交联型生物可控降解骨组织修复材料的制备及应用
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摘要
骨组织原位再生修复用材料除应具有良好的生物相容性外，还应具备适宜的亲疏水性和力学强度，并且具有与组织生长速率相匹配的降解速率。目前研究的骨组织修复材料主要有合成聚酯类，天然多糖类和无机钙磷盐类等：聚酯类材料力学性能好，但亲水性差，目前多采用在分子结构上引入亲水链段来改善其亲水性，但通常会使分子量和力学性能均有明显下降；天然多糖类材料生物相容性虽好，但加工可塑性差，降解速率难以控制；单相的无机钙磷盐类材料脆性较大，而复合胶原后的材料则因强度低和降解速度太快等问题，限制了它们在临床上的应用。目前临床上虽然有一些骨修复材料，但均难以达到临床所需要的亲疏水性，力学强度以及降解速率的调控性能等。为了解决上述问题，本研究利用可生物降解的交联剂和大分子单体作为新材料的骨架，借助水溶性分子链段的嵌入制备了新型交联型生物可控降解材料，在保证材料既具有适宜的亲疏水性和一定力学强度的同时，又具备可调控的降解速率。
本研究采用不同的含羟基单体与辛酸亚锡为共引发剂，引发丙交酯开环聚合，分别合成了疏水性的末端双键功能化聚乳酸大分子单体(MC)以及两亲性双乙烯基封端的生物降解交联剂(BC)，在与亲水性单体乙烯吡咯烷酮(NVP)反应后，成功的将亲水链段引入聚乳酸体系，制备了具有适宜亲疏水性能的交联共聚物。聚乙烯吡咯烷酮(PVP)链段的引入，使交联大分子在酯键水解后可以形成线型的水溶性分子片断，保证了材料最终完全降解并能够通过体液循环排出体外。当材料的单体组成变化时，其表面水接触角变化为51°～73°，吸水率从20％～110％可调，形成适宜细胞粘附的中等润湿表面。
与传统的注塑成型或冻干法等材料加工的过程相比，体系中引入了生物降解交联剂，在成型过程中发生交联反应，保证了材料可降解并具有亲水性的同时，又可以通过形成网状聚合物来维持材料的一定力学强度，从而满足临床使用对材料力学性能的要求。交联聚合物的最大拉伸强度在5.29～8.27MPa之间，最大伸长率为68.5～144.7％；无机粉末／交联共聚物复合材料的压缩模量为18.6～109.8MPa可调，在兔桡骨缺损修复试验中，复合异体骨基质的交联材料对组织生长主要起到支撑作用，能有效地修复骨缺损。
最后，通过调整单体的组成比例来控制材料的亲疏水微区分相结构，从而调控局部酯键的水解速度，达到调控材料的整体降解速率。对材料的体内外降解百分率-时间数据进行回归分析，其拟合方程符合假一级反应动力学模型。随着单体组成中NVP含量的增加，降解速率常数逐渐增大，降解半衰期逐渐减小。随着降解时间的延长，不同单体组成的交联共聚物的即时降解速率均逐渐下降。在降解早期，即时降解速率随着NVP含量增加而增大；而在降解后期，即时降解速率随之增加而减小。PLA交联共聚物的降解速率是由性能各异的单体在交联体系中的组成决定的，具有精细的可调性。与只靠分子量、分子量分布或结晶度来调节降解速率的纯聚乳酸材料相比，PLA交联共聚物具有更为广阔和更精细控制降解速率的优点。
本研究所获得的新型交联型组织修复材料不仅具有适宜的亲疏水性，同时保证了材料的力学强度和降解速率可调控性，基本解决了材料亲疏水性和力学性能同时改善的科学技术难题；另外，本研究还将上述研制的新材料与异种活性骨基质复合，使材料在植入缺损部位时更易与骨组织结合，为材料的尽快临床使用奠定了基础。
Biomaterials applied to bone repair and regeneration should be characterized by their biocompatibility, hydrophilicity and mechanical properties. They are also supposed to degrade at a rate which can match the growth of tissue. Most present researches are focused on three sorts of materials: polyester, polysaccharid and calcium-phosphate. Polyester has outstanding mechanical strength, nevertheless, poor hydrophilicity. It can be improved by introducing hydrophilic chain, which, however, will bring about an evident reduction in molecular weight and mechanical strength. Polysaccharids has the advantage of biocompatibility, while they are difficult to be shaped and be controlled during degradation. Although the defect of high brittleness of pure calcium-phosphate can be made up by the combination with collagen, it is often followed by lower mechanical properties and over-degradation. For these reasons, so far they only have very limited application for clinical purposes.
