医用功能性可降解聚氨酯复合体系构建的研究
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摘要
软骨组织无血管、无神经、无淋巴，在关节腔内仅靠滑液来获取营养，其代谢主要以无氧酵解为主，决定了其有限的自身修复能力。然而，现有的修复治疗技术无法实现从生物学环境及力学环境来进行构建，以适于软骨的再生修复，从而使得临床上关节软骨的修复至今难以取得突破性的进展。根据生物学环境及力学环境来重构是未来软骨再生修复的重要研究方向，而如何实现以可降解材料为基础构建软骨再生的生物学环境及力学环境是未来软骨修复材料研究的重点与热点。
本研究从上述角度出发，合成了一种新型的功能性医用可降解聚氨酯（PU），在此基础上，通过改变合成PU的软硬段比例构建了不同模量的PU材料，然后采用相转变-粒子沥滤法制备了不同孔结构特性的PU多孔支架，以满足骨和软骨再生对力学环境要求的不同。同时，通过表面改性的方法构建了适于软骨及骨再生的PU表面微环境以及通过复合的方法构建了适于软骨及骨再生的功能性微球/PU复合支架,以此来满足骨和软骨再生对生物学环境要求的不同，期望应用于一体化关节软骨组织工程。
在构建不同弹性模量的PU材料上，以赖氨酸二异氰酸乙酯为硬段，平均分子量为2000的聚己内酯二醇为软段，具有药理活性的异山梨醇为扩链剂，采用不同的软硬段比例合成了不同模量的PU。利用FTIR、1H-NMR、GPC、XRD、DSC对合成的聚合物进行了表征。FTIR、1H-NMR结果表明合成的聚合物的结构是典型PU的结构；GPC测试结果显示聚合物的数均分子量超过5万，分布指数在1.6~2.0，分子量分布较窄；DSC分析结果显示软段比例较大合成得到的聚合物在42℃存在着结晶熔融峰，而硬段比例较大合成得到的聚合物，没有结晶熔融峰；而XRD结果证明合成的聚合物存在部分结晶，但是结晶不是很完整。通过材料的拉伸力学试验，结果证明合成得到的PU材料具有很好的弹性，其断裂伸长率超过700%；同时其酶解性能也表明，相比较传统的PLGA材料的降解性能，合成得到的PU具有更慢的降解速度，且降解后溶液呈弱碱性，表现出更加理想的降解特性。该PU材料，可以满足软骨组织工程需要承受一定的负荷的要求，且解决工程支架植入到体内与自体组织相连不紧密，而在界面上产生剪切力造成植入体与自体相分离的问题，同时不至于因为材料降解而产生酸性积累，导致无菌性炎症的发生。潜在应用于骨及软骨组织工程。
在构建适于软骨及骨再生的表面微环境上，对PU进行了一系列的表面改性。首先利用1,3-丙二胺与PU链上的酯基基团发生胺解反应，在PU的表面形成游离的胺基，然后利用产生的胺基，一是通过与Ⅰ型胶原在EDC/NHS的作用下进行化学反应，使材料的表面接枝上胶原，构建骨再生的微环境，有利于骨细胞的增殖和分化；二是将游离的胺基酸化，使材料表面带正电荷，再通过静电作用力，在材料表面进行层层自组装硫酸软骨素和Ⅰ型胶原，构建软骨再生的微环境。RBITC-Col、QCM、XPS和AFM测试结果证明胶原和硫酸软骨素成功地吸附在PU的表面，使材料的表面变得更平整，形成比较均一的纳米级形貌结构，这样的一个表面纳米结构应该有利于细胞的粘附，促进细胞的增殖和分化。
在不同孔结构特性的PU支架制备上，采用相转变-粒子沥滤法，通过改变良溶剂和不良溶剂的比例以及造孔剂的比例等来控制PU支架的孔径、分布、孔之间的连通性以及支架的力学性能等。结果表明添加了不良溶剂和造孔剂制备得到的PU三维支架是由大小不同的孔构成，孔与孔之间连通性较好，大孔孔径可达几百微米，孔隙率超过75%，可以满足细胞在支架上生长、增殖的需要；同时，支架的抗压性能较好，具有较好的形变回复能力，通过加入不良溶剂得到的三维支架在压缩过程中不会发生崩塌的现象。当PU溶液的浓度为14.5%，良溶剂和不良溶剂的比例为2:1，造孔剂与PU的质量比为5:1时，且在37℃进行干燥除去溶剂制备得到的PU三维多孔支架的性能较好。此时得到的支架的孔隙率为84.2%，孔径大于100μm所占的比例为87.5%，且孔之间的连通性较好；压缩应变为20%时的抗压强度为0.31MPa，满足软骨组织工程的力学性能要求。
