生物矿化机制初探和人工骨材料的仿生制备及性能研究
摘要
纳米生物技术是纳米技术与生命科学的交叉,是在纳米尺度上形成的有关生命科学的纳米新技术和新方法。本文采用双膜扩散系统(DMDS)体外模拟了生物矿化,利用原子力显微镜(AFM)在纳米尺度研究了胶原的生物矿化行为。模拟生物矿化,采用脲酶法对羟基磷灰石基复合人工骨材料进行了仿生合成。制备了抗骨骼炎药物缓释材料——壳聚糖/羟基磷灰石-庆大霉素(CS/HA-G),并利用AFM从微观角度初步探讨药物对细菌的作用机制,同时还研究了抗生素对骨材料性能的影响。主要获得了以下具有创新性的结果：
1.本文利用双膜扩散系统对生物矿化进行了体外模拟,并利用AFM对矿化过程中胶原纤维表面形貌及微观力学性能进行了探测。结果表明胶原纤维的矿化作用是一个分步自组装过程：在矿化初期,胶原的单体分子首先组装成较大的胶原纤维,这些胶原纤维再进一步组装成了大的纤维束,纤维束仅是胶原小纤维的疏松、无规则图案的聚集。到矿化中期,疏松聚集的胶原束组装成了有序结构,胶原纤维进一步聚集使得纤维束变得更紧密、更纤细,矿化胶原纤维呈现出了周期性的横纹条带,条带间距与天然胶原的周期性横纹一致。在矿化后期,由于羟基磷灰石(HA)在胶原纤维中的深度矿化,矿化胶原纤维直径和硬度均增大。AFM观察到了矿化初期和中期磷酸钙盐颗粒大小变化以及矿化后期磷酸钙盐颗粒的消失,为“高分子诱导的液相前体”理论提供了可视化证据。同时,AFM测量的结果表明,矿化胶原纤维表面周期性横纹条带的明带与暗带间高度差为2.4-4.3nm,比天然胶原纤维(约5nm)有所下降,它为Landis的“矿物质优先沉积于胶原纤维空隙(波谷)处”理论提供了实验数据。
2.突破了传统共沉淀法的合成途径,模拟生物矿化行为,设计了脲酶法仿生制备人工骨材料壳聚糖/羟基磷灰石复合材料(CS/HA)以及胶原/羟基磷灰石复合材料(Coll/HA)。利用FTIR、TEM、XRD对两种复合材料进行了表征,同时采用激光衍射粒度分析仪(LDPSA)对材料的颗粒大小及粒径分布进行了分析；以万能材料试验机对材料的机械强度进行了测定；并对材料进行了降解实验。FTIR和XRD结果表明复合材料中HA为弱结晶；TEM和LDPSA结果表明与传统共沉淀法的制备产物相比,脲酶法制备的复合材料粉体颗粒更小,粒度分布更窄；万能材料试验机测得的复合材料的机械强度良好；降解实验结果表明材料具有良好的降解性能。
3.制备了壳聚糖/羟基磷灰石-庆大霉素(CS/HA-G)缓释材料,对CS/HA-G进行体外缓释行为研究及抗菌实验；并利用AFM观察了细胞在药物作用前后表面形态结构的变化。结果表明,CS/HA-G的抑菌效果显著,维持有效释药时间长达30d以上。AFM观察显示药物作用于细菌菌体高度和表面平均粗糙度(Ra)均下降,有内容物渗漏。CS/HA-G的缓释作用和缓释规律显示出该材料在骨髓炎的防治中具有极大的临床应用潜能。
4.为了研究抗生素对CS/HA材料性能的影响,本文采用共沉淀法制备了CS/HA-G缓释材料和CS/HA复合材料。利用红外光谱(IR)、X射线衍射(XRD)和扫描电子显微镜(SEM)对材料进行了表征。以不载药的CS/HA为对照,研究了庆大霉素对CS/HA复合材料抑菌性能、力学性能和降解性能等的影响。实验结果表明,CS/HA-G有良好的抑菌效果。负载庆大霉素后CS/HA的机械强度明显增强,而材料的降解速率有所下降。本文采用的二次成型技术显著增大了材料的机械强度。
5.壳聚糖膜无论作为组织工程支架材料还是作为定向控释材料,其微观结构及微观力学性能都至关重要。而干燥条件是影响壳聚糖膜结构与性能的一个重要因素。本文以自然风干(NW)、真空干燥(VD)及红外干燥(ID)三种干燥方式制备了壳聚糖膜。并利用原子力显微镜(AFM)研究这三种壳聚糖膜的表面形貌及微观力学性能。实验结果表明VD和ID改善了膜材料的表面平整度,膜表面粗糙度分别为(5.47±1.34)和(2.79±0.93)nm,均显著低于NW膜((30.67±8.06)nm)。干燥条件对壳聚糖膜的微观力学性能有较大影响：ID壳聚糖膜的粘附力显著大于((2595±68.5) pN) NW壳聚糖膜((982.6±149.3)pN)和VD壳聚糖膜((1817.9±279.2)pN)。而ID壳聚糖膜的杨氏模量((158.8±15.2)MPa)则低于NW壳聚糖膜((204.3±22.7)MPa)和VD壳聚糖膜((195.8±14.6)MPa)。
总之,本文利用纳米生物技术在纳米尺度对生物矿化进行了较为深入详细的研究分析,获得了大量有价值的实验数据与信息,为进一步研究生物矿化机制以及人工骨材料的仿生合成提供新的研究视角和思路。脲酶法所制备的HA基人工骨复合材料所显示的与天然骨相似的良好性能,表明这种新型仿生合成技术在骨组织工程中具有良好的应用前途。而CS/HA-G缓释材料的良好性能则显示了该材料在骨科临床应用的价值与潜力。未来,生物矿化及矿化仿生技术的进一步研究必将为骨组织工程的发展做出重大贡献。
