592677 (1) 玖、發明說明 【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 架進行淸潔與拋光，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，所以虽市有樂 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 -5- (2) (2)592677 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飮食的高脂化，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術， 此時也可以利用此種支架加以疏通，同時，同一病患的# 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。 -6 - 592677 Ο) 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2 0 - 4 0 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 除不需要的邰分’而成爲網形結構，此種方法需要相當精 (4) (4)592677 密的3 D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 會留下毛邊及粗糙面，成品邊緣所留下的毛邊及粗糙面， 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，將金屬置放在触刻溶液中 ，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，如此可能造成蝕刻處不均勻、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，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5 0,000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 樣一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 (5) (5)592677 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 -9 - (6)592677 一排孔洞的金屬網片滾圓，並利用顯微焊接 接成爲金屬網管，接著，利用電解拋光的方 行淸潔與拋光，以去除支架的毛邊及徑向粗 將生物可降解吸收性材料PLLA或是PGA， 兩種不同比率混合，使用相關溶液溶解後， 細胞增生藥物，例如，五氧化二砷，或是一 這些抗癌藥物已經經過硏磨成爲微米甚至奈 粒，將此混有抗細胞增生、消炎藥物的生物 溶液，完全霧化噴塗在支架內、外表面上， 上具有一整排小孔，所以當帶有藥物溶液噴 除了會吸附在支架表面外，也會因液體流動 象，自動滲入各個小孔內，俟溶解藥劑揮發 降解高分子材料會與藥物一起凝固成固體， 包在支架表面上，表面之塗層會像打上鉚釘 支架上不易脫落，如此即可製得具醫療效果 品0 【實施方式】 【實施方式一】 本發明一種具醫療效果支架的製造方法 爲本發明之製造支架的方法槪要流程圖。首 支架的圖形，此步驟係利用電腦輔助I Aided Design，CAD)，利用 pro-engineerin work的軟體將擬製的支架繪製成圖形，如凳 的技術將其焊 法，對支架進 糙面。然後， 使用單種或是 在其中混入抗 些抗癌藥物， 米級大小的顆 可降解性材料 因爲支架線肋 塗在上面後， 或是毛細管現 完畢，生物可 連同藥物一起 一樣，鉚附在 之血管支架成 ，第1圖所％ 先設計並繪_ έ 計（Computer g 或是 Solid、 ;2(a)、2(b)U[ -10- (7) (7)592677 所示，第2(a)圖顯示利用電腦輔助繪圖所繪血管支架之平 面展開圖。注意支架線肋上鑽有一系列之孔洞，第2(b)圖 顯示利用電腦輔助繪圖所繪血管支架平面展開之局部放大 圖。可以很明顯的看到支架線肋上鑽有一系列之孔洞。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Η示於第3圖其顯示經線切割機切割完成後之支架網 狀圖形。 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 -11 - (8) (8)592677 可，經微放電加工後鑽孔之局部放大圖圖示於第4圖其顯 示利用微精密放電加工的技術在支架線肋上鑽孔，所鑽孔 洞在掃描式電子顯微鏡圖（SEM)下之局部放大圖。放大被 率爲2 0 0倍，注意支架線肋寬度約爲220 μηι，所鑽孔洞約 爲40μιη左右，線肋厚度約爲80μιη。 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S ΕΜ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 淸潔與鏡面拋光作用’再以S ΕΜ檢驗電解拋光結果，支 架邊緣已經變得相當光滑，通過 S Ε Μ檢驗後，即可製得 支架’如第5(a)、5(b)、5(c)圖所示其分別顯示利用電腦 輔助繪圖所繪血管支架捲成管狀立體圖的情形。注意支架 線肋上鑽有一系列之孔洞，利用電腦輔助繪圖所繪血管支 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’完成後之支架網狀圖形。 接著進行藥物塗佈的步驟。首先將生物可降解材料具 聚左&Ε乳酸PLLA或是聚經基乙酸PGA (poly-glycolic a c i d)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 -12- 592677 Ο) 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，這樣會如同鉚釘般固定在支架表面上 ’如桌6圖所不其顯不已經噴塗上含有藥物的生物可降解 性溶液，可降解性材料會與藥物一起固化在支架線肋上， 生物可降解材料會從表面漸漸分解而把藥物釋放出來。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（As205)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：匚31!6〇3，單體分子量：=:::90.08，（]:11:〇 = 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、三氯甲烷，氯仿中添加 l°/〇w/w的 P L L A作成含有 2 % w / w d e X a m e t h a s ο n e 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〜3 20KD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10 μιη，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 -13- (10) (10)592677 ，則將其用高壓液態層析法（chr〇mat〇sraPhy sPectra)來測 試。至於類脂醇抗炎劑（dexamethasone)或是氧化砷 (As2〇5)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)加以檢驗所研1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-ray檢驗，以確定它的化學成分和結晶是否已經遭受 到破壞。 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。C A S註冊號碼：7 9 - 3 3 - 4 。化學結構式表示如下：592677 (1) 发明 Description of the invention [Technical field to which the invention belongs] The object of the present invention is to provide a method for manufacturing a stent in a human body with medical effects. 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 the blocked sites 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 it is rounded, it is welded into a metal mesh tube, that 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 of the stent. Rough 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 solution of the drug's bioabsorbable material is completely atomized and sprayed. On the inside and outside surfaces of the stent, 'Because there is a whole row of small holes on the ribs of the stent, although the fun solution is sprayed on it, because the liquid flows The reason and due to the capillary phenomenon, it automatically infiltrates into the small holes, the volatilizing agent is volatilized, and the biodegradable absorbent polymer material will solidify with the drug to form a solid, together with the drug -5- (2) (2) 592677 On the surface of the stent, the coating on the surface will be like rivets. The rivet is not easy to fall off on the stent. The