新型纳米改性生物玻璃/PLGA复合材料的制备及骨缺损修复的实验研究
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摘要
近年来,生物活性玻璃/聚乙交-丙交酯(BG/PLGA)复合材料以其良好的骨传导性、骨诱导性、生物降解性能、较高的机械性能得到了广泛的关注。研究结果表明,BG/PLGA复合材料能很好地把两组分各自所具有的生物可降解性、骨传导性及骨诱导性能有机地结合起来,但由于无机粒子和聚酯两相界面缺乏有效粘连,复合材料一旦暴露在生理环境中,易于未等缺损完全修复而过早地失去其有效强度。因此我们采用全新的方法对纳米BG粒子表面进行化学接枝改性,得到表面接枝聚乳酸的生物活性玻璃粒子,而后将纳米改性生物活性玻璃与聚乙交-丙交酯(PLGA)应用熔体模压-颗粒浸出法及超临界CO2发泡法制备三维多孔支架,提高无机填料与PLGA基体间的界面结合力,改善了BG在PLGA基体间的分散性,制备了新型高性能BG/PLGA复合材料,并以PLGA为对照,对该复合材料进行体外细胞学相关评价及兔颅骨缺损的动物体内骨修复实验检测其诱导成骨的能力。结果表明改性生物活性玻璃纳米粒子可以均匀地分散在PLGA基体中,通过加入合适比例的改性纳米生物玻璃,可改善聚酯类材料的表面界面性质,使之更有利于成骨细胞在材料表面的生长和增殖,提高了聚酯类材料的生物活性,同时联合应用溶解模压-颗粒浸出法及超临界CO2发泡法制备三维多孔支架,能够有效提高复合物支架的孔隙率、改善孔隙表面形貌及其粗糙度,从而进一步提高了复合物支架的生物学性能。
Bone defect caused by trauma or tumor is a common problem in clinical treatment. The state of the art in repairing, such as autologous or allogeneic bone transplantation, has some drawbacks in varying degrees, respectively. For example, although autologous bone substitution is by far the best option, however the amount of autologous bone is extremely limited and the infection in donor site may further intensify the pain of patients.While for the allogeneic bone, although the size and amount of allogeneic bone could satisfy the requirement of bone transplant, its applications are restricted sharply due to the suffering venture of inevitable immune response and disease infection. In order to surmount the limitations mentioned above, the design and development of novel artificial biomaterials as the substitute of bone transplant has attracted the interests all over the world. This research field has been an important emerging focus of medical and material even engineering sciences, consequently.
Tissue engineering is the most prosperous one among the options technically avialible for the bone repairs. The materials play a vital important role in the tissue engineering since the bioabsorbable scaffolds is the bottleneck in tissue engineering applications in clinical treatments.Till now several bioabsorbable scaffords have been developed for the application of tissue engineeing, for instance, poly lactic acid(PLA), polyglycolic acid(PGA) and polylactide-glycolide(PLGA). However, as far as bone tissue engineering is concerned, the above mentioned materials have little thing to do because of the apparent lack of bioactivities.
Bioactive Glass (BG) has been widely applied in plastic and oral surgery due to its excellent abilities since its invention by Hench and his colleagues at the University of Florida in 1971. As a kind of glass particles with high bioactivity, BG shows high affinity towards bone tissue and could form a thick cement layer on the suface of bone, thus the interface stress between transplant materials and tissue is significant suppressed. Bioactive glass can be prepared through the formation of bioactive apatites or phosphorites followed by the combination with hard (and in some cases soft) tissues without encapsulations.
The soluble Si, Ca, P and Na ions released from the surfaces reaction of BG could catalyze the intracellular and extracellular reaction of BG interface cell; promote the proliferation and differentiation of osteoblast or its precursor. In addition, its soluble product could modulate the expression of osteogenesis gene and produce growth factor. This kind of materials will induce the bone tissue to the orientation towards regeneration. Bone tissue shows rapid response to this kind of materials, thus the bone-formation rate is fast and the quality of as-formed bone is relatively high. Once repaired, these materials could be fused and further molted and/or corroded by newly formed bone tissue.At last normal bone tissue will emerge, instead of the physical mixture of materials and bone tissue.