Nanobiotechnology, as the cross-discipline of nanotechnology and life science, is a novel technology and approach to investigate life science at nanoscale level. In this paper, a dual membrane diffusion system (DMDS) was used to investigate the mineralization behaviour of collagen. Simulating the biomineralization, this paper applied a new route for preparing hydroxyapatite-based composite by enzymatic decomposition of urea. As a drug delivery system to cure osteomyelitis, chitosan/Hydroxyapatite-gentamicin was prepared for the treatment of osteomyelitis, and the antibacterial mechanism of antibiotic was detected with AFM. The effect of gentamicin on the composite material was investigated as well. From the results, we obtained a lot of valuable information shown as the following:
1. A model dual membrane diffusion system was used to detect the mineralization behaviour of collagen. The process of mineralization was observed by atomic force microscope (AFM). The micromechanical properties and microstructure changes of collagen fibers in the process of mineralization suggested that the mineralization was a step-by-step assembling process. In the initial stage, when the supersaturated condition was created in the DMDS, monomeric collagen converted into larger fibrils. These mineralized fibrils self-assembled into loose-arrayed fibers, which has no typical cross-striation patterns. In the second stage, loose-arrayed fibers arranged closely with each other and further assembled into slenderer but tighter ones. It represented the typical cross-striation pattern, which was similar with nature collagen. In the final stage, the fibers became thicker and stiffer due to the further growth of HA crystal within collagen fibrils. The phenomenon that calcium phosphate solid-phase appeared in the initial-and medium-stage and disappeared in final-stage supported the hypothesis of "polymer-induced liquid-precursor mineralization process". Moreover, the difference in height between the peak and bottom in typical cross-striation patterns on collagen fibers was measured by AFM. The differenceinheight of nature collagen fiber was about 5 nm, while it was 2.4-4.3 nm on minerized collagen fiber. The structural investigation by AFM supplied new evidence on the hypothesis that HA preferentially grows into the hole zones and interstices of the collagen fiber as reported by Landis.