在构建适于软骨及骨再生的功能性微球/PU复合支架上，分别采用乳化法制备了明胶/肝素微球和双乳化溶剂挥发法制备了内部具有多孔结构的PLGA/氧氟沙星载药微球。明胶浓度，乳化剂浓度，水油比对明胶/肝素微球的粒径和分布有较大的影响。通过明胶微球包裹肝素，为明胶微球吸附bFGF提供活性位点，尽量保持bFGF的活性，构建软骨再生的缓释结构体系。而在PLGA/氧氟沙星载药微球制备中，在内水相中加入介孔二氧化硅、透明质酸、多聚赖氨酸对微球的粒径、分布及载药效率和释放都有影响。内水相中添加剂的物理吸附作用和静电吸引作用可以改善高亲水性药物在内水相中的留存量，并提高药物的包封率，但静电作用也可能会影响表面活性剂的乳化效果，破坏乳液的稳定性，造成较低的包封率。内水相中添加剂的亲水性的增加改善了高分子材料整体的亲水性，提高了亲水性药物在微球表面的吸附率，造成初期爆释较高。通过PLGA微球包裹氧氟沙星，构建骨再生的缓释结构体系。通过制得的功能性微球与PU三维多孔支架相复合，考察微球在PU支架中的分布，结果表明微球较均匀地分布在支架的孔壁和孔的里面，说明了这一功能性PU复合体系构建的可行性。
通过PU材料的生物相容性及PU材料对滑膜干细胞分化为软骨细胞实验，对PU材料的生物学性能进行了评价。结果表明不管是PU材料还是PU自组装胶原/硫酸软骨素材料，两者都没有毒性或者毒性很小，且支持细胞的生长和增殖。相比较单纯的PU材料，在PU材料表面组装上胶原和硫酸软骨素更有利于滑膜干细胞的生长及向软骨细胞分化。
未来，单一的生物材料在复杂组织的再生中将难以起主导作用。把各种信号因子复合在材料主体结构上，以实现材料体系的多功能、多效用，将成为组织工程材料构建的发展趋势。本研究从力学环境和生物学环境角度构建了功能性PU复合支架材料体系，为一体化软骨组织工程的开发应用奠定了基础，为未来多功能复合支架材料的研究提供了一定的参考依据。
Articular cartilage is a specialized connective tissue and has a poor reparative capacitywhich lacks blood vessels, nerves, and lymphatic system. However, it is still impossible forcurrent therapy techniques to construct a biological and mechanical environment for repairingarticular cartilage defects, which makes the clinical repair of articular cartilage defects nothave gained outstanding achievements. The reconstruction of biological and mechanicalenvironment is an important research direction of regenerative repair of cartilage defects. Inaddition, it will be a focus and hotspots in future that how to use degradable materials toreconstruct the biological and mechanical environment for cartilage regeneration.
In this sutdy, the reconsturction of biological and mechanical environment based onbiodegradable polyurethane for regenerative repair of cartilage defects had been made by thesynthesis of different modulus of polyurethane(PU), the preparation of3D porous scaffoldswith different pore structures and producing micro environment on PU surface andsustained-release structure suitable for the regeneration of cartilage and bone, respectively.