The composition of bioactive BG and PLGA could improve the mechanical strength and osteogenic activity of PLGA. The state of at method, i.e. simply physical mixing of inorganic materials and polymers, suffer from the weak affinity of interfaces. In additional, the poly dispersed inorganic particles may result in aggregation and lower the mechanical response of the composition, thus application of such composition is quite limited. In the present dissertation, we put the BG into PLLA to form the polymer of PLLA-g-BG, and then polymerize it with PLGA to obtain the novel composition of PLLA-g-BG/PLGA. This novel composition can significantly overcome those drawbacks of trandtionals while maintaining bioactivities, and would possess the characteritics of more applicable biomaterials for clinics.
In the thesis, we have undertaken a quantitave aproach toward the design, preparation, and the functional evaluation of a modified bioactive glass for the clinical treatment of bone defect repair.
Several composite materials with different mixing ratio have been preparated in Chapt 1.
The weight(w: w) of PLLA-g-BG in composite materials accounted for 10%, 20% and 40%,separately, with PLGA selected as control materials.Rabbit osteoblasts were planted on the material film for in vitro culture, then the experimental data were analized using fluorescence staining, NIH Image J analysis software, MTT and flow cytometry, Real time-PCR and other means of detection cells in the surface adhesion of the average quantity, the expansion of area ratio, proliferation and cell cycle changes, comprehensive evaluation of new modified nano-composite material biocompatibility and biological activity, in order to explore the material inside the PLLA-g-BG content on the materials performance and activity of osteoblasts, finally the best composite materials the ratio of medical applications for the material which can provide a basis for industrialization was optimized.
In vitro comparison experiments of cytology with novel nano-modified bioactive glass and the modified nano-hydroxyapatite / PLGA composite materials were conducted in Chapt.2. 20%g-BG/PLGA and 20% g-HA/PLGA composite materials were preparated, PLGA also selected as the control group. After in vitro cultured on material film the rabbit osteoblasts were analized using fluorescence staining, NIH Image J image analysis software, MTT and flow cytometry, Real time-PCR detection of osteoblast gene expression by means of detection of osteoblast surface in the adhesion of the average quantity, the expansion of area ratio, proliferation and cell cycle changes. The comparison of two new experiments had been investigated to explore whether the graft-modified bioactive glass and the hydroxyapatite composite materials with PLGA differ in in biological activity and biocompatibility or not.
Complex three-dimensional porous tissue engineering scaffolds were preparated in Chapt.3. Three-dimensional porous scaffolds were preparated with the above-mentioned materials by melt casting / particulate leaching. Those further processed and modified scaffolds were obtained by combinated applications of supercritical CO2 (SC-CO2) foam before and after leaching. The surface morphology, pore size and porosity were observated, and the mechanical strength were tested to investigate the impact of the supercritical CO2 (SC-CO2) method on the preparation of the stents.
Next, the rabbit skull bone defects repair experiments were studied in Chapt.4. The bilateral bone defect animal model of rabbit parietal bone on both sides of a long sagittal every 10mm, width 10mm, depth of 1.5 ~ 2mm, thick layer of dura-wide were constructed. The new-made composite materials made from different processing methods and various proportion of mixing ratio implanted in bone defect, respectively. The CT three-dimensional reconstructions were conducted in order to evaluate the novel materials 4 w and 12w after the implantation.
The experimental results can be summarized into several lines:
1. The nano-bio-glass particle agglomeration in composite materials can be significantly improved with polylactic acid grafted surface; PLLA-g-BG can be dispersed in homogeneous materials PLGA matrix.
2. In vitro experiments indicated that: grafted BG can significantly improve the polymer capacity of cell adhesion and proliferation. Among the groups 10% and 20% g-BG/PLGA top ahead with with better ability to promote cell proliferation; the best cell adhesion and expansion were obtained in the group of 20%g-BG/PLGA material. The maximum BMP-2 and Collagen-I gene expression was observed in the group of 20%g-BG/PLGA, while the higher OCN expression produceted by 10% and 20%g-BG/PLGA.
3. The bone tissue engineering scaffolds with larger porosity and smaller pore co-existence and mutual cross-connection can be preparated by the approach of combined using fusion-particle leaching method and supercritical CO2 foaming method. The highest compressive strength of the porous scaffolds are the group of 20% (g-BG +g-HA) / PLGA, which is made by the processing methods of direct porogen leaching; the highest bending strength is by supercritical CO2 foam before the porogen leaching, of which 20% (g-BG +g-HA) / PLGA got the highest anti-bending strength; the introduction of the supercritical CO2 foam application method not only can modify the pore inner side wall to got the increased hole wall roughness, but also can make the nanoparticles exposed thoroughly, therefore make the biological activity of scaffolds increased accordingly.