2. Simulating the biomineralization, we applied a new route for preparing hydroxyapatite-based composite by enzymatic decomposition of urea. The composite materials were characterized by XRD, laser diffraction particle size analyzer, SEM and TEM. The results of FTIR and TEM indicated that chemical and crystallographic properties of the complex were similar to the properties of nature bone. Laser diffraction particle size measurement and SEM showed that the samples were of smaller particle size and narrower particle size distribution particle sizes than those prepared by traditional co-precipitation method. The degradation of the composite materials was investigated via simulation in vitro. The results showed that these materials had excellent degradability.
3. Chitosan/Hydroxyapatite-Gentamicin (CS/HA-G) was prepared, and this drug delivery system (DDS) was tested in vitro release ratio and antibacterial activity against bacteria. We used AFM to probe the surface ultrastructure of bacteria before and after CS/HA-G treatment. The results showed that CS/HA-G had considerable delayed release effectivity. It maintained effective release time of gentamicin up to 30 d, and its inactivation against bacteria was remarkable. AFM ultrastructure images showed that the height and the Ra (average roughness) of cells were all decreased. The cell content leaked via damaged cellular membrane. The CS/HA composite is a promising local biodegradable delivery system for gentamicin in treating osteomyelitis.
4. In order to investigate the effects of gentamicin on properties of hydroxyapatite/chitosan, CS/HA-G and CS/HA composites were prepared by co-precipitation method. The products were characterized by FTIR, XRD and SEM. This paper reported on comparison of chemical property and antibacterial activity between HA/CS-G and HA/CS. Comprising with HA/CS, HA/CS-G exhibitied much higher compressive strength and better antimicrobial activity. Moreover, molding technique of uniaxial pressure following cold isostatic pressure gave materials much higher compressive strength than technique of cold isostatic pressure. HA/CS-G can be used as an ideal gentamicin carrier and has great potential in osteomyelitis therapy.
5. The microstructural and micromechanical properties of chitosan were very important for its bioapplications as scaffolds for tissue engineering or carrier for drug delivery. Different drying conditions greatly affected the microstructural and micromechanical properties of chitosan. Chitosan films were prepared by wet casting followed by vacuum drying (VD) and
1.本文利用双膜扩散系统对生物矿化进行了体外模拟,并利用AFM对矿化过程中胶原纤维表面形貌及微观力学性能进行了探测。结果表明胶原纤维的矿化作用是一个分步自组装过程：在矿化初期,胶原的单体分子首先组装成较大的胶原纤维,这些胶原纤维再进一步组装成了大的纤维束,纤维束仅是胶原小纤维的疏松、无规则图案的聚集。到矿化中期,疏松聚集的胶原束组装成了有序结构,胶原纤维进一步聚集使得纤维束变得更紧密、更纤细,矿化胶原纤维呈现出了周期性的横纹条带,条带间距与天然胶原的周期性横纹一致。在矿化后期,由于羟基磷灰石(HA)在胶原纤维中的深度矿化,矿化胶原纤维直径和硬度均增大。AFM观察到了矿化初期和中期磷酸钙盐颗粒大小变化以及矿化后期磷酸钙盐颗粒的消失,为“高分子诱导的液相前体”理论提供了可视化证据。同时,AFM测量的结果表明,矿化胶原纤维表面周期性横纹条带的明带与暗带间高度差为2.4-4.3nm,比天然胶原纤维(约5nm)有所下降,它为Landis的“矿物质优先沉积于胶原纤维空隙(波谷)处”理论提供了实验数据。
