基于氨基酸兩性離子水凝膠庫的制備與眼科應(yīng)用研究
發(fā)布時間：2018-09-08 06:20
【摘要】：聚甲基丙烯酸羥乙酯(PHEMA)水凝膠和硅水凝膠在生物醫(yī)學(xué)領(lǐng)域具有重要的應(yīng)用價值,常用于制備角膜接觸鏡。然而,這類水凝膠表面顯示出較強的疏水性,特別是硅水凝膠材料的靜態(tài)水接觸角達到100。左右,導(dǎo)致淚液中的蛋白質(zhì)和脂質(zhì)易于沉積在表面,臨床上可能引發(fā)細菌感染等并發(fā)癥。因此,提高水凝膠材料表面的親水性和抗粘附性能,對于拓展其在眼科的臨床應(yīng)用非常重要。本文通過氨基引發(fā)的點擊化學(xué)反應(yīng)將一系列氨基酸或短肽接枝到水凝膠表面,以提高水凝膠表面的親水性和抗粘附性能,并探索了水凝膠在眼科領(lǐng)域的應(yīng)用。具體分為以下四個部分：第一部分,通過甲基丙烯酸羥乙酯單體(HEMA)和甲基丙烯酸縮水甘油酯單體(GMA)的自由基聚合反應(yīng),制備了一系列帶有環(huán)氧基團的共聚物膜p(HEMA-co-GMA);隨后,通過氨基酸的氨基與共聚物膜中環(huán)氧基團的開環(huán)反應(yīng),將一系列氨基酸接枝到PHEMA水凝膠表面,得到氨基酸兩性離子PHEMA水凝膠庫。衰減全反射傅里葉變換紅外光譜(ATR/FTIR)和X射線光電子能譜(XPS)證明氨基酸成功地接枝到了水凝膠表面。改性后的PHEMA水凝膠的親水性能明顯提高,而蛋白沉積量則與接枝氨基酸的種類有關(guān)：中性氨基酸兩性離子PHEMA水凝膠顯示出較強的抵抗牛血清白蛋白(BSA)和溶菌酶(Lyz)粘附的能力；帶有電荷的氨基酸兩性離子PHEMA水凝膠對帶有相同電荷的蛋白具有一定的抗沉積作用而對帶有相反電荷的蛋白沉積量明顯增加。體外細胞毒性實驗表明氨基酸兩性離子PHEMA水凝膠是無細胞毒性的。最后,制備了三種基于氨基酸兩性離子的PHEMA水凝膠接觸鏡鏡片,通過兔子的體內(nèi)配戴實驗表明該水凝膠鏡片具有良好的親水性和抗蛋白沉積的能力,同時對兔子眼組織無明顯刺激性。第二部分,通過紫外光引發(fā)的硅單體和GMA的自由基聚合反應(yīng),制備了一系列帶有環(huán)氧基團的共聚物膜p(Si-co-GMA);隨后,通過氨基酸的氨基與共聚物膜中環(huán)氧基團的開環(huán)反應(yīng),將一系列氨基酸接枝到硅水凝膠表面,得到氨基酸兩性離子硅水凝膠庫。ATR/FTIR和XPS證明氨基酸成功地接枝到了硅水凝膠表面。通過接觸角和含水率實驗對氨基酸接枝的硅水凝膠進行表征,實驗結(jié)果表明氨基酸兩性離子硅水凝膠的親水性能明顯提高。隨后,以BSA和Lyz作為目標蛋白來評價硅水凝膠的抗蛋白粘附性能。蛋白沉積實驗結(jié)果表明中性氨基酸兩性離子硅水凝膠顯示出較強的抵抗BSA和Lyz粘附的能力,這要歸功于由質(zhì)子化的仲胺陽離子與去質(zhì)子化的羧基陰離子組成的兩性離子表面的形成；而帶有電荷的氨基酸兩性離子硅水凝膠對帶有相同電荷的蛋白具有一定的抗沉積作用而對帶有相反電荷的蛋白沉積量明顯增加。體外細胞毒性實驗表明氨基酸兩性離子硅水凝膠是無細胞毒性的。最后,運用聚丙烯模具制備了三種基于氨基酸兩性離子的硅水凝膠接觸鏡鏡片。通過兔子的體內(nèi)配戴實驗和兔子眼球組織切片的病理學(xué)分析,表明該水凝膠鏡片不僅具有良好的抗蛋白粘附性能而且對兔子眼組織無明顯刺激和傷害。第三部分,首先設(shè)計并合成了一種帶有親水性基團的氟化硅氧烷大分子單體并且在不需要助溶劑的條件下能夠與親水性單體互溶,得到透明的氟化硅氧烷穩(wěn)定聚合體系。通過紫外光引發(fā)的自由基聚合反應(yīng),制備了一系列帶有環(huán)氧基團的共聚物膜p(FSi-co-GMA)；隨后,通過氨基酸的氨基與共聚物膜中環(huán)氧基團的開環(huán)反應(yīng),將一系列氨基酸接枝到氟硅水凝膠表面,得到氨基酸兩性離子氟硅水凝膠庫。接觸角和含水率的實驗結(jié)果表明改性后的氟硅水凝膠的親水性能明顯提高。蛋白沉積實驗結(jié)果表明氨基酸兩性離子氟硅水凝膠的蛋白沉積量與接枝氨基酸的種類有關(guān)：中性氨基酸兩性離子氟硅水凝膠顯示出較強的抵抗BSA和Lyz粘附的能力；帶有電荷的氨基酸兩性離子氟硅水凝膠對帶有相同電荷的蛋白具有一定的抗沉積作用而對帶有相反電荷的蛋白沉積量明顯增加。體外細胞毒性實驗表明氨基酸兩性離子氟硅水凝膠是無細胞毒性的,在眼科領(lǐng)域具有潛在的應(yīng)用。第四部分,通過紫外光引發(fā)的自由基聚合反應(yīng),制備了一系列帶有環(huán)氧基團的共聚物膜p(Si-co-GMA)；隨后,通過短肽的氨基與共聚物膜中環(huán)氧基團的開環(huán)反應(yīng),將二甘肽(GG)和二甘氨酰甘氨酸(GGG)接枝到硅水凝膠表面,得到短肽兩性離子硅水凝膠。通過ATR/FTIR,XPS和重量法對短肽兩性離子硅水凝膠進行表征,實驗結(jié)果表明短肽成功地接枝到了硅水凝膠的表面和內(nèi)部。與此同時,短肽接枝后的硅水凝膠顯示出良好的親水性和平衡含水率。隨后,以BSA和Lyz作為目標蛋白,用二喹啉甲酸法(BCA)進一步評價硅水凝膠的抗蛋白粘附性能。蛋白沉積實驗結(jié)果顯示所有的短肽兩性離子硅水凝膠都具有較強的抵抗BSA和Lyz粘附的能力；硅水凝膠所接枝短肽的鏈越長,抗蛋白沉積能力越強,因此GGG接枝的硅水凝膠具有更好的抗蛋白粘附性能。體外細胞毒性實驗表明短肽兩性離子硅水凝膠是無細胞毒性的,表明它們具有優(yōu)異的生物相容性。最后,制備了兩種基于短肽兩性離子的硅水凝膠接觸鏡鏡片,通過兔子的體內(nèi)配戴實驗表明該水凝膠鏡片具有良好的親水性和抗蛋白沉積的能力,同時對兔子眼組織無明顯刺激性。
