2012-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/685076摘要：生物間的相互作用是幾乎是非單一性的，任何生物環境的表面通常涉及複雜以及多樣的物理現象或化學反應。然而，以現有的技術而言，幾乎所有表面改質技術均局限於控制單一類型的表面功能；要實現能夠同時控制、呈現兩種或兩種以上生物分子的改質技術仍極具挑戰性。精確控制多種表面反應，同時避免不同的化學基團之間的交叉反應將是克服這項挑戰的關鍵。這種多元功能性的表面改質技術將可應用於控制細胞生長，組織工程支架的開發，再生醫學方面的研究，或製造日益複雜的micrototal analytical system (TAS)，等等。在此為期二年的研究中，我們計畫開發一種新的多元官能性高分子鍍膜塗層(multifunctional polymer coatings)，並著眼於其對植入性生醫材料的應用。在計畫中，我們將根據我們研究團隊先前開發的官能性聚對二甲苯(functionalized poly-p-xylylenes)為藍本，並採用化學氣相沉積法(CVD)來製備此多元功能性高分子鍍膜。聚對二甲苯鍍膜(poly-p-xylylenes) - 眾所皆知的商標名稱為Parylene – 於植入性生醫器材方面的使用是絕佳的材料，因為Parylene本身具備優良的生物相容性(biocompatibility)，並為第一個獲得美國食品藥物管理局 (FDA) 批准在藥物釋放支架(drug-eluting stent)上使用的鍍膜 (例如：品名為Cypher的支架-強生公司製造，使用氣相沈積的聚對二甲苯鍍膜為塗層附著促進劑)。然而，此商業上使用的聚對二甲苯塗層表面缺乏可供鍵結使用的官能基，無法有效地成為藥物載體來固定藥物分子。有鑑於此，我們已在前一計畫中 (氣相功能性高分子鍍膜之合成與特性分析，國科會NSC 99-2218-E-002-036，執行中) 改善此一性質，製備具官能性的聚對二甲苯鍍膜(functionalized poly-p-xylylenes)。而在此計畫中，我們將更進一步製備具有多元官能性的聚對二甲苯鍍膜(multifunctional poly-p-xylylene coatings)，意味著此一鍍膜將具備兩種或多種以上的官能基，並利用氣象沈積共聚法(CVD co-polymerization)來控制不同官能基之間的比例，進而在對等的比例下來固定生物分子，例如：藥物分子。研究重點將針對此多元官能性聚對二甲苯鍍膜的合成技術進行最適化的研究，並系統化地研究分析此塗層的化學性質以及其對應的生物特性。我們將進行以下分析研究： 1. 目的一：建立化學氣象沈積共聚法(CVD co-polymerization)製備多元官能性的聚對二甲苯鍍膜的最適化製程 • 昇華溫度(Ts)此參數，是否可以確保此多元官能性的聚對二甲分子能正確地以共聚物(copolymer)方式組成，而非以層疊的方式組成？Ts的最適範圍？ • 單體進料的配比變化是否對等於共聚物的組成比例？ • 合成勻相共聚物所需最適的基板溫度範圍？此基板溫度與共聚物組成比例間的關係為何？ 2. 目的二：研究此鍍膜以多元鍵結方式固定不同生物分子時的功能與特性 • 此多元官能性鍍膜用於鍵結不同生物分子時的穩定性？ • 不同的生物分子固定後，是否仍保有其應有的生物活性？ 最終，我們將彙整此計畫中對於多元官能性的聚對二甲苯鍍膜製程以及分析的各項資料，提供爾後在複雜生物環境界面改質技術以及仿生技術的應用。我們並期望此多元官能性鍍膜能有實際應用於控制細胞生長，植入性生醫器材，組織工程支架的開發，以及再生醫學方面的研究。<br> Abstract: Biological interactions are hardly ever unitary and typically involve a complex cascade of immobilizations and simultaneous manipulation of several physical and chemical properties on surfaces. Yet, almost all synthetic surface modification concepts rely on a single type of surface cues; achieving controlled, simultaneous presentation of two or more biomolecules remains challenging. The precise control of multiple surface reactions, while avoiding crossreactivity between the different chemical groups is key to overcome challenges to this field and will benefit applications such as the regulation of cell shape, the development of advanced biological assays and scaffolds for regenerative medicine, or the fabrication of increasingly complex micrototal analytical systems (TAS) that all demand defined surface architectures and usually require precise immobilization of multiple biomolecules. In response to this request, this proposal aims to develop a new manufacturing process for multifunctional coatings of biomedical implants. Towards this goal, polymer coatings applied by chemical vapor deposition (CVD) are exceptional candidates for the coating of implanted biomedical devices. This is because of their advanced processibility and their excellent intrinsic biotolerability. For instance, the first FDA approved drug-eluting stent (Cypher stent, J&J) uses a vapor deposited polymer (parylene) as adhesion promoter. The commercially available non-functionalized parylene coatings lack, however, anchor groups for further modification and therefore would fail as potential coating candidates to anchor appropriate drug molecules to the surface of the devices. In contrast, we have recently developed biomedical coatings based on a novel class of vapor-deposited polymers: functionalized poly-p-xylylenes. The herein proposed technology will further identify necessary specifications for the CVD copolymerization, while demonstrating the fundamental feasibility of multi-functional coatings. Moreover, the CVD-based coatings can be generically applied to a wide variety of substrates – including polymer, such as PTFE, stainless steel, Nitinol, and tungsten being the most common materials used in cardiovascular implants. This proposed work will be conducted with an existing CVD polymerization system in PI’s laboratory and will include: Aim #1: Establish missing specifications for the CVD co-polymerization manufacturing process. • Is the sublimation temperature (Ts) an appropriate control parameter to ensure manufacturing of multifunctional coatings with defined polymer composition, while avoiding layering effects? In which range can and need Ts be varied? • Will a variation of monomer ratios result in defined polymer ratios? • What is the optimum substrate temperature to obtain homogeneous and defined polymer ratios? In which range can and need the substrate temperature be varied? Aim #2: Demonstrate dual drug immobilization onto multi-functional coatings fabricated by CVD copolymerization. • Can multifunctional coatings support the dual immobilization of two different biomolecules? • After dual immobilization, is the biological activity of both biomolecules maintained? The outcome of this study will support future studies in biointerface engineering and biomimetic technology. We foresee the practical use of these multifunctional coatings in the regulation of cell behavior, implant biomedical devices, and the development of advanced biological assays and scaffolds for regenerative medicine.化學氣相沈積法合成多元官能性高分子鍍膜及其在生醫材料上之應用