biodegradable material slowly decomposes over time, and the drug is gradually released directly at the lesion. Block to achieve the effect of treatment. In this way, using the existing precision machinery manufacturing technology in Taiwan, people with low cost and medical effects can be produced. Within the holder with the finished product. [Previous technology] In recent years, due to the high fat intake in most industrialized countries, cardiovascular disease has become one of the major fatal diseases of people in various countries. In this regard, atherosclerosis has narrowed blood vessels, and even Occurrence of 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 implant the blood vessels directly to clear it. Without surgery, it has almost become a most common treatment. In addition, as a result of the high industrialization of modern society, human beings have suffered considerable social pressure, which is accompanied by abnormal dysfunction of human tissues, which causes many diseases and causes the human body. Intraluminal obstruction, such as obstruction of the bile duct, pancreatic duct, vas deferens, ureters, fallopian tubes, etc., or obstruction caused by abnormal proliferation of cancer cells in end-stage cancer patients. Painful, poor quality of life, but not suitable for major surgery This kind of stent can also be used for dredging. At the same time, there are often more than one place where this kind of stent needs to be placed on the same patient's #, which shows its wide application and demand. -6-592677 〇) In the way of vascular stent to unblock blood vessels, the vascular stent is placed in the occluded part of the blood vessel. Because the stent itself has elasticity, the blood vessel can be opened by the inside of the blood vessel to allow the blood to flow unimpeded. There are generally two types of vascular stents. 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 cardiac catheter surgery. , The vascular stent device is placed in the stent with an uninflated balloon, transported along the human blood vessel to the positioning, and then the balloon in the stent is inflated, using its expansion force, to expand the stent and blood vessels together, and then deflate the balloon together with Withdraw the catheter together. 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 A mesh 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 a blood vessel, and the diameter of the stent after opening is based on the diameter of the blood vessel where it is placed' Between 2-4 mm. In addition, for example, the stent size of the bile duct, pancreatic duct, vas deferens, ureter, fallopian tubes, etc. 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 a stent, one of which is to cut stainless steel into a net-shaped stent by using a high-power laser. When cutting, the laser is used to remove unwanted particles to form a mesh structure. This method requires Quite fine (4) (4) 592677 Dense 3D mechanical operation and cutting positioning, the operation is not easy. 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 surfaces may be left after cutting. The burrs and rough surfaces left by the edges of the finished product may hinder blood flow and even damage blood cells. Or other components in the blood, another way is to use the technique of lithographic exposure, cover the metal tube with a photoresist, and then develop through a photomask, place the metal in the engraving solution, and protect the unprotected photoresist Place 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 masking place from the side, which may cause uneven and irregular etching, and the network structure of the bracket is difficult to control and easy to fail. In addition, the equipment required for the above two processes is more expensive, which increases the cost of the bracket. In Taiwan, the price of a bracket is about NT $ 50,000. When multiple stents are needed in a 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, these two treatments will require the doctor to increase the amount of medication for the patient. On the one hand, it is a waste of valuable drug resources, and 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 implantation, generally, the rate of recurrence of patients with this type of embolism is at the lesion. (5) (5) 592677 is very high, so the stent must be regularly followed up for tracking between three months and half a year after implantation to ensure safety. So, if a layer of drug can be directly applied on the stent, directly Treatment at the lesion will be a great boon for patients. It is a pity that currently there is 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 a large number 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 coated. 