4. A series of cytologic evaluation carried out on the two new bone repair materials (PLLA-g-BG, PLLA-g-HA) show that, modified bioglass with PLGA nano-more complex contribute to the promotion of the expansion of osteoblasts, but also has a role in promoting cell proliferation, compared to 20% g-HA/PLGA group. The amount of cells in the S phase (DNA synthesis phase) is higher than the proportion of 20%g-HA/PLGA group can be seen from the osteoblast cell cycle flow cytometry results of 20% g-BG/PLGA group, which indicates that nano-modified bioactive glass is more conducive to osteoblast proliferation in the material surface. BMP-2 of the 20% g-BG/PLGA group is significantly higher than that of 20% g-HA/PLGA group.
5. Experimental results of skull bone defect repair show that:
There is no significant callus growth and the density of bone defect area is relatively low the control group after 4w.
There is a small number of defect regions formed callus in PLGA control group, while obvious callus growth and significantly reduced transmission area in three-dimensional reconstruction defect model occurs in 20% (g-BG +g-HA)/PLGA group and 20%g-BG/PLGA group skull defect has, forthermore the defect high-density areas can be seen clearly in 20% g-BG/PLGA group, its complete transmission of low-density area is relatively minimal.
As far as different methods (leaching method, SC-CO2 foam + leaching method, and leaching method + SC-CO2 foam method) are concerned, there is a small amount of callus formation in the stent bone defect region made by leaching method, while the stents from SC-CO2 foam + leaching, leaching method + SC-CO2 foam skull defect Law Group have significant callus growth and the smaller the transmission area. The result from the stent made by supercritical CO2 foaming first is better than that on the contrary.
After 12 w, the control group appears that a small amount of bone defect bone region emerges with lower density. There is a small amount of the central high-density video cloudinesses connected.
The regional transmission areas still exist in that porogen leaching stent in the skull bone defect, while the skull defects in the stent of the other two basic tynthetic methods almostly restitute a closure, with a higher bone density but still uneven surface depression.
Among group comparison with the different materials, the 20% g-BG/PLGA experimental group and the 20% (g-BG +g-HA)/PLGA group act better than PLGA control group after a period of 3 months implanted, while the bone defect of 20 % g-BG/PLGA group gets a closure alomost, and there is a higher bone formation connected with the surrounding marginal exists in 20% (g-BG +g-HA)/PLGA group.
The thesis was conclued as followed: The novel type of scaffolds can be used in bone repair, PLLA-g-BG/PLGA, possesses good biocompatibility, perfect cell adhesion and proliferation properties. The increased the combination force two-phase composite interface, and enhanced material dispersion and stability can be otained by modified PLLA-g-BG materials. The ratio of PLLA-g-BG in composite materials is sensitive, the mechanical properties and repair results will get worse if it is too high or too low, while 20% sounds good in general. The osteoblast activity of new-born bones has been further improved after the introduction of Supercritical CO2 foam during the process.
Bone defect caused by trauma or tumor is a common problem in clinical treatment. The state of the art in repairing, such as autologous or allogeneic bone transplantation, has some drawbacks in varying degrees, respectively. For example, although autologous bone substitution is by far the best option, however the amount of autologous bone is extremely limited and the infection in donor site may further intensify the pain of patients.While for the allogeneic bone, although the size and amount of allogeneic bone could satisfy the requirement of bone transplant, its applications are restricted sharply due to the suffering venture of inevitable immune response and disease infection. In order to surmount the limitations mentioned above, the design and development of novel artificial biomaterials as the substitute of bone transplant has attracted the interests all over the world. This research field has been an important emerging focus of medical and material even engineering sciences, consequently.
Tissue engineering is the most prosperous one among the options technically avialible for the bone repairs. The materials play a vital important role in the tissue engineering since the bioabsorbable scaffolds is the bottleneck in tissue engineering applications in clinical treatments.Till now several bioabsorbable scaffords have been developed for the application of tissue engineeing, for instance, poly lactic acid(PLA), polyglycolic acid(PGA) and polylactide-glycolide(PLGA). However, as far as bone tissue engineering is concerned, the above mentioned materials have little thing to do because of the apparent lack of bioactivities.
