聚（DL—乳酸）的改性及体外降解和细胞相容性研究
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摘要
本文从优化聚（DL-乳酸）（PDLLA）的制备工艺，制备超高分子量PDLLA入手，用马来酸酐（MAH）、乙二胺和Ⅰ型胶原对PDLLA进行整体（而不是表面）化学改性，制得了一系列改性聚乳酸，旨在开发一种基于超高分子量PDLLA的降解产物不呈酸性、降解速率可调、具有优良细胞相容性和生物特异性的生物医用材料，尽可能多地满足人体的需求。用化学分析、FTIR、1H-NMR、13C-NMR和荧光标记表征了它们的化学结构，用DSC表征了它们的热学性能，用Instron1011万能材料试验机测试了它们的力学性能，并考查了其亲疏水性、体外生物降解和细胞相容性。主要研究内容和结论如下：
（1）以DL-丙交酯为原料，辛酸亚锡为引发剂，采用熔融开环聚合方法制备PDLLA，考查了DL-丙交酯的纯度、聚合时间、聚合温度和引发剂（辛酸亚锡）用量等因素对PDLLA分子量的影响，优化出了一套制备超高分子量PDLLA（粘均分子量高达220万）的制备工艺，并测试了超高分子量PDLLA的脆化温度、拉抻（压缩）强度和模量。结果表明：
① 丙交酯的纯度是影响PDLLA分子量的一个重要因素，高纯丙交酯是制备高分子量PDLLA的必备条件；以纯度>99.8%、熔点为126.3-126.4℃的DL-丙交酯为原料，在160℃下聚合36h，可制得粘均分子量高达220万的超高分子量PDLLA。
② 超高分子量PDLLA相对于低分子量PDLLA（粘均分子量为80万），其拉伸（压缩）强度和模量、韧性及延展性都已大大提高，表现为韧性断裂，而低分子量PDLLA表现为脆性断裂，从而使超高分子量PDLLA可望在各医学领域如作为骨螺钉、手术缝合线、组织工程支架材料和通用完全可降解塑料方面得到广泛的应用。
（2）采用溶液混合、自由基聚合技术将MAH共价接枝到PDLLA骨架上，制得马来酸酐改性PDLLA（MPLA），旨在向PDLLA中引入高反应活性的酸酐键，为进一步化学改性奠定化学基础。
① FTIR、13C-NMR和DSC分析结果表明，MAH已成功地共价接枝到PDLLA骨架上；MPLA只有一个玻璃化转移峰值温度41.7℃，且低于PDLLA的玻璃化转移峰值温度56.5℃，提示MAH已对PDLLA成功改性，且采用本研究所述之分离提纯技术可得到纯净的MPLA。
② 化学滴定分析结果表明，MAH投料量为PDLLA质量的5%和10%时，MAH接枝率分别为1.86%和2.36%。
（3）用乙二胺对MPLA进行化学改性制得二胺改性PDLLA（DMPLA），旨
在通过碱性二胺的共价引入克服PDLLA和MPLA降解产物的酸性，改变PDLLA和MPLA的酸致自催化降解特点，开发出一种降解产物不呈酸性且具有良好亲水性的生物医用材料DMPLA，且DMPLA中的反应活性基团-COOH和-NH2为进一步引入胶原和多肽等生物活性分子，制备具有生物特异性和全面生理功能的生物医用材料奠定了化学基础。通过MPLA中高反应活性酸酐键的N-酰化开环将乙二胺共价引入到MPLA中，建立了一套二胺改性MPLA的改性技术。
① 化学滴定分析结果表明，MPLA中的酸酐键能完全与二胺反应；
② FTIR、13C-NMR、1H-NMR和DSC分析结果表明，二胺已被成功地共价引入到MPLA中；DMPLA的玻璃化转移峰值温度为59.5℃，高于PDLLA和MPLA的玻璃化转移峰值温度，可能是DMPLA中的伯胺与羧基形成内盐所致；唯一的玻璃化转移温度提示，按本研究所述之分离技术能得到纯净的DMPLA。
（4）以二环己基碳二亚胺（DCC）为缩合剂用Ⅰ型胶原对DMPLA进行整体（而不是表面）化学改性制得了胶原改性聚乳酸（CPLA），旨在开发一种降解产物不呈酸性且具有良好生物相容性、生物特异性的生物医用材料，并建立一套适用于多肽或蛋白质对DMPLA进行整体化学改性的制备工艺，为制备具有全面生理功能的组织材料奠定技术基础。异硫氰酸荧光素（FITC）标记测定结果表明，采用本研究所述之制备和提纯工艺能成功地将Ⅰ型胶原共价引入到DMPLA整体中获得纯净的CPLA。
（5）用吸水率和静态水接触角表征了PDLLA、MPLA、DMPLA和CPLA的亲疏水性。结果表明，DMPLA和CPLA的亲水性相对于PDLLA已大大提高，CPLA具有最好的亲水性，DMPLA略次之，提示DMPLA和CPLA都可望成为一种具有良好亲水性和细胞亲和性的生物医用材料。
（6）考查了PDLLA、MPLA、DMPLA在降解过程中的pH值变化（介质pH=6.45蒸馏水，温度37.0±0.5℃）以及分子量和失重率变化（介质：0.1M PBS溶液，pH=7.4；温度37.0±0.5℃）。在整个降解实验中始终不更换介质。结果表明：
① MPLA在降解过程酸性增加最快，酸致自催化程度最大，由此而引起的降解速率最快，失重率也最大，比PDLLA呈现更严重的整体溶蚀降解，即体型降解特点。因此，尽管MPLA在水解后其亲水性已较PDLLA有较大改善，但仍不适于单独用作生物医用材料。
DMPLA已基本克服了降解过程中的酸性增强；其降解速率较PDLLA和MPLA均匀，不呈现PDLLA和MPLA的体型降解特征，且随二胺含量的增加，其降解速率逐渐减小；尽管DMPLA在前6周的失重率略高于PDLLA和MPLA，但经12周降解，其失重率不到50%，低于PDLLA和MPLA，且随二胺含量增加，失重也减少。上述结果提示，DMPLA是一种降解产物不呈现酸性、降解速率可调
② 且降解过程不呈现体型降解特征的生物材料。
（7）采用细胞形态学观察法和细胞增殖法，以玻璃为对照，初步考查了P
Poly(DL-lactic acid) (PDLLA) with ultra-high molecular weight was prepared and a series of bulk modifications (non-surface modifications) of PDLLA were carried out with maleic anhydride(MAH), ethylenediamine and collagen type Ⅰ, aiming to develop an ideal PDLLA-based tissue engineering biomaterial with controlled degrading rate, excellent cell compatibility and biospecificty and whole physiological functions, whose degrading products are not of acidity. Their chemical structures were characterized by means of chemical analysis, FTIR (Fourier Transform Infred), 1H-NMR (Nuclear Magnetic Resonance), 13C-NMR and fluorescence labeling, their thermal properties done by DSC (Differential Scanning Calorimeter) and the mechanical properties by Instron 1011. Thereafter, the hydrophilicity, degradation and cell compatibility of PDLLA and those modified PDLLAs were investigated. The main works and conclusions are included as follows:
