-Lactic acid; (S)-Lactic acid; (S)-(+)-Lactic acid; Paralactic acid; Propel; Sarcolactic acid; SY-83; Tisulac o 另外一種高分子可降解性材料爲聚羥基乙酸PGA (poly-glycolic add)，可以單種或 是配合混入PLLA使用，彼此間的添加百分比分別爲100_0%，75-25%，50-50%， 25-75%，0-100%等五種混合比値，兩種生物可降解高分子材料的降解速率，藥物的 配合性，與生物的相容性各有不同效果，將因病人的需要而異。混合好的生物可降 解吸收性材料鍍在支架前、後皆會使用x-ray加以檢驗它的結晶度’結晶度越大者 的生物相容性越差，因此在保存上有必要特別注意，一定會根據美國原廠規定放置 在冰箱內維持溫度在2〜8 °C，以避免高分子產生結晶現象’根據我們目前初期 的測試顯示，一開始所購得的生物降解材料爲透明，置放在攪拌的培養液中經過一 段時間後，變成白色。 第二種鍍層處理是在支架上滴上由纖維蛋白素(fibrinogen)溶液和凝血酵素 (thrombin)溶液，這種纖維蛋白(fibrin)屬於一種天然的高分子材料，經過高分子化之 後，纖維蛋白質(fibrin mass)會包覆整個支架，當然該溶液的PH値，fibrin與thrombin 之間的比率濃度，會影響纖維蛋白素的表面粗糙度。第三種是使用含有forskolm藥 物的polyurethane高分子鑛層，forskolin屬於一種抗血小板(antiplatelet)可使血管擴張 (vasodilator)的藥物，第四種是在支架表面上鍍上一層與肝燐脂(heparin)藥物共價鍵結 的polyurethane-polyethylene oxide所合組而成的混合局分子材料。 200425880 鍍層處理時是在手套箱內進行，主要採取噴霧的方式做霧化噴塗處理’陰乾後再 取出，如此以製造一層具有藥物之高分子鍍層(drug-eluting polymer coating)。因爲每 一種藥物的用量基本上都不太一樣，而且以前用的是藥劑量，因爲有一部分會被身 體其他部分所吸收消化，所以產生療效的用量當然較多，重量濃度各爲0.1%，1%， 3%，10%。因爲使用的是高分子鍍層，因此是用傳統的氧化乙烯氣體(ethylene oxide gas)進行殺菌工作後，再將完成的支架在無菌室內套在心導管上，外環再套以一高 分子塑膠套，縮小支架的直徑，當支架沿著血管進入定位後，用心導管將塑膠外套 拉出，利用支架本身原有的金屬彈性，即可讓支架自行撐開。植入動物體內後，讓 植入的支架能夠逐漸的釋放所埋藏的藥物，幫助內皮細胞的成長，或是能夠抑制血 管栓塞(thrombus)或再狹窄的現象。這種方式正如同製造一般常用的肌肉酸痛用的貼 布原理是一樣的，讓貼布內的藥物逐漸釋放。 爲了證明當支架受氣球張力往外擴張撐開時，支架線肋並未受到太大的拉伸應 力，造成線肋因爲具有孔洞而產生斷裂的現象，因此本發明已經應用ANSYS有限 元素力學分析軟體，分析流程圖示於第7圖。模擬計算支架撐開時會產生的線肋內 應力，證實支架經過兩種氣球擴張壓力，其線肋的應力並未變化增加太多，而且， 此具有一系列孔洞的支架線肋並不會影響支架之抗壓縮強度，只會巨觀的增加網形 結構支架的直徑，如第8⑻、（b)圖所示。因此，經過藥物塗層處理之後，因爲線肋 的應變量很小，氣球在撐開時不會造成塗層脫落的現象，如此將藥物隨著支架送到 病灶處，並藉由降解材料會漸漸分解的原理，將藥物緩慢的釋放出來，濃度不會太 高，使支架具有確實可行的醫療效果。 由上述可知本發明所提供之製造血管支架的方法確實可提供品質優良且邊緣光 華之血管支架。再者，若與習知的製造方法相比，本發明所用之設備皆爲國內已經 相當成熟的產業技術，低廉、易於取得，且製程簡單，可大幅降低成本。 13 200425880 【實施方式二】 根據實施例一所述的方法製造具醫療效果的人體內支架所製成之代表生醫元件 …血管支架，並將此種生醫元件血管支架植入紐西蘭白兔的腹主動脈，經一個月後，將 動物犧牲，取出血管支架並檢驗其結果，結果由第9圖所示，由圖上顯示，支架已經完 全張開。因此上述可證明本發明所製造之支架，已成功地應用於動物內，且具有生物相 容性。 綜上所述，本發明所提出的具醫療效果人體內支架之製造方法，使用本國已經相當 成熟的產業技術，製程簡單易於控制，可大幅降低生產的成本。另一方面，本發明所製 ia的支架，成品品質優良，邊緣無毛邊及徑向粗糖面，且生物相容彳生良好，當生物可降 解材料隨著時間而分解時，會陸陸續續的緩慢的釋放出藥物來，控制細胞增生的現象， 讓管栓塞的現象不會再複發。達到徹底治療的效果。經查相關前案之文獻資料，並未發 現相同之前案，申請人因而依法提出發明申請，祈請貴審查委員撥冗詳爲審查，並求早 曰賜准本案爲禱。 【圖式簡單說明】 第1圖 本發明具醫療效果人體內用支架之製造流程圖。 第2(a)圖利用電腦輔助繪圖所繪支架之平面展開圖。注意支架線肋上鑽有一系列之孔 洞。 ^ 2(b)0 弟一圖⑻之局部放大圖’可以很清楚的看到線肋上佈滿一系列孔洞之情形。 第3圖 經線切割完成後之支架網狀結構圖。 第4圖 利用微精密放電加工的技術在支架線肋上鑽孔之局部放大圖。 第5⑻圖利用電腦輔助繪圖所繪支架捲成管狀立體圖的情形。注意支架線肋±_胃一 系列之孔洞。 第5(b)圖利用電腦輔助繪圖所繪支架捲成管狀立體局部放大圖。可以很明顯的看到支 架線肋上鑽有一系列之孔洞。 第5©圖經過精密機械切割完成之支架外型，可以很明顯的看出他是直徑丨.5 mm長 度16 mm左右之網狀結構。 第6圖 已經噴塗上含有藥物的生物可降解吸收溶液，可降解吸收材料會與藥物—起 14 200425880 固化在支架線肋上，生物可吸收材奴命u 1枓會i>t表面漸漸分解而把藥物釋放出來。 第7圖編輯ANSYS血管支架應力應變分析程式流程圖。 第8(a)圖利_腦助繪圖騰支架，注_架線肋上蝕贿一系列之孔洞。娜 受7大麵膨腿驅力時，軸ANSYS補元雜力學分讎肋之励 及變形量分佈圖。 第8(b)圖利用電腦輔助繪圖所繪支架，注意支架線肋上蝕刻有一系列之孔洞。支架承 受7大氣壓膨脹展開壓力時，經由ANSYS有限元素法力學分析線肋應力及 變形量分佈之局部放大圖。 第9圖 支架經過動物實驗（植入紐西蘭白兔腹主動脈血管)之後一個月’犧牲動物 將支架取出。從圖中可以很明顯的看到內皮細胞很成功的長在支架上。 15Other names: Lactic acid; L-(+)-Lactic acid; Propanoic acid, 2-hydroxy-, (S)-; Lactic acid, L-; Espiritin; (S) -2-Hydroxypropionic acid; (+)-Lactic acid; d-Lactic acid; L-Lactic acid; (S) -Lactic acid; (S)-(+)-Lactic acid; Paralactic acid; Propel; Sarcolactic acid; SY-83; Tisulac o Another polymer is degradable The material is poly-glycolic acid PGA (poly-glycolic add), which can be used alone or mixed with PLLA. The percentages of addition are 100_0%, 75-25%, 50-50%, 25-75%, 0 -100% and other five mixing ratios, the degradation rate of two biodegradable polymer materials, the compatibility of drugs, and biocompatibility have different effects, which will vary according to the needs of patients. The mixed biodegradable absorbent material is plated on the front and back of the stent. X-ray will be used to check its crystallinity. The greater the crystallinity, the worse the biocompatibility, so it is necessary to pay special attention to preservation. It must be placed in the refrigerator at a temperature of 2 ~ 8 ° C according to the original US regulations to avoid crystallization of polymers. According to our current initial tests, the biodegradable materials