多功能有機-無機珍珠層結構的材料開發應用於腦機介面的研究

Abstract

植入式神經探針在改善神經變性疾病上已經受到相當大的關注。對於植入腦部的裝置而言，材料設計必須考量到幾個會引起發炎而導致元件失效的重要因素，包含了機械性質上的不相容，星形膠質細胞的生物淤積以及急性損傷誘發的慢性炎症。因此在研究中我們引入了具有以下特性的奈米複合材料作為植入式的基材（1）穿刺時具有高的楊氏模數，並且能夠在植入後轉變成和腦組織相符的機械性質，（2）減少長期植入時的細胞貼附，和（3）延長抗炎藥物的釋放以減少組織反應。 在製作上，混和等比的原花青素、氧化石墨以及以共沉澱法合成的鈣鋁基雙層水滑石，接著加入不同比例的聚乙烯醇做混合，然後用澆注的方式來製作具有珍珠層結構的混合薄膜。在研究中探討了不同聚乙烯醇比例下作為植入式基材的潛力，探討的範圍包含複合材料的物理性質，用結構特性以及鍵結去判原花青素的插層行為，在乾溼情況下不同比例的聚乙烯醇含量的應力變化。由實驗中的觀察發現聚乙烯醇含量最少的組別具有最低的膨潤情形(39%)，卻具有最大的應力變化使楊氏模數從5 GPa降至40 MPa，以及相當低的導電性，此現象可歸因於材料內部孔隙的差異以及介面作用力的差異，在高孔隙的情況下會造成電子傳遞的能障增加以及應力上的集中導致應力在濕潤的情況下大幅的下降。 不僅如此，藉由研究原花青素的釋放行為，可以從動力學的分析結果推斷出短期的釋放包含了雙層水滑石層間的藥物釋放以及外圍表層藥物的脫附，而長期的釋放則是由外圍表層的吸附物所主導，同時結構上的限制使藥物能更為緩慢地釋放而達到超過70天以上的長期釋放。最後探討了細胞對於人造珍珠層複合材料的反應，發現材料皆表現相當低的生物毒性，同時由於原花青素的釋放使細胞具有更高的存活率。材料表面的負電荷提供了良好的抗貼附能力，而抗貼附能力與材料在濕潤情況下的機械性質呈現明顯的關聯，在穿刺實驗中顯示珍珠層結構具有穩定整體結構的作用而使基材在穿刺時不會產生任何的彎曲，顯示了多功能珍珠層結構在植入上應用的潛力。

Implanted neural probes have raised great appeal over years with the improvement of neurodegenerative disorders. For brain implant devices, a key factors resulting in the formation of glial scar such as mechanical mismatch, biofouling by astrocytes, and acute injury-induced chronic inflammation, should be considered for materials design. Therefore, in our study, we introduced a new kind of nanocomposite as a substrate of neural implants with the following functions: (1) high Young’s modulus for penetration which transfers to become brain tissue-mimicked after insertion in brain, (2) reduction of cells adhesion for long-term implantation, and (3) prolonged anti-inflammatory drug release to reduce tissue responses. Ca-Al layered double hydroxide (Ca-Al-LDH) was synthesized by co-precipitated method, then mixed with oligo proanthocyanidin (OPC) and graphene oxide (GO) with same mass ratio. Follow by mixing with different ratio of polyvinyl alcohol (PVA) then used casting process to form the nacre-like hybrid films. The study discussed the potential of implantable substrates at different ratios of PVA. The physical properties of composites were discussed. Intercalation behavior of OPC was determined by the structural properties and bonding. The mechanical properties and the stress changed under wet conditions of composites with different PVA ratios were investigated. It was found that sample with the lowest PVA content had the lowest swelling (39%), but the maximum Young's modulus changed from 5 GPa to 40 MPa under wet conditions and had a relatively low electrical conductivity. This phenomenon could be attributed to the differences void fraction and interfacial forces in the material. High void fraction in material resulted in increasing the energy gap of electrons transfer and the concentration of stress which caused a significant decrease of Young’s modulus under wet conditions. Moreover, by investigating the release behavior of OPC, the kinetic analysis explained that the short-term release was attributed to the release of interlayers of LDH and desorption from LDH surfaces, however long-term release only dominated by the adsorbate on LDH surfaces. While, the structural hindrance limited the release of drugs leading to more slowly release and reach more than 70 days of long-term release. Finally, the cell response to artificial nacreous composite was investigated. The results showed that the materials exhibited relatively low bio-toxic, and the showed even higher survival rate due to release of proanthocyanidins from composites. The negative charge on the surface provided a great resistance to adhesion, and the ability of anti-adhesion had a correlation with the mechanical properties of the material in wet conditions. Insertion experiment showed the multifunctional nacre-like substrate had a potential for implant application with structure stabilizing the whole structure without any bending in insertion experiment.