[Abstract]:Poly (hydroxyethyl methacrylate) (PHEMA) hydrogel and silicone hydrogel have important application value in biomedical field and are often used to prepare corneal contact lenses. Therefore, it is very important to improve the hydrophilicity and anti-adhesion of the surface of hydrogel materials for expanding its clinical application in ophthalmology. In this paper, a series of amino acids or peptides were grafted onto the surface of hydrogel by click chemical reaction initiated by amino acids to improve the hydrogel coagulation. The hydrophilic and anti-adhesion properties of the adhesives were investigated, and the applications of hydrogels in ophthalmology were explored. The following four parts were included: Part I: A series of copolymer membranes P (HEM) with epoxy groups were prepared by free radical polymerization of hydroxyethyl methacrylate monomer (HEMA) and glycidyl methacrylate monomer (GMA). Amino acid amphoteric PHEMA hydrogel library was obtained by grafting a series of amino acids onto the surface of PHEMA hydrogel through the ring opening reaction of amino acids with epoxy groups in the copolymer membrane. Attenuated total reflection Fourier transform infrared spectroscopy (ATR/FTIR) and X-ray photoelectron spectroscopy (XPS) showed that amino acids were successfully grafted onto the surface of PHEMA hydrogel. The hydrophilicity of modified PHEMA hydrogel was obviously improved, while the protein deposition was related to the types of grafted amino acids: neutral amino acid amphoteric PHEMA hydrogel showed strong resistance to BSA and Lyz adhesion; charged amino acid amphoteric PHEMA water In vitro cytotoxicity test showed that amino acid amphoteric PHEMA hydrogel was non-cytotoxic. Finally, three kinds of PHEMA hydrogel contact lenses based on amino acid amphoteric ions were prepared and passed through rabbits. In the second part, a series of copolymer membranes P (Si-co-GMA) with epoxy groups were prepared by free radical polymerization of silicon monomer and GMA initiated by ultraviolet light. Amino acids were grafted onto the surface of silica hydrogels by ring-opening reaction of amino acids with epoxy groups in the copolymer membranes. Amino acids were successfully grafted onto the surface of silica hydrogels by ATR/FTIR and XPS. The results showed that the hydrophilicity of amino acid amphoteric silica hydrogel was improved obviously. Then, BSA and Lyz were used as target proteins to evaluate the anti-protein adhesion of the silica hydrogel. Protein deposition experiments showed that the neutral amino acid amphoteric silica hydrogel showed strong resistance to BSA and Lyz adhesion, which was attributed to the strong anti-protein adhesion ability of the neutral amino acid amphoteric silica hydrogel. In vitro cytotoxicity test table Amino acid amphoteric silicone hydrogel is non-cytotoxic. Finally, three kinds of silicone hydrogel contact lenses based on amino acid amphoteric ions were prepared by polypropylene mold. The wearing experiment in rabbits and pathological analysis