purchased at the beginning are transparent and placed. After a period of time in the stirred culture medium, it turned white. The second coating process is to drop a fibrinogen solution and a thrombin solution on the stent. This fibrin belongs to a natural polymer material. After the polymerization, the fibrin (Fibrin mass) will cover the entire scaffold. Of course, the pH of the solution, the ratio between fibrin and thrombin, will affect the surface roughness of fibrin. The third is to use a polyurethane polymer mineral layer containing forskolm. Forskolin is an antiplatelet drug that can vasodilator. The fourth is to coat the surface of the stent with heparin. ) A mixed local molecular material composed of a covalently bonded polyurethane-polyethylene oxide of a drug. 200425880 The plating process is carried out in a glove box. The spraying method is mainly used for atomizing spraying treatment ', and then it is taken out after being dried to make a layer of drug-eluting polymer coating. Because the dosage of each drug is basically different, and the dosage used in the past, because a part will be absorbed and digested by other parts of the body, of course, there are more dosages that produce curative effects, each with a concentration of 0.1%, 1 %, 3%, 10%. Because the polymer coating is used, after the traditional ethylene oxide gas is used for sterilization, the completed stent is placed on the cardiac catheter in a sterile room, and the outer ring is covered with a polymer plastic cover. Reduce the diameter of the stent. After the stent enters and locates along the blood vessel, use a heart catheter to pull the plastic jacket out, and use the original metal elasticity of the stent itself to allow the stent to open itself. After being implanted in an animal, the implanted stent can gradually release the buried drugs, help the growth of endothelial cells, or inhibit thromboembolism (thrombus) or restenosis. This method is the same as the principle used to make the commonly used patch for muscle soreness, so that the drug in the patch is gradually released. In order to prove that when the stent is expanded and expanded by balloon tension, the stent wire ribs are not subjected to too much tensile stress, which causes the wire ribs to break due to holes. Therefore, the present invention has applied ANSYS finite element mechanical analysis software. The analysis flow diagram is shown in Figure 7. The simulation calculation of the internal stress of the wire ribs when the stent is stretched out, it is confirmed that the stress of the wire ribs has not changed much by the expansion pressure of the two types of balloons, and the stent wire ribs with a series of holes will not affect The compressive strength of the stent will only increase the diameter of the stent with a mesh structure, as shown in Figure 8 (b). Therefore, after the drug coating treatment, because the strain of the wire ribs is small, the balloon will not cause the coating to fall off when the balloon is stretched, so the drug will be sent to the lesion with the stent, and the material will gradually degrade The principle of decomposition, the drug is slowly released, and the concentration will not be too high, so that the stent has a really feasible medical effect. From the above, it can be seen that the method for manufacturing a vascular stent provided by the present invention can indeed provide a vascular stent with excellent quality and bright edges. Furthermore, if compared with the conventional manufacturing method, the equipment used in the present invention is a mature industrial technology in the country, which is cheap, easy to obtain, simple in manufacturing process, and can greatly reduce costs. 