(1) PDLLA was prepared from DL-lactide by melt ring-opening polymerization. The effects of DL-lactide purity, polymerization time, temperature and the percent of initiator in lactide were investigated in detail, resulting in an optimum condition to synthesize PDLLA with 2200000 of viscosity-average molecular weight (Mv). The obtained results show that:
① The DL-lactide purity has significant influence on PDLLA's Mv. Ultrahigh molecular weight PDLLA with 2200000 of Mv could be obtained from lactide with purity of more than 99.8% and melting point of 126.3~126.4℃ at 160℃ for 36h.
② The stretching (compressing) strength and module, tenacity and elongation of ultrahigh PDLLA are significantly improved compared to PDLLA with 800000 of Mv, suggesting its potentially wide applications in medical areas as bone screw, surgical suture and tissue scaffolds and in general plastics as full degradable plastics.
(2) MAH modified PDLLA (MPLA) was synthesized by solution blending and subsequent free radical polymerization, attempting to introduce highly reactive anhydride into PDLLA backbone and providing chemical basis for further chemical modification.
FTIR, 13C-NMR and DSC analysis showed the successful covalent grafting of MAH into PDLLA. Furthermore, the unique Tg of 41.7℃ for MPLA and the greater Tg of 56.5℃ for PDLLA indicated in DSC proved that the purification method in this
① study was efficient enough to produce pure MPLA.
② The results of chemical titration showed that MAH grafting ratio in MPLA was 1.86% and 2.36% respectively when the percentage of fed MAH in PDLLA was 5% and 10% in weight.
(3) Diamine modified PDLLA (DMPLA) from ethylenediamine and MPLA was synthesized and its preparing technique well established. The modification of PDLLA with diamine is to eliminate or weaken acidity of degraded products from PDLLA and MPLA with the help of basic diamines and change the acid catalyzed auto-accelerating degradation, developing a new family of biomaterials with no acidic degrading products. Furthermore, DMPLA could provide reactive groups -COOH and -NH2 for further bulk modification with collagen, peptides or growth factors to obtain biospecific biomaterial with whole physiological functions.
① The chemical titration indicated the bonds in anhydride had thoroughly reacted with diamine.
② FTIR, 1H-NMR, 13C-NMR and DSC analysis exhibited the successful covalent introduction of daimine into MPLA. Furthermore, the unique Tg of 59.5℃ for DMPLA proved the efficiency of the purification method for DMPLA. The Tg of DMPLA is much greater than those of both PDLLA and MPLA. It maybe lie in the formation of inner salt between -NH2 and -COOH in DMPLA.
