以疏水/親水共聚高分子開發可摺疊式人工水晶體及其配方/性質關聯研究

Abstract

本研究之目標為開發可摺疊式人工水晶體材料，藉由其柔軟可折疊之特性，於水晶體植入手術中，利用內徑在數毫米(2-3mm)的注射器注入到眼囊中展開固定，因此較傳統硬式水晶體，大幅降低傷口之大小，增進術後恢復與成功率。為了達到此目的，本研究利用混合三種類型之單體: tetraethylene glycol phenyl ether acrylate (P4)，2-hydroxyethyl methacrylate (H)以及styrene (S)，配合加入ethylene glycol dimethacrylate (E)作為交聯劑以及光起始劑(I)，以UV光照之方式形成水晶體之共聚高分子交聯網路。本研究探討調配上述各種配方之組合以及其配方對於水晶體材料性質(含水率，透光度，拉伸性質，動態機械性質(DMA)，小角度X光散射(SAXS)結構分析)之影響。由於P單體為側鏈具備有4個ethylene oxide (EO)鏈段的分子，本研究探討利用diethylene glycol phenyl ether acrylate (P2)以及ethylene glycol phenyl ether acrylate (P1)取代tetraethylene glycol phenyl ether acrylate，以探討側鏈長度對於水晶體性質之影響。由於過去許多疏水性水晶體在長期使用上，常發生水晶體內部產生香檳液泡(glistening)，影響病人視力，本研究同時探討材料配方對於香檳液泡出現的關聯。 首先對P4，H，S三種單體組成(P4HS系列)進行配方最佳化研究。在固定交聯劑(4%)及光起始劑(1%)用量下，分成三組，第一組為改變單體P4含量30%~ 60%，第二組H含量為20%~50%，第三組S含量為16%~46%。在第一組中，當增加P含量，受到長鏈段側鏈影響，其自由體積(free volume)增加，P4HS材料呈現較柔軟之性質，且玻璃轉移溫度(Tg)因而降低。但若P含量達到60%，斷裂應變僅達26%，因此材料極易破碎。在第二組中，當H含量增加(20%至50%)，其含水率變化達三倍(由3.6%至10.3%)，大幅增加親水性，但在H含量增加同時，P含量下降，使楊氏係數增加及斷裂應變下降。第三組中，當增加S含量，受側鏈苯環影響，其主鏈不易運動，P4HS材料呈現較堅硬性質，且Tg上升。若S含量達46%，在室溫下楊氏係數高達390MPa，斷裂應變僅有11%，材料硬而脆因此不可摺疊。 對交聯劑E用量變化(P4HSE系列)進行配方最佳化研究，在固定P4 (40%)，H(30%)，S(26%)，光起始劑(1%)用量下，改變交聯劑E用量為1%~4%。當增加E含量，由DMA測試中，在高溫橡膠平坦區之儲存模量增加，推斷交聯密度增加，因此其楊氏係數增高，斷裂長度則下降。 為探討側鏈長度對於水晶體性質之影響，以P2以及P1取代P4 (分別為P2HSE系列及P1HSE系列)，在固定P2及P1含量為40%，H(30%)，S(26%)，光起始劑(1%)用量下，改變交聯劑E用量1%至4%，並和P4HSE系列作對比。當EO鏈段長度縮短，其側鏈產生的自由體積減少，使材料越加堅硬；由DMA測試Tg也隨著EO鏈段縮短而升高，因此材料在室溫下楊氏係數越高，斷裂長度也是隨之下降，當EO鏈段長度為1，其楊氏係數達443MPa，斷裂長度低於50%，材料過硬且脆，不適合摺疊。 為探討光起始劑用量(P4HSE1I系列)對於水晶體性質之影響，在固定單體P4 (40%)，H (30%)，S (26%)，交聯劑E( 1%)用量下，改變光起始劑I用量0.5%至2%。；隨光起始劑用量增加，楊氏係數也降低，而斷裂應變都在200%以上，推估原因為自由基反應中聚合高分子其平均分子量(Mn)和光起始劑濃度呈負相關 ，因此造成交聯密度下降。 為探討材料配方對於香檳液泡出現之關聯，藉由加速老化實驗(50°C , 1day / 7days/ 14days)後，香檳液泡發現於下列系列: 1. P4HS系列第三組中S濃度最高(46%)及次高(36%)配方。2. P4HS系列第二組H濃度最低(20%)的配方。3. P2HSE系列4. P1HSE系列所有配方。以上系列之共同特性為含水率較低之配方( < 4%)，含水率表現出材料親水性。當親水性差，出現香檳氣泡機率增高。另外，5. P4HSE系列中其E含量最低(1%)之配方，6. P4HSE1I系列所有配方也出現香檳液泡，其共通點為交聯劑都為最低(1%)之配方。當交聯密度低，出現香檳氣泡機率增高。 在SAXS的實驗，各系列藉由特徵峰發現存在約為5nm的微泡緊靠在一起出現在高分子網絡中，而P4HSE系列藉由模型擬合證明當化學交聯劑E減少，會使物理交聯之特徵長度變大，因此有利液泡的聚集，在E含量為1%時產生光學顯微鏡可觀察到的香檳液泡。 藉由上述研究探討，機械性質上優先選楊氏係數在80MPa以下可以折疊，斷裂長度為80%以上摺疊不易破碎，透光度高於90%且無香檳液泡之設計原理；選擇tetraethylene glycol phenyl ether acrylate側鏈相對P2及P1較長具柔軟性和親水性，但又不使材料易碎的含量( < 50%)，2-hydroxyethyl methacrylate可增加材料親水性且含量足夠( > 30%)降低香檳液泡出現機率，styrene具備高折射率並使材料維持硬度，但不使材料親水性過差的含量( < 26% )，交聯劑EGDMA形成完整的網絡並在特定含量以上( > 2%)使交聯密度足夠抑制香檳液泡，光起始劑能將單體聚合成高分子且含量不會多到嚴重影響交聯密度( < 1% )，聚合而成有潛力的疏水/親水共聚高分子之人工水晶體材料。

In this study, foldable artificial intraocular lenses (IOL) are developed. Newly established IOL can be inserted in posterior chamber through an ID of ~2-3 mm needle fitted to a polypropylene delivery system, ensuring smaller insertion wound, therefore, speedy recovery after implant surgery. To this end, a formulation system consisting of three types of monomers including tetraethylene glycol phenyl ether acrylate (P4), 2-hydroxyethyl methacrylate (H) and styrene (S), crosslinker of ethylene glycol dimethacrylate (E) and photoinitiator (I) is used to fabricate the desired IOL of crosslinked copolymer network via UV light exposure. Properties critical to IOL performance including water content, transparency, tensile property, dynamic mechanical property, as well as