In order to synthesize PU with different elastic moduli, A two-step method was used tosynthesize the PU composed by different proportions of L-lysine ethyl ester diisocyanate(LDI) hard segment, poly (ε-caprolactone) diols (PCL-diol) soft segment,1,4:3,6-dianhydro-D-sorbitol (Isosorbide) chain extender. FTIR,1H-NMR results revealed the products hadtypical PU structures. GPC results showed the synthesized polyurethane had narrow,unimodal molecular weight distribution with the number average molecular weight of morethan50000and a polydispersity of1.6~2.0. DSC results displayed the proportion of softsegment to hard segment influenced the thermal property of PU. When the materialscontained more soft segment, they showed a melting peak at42℃.There was incompletecrystal structure in PU based on the XRD result. Tensile mechanical tests proved that the PUhad good flexibility and its tensile elongation at break was more than700%. In addition, thePU could be degraded by lipase solution with slow speed and made the solution weakalkalescence. The PU can be potentially applied to cartilage tissue engineering.
In order to build micro environment on PU surface suitable for the regeneration ofcartilage and bone respectively, PU was modified to improve its surface performance with aseries of technique. Surface aminolyzing of the PU membrane was performed by reacting itwith1,3-propanediamine under alkaline condition. Then, type I collagen was grafted on thePU surface by EDC/NHS coupling method to improve PU’s biocompatibility. The secondway was alternate deposition of type Ⅰcollagen (Col) and chondroitin sulfate (CS) on the aminolyzed PU films through layer-by-layer (LBL) assembly technology. Rhodamine Bisothiocyanate (RBITC) fluorescence spectrum presented that both amino group (-NH2) andtype I collagen were successfully introduced on the PU surface. The results of QCM,RBITC-Col fluorescence spectroscopy monitoring the LBL assemble process, XPS and AFMpresented that the Col/CS deposited alternately on the PU surface. The surface of theassembled PU became rougher and the hydrophilicity of the PU membrane enhanced greatlythough LBL assembly of Col/CS.
A combined salt leaching-phase inverse technique was used to produce the PU scaffoldswith different pore structure. The pore szie, pore size distribution, connectivity between thepore and mechanical properties of the scaffolds were controlled by changing the ratio of thesolvent/nonsolvent and the proportion of the solid porogen. The results showed that thescaffolds revealed multi-size distribution of pores with diameter from several microns toseveral hundred microns and high porosity (more than75%). In addition, the scaffoldsshowed good elasticity and deformability properties.
To design the sustained-release structure suitable for the regeneration of cartilage andbone respectively, Gelatin/heparin microspheres and PLGA microspheres containingofloxacine were prepared through emulsion chemical-crossline method and double-emulsion(water-in-oil-in-water) solvent extraction/evaporation method, respectively. The resultsshowed that gelatin concentration, emulsifier dosage and ratio of water to oilphase had effecton particle size and particle size distribution of gelatin/heparin microspheres. The heparinwrapped in gelatin microspheres was to provide active sites for adsorbing and maintaining theactivity of bFGF, which was constructed sustained-release structural system for cartilageregeneration. As for PLGA microsphere containing ofloxacine, the internal aqueous phaseadded had effect on the particle size and particle size distribution of the microspheres,encapsulation efficiency, initial burst and release profile of hydrophilic drug containingmicrospheres. Promoting hydrophilic drug loading efficiency was dominated by adsorptionand electrostatic attraction mechanism between the internal aqueous phase additives and thedrug. Release profile and initial burst release was a balance between the wall materialsdegradation and the interactions between the internal aqueous phase additives and the drug.The functional PU compsoites was prepared by the microspheres added to PU scaffolds.
The biological properties of PU were evaluated with the study of biocompatibility andchondrogenic differentiation of synovium-derived stem cells in vitro. The results displayedthat both the PU and PU-LBL-Col/CS PU had no or low cytotoxicity and could support thecells live and proliferation on them. Compared to the pure PU materials, the PU/Col/CS materials was more beneficial to the growth and differentiation to chondrocyte of synovialstem cell.