Bioactive Glass (BG) has been widely applied in plastic and oral surgery due to its excellent abilities since its invention by Hench and his colleagues at the University of Florida in 1971. As a kind of glass particles with high bioactivity, BG shows high affinity towards bone tissue and could form a thick cement layer on the suface of bone, thus the interface stress between transplant materials and tissue is significant suppressed. Bioactive glass can be prepared through the formation of bioactive apatites or phosphorites followed by the combination with hard (and in some cases soft) tissues without encapsulations.
The soluble Si, Ca, P and Na ions released from the surfaces reaction of BG could catalyze the intracellular and extracellular reaction of BG interface cell; promote the proliferation and differentiation of osteoblast or its precursor. In addition, its soluble product could modulate the expression of osteogenesis gene and produce growth factor. This kind of materials will induce the bone tissue to the orientation towards regeneration. Bone tissue shows rapid response to this kind of materials, thus the bone-formation rate is fast and the quality of as-formed bone is relatively high. Once repaired, these materials could be fused and further molted and/or corroded by newly formed bone tissue.At last normal bone tissue will emerge, instead of the physical mixture of materials and bone tissue.
The composition of bioactive BG and PLGA could improve the mechanical strength and osteogenic activity of PLGA. The state of at method, i.e. simply physical mixing of inorganic materials and polymers, suffer from the weak affinity of interfaces. In additional, the poly dispersed inorganic particles may result in aggregation and lower the mechanical response of the composition, thus application of such composition is quite limited. In the present dissertation, we put the BG into PLLA to form the polymer of PLLA-g-BG, and then polymerize it with PLGA to obtain the novel composition of PLLA-g-BG/PLGA. This novel composition can significantly overcome those drawbacks of trandtionals while maintaining bioactivities, and would possess the characteritics of more applicable biomaterials for clinics.
In the thesis, we have undertaken a quantitave aproach toward the design, preparation, and the functional evaluation of a modified bioactive glass for the clinical treatment of bone defect repair.
Several composite materials with different mixing ratio have been preparated in Chapt 1.
The weight(w: w) of PLLA-g-BG in composite materials accounted for 10%, 20% and 40%,separately, with PLGA selected as control materials.Rabbit osteoblasts were planted on the material film for in vitro culture, then the experimental data were analized using fluorescence staining, NIH Image J analysis software, MTT and flow cytometry, Real time-PCR and other means of detection cells in the surface adhesion of the average quantity, the expansion of area ratio, proliferation and cell cycle changes, comprehensive evaluation of new modified nano-composite material biocompatibility and biological activity, in order to explore the material inside the PLLA-g-BG content on the materials performance and activity of osteoblasts, finally the best composite materials the ratio of medical applications for the material which can provide a basis for industrialization was optimized.
In vitro comparison experiments of cytology with novel nano-modified bioactive glass and the modified nano-hydroxyapatite / PLGA composite materials were conducted in Chapt.2. 20%g-BG/PLGA and 20% g-HA/PLGA composite materials were preparated, PLGA also selected as the control group. After in vitro cultured on material film the rabbit osteoblasts were analized using fluorescence staining, NIH Image J image analysis software, MTT and flow cytometry, Real time-PCR detection of osteoblast gene expression by means of detection of osteoblast surface in the adhesion of the average quantity, the expansion of area ratio, proliferation and cell cycle changes. The comparison of two new experiments had been investigated to explore whether the graft-modified bioactive glass and the hydroxyapatite composite materials with PLGA differ in in biological activity and biocompatibility or not.
Complex three-dimensional porous tissue engineering scaffolds were preparated in Chapt.3. Three-dimensional porous scaffolds were preparated with the above-mentioned materials by melt casting / particulate leaching. Those further processed and modified scaffolds were obtained by combinated applications of supercritical CO2 (SC-CO2) foam before and after leaching. The surface morphology, pore size and porosity were observated, and the mechanical strength were tested to investigate the impact of the supercritical CO2 (SC-CO2) method on the preparation of the stents.
Next, the rabbit skull bone defects repair experiments were studied in Chapt.4. The bilateral bone defect animal model of rabbit parietal bone on both sides of a long sagittal every 10mm, width 10mm, depth of 1.5 ~ 2mm, thick layer of dura-wide were constructed. The new-made composite materials made from different processing methods and various proportion of mixing ratio implanted in bone defect, respectively. The CT three-dimensional reconstructions were conducted in order to evaluate the novel materials 4 w and 12w after the implantation.
