TWI638668B - Surface modification method and surface modification structure for improving blood compatibility of biomedical metal substrate - Google Patents

Surface modification method and surface modification structure for improving blood compatibility of biomedical metal substrate Download PDF

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TWI638668B
TWI638668B TW104129830A TW104129830A TWI638668B TW I638668 B TWI638668 B TW I638668B TW 104129830 A TW104129830 A TW 104129830A TW 104129830 A TW104129830 A TW 104129830A TW I638668 B TWI638668 B TW I638668B
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substrate
blood
metal substrate
surface modification
biomedical metal
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TW201709937A (zh
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林淑萍
翁培傑
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國立中興大學
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/0076—Chemical modification of the substrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00592—Coating or prosthesis-covering structure made of ceramics or of ceramic-like compounds
    • A61F2310/00598—Coating or prosthesis-covering structure made of compounds based on metal oxides or hydroxides
    • A61F2310/0061—Coating made of silicon oxide or hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00592—Coating or prosthesis-covering structure made of ceramics or of ceramic-like compounds
    • A61F2310/00856—Coating or prosthesis-covering structure made of compounds based on metal nitrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00389—The prosthesis being coated or covered with a particular material
    • A61F2310/00592—Coating or prosthesis-covering structure made of ceramics or of ceramic-like compounds
    • A61F2310/00916—Coating or prosthesis-covering structure made of compounds based on metal sulfides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment

Abstract

一種增進生醫金屬基材血液相容性之表面修飾方法，包括：於一表面具有氧化層之生醫金屬基材通過分子自組裝之手段於該氧化層之表面固定含硫之單分子膜。本發明具體的增進了與血液接觸之生醫金屬基材之親水性、血液相容性，並確保對血管內皮細胞無毒性。