In future, it will be impossible for a single biomaterials to play a leading role on acomplex tissue regeneration. Various signals and growth factors will be combined with thematerials to build multi-functional and multi-purpose system. It will become the developmenttrend of design for tissue engineering materials. In this paper, the functional PU compositeswas reconstructed from the biological and mechanical environment for cartilage regeneration,which proved that it was feasibility to construct a multi-functional composite scaffold systemand provided some reference for research on multi-functional composite scaffold in future.
本研究从上述角度出发，合成了一种新型的功能性医用可降解聚氨酯（PU），在此基础上，通过改变合成PU的软硬段比例构建了不同模量的PU材料，然后采用相转变-粒子沥滤法制备了不同孔结构特性的PU多孔支架，以满足骨和软骨再生对力学环境要求的不同。同时，通过表面改性的方法构建了适于软骨及骨再生的PU表面微环境以及通过复合的方法构建了适于软骨及骨再生的功能性微球/PU复合支架,以此来满足骨和软骨再生对生物学环境要求的不同，期望应用于一体化关节软骨组织工程。
在构建不同弹性模量的PU材料上，以赖氨酸二异氰酸乙酯为硬段，平均分子量为2000的聚己内酯二醇为软段，具有药理活性的异山梨醇为扩链剂，采用不同的软硬段比例合成了不同模量的PU。利用FTIR、1H-NMR、GPC、XRD、DSC对合成的聚合物进行了表征。FTIR、1H-NMR结果表明合成的聚合物的结构是典型PU的结构；GPC测试结果显示聚合物的数均分子量超过5万，分布指数在1.6~2.0，分子量分布较窄；DSC分析结果显示软段比例较大合成得到的聚合物在42℃存在着结晶熔融峰，而硬段比例较大合成得到的聚合物，没有结晶熔融峰；而XRD结果证明合成的聚合物存在部分结晶，但是结晶不是很完整。通过材料的拉伸力学试验，结果证明合成得到的PU材料具有很好的弹性，其断裂伸长率超过700%；同时其酶解性能也表明，相比较传统的PLGA材料的降解性能，合成得到的PU具有更慢的降解速度，且降解后溶液呈弱碱性，表现出更加理想的降解特性。该PU材料，可以满足软骨组织工程需要承受一定的负荷的要求，且解决工程支架植入到体内与自体组织相连不紧密，而在界面上产生剪切力造成植入体与自体相分离的问题，同时不至于因为材料降解而产生酸性积累，导致无菌性炎症的发生。潜在应用于骨及软骨组织工程。
在构建适于软骨及骨再生的表面微环境上，对PU进行了一系列的表面改性。首先利用1,3-丙二胺与PU链上的酯基基团发生胺解反应，在PU的表面形成游离的胺基，然后利用产生的胺基，一是通过与Ⅰ型胶原在EDC/NHS的作用下进行化学反应，使材料的表面接枝上胶原，构建骨再生的微环境，有利于骨细胞的增殖和分化；二是将游离的胺基酸化，使材料表面带正电荷，再通过静电作用力，在材料表面进行层层自组装硫酸软骨素和Ⅰ型胶原，构建软骨再生的微环境。RBITC-Col、QCM、XPS和AFM测试结果证明胶原和硫酸软骨素成功地吸附在PU的表面，使材料的表面变得更平整，形成比较均一的纳米级形貌结构，这样的一个表面纳米结构应该有利于细胞的粘附，促进细胞的增殖和分化。
在不同孔结构特性的PU支架制备上，采用相转变-粒子沥滤法，通过改变良溶剂和不良溶剂的比例以及造孔剂的比例等来控制PU支架的孔径、分布、孔之间的连通性以及支架的力学性能等。结果表明添加了不良溶剂和造孔剂制备得到的PU三维支架是由大小不同的孔构成，孔与孔之间连通性较好，大孔孔径可达几百微米，孔隙率超过75%，可以满足细胞在支架上生长、增殖的需要；同时，支架的抗压性能较好，具有较好的形变回复能力，通过加入不良溶剂得到的三维支架在压缩过程中不会发生崩塌的现象。当PU溶液的浓度为14.5%，良溶剂和不良溶剂的比例为2:1，造孔剂与PU的质量比为5:1时，且在37℃进行干燥除去溶剂制备得到的PU三维多孔支架的性能较好。此时得到的支架的孔隙率为84.2%，孔径大于100μm所占的比例为87.5%，且孔之间的连通性较好；压缩应变为20%时的抗压强度为0.31MPa，满足软骨组织工程的力学性能要求。