The experimental results can be summarized into several lines:
1. The nano-bio-glass particle agglomeration in composite materials can be significantly improved with polylactic acid grafted surface; PLLA-g-BG can be dispersed in homogeneous materials PLGA matrix.
2. In vitro experiments indicated that: grafted BG can significantly improve the polymer capacity of cell adhesion and proliferation. Among the groups 10% and 20% g-BG/PLGA top ahead with with better ability to promote cell proliferation; the best cell adhesion and expansion were obtained in the group of 20%g-BG/PLGA material. The maximum BMP-2 and Collagen-I gene expression was observed in the group of 20%g-BG/PLGA, while the higher OCN expression produceted by 10% and 20%g-BG/PLGA.
3. The bone tissue engineering scaffolds with larger porosity and smaller pore co-existence and mutual cross-connection can be preparated by the approach of combined using fusion-particle leaching method and supercritical CO2 foaming method. The highest compressive strength of the porous scaffolds are the group of 20% (g-BG +g-HA) / PLGA, which is made by the processing methods of direct porogen leaching; the highest bending strength is by supercritical CO2 foam before the porogen leaching, of which 20% (g-BG +g-HA) / PLGA got the highest anti-bending strength; the introduction of the supercritical CO2 foam application method not only can modify the pore inner side wall to got the increased hole wall roughness, but also can make the nanoparticles exposed thoroughly, therefore make the biological activity of scaffolds increased accordingly.
4. A series of cytologic evaluation carried out on the two new bone repair materials (PLLA-g-BG, PLLA-g-HA) show that, modified bioglass with PLGA nano-more complex contribute to the promotion of the expansion of osteoblasts, but also has a role in promoting cell proliferation, compared to 20% g-HA/PLGA group. The amount of cells in the S phase (DNA synthesis phase) is higher than the proportion of 20%g-HA/PLGA group can be seen from the osteoblast cell cycle flow cytometry results of 20% g-BG/PLGA group, which indicates that nano-modified bioactive glass is more conducive to osteoblast proliferation in the material surface. BMP-2 of the 20% g-BG/PLGA group is significantly higher than that of 20% g-HA/PLGA group.
5. Experimental results of skull bone defect repair show that:
There is no significant callus growth and the density of bone defect area is relatively low the control group after 4w.
There is a small number of defect regions formed callus in PLGA control group, while obvious callus growth and significantly reduced transmission area in three-dimensional reconstruction defect model occurs in 20% (g-BG +g-HA)/PLGA group and 20%g-BG/PLGA group skull defect has, forthermore the defect high-density areas can be seen clearly in 20% g-BG/PLGA group, its complete transmission of low-density area is relatively minimal.
As far as different methods (leaching method, SC-CO2 foam + leaching method, and leaching method + SC-CO2 foam method) are concerned, there is a small amount of callus formation in the stent bone defect region made by leaching method, while the stents from SC-CO2 foam + leaching, leaching method + SC-CO2 foam skull defect Law Group have significant callus growth and the smaller the transmission area. The result from the stent made by supercritical CO2 foaming first is better than that on the contrary.
After 12 w, the control group appears that a small amount of bone defect bone region emerges with lower density. There is a small amount of the central high-density video cloudinesses connected.
The regional transmission areas still exist in that porogen leaching stent in the skull bone defect, while the skull defects in the stent of the other two basic tynthetic methods almostly restitute a closure, with a higher bone density but still uneven surface depression.
Among group comparison with the different materials, the 20% g-BG/PLGA experimental group and the 20% (g-BG +g-HA)/PLGA group act better than PLGA control group after a period of 3 months implanted, while the bone defect of 20 % g-BG/PLGA group gets a closure alomost, and there is a higher bone formation connected with the surrounding marginal exists in 20% (g-BG +g-HA)/PLGA group.
The thesis was conclued as followed: The novel type of scaffolds can be used in bone repair, PLLA-g-BG/PLGA, possesses good biocompatibility, perfect cell adhesion and proliferation properties. The increased the combination force two-phase composite interface, and enhanced material dispersion and stability can be otained by modified PLLA-g-BG materials. The ratio of PLLA-g-BG in composite materials is sensitive, the mechanical properties and repair results will get worse if it is too high or too low, while 20% sounds good in general. The osteoblast activity of new-born bones has been further improved after the introduction of Supercritical CO2 foam during the process.
引文
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