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 the blood vessel from being blocked again, and can treat the obstruction according to different causes of obstruction to achieve the therapeutic effect. 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, round the metal mesh with a row of -9-(6) 592677 holes on the wire ribs, and use micro-welding to form a metal mesh tube. Then, use electrolytic polishing to clean and polish to remove the bracket. The burr and the radial are thick. The biodegradable absorbent material PLLA or PGA is mixed in two different ratios. After dissolving in the relevant solution, cell proliferation drugs, such as arsenic pentoxide, or one of these anti-cancer drugs has been treated. Grind to micron or even nano-particles. This biological solution mixed with anti-cell proliferation and anti-inflammatory drugs is completely atomized and sprayed on the inner and outer surfaces of the stent, with a whole row of small holes, so when sprayed with the drug solution, it will Absorbed on the surface of the stent, it will automatically infiltrate into the small holes due to the flow of the liquid. The volatilized dissolving agent will degrade and polymer material will solidify with the drug to form a solid, and it will be wrapped on the surface of the stent. The stent is not easy to fall off, so that a medically effective product can be obtained. [Embodiment] [Embodiment 1] A method for manufacturing a medically effective stent according to the present invention The flowchart of the method for manufacturing a stent according to the present invention is summarized. This step uses the computer-aided I Aided Design (CAD) to draw the prepared bracket into a graphic using the software of pro-engineerin work. For example, the technique of a stool is used to weld the bracket to the rough surface of the bracket. Then, use a single type or mix some anti-cancer drugs in it. The degradable material of meter size is coated with the stent wire ribs, or the capillary is now completed. The organism can be riveted together with the drug. The vascular stent is completed. The first figure is designed and drawn first (Computer g or Solid,; 2 (a), 2 (b) U [-10- (7) (7) 592677 as shown in the first. Figure 2 (a) shows a plane expansion of a vascular stent drawn using computer-aided drawing. Note that a series of holes are drilled in the ribs of the stent. Figure 2 (b) shows a partial enlargement of the plane expansion of a vascular stent drawn using computer-aided drawing. Figure. It can be clearly seen that a series of holes are drilled in the wire ribs of the bracket. Then, a program is written and tested. This program includes the subsequent positioning drilling and the cutting of raw metal foil. Control the program used by the wire cutting machine. The positioning program used by the two machines must be the same to prevent the defective product due to incorrect positioning. 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 and then use a precision drilling machine to perform positioning drilling. After the positioning drilling is completed, check whether the hole position is correct, and if it is correct You can use a wire cutter to cut it. 'Here, you can use a CNC machine tool to cut it to cut the desired stent pattern and then check the semi-finished product.' You can use a scanning electron microscope (scanning electron microscopy (SEM) to observe whether the stent has different widths or the ribs are broken. A photo of the shape of the stent cut by the wire cutter is shown in Figure 3, which shows that the warp cutter has completed the cut. Next, the mesh pattern of the bracket. Then use micro-discharge machining technology to drill a series of holes in each wire rib of the bracket, the diameter of the hole is about one-third of the width of the wire rib, depending on the strength of the material of the bracket. Appropriate adjustment. The holes do not have to be round. They can be any shape like a triangle or a square. The hole spacing is about twice the diameter of the holes. Or it can be adjusted to several times more than necessary according to the need. -11-(8) (8) 592677 Yes, the partial enlarged view of the drilled hole after micro discharge machining is shown in Figure 4. It shows the technology using micro precision discharge machining Drill holes in the ribs of the stent. The enlarged view of the holes under the scanning electron microscope (SEM) is magnified. The magnification is 200 times. Note that the width of the ribs of the stent is about 220 μηι. It is about 40μιη, and the thickness of the wire rib is about 80μιη. Then, the semi-finished product at this stage is subjected to the steps of rounding and micro-precision welding. This step uses a mechanical fixture to roll the flat metal mesh into a cylindrical metal mesh tube, and then performs precision microscopy. Welding, and then using S EM to check whether the welding result is appropriate, and then electrolytic polishing this cylindrical metal mesh tube to remove the burr and radial rough surface of the bracket, and at the same time to clean and mirror the surface of the bracket. S EM inspection results of electrolytic polishing, the edge of the bracket has become quite smooth, after passing the SEM inspection, the stent can be prepared. 