of rabbit eyeball tissue sections showed that the hydrogel lenses not only had good anti-protein adhesion. In the third part, a kind of fluorosiloxane macromonomer with hydrophilic group was designed and synthesized, which can be soluble with hydrophilic monomer without cosolvent, and a transparent stable polymerization system of siloxane fluoride was obtained. A series of copolymer membranes P (FSi-co-GMA) with epoxy groups were prepared by radical polymerization, and then a series of amino acids were grafted onto the surface of fluorosilicone hydrogel by ring-opening reaction of amino acids with epoxy groups in the copolymer membranes. The experimental results of contact angle and water content were obtained. The results showed that the hydrophilicity of modified fluorosilicone hydrogel was improved obviously. The protein deposition of amino acid amphoteric fluorosilicone hydrogel was related to the types of grafted amino acids. Amino acid amphoteric fluorosilicone hydrogel has a certain anti-deposition effect on proteins with the same charge but a significant increase in the deposition of proteins with the opposite charge. Cytotoxicity tests in vitro show that amino acid amphoteric fluorosilicone hydrogel is non-cytotoxic and has potential applications in ophthalmology. Part IV, UV light-induced A series of copolymer membranes P (Si-co-GMA) with epoxy groups were prepared by hair radical polymerization, and then the short peptide amphoteric silica hydrogels were prepared by grafting diglyceride (GG) and diglyceryl glycine (GGG) onto the surface of the silica hydrogels via ring opening reaction of epoxy groups in the copolymer membranes with amino groups of short peptides. The short peptide amphoteric silica hydrogel was characterized by gravimetric method. The results showed that the short peptide grafted onto the surface and interior of the silica hydrogel successfully. At the same time, the short peptide grafted silica hydrogel showed good hydrophilicity and equilibrium water content. The results of protein deposition test showed that all short peptide amphoteric silica hydrogels had strong resistance to BSA and Lyz adhesion. The longer the chain of short peptide grafted on silica hydrogel, the stronger the resistance to protein deposition, so the GGG grafted silica hydrogel had better resistance to protein adhesion in vitro. Cytotoxicity test showed that short peptide amphoteric silica hydrogels were non-cytotoxic, indicating that they had excellent biocompatibility. Finally, two kinds of short peptide amphoteric silica contact lenses were prepared. The wearing experiments in rabbits showed that the hydrogels had good hydrophilicity and anti-protein deposition. It has no obvious irritation to rabbit's eye tissue.