Description

增進生醫金屬基材血液相容性之表面修飾方法及表面修飾結構
本發明之技術領域涉及生醫金屬基材之表面修飾，所述之表面修飾是為增進生醫金屬基材之生物相容性。與本發明有關之生物相容性是指血液相容性。
已知的生醫金屬材料包括鉑、金、鎢、錸、鈀、銠、釕、鈦、鎳，及這些金屬的合金，如：不銹鋼，鈦/鎳，鎳鈦合金，和鉑/銥合金等。這些金屬材可製成與活體組織接觸或長期暴露於血液之植入物，也可以當作其他基材的表面塗覆材料。暴露於血液之植入物應具備優異的血液相容性。以血管支架為例，裸金屬血管支架通常是由316L不銹鋼、鈷基合金、鉭或鈦合金製成。塗藥血管支架則於金屬支架的表面披覆含藥塗層，於血管中持續釋放塗層中的藥物。所述塗層可為聚合物塗層，例如polyethylene-co-vinyl acetate(PEVA)、poly n-butyl methacrylate(PBMA)，含於聚合物塗層的藥物可為抗凝血劑，例如肝素，或抑制平滑肌細胞生長的藥物，例如：sirolimus、paclitaxel(紫杉醇)。
專利文獻WO2014169281揭露於一血管支架表面塗覆由聚陽離子和聚陰離子所構成之多層聚電解質，優選的聚陽離子為殼聚醣(chitosan)，優選的聚陰離子為糖胺聚醣(glycosaminoglycan)；一氧化碳釋放基團可修飾 於聚陽離子層或聚陰離子層，達到血小板活化減少之目的；此外，在至少一個聚電解質層上吸附生長因子，所述之為血管內皮生長因子(VEGF)。
專利文獻US20130224795揭露藉由多酚氧化酶(polyphenol oxidase)將生物活性分子固定到基板表面的技術。在多酚氧化酶存在的情況下，將含有苯酚(phenol)或鄰苯二酚(catechol)基團的生物活性分子在短時間內原位氧化成與生醫金屬或聚合物基板鍵結的多巴(dopa)或多巴醌(dopaquinone)，從而將生物活性分子穩固的固定在基板表面。所述之生物活性分子包含細胞黏附肽(cell adhesion peptides)、生長因子(growth factors)、生長激素(growth hormones)、蛋白質(proteins)、抗血栓劑(antithrombotic agents)、內皮化誘導劑(entothelialization inducing agents)。細胞黏附肽(cell adhesion peptides)、生長因子(growth factors)可應用到整型外科或牙科植入物，抗血栓劑(antithrombotic agents)、內皮化誘導劑(entothelialization inducing agents)可應用到血管支架或人工血管。
塗覆技術被廣泛的應用在生醫基材的表面改質，然而被塗覆的膜層只是以物理結合的方式依附在生醫基材的表面，相對於活性分子固定技術，物理結合的穩固性是比較弱的。然而活性分子固定技術的缺點是操作複雜、反應時間長、且難以去除或控制生物活性分子副產物的生成及其引發的副作用。
本發明之目的是在提供一種增進生醫金屬基材血液相容性之表 面修飾方法，通過分子自組裝的方式於生醫金屬基材之氧化層表面修飾含硫之單分子膜，增進與血液接觸之生醫金屬基材之親水性、血液相容性， 並確保對血管內皮細胞無毒性。
本發明增進生醫金屬基材血液相容性之表面修飾方法，包括： 於一表面具有氧化層之生醫金屬基材通過分子自組裝之手段於該氧化層之表面固定含硫之單分子膜。
在本發明實施例中，優選的生醫金屬為鈦或鈦合金。所述氧化 層可為自身氧化層(native oxide)，或是經由表面處理技術所產生之氧化層。 所述分子自組裝之手段為：將表面具有氧化層之生醫金屬基材與含有3-氫硫丙基三甲氧基矽烷(3-mercaptopropyltrimethoxysilane,MPTMS)之溶液接觸一段預定時間，於該氧化層的表面經分子自組裝固定含硫之單分子膜。