'As shown in Figures 5 (a), 5 (b), and 5 (c), they are shown separately. Computer assisted drawing scenario depicted a vascular stent into a tube the perspective of FIG. Note that there are a series of holes drilled in the wire ribs of the stent. The vascular stent drawn by computer-assisted drawing is rolled into a tubular three-dimensional enlarged view. It can be clearly seen that a series of holes are drilled in the wire ribs of the stent after the mesh pattern of the stent is completed. The drug coating step is then performed. First dissolve the biodegradable material with poly-Le & E lactic acid PLLA or poly-glycolic acid PGA (poly-glycolic acid) with an appropriate solvent, such as acetone or chloroform, and dissolve it into a solution. Drugs, such as arsenic pentoxide or dexamethasone, are honed into micron-sized or even nano-sized powders, poured into the solution, and stirred evenly with an ultrasonic vibration magnet. Spray it out and spray it on the inside and outside surfaces of the prepared blood -12- 592677 〇). After the solvent is evaporated, the biodegradable polymer material will adhere to the nanometer drug in a solid state. On the surface of the stent 'including the inside of the hole, so that it will be fixed on the surface of the stent like a rivet'. As shown in Table 6, the biodegradable solution containing the drug has been sprayed. The degradable material will be cured with the drug. On the stent ribs, the biodegradable material will gradually decompose from the surface to release the drug. 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 binder, binder) (Medisorb Technologies International), PLLA is also known as poly-L-lactic acid 'Chemical formula: 匚 31! 6〇3, monomer molecular weight: = ::: 90.08, (]: 11: 〇 = 40: 6.71: 53.29, boiling point 392.2 K. The color is transparent, basically amorphous, or has a small amount of crystals. X-ray is used to check its crystallinity before use. There are three types of solvents that can be dissolved: chloroform, acetone, Trichloromethane and chloroform are added with 1 ° / 〇w / w of PLLA to make a suspension containing 2% w / wde X amethas ο ne. There are two kinds of PLLA used, one is low molecular weight ~ 80KD and the other is high molecular weight ~ 3 20KD of PLLA, and then spray the synthesized solution on the stent. The ratio of dexamethasone to PLLA is 2: 1. Each stent is sprayed with about 0.8 mg of dexamethasone and 0.4 mg of PLLA. The plating thickness is expected to be about 10 μιη in the mist At the same time of spraying, as for the chemical stability of dexamethasone after drying and sterilizing and washing, -13- (10) (10) 592677, it was tested by high pressure liquid chromatography (chromatosraPhy sPectra). Before use, the fatty alcohol anti-inflammatory agent (dexamethasone) or arsenic oxide (As205) will be manufactured using the well-established nano-powder manufacturing technology in our laboratory. Technology The present inventor has studied for many years and published a paper that uses a roller mill to make nano-grade cell-killing drugs. Of course, it will be tested by a transmission electron microscope (TEM) before use. Whether the drug has become nano-grade, the smaller the powder of the drug, the slower the release of the drug with the gradual degradation of the polymer degradation material, so that the amount of drug released will be more uniform, and the local concentration will be smaller, which will not stimulate Intravascular entrapment causes inflammation. The mixing ratio of this polymer to the drug is 1% by weight and 2% by weight. Of course, the drugs after honing will use EDS and x-ray. Test to determine whether its chemical composition and crystals have been damaged. PLLA itself is non-toxic and exists in small amounts in the blood vessels and muscles of humans and animals. The human body will increase its content in the body after strenuous exercise. It also exists in the liver, Kidney, thymus, or other fluids in the body, so it is a bioabsorbable material. C A S registration number: 7 9-3 3-4. The chemical structural formula is expressed as follows:
OHOH
其他名字：Lactic acid; L-(+)-Lactic acid; Propanoic -14- (11) (11)592677 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;Other names: Lactic acid; L-(+)-Lactic acid; Propanoic -14- (11) (11) 592677 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 acid)，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%，7 5 -25 %，5 0-5 0% ，2 5 -75 %，0-1 0 0%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 -15- (12) (12)592677 forskolin 藥物的 polyurethane 高分子鍍層，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 所合組而成的混合高分子材料。 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 %， 1 〇%。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（t h r 〇 m b u s )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 •16- (13) (13)592677 學分析軟體，分析流程圖示於第7圖，其顯示編輯 ANSYS血管支架應力應變分析程式流程圖。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8(a)、（b)圖所 示其分別顯示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之應力及變形 量分佈圖’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。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。 【實施方式二】 -17- (14) (14)592677 根據實施例一所述的方法製造具醫療效果的血管支架 所製成之代表生醫元件-一血管支架，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 其顯不支架經過動物貫驗（植入紐西蘭白兔主動脈血管）之 後一個月，犧牲動物將心血管取出。從圖中可以很明顯的 看到內皮細胞很成功的長在血管支架上。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 製造的支架’成品品質優良，邊緣無毛邊及徑向粗縫面， 且生物相容性良好，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， 並求早日賜准本案爲禱。 【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 -18- (15) (15)592677 。注意支架線肋上鑽有一系列之孔洞。 第2(b)圖 第二圖（a)之局部放大圖，可以很淸楚的 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5 (a)圖 利用電腦輔助繪圖所繪支架捲成管狀立體 圖的情形。注意支架線肋上鑽有一系列之孔洞。 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(c)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1.5 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一起固化在支架線肋上，生物 可吸收材料會從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之應力及變 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 -19- (16) (16)592677 肋上触刻有一系列之孔洞。支架承受7大氣壓膨脹展開壓 力時’經由AN S Y S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。從途中可以 很明顯的看到內皮細胞很成功的長在支架上。 -20-Paralactic acid; Propel; Sarcolactic acid; SY-83; Tisulac o Another polymer degradable material is poly-glycolic acid PGA (poly-glycolic acid), which can be used alone or in combination with PLLA. Five mixing ratios of 100-0%, 7 5 -25%, 50 0-50%, 2 5-75%, 0-100%, etc., the degradation rate of two biodegradable polymer materials, Drug compatibility and biocompatibility have different effects, and will vary depending on the needs of the patient. X-ray is used to check the crystallinity of the mixed biodegradable absorbent material before and after plating on the stent. The greater the crystallinity, the worse the biocompatibility. Therefore, it is necessary to pay special attention to preservation. It must be placed in the refrigerator to maintain the temperature at 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 drip the fibrinogen solution and 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 a polyurethane polymer coating containing -15- (12) (12) 592677 forskolin. Forskolin is an antiplatelet drug that can vasodilator. The fourth is on the surface of the stent. It is coated with a hybrid polymer material composed of a polyurethane-polyethylene oxide covalently bonded to a heparin drug. The coating process is carried out in a glove box. The spray method is mainly used for atomizing spraying treatment, and then it is taken out after drying in the shade, so as to make a layer of drug-eluting polymer coating. 1% Because the amount of each drug is basically different, and the dose used in the past, because a part will be absorbed and digested by other parts of the body, so the amount of curative effect is certainly more, the weight concentration is 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 can inhibit the phenomenon of vascular embolism (t h r om m b s) 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 subject to too much tensile stress, which causes the wire ribs to break due to holes. Therefore, ANSYS finite element force has been applied to the present invention. 