This paper is to discuss a novle kind of biomaterial different from the aforesaid. Biodegradable cross-linker and macromer were employed to construct the molecular backbone, which could ensure the mechanical strength of the material. The incorporation of water-soluble chains into the molecular networks could maintain the hydrophilicity of the material. Also, it played an crucial part in control of the degrading rate.
The study began with syntheses of the macromers of poly [D,L-lactide-co-(2-hydroxyethyl methacrylate)] (PLA-HEMA, MC) and the biodegradable cross-linker of poly (lactic acid)- poly (ethylene glycol)(PLA-PEG-PLA) plus terminal groups of vinyl(BC). Both of them were then reacted with vinylpyrrolidone (NVP) and brought forth a series of cross-linked terpolymer, whose physicochemical properties were adjustable due to their ingredient, specifically, hydrophobic MC, amphiphilic BC and hydrophilic NVP. As the molar ratio n(BC)/n(MC)/n(NVP) changed from 1:1:10 to 1:4:30, the surface contact angles varied between 51°and 73°, and the water adsorption between 20％and 110％. PVP chains polymerized with NVP were introduced into the networks, which evidently improved the hydrophilicity of the cross-linked materials and the surface condition for cell adhesion. Furthermore, it proved to be possible that the network associated with PVP entirely degraded. With the hydrolysis of the PLA segment, the kinetic chains (polyacrylate-polymethacrylate-PVP) could readily dissolve into water.
In the second step, the biodegradable cross-linker was used to knit networks so as to maintain the mechanical strength. Compared with those traditional processing methods, such as injection molding and freezing drying, the chemical cross-linking technique could contribute to better degradability and mechanical strength, therefore, could meet the clinical requirements better. Tensile strength of the cross-linked terpolymer ranged between 5.29 and 8.27MPa, and elongation at break between 68.5％and 144.7％; Compression modulus of the inorganic matrix/cross-linked terpolymers ranged between 18.6 and 109.8MPa, which were to serve as scaffolds for tissue growing in rabbit radius defeat experiments.
Relative length of the molecular chain in the networks were dependent on the n(BC)/n(MC)/n(NVP), and so were the hydrophobic-hydrophilic discrete micro-districts. In this way the degradation rate of the cross-linked terpolymer could be controlled. Regression analysis of sample mass loss％-degradation time showed that the degrading behavior were in accordance with pseudo first-order kinetics. As the ratio of NVP content going up, the pseudo first-order reaction rate constant k' increased, while the degradation half-life decreased. In the early stage of the degradation, the instant degradation rate went up with the increase of n(NVP); While in the late stage, the rate decreased with the increase of n(NVP). The study showed that the degradation of cross-linked PLA terpolymer was possible to be adjusted delicately. That was the development in this study compared with pure PLA which could be controlled only by molecular weight or crystallization degree.
The cross-linked controllable biodegradable biomaterials obtained in this study have shown the remarkable improvement in terms of hydrophilicity, mechanical properties, controllable degrading rate and cellular biocompatibility.
本研究采用不同的含羟基单体与辛酸亚锡为共引发剂，引发丙交酯开环聚合，分别合成了疏水性的末端双键功能化聚乳酸大分子单体(MC)以及两亲性双乙烯基封端的生物降解交联剂(BC)，在与亲水性单体乙烯吡咯烷酮(NVP)反应后，成功的将亲水链段引入聚乳酸体系，制备了具有适宜亲疏水性能的交联共聚物。聚乙烯吡咯烷酮(PVP)链段的引入，使交联大分子在酯键水解后可以形成线型的水溶性分子片断，保证了材料最终完全降解并能够通过体液循环排出体外。当材料的单体组成变化时，其表面水接触角变化为51°～73°，吸水率从20％～110％可调，形成适宜细胞粘附的中等润湿表面。
与传统的注塑成型或冻干法等材料加工的过程相比，体系中引入了生物降解交联剂，在成型过程中发生交联反应，保证了材料可降解并具有亲水性的同时，又可以通过形成网状聚合物来维持材料的一定力学强度，从而满足临床使用对材料力学性能的要求。交联聚合物的最大拉伸强度在5.29～8.27MPa之间，最大伸长率为68.5～144.7％；无机粉末／交联共聚物复合材料的压缩模量为18.6～109.8MPa可调，在兔桡骨缺损修复试验中，复合异体骨基质的交联材料对组织生长主要起到支撑作用，能有效地修复骨缺损。
最后，通过调整单体的组成比例来控制材料的亲疏水微区分相结构，从而调控局部酯键的水解速度，达到调控材料的整体降解速率。对材料的体内外降解百分率-时间数据进行回归分析，其拟合方程符合假一级反应动力学模型。随着单体组成中NVP含量的增加，降解速率常数逐渐增大，降解半衰期逐渐减小。随着降解时间的延长，不同单体组成的交联共聚物的即时降解速率均逐渐下降。在降解早期，即时降解速率随着NVP含量增加而增大；而在降解后期，即时降解速率随之增加而减小。PLA交联共聚物的降解速率是由性能各异的单体在交联体系中的组成决定的，具有精细的可调性。与只靠分子量、分子量分布或结晶度来调节降解速率的纯聚乳酸材料相比，PLA交联共聚物具有更为广阔和更精细控制降解速率的优点。
本研究所获得的新型交联型组织修复材料不仅具有适宜的亲疏水性，同时保证了材料的力学强度和降解速率可调控性，基本解决了材料亲疏水性和力学性能同时改善的科学技术难题；另外，本研究还将上述研制的新材料与异种活性骨基质复合，使材料在植入缺损部位时更易与骨组织结合，为材料的尽快临床使用奠定了基础。