【學(xué)位授予單位】：東南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：TQ427.26;R318.08
本文編號：2229630
[Abstract]:Poly (hydroxyethyl methacrylate) (PHEMA) hydrogel and silicone hydrogel have important application value in biomedical field and are often used to prepare corneal contact lenses. Therefore, it is very important to improve the hydrophilicity and anti-adhesion of the surface of hydrogel materials for expanding its clinical application in ophthalmology. In this paper, a series of amino acids or peptides were grafted onto the surface of hydrogel by click chemical reaction initiated by amino acids to improve the hydrogel coagulation. The hydrophilic and anti-adhesion properties of the adhesives were investigated, and the applications of hydrogels in ophthalmology were explored. The following four parts were included: Part I: A series of copolymer membranes P (HEM) with epoxy groups were prepared by free radical polymerization of hydroxyethyl methacrylate monomer (HEMA) and glycidyl methacrylate monomer (GMA). Amino acid amphoteric PHEMA hydrogel library was obtained by grafting a series of amino acids onto the surface of PHEMA hydrogel through the ring opening reaction of amino acids with epoxy groups in the copolymer membrane. Attenuated total reflection Fourier transform infrared spectroscopy (ATR/FTIR) and X-ray photoelectron spectroscopy (XPS) showed that amino acids were successfully grafted onto the surface of PHEMA hydrogel. The hydrophilicity of modified PHEMA hydrogel was obviously improved, while the protein deposition was related to the types of grafted amino acids: neutral amino acid amphoteric PHEMA hydrogel showed strong resistance to BSA and Lyz adhesion; charged amino acid amphoteric PHEMA water In vitro cytotoxicity test showed that amino acid amphoteric PHEMA hydrogel was non-cytotoxic. Finally, three kinds of PHEMA hydrogel contact lenses based on amino acid amphoteric ions were prepared and passed through rabbits. In the second part, a series of copolymer membranes P (Si-co-GMA) with epoxy groups were prepared by free radical polymerization of silicon monomer and GMA initiated by ultraviolet light. Amino acids were grafted onto the surface of silica hydrogels by ring-opening reaction of amino acids with epoxy groups in the copolymer membranes. Amino acids were successfully grafted onto the surface of silica hydrogels by ATR/FTIR and XPS. The results showed that the hydrophilicity of amino acid amphoteric silica hydrogel was improved obviously. Then, BSA and Lyz were used as target proteins to evaluate the anti-protein adhesion of the silica hydrogel. Protein deposition experiments showed that the neutral amino acid amphoteric silica hydrogel showed strong resistance to BSA and Lyz adhesion, which was attributed to the strong anti-protein adhesion ability of the neutral amino acid amphoteric silica hydrogel. In vitro cytotoxicity test table Amino acid amphoteric silicone hydrogel is non-cytotoxic. Finally, three kinds of silicone hydrogel contact lenses based on amino acid amphoteric ions were prepared by polypropylene mold. The wearing experiment in rabbits and pathological analysis of rabbit eyeball tissue sections showed that the hydrogel lenses not only had good anti-protein adhesion. In the third part, a kind of fluorosiloxane macromonomer with hydrophilic group was designed and synthesized, which can be soluble with hydrophilic monomer without cosolvent, and a transparent stable polymerization system of siloxane fluoride was obtained. A series of copolymer membranes P (FSi-co-GMA) with epoxy groups were prepared by radical polymerization, and then a series of amino acids were grafted onto the surface of fluorosilicone hydrogel by ring-opening reaction of amino acids with epoxy groups in the copolymer membranes. The experimental results of contact angle and water content were obtained. The results showed that the hydrophilicity of modified fluorosilicone hydrogel was improved obviously. The protein deposition of amino acid amphoteric fluorosilicone hydrogel was related to the types of grafted amino acids. Amino acid amphoteric fluorosilicone hydrogel has a certain anti-deposition effect on proteins with the same charge but a significant increase in the deposition of proteins with the opposite charge. Cytotoxicity tests in vitro show that amino acid amphoteric fluorosilicone hydrogel is non-cytotoxic and has potential applications in ophthalmology. Part IV, UV light-induced A series of copolymer membranes P (Si-co-GMA) with epoxy groups were prepared by hair radical polymerization, and then the short peptide amphoteric silica hydrogels were prepared by grafting diglyceride (GG) and diglyceryl glycine (GGG) onto the surface of the silica hydrogels via ring opening reaction of epoxy groups in the copolymer membranes with amino groups of short peptides. The short peptide amphoteric silica hydrogel was characterized by gravimetric method. The results showed that the short peptide grafted onto the surface and interior of the silica hydrogel successfully. At the same time, the short peptide grafted silica hydrogel showed good hydrophilicity and equilibrium water content. The results of protein deposition test showed that all short peptide amphoteric silica hydrogels had strong resistance to BSA and Lyz adhesion. The longer the chain of short peptide grafted on silica hydrogel, the stronger the resistance to protein deposition, so the GGG grafted silica hydrogel had better resistance to protein adhesion in vitro. Cytotoxicity test showed that short peptide amphoteric silica hydrogels were non-cytotoxic, indicating that they had excellent biocompatibility. Finally, two kinds of short peptide amphoteric silica contact lenses were prepared. The wearing experiments in rabbits showed that the hydrogels had good hydrophilicity and anti-protein deposition. It has no obvious irritation to rabbit's eye tissue.
【學(xué)位授予單位】：東南大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：TQ427.26;R318.08
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