本文選題：傷口敷料 + 殼聚糖��； 參考：《安徽大學》2017年博士論文

【摘要】：傷口敷料是用于傷口護理的重要醫(yī)藥產(chǎn)品,新型傷口敷料可通過吸收傷口多余滲液或者持有水分從而保持創(chuàng)面的濕潤,從而促進傷口愈合。殼聚糖及其衍生物為原料所制備的生物醫(yī)學材料,因其生物相容性優(yōu)異,能夠止血并具有一定的抗菌性能,在促進傷口愈合方面的作用被廣泛認可。本工作選擇殼聚糖作為起始原料,以化學交聯(lián)為主要技術手段,制備了三種殼聚糖復合交聯(lián)薄膜/海綿及一種酸溶性竣甲基殼聚糖原位凝膠傷口敷料,并通過核磁共振(NMR)、傅里葉變換紅外光譜(FTIR)、X-射線衍射(XRD)、熱重分析(TGA)、掃描電子顯微鏡(SEM)等手段表征其結(jié)構;通過溶脹率檢測、水蒸氣及氧氣透過率檢測、細胞毒性實驗、血液相容性實驗、動物實驗等方法測試其性能,并評價它們的應用前景。本論文的主要創(chuàng)新點在于:(1)制備了一種纖維素衍生物,丁二酰羥丙基甲基纖維素(HPMCS),并在EDC/NHS催化作用下將其與殼聚糖交聯(lián)形成復合交聯(lián)凝膠膜,對凝膠膜進行了結(jié)構表征并評估了其作為傷口敷料材料的性能;(2)研究了羧甲基魔芋葡甘聚糖(CMKGM)的制備條件,制備了高溶脹性CMKGM/CS復合交聯(lián)海綿傷口敷料;(3)不使用任何有毒的交聯(lián)劑或引發(fā)劑,采用PEG衍生物(SC-PEG-SC)與殼聚糖在溶液中直接反應生成凝膠,再干燥成膜。并通過小鼠全層皮膚傷口模型評估了其促進傷口愈合的效果;(4)制備了酸溶性羧甲基殼聚糖原位凝膠并研究了其傷口止血密封性能及在稀醋酸中的溶解性;合成的PEG-原酸酯活性酯(SC-OE-PEG-OE-SC)具有酸敏感原酸酯鍵,可在稀酸作用下降解。SC-OE-PEG-OE-SC溶液和羧甲基殼聚糖溶液混合即可生成原位凝膠;此原位凝膠不僅可以在緊急情況下用于止血并封閉傷口,還可以被稀醋酸溶解去除,便于傷口的進一步外科處理,防止傷口部位的二次傷害。本論文的主要研究內(nèi)容和結(jié)論如下:(1)將羥丙甲纖維素(HPMC)經(jīng)丁二酸酐改性生成具有游離羧基的丁二酰羥丙基甲基纖維素(HPMCS),然后用EDC/NHS作為催化劑,交聯(lián)HPMCS和殼聚糖(CS),制備出三種不同配比的HPMCS/CS復合交聯(lián)水凝膠薄膜;測試了該薄膜的拉伸性能、溶脹比、水蒸汽透過率和氧滲透性等理化性質(zhì);采用NIH3T3細胞培養(yǎng)和MTT法測定了其細胞毒性,采用兔血紅細胞測定了其溶血情況;以慶大霉素為模型藥物測試了交聯(lián)膜的體外藥物釋放和殺菌性能,結(jié)果表明,HPMCS/CS復合交聯(lián)水凝膠薄膜具有良好的抗拉強度與斷裂伸長率,適宜的氣體透過性,生物相容性好,對細胞無毒,無溶血性,載藥凝膠薄膜能有效抑制大腸桿菌和金黃色葡萄球菌的生長。(2)采用異丙醇為反應介質(zhì),用氯乙酸在NaOH催化下使KGM上的部分羥基被羧甲基取代,得到羧甲基魔芋葡甘聚糖(CMKGM);在EDC/NHS催化作用下使CMKGM與殼聚糖交聯(lián),經(jīng)冷凍干燥制備了不同比例的CMKGM/CS復合交聯(lián)海綿;使用FTIR,XRD,SEM,TGA等方法對復合海綿的理化結(jié)構、熱穩(wěn)定性等性質(zhì)進行了表征,測定了 CMKGM/CS復合交聯(lián)海綿的溶脹性,孔隙率,水蒸氣透過率,最后對其生物相容性和血液相容性進行了測定。結(jié)果表明,CMKGM/CS復合交聯(lián)海綿具有良好的吸水溶脹性能及熱穩(wěn)定性,能有效減少水分蒸發(fā)損失,對細胞無毒,無溶血性。(3)以乙腈為溶劑,DMAP為催化劑,PEG和二琥珀酰亞胺碳酸酯(DSC)反應,得到兩端含活性酯的PEG衍生物(二琥珀酰亞胺聚乙二醇酯,SC-PEG-SC),將SC-PEG-SC溶液與殼聚糖溶液混合,SC-PEG-SC兩端的活性酯與殼聚糖的氨基反應,形成凝膠,經(jīng)干燥后制得PEG活性酯/殼聚糖薄膜;采用NMR,FTIR,XRD,TGA等方法對復合交聯(lián)膜的結(jié)構、熱穩(wěn)定性等性質(zhì)進行了表征,并通過拉伸性能檢測、水蒸氣及氧氣透過率檢測研究了不同比例原料形成凝膠薄膜的性能差異;最后通過ICR小鼠全層皮膚傷口模型測試了 PEG活性酯/殼聚糖水凝膠膜作為傷口敷料的性能。結(jié)果表明,此復合交聯(lián)膜熱穩(wěn)定性及吸水性能良好,拉伸強度和斷裂延伸率都有明顯提高,能有效減少水分蒸發(fā)損失,對細胞無毒,無溶血性,動物實驗結(jié)果表明這種復合交聯(lián)膜能促進ICR小鼠傷口愈合。(4)設計了一種用于緊急情況下處理傷口的酸溶性羧甲基殼聚糖原位水凝膠密封劑;先采用五步反應合成PEG-原酸酯活性酯(SC-OE-PEG-OE-SC),并與羧甲基殼聚糖溶液混合,使二者在傷口部位發(fā)生交聯(lián)反應生成SC-OE-PEG-OE-SC凝膠并粘附于組織、封閉傷口;由于原酸酯鍵對酸敏感,采用稀醋酸溶液即可將凝膠溶解;對SC-OE-PEG-OE-SC的結(jié)構進行了 1HNMR檢測,并測定了其細胞毒性,降解產(chǎn)物細胞毒性,聚合物及降解產(chǎn)物血液相容性;將SC-OE-PEG-OE-SC溶液和羧甲基殼聚糖溶液按不同的體積比制成復合凝膠后,研究了原料濃度對凝膠化時間的影響,凝膠的皮膚粘附性能、溶解性能,最后進行了封閉傷口動物實驗;結(jié)果顯示,SC-OE-PEG-OE-SC合成成功,聚合物及降解產(chǎn)物對細胞均無毒,無溶血反應;從原料濃度對SC-OE-PEG-OE-SC/CMC復合凝膠凝固時間的影響結(jié)果可見,SC-OE-PEG-OE-SC和CMC濃度越大,凝固時間越短,原位凝膠可牢固粘附于組織表面并隨組織形變而扭曲,能緊密貼合于大鼠傷口表面,形成凝膠并將傷口止血封閉,用5%醋酸溶液脫脂棉覆蓋可完全溶解凝膠。綜上所述,本工作得到了既有抗菌性的透明薄膜敷料材料,也有高吸收性海綿敷料材料,還有用于緊急傷口護理的酸溶性原位凝膠材料,不僅功能齊全,可滿足不同類型的傷口護理之需求,而且安全無毒,制備方法簡便,因此具有較強的理論價值和實際應用前景。
[Abstract]:Wound dressing is an important medical product for wound care. The new wound dressing can keep the wound healed by absorbing excess seepage or holding water to keep the wound healed. The biomedical materials prepared by chitosan and its derivatives as raw materials can stop bleeding and have a certain degree of hemostasis because of its excellent biocompatibility. Antibacterial properties have been widely recognized in promoting wound healing. In this work, three chitosan composite crosslinked films / sponges and an acid soluble chitosan in situ gel wound dressing were prepared with chitosan as the starting material and chemical crosslinking as the main technical means. Infrared spectroscopy (FTIR), X- ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscope (SEM) and other means were used to characterize their structures. The properties of the water vapor and oxygen transmittance detection, cytotoxicity test, blood compatibility test and animal experiment were tested by means of swelling rate detection, and their application prospects were evaluated. The main innovations in this paper The points are: (1) a cellulose derivative, butylene hydroxypropyl methyl cellulose (HPMCS) was prepared and crosslinked with chitosan to form a composite crosslinked gel membrane under the catalysis of EDC/NHS. The structure of the gel membrane was characterized and its performance as a wound dressing material was evaluated. (2) the carboxymethyl konjac glucomannan (CMKGM) was studied. High swelling CMKGM/CS composite crosslinked sponge wound dressing was prepared. (3) without any toxic crosslinking agent or initiator, PEG derivative (SC-PEG-SC) and chitosan were used to react directly to the gel to form the gel and then dry into the film. The effect of the wound healing was evaluated by the whole layer skin wound model of mice. (4) The acid soluble carboxymethyl chitosan in situ gel was prepared and its wound sealing performance and solubility in dilute acetic acid were studied. The synthesized PEG- active ester (SC-OE-PEG-OE-SC) had acid sensitive ester bond, which could be used to degrade.SC-OE-PEG-OE-SC solution and carboxymethyl chitosan solution under dilute acid to produce in-situ coagulation. The gel can not only be used to stop bleeding and close the wound in an emergency, but also can be dissolved by dilute acetic acid to facilitate further surgical treatment of the wound and prevent the two injury of the wound site. The main contents and conclusions of this paper are as follows: (1) the hydroxypropyl methylene cellulose (HPMC) is modified by butyl two anhydride to be free. The carboxyl group of Ding Erxian hydroxypropyl methyl cellulose (HPMCS), then EDC/NHS as a catalyst, crosslinked HPMCS and chitosan (CS), was used to prepare three different HPMCS/CS composite crosslinked hydrogel films. The tensile properties, swelling ratio, water vapor transmittance and oxygen permeability of the film were tested, and NIH3T3 cell culture and MTT were used. The results showed that the HPMCS/CS composite crosslinked hydrogel film had good tensile strength and elongation at break, suitable gas permeability and good biocompatibility, and the results showed that the composite crosslinked hydrogel film had good tensile strength and elongation at break. The cells are nontoxic and non hemolytic. The film of drug carrier gel can effectively inhibit the growth of Escherichia coli and Staphylococcus aureus. (2) using isopropanol as the reaction medium, chloroacetic acid is used as a catalyst to replace the hydroxyl group on KGM by NaOH, and the carboxymethyl konjac glucomannan (CMKGM) is obtained; and CMKGM and chitosan are made under the catalysis of EDC/NHS. Different proportions of CMKGM/CS composite crosslinked sponges were prepared by freeze-drying. The physicochemical structure and thermal stability of the composite sponge were characterized by FTIR, XRD, SEM, TGA and other properties. The swelling, porosity and vapor permeability of the CMKGM/CS composite sponge were measured. Finally, the biocompatibility and blood compatibility of the sponges were obtained. The results showed that the CMKGM/CS composite crosslinked sponge had good swelling property