在构建适于软骨及骨再生的功能性微球/PU复合支架上，分别采用乳化法制备了明胶/肝素微球和双乳化溶剂挥发法制备了内部具有多孔结构的PLGA/氧氟沙星载药微球。明胶浓度，乳化剂浓度，水油比对明胶/肝素微球的粒径和分布有较大的影响。通过明胶微球包裹肝素，为明胶微球吸附bFGF提供活性位点，尽量保持bFGF的活性，构建软骨再生的缓释结构体系。而在PLGA/氧氟沙星载药微球制备中，在内水相中加入介孔二氧化硅、透明质酸、多聚赖氨酸对微球的粒径、分布及载药效率和释放都有影响。内水相中添加剂的物理吸附作用和静电吸引作用可以改善高亲水性药物在内水相中的留存量，并提高药物的包封率，但静电作用也可能会影响表面活性剂的乳化效果，破坏乳液的稳定性，造成较低的包封率。内水相中添加剂的亲水性的增加改善了高分子材料整体的亲水性，提高了亲水性药物在微球表面的吸附率，造成初期爆释较高。通过PLGA微球包裹氧氟沙星，构建骨再生的缓释结构体系。通过制得的功能性微球与PU三维多孔支架相复合，考察微球在PU支架中的分布，结果表明微球较均匀地分布在支架的孔壁和孔的里面，说明了这一功能性PU复合体系构建的可行性。
通过PU材料的生物相容性及PU材料对滑膜干细胞分化为软骨细胞实验，对PU材料的生物学性能进行了评价。结果表明不管是PU材料还是PU自组装胶原/硫酸软骨素材料，两者都没有毒性或者毒性很小，且支持细胞的生长和增殖。相比较单纯的PU材料，在PU材料表面组装上胶原和硫酸软骨素更有利于滑膜干细胞的生长及向软骨细胞分化。
未来，单一的生物材料在复杂组织的再生中将难以起主导作用。把各种信号因子复合在材料主体结构上，以实现材料体系的多功能、多效用，将成为组织工程材料构建的发展趋势。本研究从力学环境和生物学环境角度构建了功能性PU复合支架材料体系，为一体化软骨组织工程的开发应用奠定了基础，为未来多功能复合支架材料的研究提供了一定的参考依据。
Articular cartilage is a specialized connective tissue and has a poor reparative capacitywhich lacks blood vessels, nerves, and lymphatic system. However, it is still impossible forcurrent therapy techniques to construct a biological and mechanical environment for repairingarticular cartilage defects, which makes the clinical repair of articular cartilage defects nothave gained outstanding achievements. The reconstruction of biological and mechanicalenvironment is an important research direction of regenerative repair of cartilage defects. Inaddition, it will be a focus and hotspots in future that how to use degradable materials toreconstruct the biological and mechanical environment for cartilage regeneration.
In this sutdy, the reconsturction of biological and mechanical environment based onbiodegradable polyurethane for regenerative repair of cartilage defects had been made by thesynthesis of different modulus of polyurethane(PU), the preparation of3D porous scaffoldswith different pore structures and producing micro environment on PU surface andsustained-release structure suitable for the regeneration of cartilage and bone, respectively.