nanostructure indentification through small angle x-ray scattering are optimized by adjusting the above formulation system. In addition, substituting P with diethylene glycol phenyl ether acrylate (P2) or ethylene glycol phenyl ether acrylate (P1) in the formulation system is studied in order to investigate the effect of the side chain length on one of the monomer on the aforementioned IOL properties. In particular, some commercially available IOLs often suffer from glistenings, a problem related to formation of fluid-filled microvacuoles, leading to degredation of vision quality. In this study, the effect of formulation on the propensity to have glistenings is also studied through an accelerated aging experiment. First, studying the optimization of formulation that the composition of P4, H, and S three monomers (P4HS series). fixed content of crosslinker (4%) and photoinitiator (1%), it was divided into three groups, the first group was to change the content of monomer P by 30%~60%, the second group was to change the content of monomer H by 20%~50%, the third group was to change the content of monomer S by 16%~46%. In the first group, the P4HS material exhibits softer properties, and the glass transition temperature (Tg) decreases when the content of P4 was increased because the free volume of the P4HS material increases by the long-segment side chains. However, if the content of P4 reaches 60%, breaking strain of the material was only 26% which was easily broken. In the second group, the change in water content reaches threefold (from 3.6% to 10.3%) when the content of H increases (20% to 50%), greatly increasing the hydrophilicity. But at the same time as the content of H increased, the content of P4 decreased, Young's modulus increased, and breaking strain decreased. In the third group, the P4HS material is harder, and the Tg increases when the content of S increased because the main chain was not easy to move by the benzene ring structure of the side chain. However, at room temperature, the material was hard and brittle when the content of S reaches 46% that Young's modulus was as high as 390 MPa, and breaking strain was only 11%, therefore the material cannot be folded. studying the optimization of formulation that changed the content of crosslinker E (P4HSE series). fixed content of P4 (40%), H (30%), S (26%), and photoinitiator (1%), changed the content of E by 1%~4%. the storage modulus in high temperature rubbery plateau region increased in the DMA when the content of E increased, inferring that the crosslinking density increased. So that Young's modulus increased and breaking strain decreased. In order to investigate the effect that the change of materials properties by side chain length, replaced P4 with P2 and P1 (P2HSE series and P1HSE series) and the contents of P2 and P1 were fixed at 40%, H (30%), S (26%), and photoinitiator (1%), changed the content of crosslinker E from 1% to 4%, and compare with the P4HSE series. The material was hard when the length of the EO chains was shortened because the free volume generated by the side chain decreased, the Tg measured by DMA also increased with the shortening of the EO chain, so Young's modulus