本發明於生醫金屬基材的氧化層表面修飾含硫之單分子膜，使 基材表現親水性及血液相容性。在本發明中所述血液相容性乃是關於血液與本發明生醫金屬基材接觸後，其血液凝血時間的評估，包括：保持凝血酶原時間(prothrombin time,PT)及活化部分凝血活酶時間(activated partial thromboplastin time，aPTT)於正常範圍值，以及，降低接觸基材表面之血液纖維蛋白原濃度(fibrinogen concentration)。此外，接觸基材表面之血液無血小板活化作用，無紅血球吸附聚團現象，而且，基材對於血管內皮細胞無毒性。
PT及aPTT保持於正常範圍，表示本發明對於血液之外源凝血途 徑和內源凝血途徑不生負面影響，維持血液凝血和抗凝血的動態平衡。
血液的纖維蛋白原(fibrinogen)是一種蛋白質，血小板破裂 時，會釋出凝血致活酶，在鈣離子的作用下催化凝血酶原變成凝血酶，凝血酶將血漿中原本可水溶的纖維蛋白原凝固變成不溶於水的纖維蛋白，纖 維蛋白扭結其他血細胞成團，凝固成為血塊。本發明基材可降低與之接觸之血液的纖維蛋白原(fibrinogen)濃度，使扭結血細胞成團的纖維蛋白無法產生，從而確保基材表面無凝血血塊。因此，fibrinogen濃度低，可預期的生理效應是降低凝血血塊的生成。
血小板活化會啟動更高的凝血作用，本發明使接觸基材表面之 血液不產生血小板活化作用，確保基材表面無凝血血塊。
紅血球吸附易導致血球團聚的不正常現象，血球團聚成為血栓 形成的基床。本發明於基材表面無紅血球吸附現象，可預期的生理效應是不激發血栓形成。
血管之內皮細胞確保血管內壁之完整並可促進血管內壁自然癒 合的作用。血管內皮不完整或癒合遲延將導致細胞外基質被高度曝露，將會激活凝血反應而形成血栓。本發明之基材對於內皮細胞完全無毒性，使內皮細胞可在基材表面正常生長，可預期的生理效應是不破壞血管內皮細胞，不激活凝血反應和血栓形成。
本發明增進生醫金屬基材血液相容性之表面修飾方法，更進一 步包括於生醫金屬基材表面所修飾之單分子膜上形成一氧化氮(NO)膜層。
本發明增進生醫金屬基材血液相容性之表面修飾方法，更進一 步包括於一生醫金屬基材之氧化層表面形成一氧化氮(NO)膜層，通過分子自組裝之手段於該一氧化氮(NO)膜層表面形成含硫之單分子膜。
通過一氧化氮(NO)膜層之附加，更進一步降低本發明基板之血 小板活化作用以及血球黏附作用。
本發明通過分子自組裝之方式於生醫金屬基材表面固定含硫單 分子膜，相對於活性分子固定技術而言，本發明所需反應時間短、容易操作實施，且沒有難以去除或無法控制之副產物產生。
第一圖為本發明於二氧化鈦基材表面修飾含硫單分子膜之化學結構。
第二圖為本發明實施例中四組樣本進行ESCA掃描S2p區段分析圖。
第三圖為本發明實施例中四組樣本進行水滴角量測之親水性評估結果。
第四圖為本發明實施例中四組樣本表面吸附血小板的FESEM圖。
第五圖為本發明實施例中四組樣本表面吸附紅血球的FESEM圖。
第六圖為本發明實施例中四組樣本表面內皮細胞培養之螢光染色圖。
第七圖為本發明實施例中四組樣本表面內皮細胞培養之量化條棒圖。
本發明增進以鈦或鈦合金為生醫金屬基材血液相容性之表面修飾方法，包括：於一表面具有氧化層之生醫金屬基材通過分子自組裝之手段於該氧化層之表面形成含硫之單分子膜。
所述氧化層可為自身氧化層(native oxide)，或是經由表面處理技術所產生之氧化層。在本發明中通過陽極氧化處理法或氣體電漿表面處理法於鈦金屬或鈦合金基材表面生成氧化層(-Ti-O-)(以下簡稱二氧化鈦基材)。該氧化層提供後續分子自組裝所需之化學鍵。
在本發明實施例中，所述分子自組裝之手段為：將二氧化鈦基材浸泡於體積濃度0.1%-20%之3-氫硫丙基三甲氧基矽烷(3-mercaptopropyltrimethoxysilane,MPTMS)之溶液中，浸泡時間範圍為10分鐘 -24小時。浸泡過程中於所述氧化層上進行分子自組裝反應，MPTMS於氧化層的表面形成含硫之單分子膜。自組裝反應結束後，取出鈦基材，以無水酒精清洗脫除未參與反應的MPTMS，清洗之基材以烤箱烘烤乾燥。
如第一圖，通過鈦氧化物與MPTMS的矽氧基鍵結(-Ti-O-Si-)將MPTMS的含硫官能基(-SH)修飾於二氧化鈦基材的表面。
此外，進一步透過電漿處理技術於所述含硫之單分子膜表面修飾一氧化氮(NO)膜層；或者將一氧化氮(NO)膜層修飾在二氧化鈦基材表面，再按上述分子自組裝技術將含硫之單分子膜修飾於一氧化氮膜層表面。