13 200425880 [Embodiment 2] According to the method described in Example 1, a representative biomedical element ... a vascular stent made by manufacturing a stent with a medical effect in a human body is implanted into a New Zealand white blood vessel stent. After a month in the abdominal aorta of the rabbit, the animal was sacrificed, the vascular stent was removed and the results were examined. The results are shown in Figure 9, which shows that the stent has been fully opened. Therefore, the above can prove that the stent manufactured by the present invention has been successfully used in animals and has biocompatibility. To sum up, the method for manufacturing a human body stent with medical effects provided by the present invention uses a country's already mature industrial technology, the process is simple and easy to control, and the production cost can be greatly reduced. On the other hand, the IA stent produced by the present invention has excellent finished products, no burrs on the edges, and coarse coarse sugar surface, and has good biocompatibility. When the biodegradable material decomposes over time, it will be successively produced. Slowly release the drug to control the phenomenon of cell proliferation so that the phenomenon of tube embolism will not recur. To achieve the effect of thorough treatment. After reviewing the relevant documents of the previous case, the same previous case was not found. Therefore, the applicant filed an application for invention according to law, and I ask your reviewing committee to set aside time for detailed examination and ask for your permission in the present case as soon as possible. [Brief description of the drawings] FIG. 1 is a flowchart of manufacturing a stent for human body with medical effect according to the present invention. Figure 2 (a) is a plan unfolded view of the stent drawn by computer-aided drawing. Note that a series of holes are drilled in the bracket ribs. ^ 2 (b) 0 Partially enlarged view of Di Yitu⑻ 'It can be clearly seen that the ribs are covered with a series of holes. Figure 3 The mesh structure of the stent after warp cutting. Fig. 4 is a partial enlarged view of drilling holes in the ribs of the bracket using micro-precision electrical discharge machining technology. Figure 5 shows the situation where the scaffold drawn by computer-aided drawing is rolled into a tubular three-dimensional view. Note the holes in the stent line ribs. In Fig. 5 (b), the scaffold drawn by computer-assisted drawing is rolled into a tubular three-dimensional partial enlarged view. It can be clearly seen that a series of holes are drilled in the support wire ribs. Figure 5 © The shape of the stent completed by precision mechanical cutting. It can be clearly seen that it is a mesh structure with a diameter of 1.5 mm and a length of about 16 mm. Figure 6 has been sprayed with a biodegradable absorption solution containing a drug, the degradable absorbent material and the drug—from 14 200425880 are cured on the ribs of the stent, and the bioabsorbable material is destined to be broken down gradually. Release the drug. Figure 7 Edit ANSYS vascular stent stress-strain analysis program flowchart. Figure 8 (a) Tuli_Brain Assisted Teng Teng, Note_ A series of holes in the wire ribs. When under the driving force of the 7 large-face swelling legs, the axis ANSYS complements the hetero-mechanical analysis of the ribs and the deformation distribution map. Figure 8 (b) uses a computer-assisted drawing to draw the bracket. Note that a series of holes are etched in the ribs of the bracket. When the stent is subjected to the expansion pressure of 7 atmospheres, a partial enlarged view of the stress and deformation distribution of the wire ribs is analyzed mechanically by ANSYS finite element method. Fig. 9 One month after the stent was subjected to animal experiments (implanted into the abdominal aorta of New Zealand white rabbits), the animal was sacrificed and the stent was removed. It is clear from the figure that the endothelial cells successfully grow on the scaffold. 15