16- (13) (13) 592677 The scientific analysis software, the analysis flow chart is shown in Figure 7, which shows the flow chart of editing ANSYS vascular stent stress-strain analysis program. The calculation of the internal stress of the wire ribs when the stent is stretched is simulated, and 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 it. The compressive strength of the stent will only increase the diameter of the stent with a mesh structure. As shown in Figures 8 (a) and (b), it shows that the stent is drawn using computer-assisted drawing. Note that there is an etched pattern on the ribs of the stent. Holes in the series. When the stent is subjected to 7 atmospheres of expansion and expansion pressure, the stress and deformation distribution of the wire ribs is analyzed mechanically through ANSYS finite element method. The scaffold is drawn using computer-aided drawing. Note that a series of holes are etched in the wire ribs of the stent. When the stent is subjected to 7 atmospheres of expansion and deployment pressure, the partial enlarged view of the stress and deformation distribution of the wire ribs is analyzed mechanically through ANSYS finite element method. 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 it is stretched out. 'This way the drug is 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 an industrial technology already well-developed in China ', which is cheap, easy to obtain, and simple in manufacturing process, which can greatly reduce the cost. [Embodiment 2] -17- (14) (14) 592677 According to the method described in Example 1, a representative biomedical element made by manufacturing a vascular stent with medical effects-a vascular stent, and using such a biomedical element The vascular stent was implanted into the abdominal aorta of a New Zealand white rabbit. After one month, the animal was sacrificed and the vascular stent was removed and the results were examined. One month later, the Zelen White Rabbit aortic vessels) were sacrificed to remove the cardiovascular system. It is clear from the figure that the endothelial cells successfully grow on the vascular scaffold. The picture shows that the stand is fully open. 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 mature industrial technology in the country, the process is simple and easy to control, and the production cost can be greatly reduced. On the other hand, the stent manufactured by the present invention has excellent quality, no burrs on the edges and radial rough seam surface, and good biocompatibility. When the biodegradable material decomposes over time, it will be gradually slower. The drug is released 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 previous case documents, the same previous case was not found. Therefore, the applicant filed an application for an invention in accordance with the law. I ask your reviewing committee to set aside time for detailed examination and ask for your approval as soon as possible. [Brief Description of the Drawings] FIG. 1 is a flow chart of manufacturing a stent for human body with medical effect according to the present invention. Figure 2 (a) Expansion plan of the bracket drawn by computer-aided drawing -18- (15) (15) 592677. Note that a series of holes are drilled in the bracket ribs. Figure 2 (b) A partially enlarged view of Figure 2 (a), you can clearly see the line ribs 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. Fig. 5 (a) The stent drawn by computer-aided drawing is rolled into a tubular three-dimensional view. Note that a series of holes are drilled in the bracket ribs. Fig. 5 (b) The computer-aided drawing of the stent is rolled into a tube-shaped three-dimensional enlarged view. It is obvious that a series of holes are drilled in the ribs of the bracket. Fig. 5 (c) The appearance of the stent after precision mechanical cutting shows that it is a net-like structure with a diameter of 1.5 mm and a length of about 16 mm. Figure 6 The biodegradable absorption solution containing the drug has been sprayed on. The degradable absorption material will be cured with the drug on the ribs of the stent. The bioabsorbable material will gradually decompose from the surface to release the drug. Figure 7 Edit the ANSYS vascular stent stress-strain analysis program flow chart. Figure 8 (a) The bracket is drawn using computer-aided drawing. 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, the stress and deformation distribution of the wire ribs are analyzed mechanically by ANSYS finite element method. Figure 8 (b) Use computer-assisted drawing to draw the bracket. Note the bracket line. -19- (16) (16) 592677 A series of holes are engraved on the ribs. A partial enlarged view of the stress and deformation distribution of the wire ribs through the AN S Y S finite element method when the stent is subjected to an expansion and expansion pressure of 7 atmospheres. Figure 9 One month after the stent has been subjected to animal experiments (implanted into the abdominal vein of New Zealand white rabbits), the stent is removed at the expense of the animal. It is obvious from the way that the endothelial cells successfully grow on the scaffold. -20-