2.突破了传统共沉淀法的合成途径,模拟生物矿化行为,设计了脲酶法仿生制备人工骨材料壳聚糖/羟基磷灰石复合材料(CS/HA)以及胶原/羟基磷灰石复合材料(Coll/HA)。利用FTIR、TEM、XRD对两种复合材料进行了表征,同时采用激光衍射粒度分析仪(LDPSA)对材料的颗粒大小及粒径分布进行了分析；以万能材料试验机对材料的机械强度进行了测定；并对材料进行了降解实验。FTIR和XRD结果表明复合材料中HA为弱结晶；TEM和LDPSA结果表明与传统共沉淀法的制备产物相比,脲酶法制备的复合材料粉体颗粒更小,粒度分布更窄；万能材料试验机测得的复合材料的机械强度良好；降解实验结果表明材料具有良好的降解性能。
3.制备了壳聚糖/羟基磷灰石-庆大霉素(CS/HA-G)缓释材料,对CS/HA-G进行体外缓释行为研究及抗菌实验；并利用AFM观察了细胞在药物作用前后表面形态结构的变化。结果表明,CS/HA-G的抑菌效果显著,维持有效释药时间长达30d以上。AFM观察显示药物作用于细菌菌体高度和表面平均粗糙度(Ra)均下降,有内容物渗漏。CS/HA-G的缓释作用和缓释规律显示出该材料在骨髓炎的防治中具有极大的临床应用潜能。
4.为了研究抗生素对CS/HA材料性能的影响,本文采用共沉淀法制备了CS/HA-G缓释材料和CS/HA复合材料。利用红外光谱(IR)、X射线衍射(XRD)和扫描电子显微镜(SEM)对材料进行了表征。以不载药的CS/HA为对照,研究了庆大霉素对CS/HA复合材料抑菌性能、力学性能和降解性能等的影响。实验结果表明,CS/HA-G有良好的抑菌效果。负载庆大霉素后CS/HA的机械强度明显增强,而材料的降解速率有所下降。本文采用的二次成型技术显著增大了材料的机械强度。
5.壳聚糖膜无论作为组织工程支架材料还是作为定向控释材料,其微观结构及微观力学性能都至关重要。而干燥条件是影响壳聚糖膜结构与性能的一个重要因素。本文以自然风干(NW)、真空干燥(VD)及红外干燥(ID)三种干燥方式制备了壳聚糖膜。并利用原子力显微镜(AFM)研究这三种壳聚糖膜的表面形貌及微观力学性能。实验结果表明VD和ID改善了膜材料的表面平整度,膜表面粗糙度分别为(5.47±1.34)和(2.79±0.93)nm,均显著低于NW膜((30.67±8.06)nm)。干燥条件对壳聚糖膜的微观力学性能有较大影响：ID壳聚糖膜的粘附力显著大于((2595±68.5) pN) NW壳聚糖膜((982.6±149.3)pN)和VD壳聚糖膜((1817.9±279.2)pN)。而ID壳聚糖膜的杨氏模量((158.8±15.2)MPa)则低于NW壳聚糖膜((204.3±22.7)MPa)和VD壳聚糖膜((195.8±14.6)MPa)。
总之,本文利用纳米生物技术在纳米尺度对生物矿化进行了较为深入详细的研究分析,获得了大量有价值的实验数据与信息,为进一步研究生物矿化机制以及人工骨材料的仿生合成提供新的研究视角和思路。脲酶法所制备的HA基人工骨复合材料所显示的与天然骨相似的良好性能,表明这种新型仿生合成技术在骨组织工程中具有良好的应用前途。而CS/HA-G缓释材料的良好性能则显示了该材料在骨科临床应用的价值与潜力。未来,生物矿化及矿化仿生技术的进一步研究必将为骨组织工程的发展做出重大贡献。
Nanobiotechnology, as the cross-discipline of nanotechnology and life science, is a novel technology and approach to investigate life science at nanoscale level. In this paper, a dual membrane diffusion system (DMDS) was used to investigate the mineralization behaviour of collagen. Simulating the biomineralization, this paper applied a new route for preparing hydroxyapatite-based composite by enzymatic decomposition of urea. As a drug delivery system to cure osteomyelitis, chitosan/Hydroxyapatite-gentamicin was prepared for the treatment of osteomyelitis, and the antibacterial mechanism of antibiotic was detected with AFM. The effect of gentamicin on the composite material was investigated as well. From the results, we obtained a lot of valuable information shown as the following:
1. A model dual membrane diffusion system was used to detect the mineralization behaviour of collagen. The process of mineralization was observed by atomic force microscope (AFM). The micromechanical properties and microstructure changes of collagen fibers in the process of mineralization suggested that the mineralization was a step-by-step assembling process. In the initial stage, when the supersaturated condition was created in the DMDS, monomeric collagen converted into larger fibrils. These mineralized fibrils self-assembled into loose-arrayed fibers, which has no typical cross-striation patterns. In the second stage, loose-arrayed fibers arranged closely with each other and further assembled into slenderer but tighter ones. It represented the typical cross-striation pattern, which was similar with nature collagen. In the final stage, the fibers became thicker and stiffer due to the further growth of HA crystal within collagen fibrils. The phenomenon that calcium phosphate solid-phase appeared in the initial-and medium-stage and disappeared in final-stage supported the