increased and the breaking strain decreased. The material is hard and brittle when the length of the EO chain was 1 that Young's modulus was higher than 443 MPa, and breaking strain was less than 50%, therefore the material cannot be folded. In order to investigate the effect that the change of materials properties by the amount of photoinitiator (P4HSE1I series), fixed the content of monomers P4 (40%), H (30%), S (26%), and crosslinker E (1%), changed the content of I by 0.5% to 2%. Young's modulus decreases when the content of P4 increased, and breaking strain was above 200%, inferred that the reason was the average molecular weight (Mn) of the polymerized polymer by free radical was negatively correlated with the concentration of the photoinitiator. As a result, the crosslinking density decreases. In order to investigate the relationship between formulation and glistening, after accelerated life test (50°C, 1day / 7days/ 14days), glistening was found in the following series: 1. the third group of the P4HS series had the highest content of S (46%) and the next highest (36%) formula. 2. The formula with the content of H lowest (20%) in the second group of the P4HS series. 3. All formulas in P2HSE series, 4. all formulas in P1HSE series. The common property of the above series was low water content (< 4%), and the water content shows the hydrophilicity of the material, so the probability of glistening increased when the hydrophilicity was poor. In addition, 5. The formula with the content of E lowest (1%) in the P4HSE series, and 6. all formulas in P4HSE1I series, also could find glistening. The common property of those series was formulas with the content of crosslinker lowest (1%), so the probability of glistening increased when the crosslinking density was low. In the SAXS, all series found that there are microbubbles of about 5 nm close together in the polymer network through the characteristic peaks, and the P4HSE series proved by model fitting that when the content of chemical crosslinker E decreased, the physical characteristic length increased, at the same time, glistening was found by light microscopy at 1% E content. Based on the above research and discussion, the preferred design principle is that Young's modulus was below 80MPa, which could be folded, the breaking length is more than 80%, which is not easy to break when it was folded, and the transmittance is higher than 90% and glistening-free. Selected tetraethylene glycol phenyl ether acrylate compared with P2 and P1 was soft and hydrophilic, but the content didn’t make the material brittle (< 50%). 2-hydroxyethyl methacrylate that could increase the hydrophilicity of the material and the content was enough (> 30%) to inhibition the probability of glistening, styrene that had a high refractive index and hardness of the material, but didn’t make the material too hydrophilic (< 26%). Crosslinker EGDMA forms a complete network, and content (> 2%) was enough to inhibit glistening. Photoinitiator that could polymerize monomers into polymer, and content wasn’t too much to decrease the cross-linking density (< 1%). Polymerized to form a potential hydrophobic/hydrophilic copolymer Intraocular lens materials.