In order to synthesize PU with different elastic moduli, A two-step method was used tosynthesize the PU composed by different proportions of L-lysine ethyl ester diisocyanate(LDI) hard segment, poly (ε-caprolactone) diols (PCL-diol) soft segment,1,4:3,6-dianhydro-D-sorbitol (Isosorbide) chain extender. FTIR,1H-NMR results revealed the products hadtypical PU structures. GPC results showed the synthesized polyurethane had narrow,unimodal molecular weight distribution with the number average molecular weight of morethan50000and a polydispersity of1.6~2.0. DSC results displayed the proportion of softsegment to hard segment influenced the thermal property of PU. When the materialscontained more soft segment, they showed a melting peak at42℃.There was incompletecrystal structure in PU based on the XRD result. Tensile mechanical tests proved that the PUhad good flexibility and its tensile elongation at break was more than700%. In addition, thePU could be degraded by lipase solution with slow speed and made the solution weakalkalescence. The PU can be potentially applied to cartilage tissue engineering.
In order to build micro environment on PU surface suitable for the regeneration ofcartilage and bone respectively, PU was modified to improve its surface performance with aseries of technique. Surface aminolyzing of the PU membrane was performed by reacting itwith1,3-propanediamine under alkaline condition. Then, type I collagen was grafted on thePU surface by EDC/NHS coupling method to improve PU’s biocompatibility. The secondway was alternate deposition of type Ⅰcollagen (Col) and chondroitin sulfate (CS) on the aminolyzed PU films through layer-by-layer (LBL) assembly technology. Rhodamine Bisothiocyanate (RBITC) fluorescence spectrum presented that both amino group (-NH2) andtype I collagen were successfully introduced on the PU surface. The results of QCM,RBITC-Col fluorescence spectroscopy monitoring the LBL assemble process, XPS and AFMpresented that the Col/CS deposited alternately on the PU surface. The surface of theassembled PU became rougher and the hydrophilicity of the PU membrane enhanced greatlythough LBL assembly of Col/CS.
A combined salt leaching-phase inverse technique was used to produce the PU scaffoldswith different pore structure. The pore szie, pore size distribution, connectivity between thepore and mechanical properties of the scaffolds were controlled by changing the ratio of thesolvent/nonsolvent and the proportion of the solid porogen. The results showed that thescaffolds revealed multi-size distribution of pores with diameter from several microns toseveral hundred microns and high porosity (more than75%). In addition, the scaffoldsshowed good elasticity and deformability properties.
To design the sustained-release structure suitable for the regeneration of cartilage andbone respectively, Gelatin/heparin microspheres and PLGA microspheres containingofloxacine were prepared through emulsion chemical-crossline method and double-emulsion(water-in-oil-in-water) solvent extraction/evaporation method, respectively. The resultsshowed that gelatin concentration, emulsifier dosage and ratio of water to oilphase had effecton particle size and particle size distribution of gelatin/heparin microspheres. The heparinwrapped in gelatin microspheres was to provide active sites for adsorbing and maintaining theactivity of bFGF, which was constructed sustained-release structural system for cartilageregeneration. As for PLGA microsphere containing ofloxacine, the internal aqueous phaseadded had effect on the particle size and particle size distribution of the microspheres,encapsulation efficiency, initial burst and release profile of hydrophilic drug containingmicrospheres. Promoting hydrophilic drug loading efficiency was dominated by adsorptionand electrostatic attraction mechanism between the internal aqueous phase additives and thedrug. Release profile and initial burst release was a balance between the wall materialsdegradation and the interactions between the internal aqueous phase additives and the drug.The functional PU compsoites was prepared by the microspheres added to PU scaffolds.
The biological properties of PU were evaluated with the study of biocompatibility andchondrogenic differentiation of synovium-derived stem cells in vitro. The results displayedthat both the PU and PU-LBL-Col/CS PU had no or low cytotoxicity and could support thecells live and proliferation on them. Compared to the pure PU materials, the PU/Col/CS materials was more beneficial to the growth and differentiation to chondrocyte of synovialstem cell.
In future, it will be impossible for a single biomaterials to play a leading role on acomplex tissue regeneration. Various signals and growth factors will be combined with thematerials to build multi-functional and multi-purpose system. It will become the developmenttrend of design for tissue engineering materials. In this paper, the functional PU compositeswas reconstructed from the biological and mechanical environment for cartilage regeneration,which proved that it was feasibility to construct a multi-functional composite scaffold systemand provided some reference for research on multi-functional composite scaffold in future.
引文
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