and thermal stability, and could effectively reduce the loss of evaporation of water, and was nontoxic and hemolytic to cells. (3) the reaction of acetonitrile as a solvent, DMAP as a catalyst, PEG and two succinimide carbonate (DSC), obtained the PEG derivatives (two amber) containing active esters at both ends (two amber) SC-PEG-SC solution is mixed with chitosan solution, the active ester of the SC-PEG-SC at both ends of SC-PEG-SC is reacted with the amino group of chitosan to form the gel and the PEG active ester / chitosan film is prepared after drying. The structure and thermal stability of the composite crosslinked membrane are characterized by NMR, FTIR, XRD, TGA and so on. The properties of the gel films formed by different proportion of raw materials were studied by the test of tensile properties and the permeability of water vapor and oxygen. Finally, the performance of the PEG active ester / chitosan hydrogel membrane was tested by the full layer skin wound model of ICR mice as wound dressing. The results showed that the thermal stability and water absorption of the composite crosslinked membrane were good. The tensile strength and elongation at break were improved obviously, and the loss of water evaporation was reduced, the cells were nontoxic and non hemolytic. The results of animal experiments showed that the composite crosslinking membrane could promote the healing of wound in ICR mice. (4) an acid soluble carboxymethyl chitosan in situ hydrogel sealant used in emergency treatment was designed. A five step reaction was used to synthesize PEG- active ester (SC-OE-PEG-OE-SC), and mixed with carboxymethyl chitosan solution to make the two groups crosslinked at the wound site to produce SC-OE-PEG-OE-SC gel and adhere to the tissue and seal the wound. The cytotoxicity, cytotoxicity of degradation products, and the blood compatibility of polymer and degradation products were measured, and the effect of the concentration of SC-OE-PEG-OE-SC and carboxymethyl chitosan on the gelation time, the skin adhesion and solubility of the gel were studied. The 1HNMR and the carboxymethyl chitosan solution were prepared by different volume ratio. Finally, the closed wound animal experiment was carried out. The results showed that the SC-OE-PEG-OE-SC synthesis was successful. The polymer and the degradation products were non-toxic and no hemolytic reaction. The effect of the concentration of raw materials on the coagulation time of SC-OE-PEG-OE-SC/CMC composite gel showed that the greater the concentration of SC-OE-PEG-OE-SC and CMC, the shorter the solidification time, the gel in situ could be secured. It adheres to the surface of the tissue and distorts with the deformation of the tissue. It can close to the surface of the wound of the rat, form the gel and seal the wound, and cover the gel with the 5% acetic acid solution. To sum up, we have obtained the transparent film dressing materials with both antibacterial properties and high absorbability sponge dressing. The acid soluble in situ gel material used for emergency wound care is not only fully functional, but also meets the needs of different types of wound care. It is safe and non-toxic, and the preparation method is simple. Therefore, it has strong theoretical value and practical application prospects.

【學位授予單位】：安徽大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：TQ427.26;R318.08

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