hypothesis of "polymer-induced liquid-precursor mineralization process". Moreover, the difference in height between the peak and bottom in typical cross-striation patterns on collagen fibers was measured by AFM. The differenceinheight of nature collagen fiber was about 5 nm, while it was 2.4-4.3 nm on minerized collagen fiber. The structural investigation by AFM supplied new evidence on the hypothesis that HA preferentially grows into the hole zones and interstices of the collagen fiber as reported by Landis.
2. Simulating the biomineralization, we applied a new route for preparing hydroxyapatite-based composite by enzymatic decomposition of urea. The composite materials were characterized by XRD, laser diffraction particle size analyzer, SEM and TEM. The results of FTIR and TEM indicated that chemical and crystallographic properties of the complex were similar to the properties of nature bone. Laser diffraction particle size measurement and SEM showed that the samples were of smaller particle size and narrower particle size distribution particle sizes than those prepared by traditional co-precipitation method. The degradation of the composite materials was investigated via simulation in vitro. The results showed that these materials had excellent degradability.
3. Chitosan/Hydroxyapatite-Gentamicin (CS/HA-G) was prepared, and this drug delivery system (DDS) was tested in vitro release ratio and antibacterial activity against bacteria. We used AFM to probe the surface ultrastructure of bacteria before and after CS/HA-G treatment. The results showed that CS/HA-G had considerable delayed release effectivity. It maintained effective release time of gentamicin up to 30 d, and its inactivation against bacteria was remarkable. AFM ultrastructure images showed that the height and the Ra (average roughness) of cells were all decreased. The cell content leaked via damaged cellular membrane. The CS/HA composite is a promising local biodegradable delivery system for gentamicin in treating osteomyelitis.
4. In order to investigate the effects of gentamicin on properties of hydroxyapatite/chitosan, CS/HA-G and CS/HA composites were prepared by co-precipitation method. The products were characterized by FTIR, XRD and SEM. This paper reported on comparison of chemical property and antibacterial activity between HA/CS-G and HA/CS. Comprising with HA/CS, HA/CS-G exhibitied much higher compressive strength and better antimicrobial activity. Moreover, molding technique of uniaxial pressure following cold isostatic pressure gave materials much higher compressive strength than technique of cold isostatic pressure. HA/CS-G can be used as an ideal gentamicin carrier and has great potential in osteomyelitis therapy.
5. The microstructural and micromechanical properties of chitosan were very important for its bioapplications as scaffolds for tissue engineering or carrier for drug delivery. Different drying conditions greatly affected the microstructural and micromechanical properties of chitosan. Chitosan films were prepared by wet casting followed by vacuum drying (VD) and
引文
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