為證明上述經表面修飾的基材之血液相容性，備四種樣本進行相關之量測和分析。所述的四種樣本包括：A.鈦金屬基材(Ti)；B.表面以MPTMS修飾之二氧化鈦基材(MPTMS-ATN)；C.表面以一氧化氮處理再經MPTMS修飾之二氧化鈦基材(NO-MPTMS-ATN)；D.表面以MPTMS修飾再經一氧化氮處理之二氧化鈦基材(MPTMS-NO-ATN)。上述四種樣本中A、B、C基材為對照組；B、C、D基材則為本發明。
關於含硫官能基(-S)是否成功修飾於基材的表面，將上述四組基材以電子能譜化學分析儀(ESCA)分析表面所含的化學元素。結果如第二圖，經ESCA掃描S2p區段，於上述B基材(MPTMS-ATN)、C基材(NO-MPTMS-ATN)及D基材(MPTMS-NO-ATN)分別具有(1)-SH S2p3/2為163.6eV；(2)-SH S2p1/2 164.6eV；(3)-SO4 2-為169eV；(4)-SO4 2-為169eV訊號，A基材則無S訊號。證明含硫官能基成功修飾於本發明B、C、D基材表面。
以水滴角量測對四組基材樣本進行親水特性評估，結果如第三 圖，其中，A基材(Ti)接觸角幾乎為90°，呈現疏水性。B基材(MPTMS-ATN)；C基材(NO-MPTMS-ATN)；D基材(MPTMS-NO-ATN)之接觸角小於60°，表示本發明B、C、D基材具有親水性。
血液測試。將上述四組基材分別與新鮮血液接觸進行培養，並 探討各基材的凝血作用和抗凝血作用。抽取新鮮健康血液經離心分離取出低濃度血小板血漿(PPP)、高濃度血小板血漿(PRP)、紅血球(RBC)。將PPP分別與四組基材接觸，於二氧化碳培養箱(CO2 Incubator)中以37℃靜置培養一小時，之後進行PT及aPTT與fibrinogen concentration等檢測。另外，將四組基材分別與PRP及RBC接觸，於二氧化碳培養箱(CO2 Incubator)中以37℃靜置培養一小時，之後透過FESEM觀察四組基材表面是否出現血小板或血球貼附現象。
關於PT、aPTT、fibrinogen concentration之檢測結果，如 下表一。結果顯示四組基材的PT及aPTT均表現於正常值範圍，表示對於血液之外源凝血途徑和內源凝血途徑不生負面影響，維持血液凝血和抗凝血的動態平衡。四組基材表面的fibrinogen concentration均低於正常值，基材表面無凝血血塊。
關於四組基材表面是否吸附血小板的FESEM觀察結果如第四 圖。其中，A基材(Ti)的表面吸附多量血小板；B基材(MPTMS-ATN)、C基材(NO-MPTMS-ATN)及D基材(MPTMS-NO-ATN)表面則完全沒有吸附血小板。此結果顯示A基材表面有血小板活化作用產生，本發明B、C、D基材則沒有血小板活化作用。血小板活化會啟動更高的凝血現象，本發明B、C、D基材表面無血小板活化作用，可確保基材表面無凝血血塊。
關於四組基材表面是否吸附紅血球(RBC)的FESEM觀察結果如 第五圖。四組基材表面均無吸附紅血球(RBC)。本發明於基材表面無紅血球吸附現象，可預期的生理效應是不激發血栓形成。
血管內皮細胞實驗。將血管內皮細胞分別貼附於四組基材表 面，透過螢光染劑DAPI染色內皮細胞細胞核，利用螢光顯微鏡觀察螢光染色情形。如第六圖，顯示四組基材於第1天、第3天、第5天的內皮細胞增長情形。第七圖為四組基材內皮細胞增長數目統計圖表。第六圖和第七圖描述按著天數增加四組基材的內皮細胞均持續增長，特別是B、C、D基材內皮細胞增長較A基材多。此結果說明本發明B、C、D基材對於內皮細胞完全無毒性，促進內皮細胞在基材表面正常生長，可預期的生理效應是不激活凝血反應和血栓形成。

Claims (1)

  1. 一種增進生醫金屬基材血液相容性之表面修飾結構，其特徵在於含有NO及官能基-SNO或-SH且包括：形成於一生醫金屬基材表面之氧化層，修飾於該氧化層表面之含硫單分子膜，以及形成於該含硫單分子膜表面或形成於該氧化層與該含硫單分子膜之間的一氧化氮(NO)膜層。
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