Biomaterials applied to bone repair and regeneration should be characterized by their biocompatibility, hydrophilicity and mechanical properties. They are also supposed to degrade at a rate which can match the growth of tissue. Most present researches are focused on three sorts of materials: polyester, polysaccharid and calcium-phosphate. Polyester has outstanding mechanical strength, nevertheless, poor hydrophilicity. It can be improved by introducing hydrophilic chain, which, however, will bring about an evident reduction in molecular weight and mechanical strength. Polysaccharids has the advantage of biocompatibility, while they are difficult to be shaped and be controlled during degradation. Although the defect of high brittleness of pure calcium-phosphate can be made up by the combination with collagen, it is often followed by lower mechanical properties and over-degradation. For these reasons, so far they only have very limited application for clinical purposes.
This paper is to discuss a novle kind of biomaterial different from the aforesaid. Biodegradable cross-linker and macromer were employed to construct the molecular backbone, which could ensure the mechanical strength of the material. The incorporation of water-soluble chains into the molecular networks could maintain the hydrophilicity of the material. Also, it played an crucial part in control of the degrading rate.
The study began with syntheses of the macromers of poly [D,L-lactide-co-(2-hydroxyethyl methacrylate)] (PLA-HEMA, MC) and the biodegradable cross-linker of poly (lactic acid)- poly (ethylene glycol)(PLA-PEG-PLA) plus terminal groups of vinyl(BC). Both of them were then reacted with vinylpyrrolidone (NVP) and brought forth a series of cross-linked terpolymer, whose physicochemical properties were adjustable due to their ingredient, specifically, hydrophobic MC, amphiphilic BC and hydrophilic NVP. As the molar ratio n(BC)/n(MC)/n(NVP) changed from 1:1:10 to 1:4:30, the surface contact angles varied between 51°and 73°, and the water adsorption between 20％and 110％. PVP chains polymerized with NVP were introduced into the networks, which evidently improved the hydrophilicity of the cross-linked materials and the surface condition for cell adhesion. Furthermore, it proved to be possible that the network associated with PVP entirely degraded. With the hydrolysis of the PLA segment, the kinetic chains (polyacrylate-polymethacrylate-PVP) could readily dissolve into water.
In the second step, the biodegradable cross-linker was used to knit networks so as to maintain the mechanical strength. Compared with those traditional processing methods, such as injection molding and freezing drying, the chemical cross-linking technique could contribute to better degradability and mechanical strength, therefore, could meet the clinical requirements better. Tensile strength of the cross-linked terpolymer ranged between 5.29 and 8.27MPa, and elongation at break between 68.5％and 144.7％; Compression modulus of the inorganic matrix/cross-linked terpolymers ranged between 18.6 and 109.8MPa, which were to serve as scaffolds for tissue growing in rabbit radius defeat experiments.
Relative length of the molecular chain in the networks were dependent on the n(BC)/n(MC)/n(NVP), and so were the hydrophobic-hydrophilic discrete micro-districts. In this way the degradation rate of the cross-linked terpolymer could be controlled. Regression analysis of sample mass loss％-degradation time showed that the degrading behavior were in accordance with pseudo first-order kinetics. As the ratio of NVP content going up, the pseudo first-order reaction rate constant k' increased, while the degradation half-life decreased. In the early stage of the degradation, the instant degradation rate went up with the increase of n(NVP); While in the late stage, the rate decreased with the increase of n(NVP). The study showed that the degradation of cross-linked PLA terpolymer was possible to be adjusted delicately. That was the development in this study compared with pure PLA which could be controlled only by molecular weight or crystallization degree.
The cross-linked controllable biodegradable biomaterials obtained in this study have shown the remarkable improvement in terms of hydrophilicity, mechanical properties, controllable degrading rate and cellular biocompatibility.
引文
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