(4) The bulk-modification of PDLLA (CPLA) was carried out from collagen type Ⅰ and DMPLA with dicyclohexylcarbodiimide (DCC) as condensating agent, and a solution reaction technique suitable to the reaction between collagen or peptide or protein and DMPLA was well established. The purpose of bulk modification of DMPLA with collagen, peptides or proteins are to obtain a biomaterial with no acidic degrading products but exce
（1）以DL-丙交酯为原料，辛酸亚锡为引发剂，采用熔融开环聚合方法制备PDLLA，考查了DL-丙交酯的纯度、聚合时间、聚合温度和引发剂（辛酸亚锡）用量等因素对PDLLA分子量的影响，优化出了一套制备超高分子量PDLLA（粘均分子量高达220万）的制备工艺，并测试了超高分子量PDLLA的脆化温度、拉抻（压缩）强度和模量。结果表明：
① 丙交酯的纯度是影响PDLLA分子量的一个重要因素，高纯丙交酯是制备高分子量PDLLA的必备条件；以纯度>99.8%、熔点为126.3-126.4℃的DL-丙交酯为原料，在160℃下聚合36h，可制得粘均分子量高达220万的超高分子量PDLLA。
② 超高分子量PDLLA相对于低分子量PDLLA（粘均分子量为80万），其拉伸（压缩）强度和模量、韧性及延展性都已大大提高，表现为韧性断裂，而低分子量PDLLA表现为脆性断裂，从而使超高分子量PDLLA可望在各医学领域如作为骨螺钉、手术缝合线、组织工程支架材料和通用完全可降解塑料方面得到广泛的应用。
（2）采用溶液混合、自由基聚合技术将MAH共价接枝到PDLLA骨架上，制得马来酸酐改性PDLLA（MPLA），旨在向PDLLA中引入高反应活性的酸酐键，为进一步化学改性奠定化学基础。
① FTIR、13C-NMR和DSC分析结果表明，MAH已成功地共价接枝到PDLLA骨架上；MPLA只有一个玻璃化转移峰值温度41.7℃，且低于PDLLA的玻璃化转移峰值温度56.5℃，提示MAH已对PDLLA成功改性，且采用本研究所述之分离提纯技术可得到纯净的MPLA。
② 化学滴定分析结果表明，MAH投料量为PDLLA质量的5%和10%时，MAH接枝率分别为1.86%和2.36%。
（3）用乙二胺对MPLA进行化学改性制得二胺改性PDLLA（DMPLA），旨
在通过碱性二胺的共价引入克服PDLLA和MPLA降解产物的酸性，改变PDLLA和MPLA的酸致自催化降解特点，开发出一种降解产物不呈酸性且具有良好亲水性的生物医用材料DMPLA，且DMPLA中的反应活性基团-COOH和-NH2为进一步引入胶原和多肽等生物活性分子，制备具有生物特异性和全面生理功能的生物医用材料奠定了化学基础。通过MPLA中高反应活性酸酐键的N-酰化开环将乙二胺共价引入到MPLA中，建立了一套二胺改性MPLA的改性技术。
① 化学滴定分析结果表明，MPLA中的酸酐键能完全与二胺反应；
② FTIR、13C-NMR、1H-NMR和DSC分析结果表明，二胺已被成功地共价引入到MPLA中；DMPLA的玻璃化转移峰值温度为59.5℃，高于PDLLA和MPLA的玻璃化转移峰值温度，可能是DMPLA中的伯胺与羧基形成内盐所致；唯一的玻璃化转移温度提示，按本研究所述之分离技术能得到纯净的DMPLA。
（4）以二环己基碳二亚胺（DCC）为缩合剂用Ⅰ型胶原对DMPLA进行整体（而不是表面）化学改性制得了胶原改性聚乳酸（CPLA），旨在开发一种降解产物不呈酸性且具有良好生物相容性、生物特异性的生物医用材料，并建立一套适用于多肽或蛋白质对DMPLA进行整体化学改性的制备工艺，为制备具有全面生理功能的组织材料奠定技术基础。异硫氰酸荧光素（FITC）标记测定结果表明，采用本研究所述之制备和提纯工艺能成功地将Ⅰ型胶原共价引入到DMPLA整体中获得纯净的CPLA。
（5）用吸水率和静态水接触角表征了PDLLA、MPLA、DMPLA和CPLA的亲疏水性。结果表明，DMPLA和CPLA的亲水性相对于PDLLA已大大提高，CPLA具有最好的亲水性，DMPLA略次之，提示DMPLA和CPLA都可望成为一种具有良好亲水性和细胞亲和性的生物医用材料。
（6）考查了PDLLA、MPLA、DMPLA在降解过程中的pH值变化（介质pH=6.45蒸馏水，温度37.0±0.5℃）以及分子量和失重率变化（介质：0.1M PBS溶液，pH=7.4；温度37.0±0.5℃）。在整个降解实验中始终不更换介质。结果表明：
① MPLA在降解过程酸性增加最快，酸致自催化程度最大，由此而引起的降解速率最快，失重率也最大，比PDLLA呈现更严重的整体溶蚀降解，即体型降解特点。因此，尽管MPLA在水解后其亲水性已较PDLLA有较大改善，但仍不适于单独用作生物医用材料。
DMPLA已基本克服了降解过程中的酸性增强；其降解速率较PDLLA和MPLA均匀，不呈现PDLLA和MPLA的体型降解特征，且随二胺含量的增加，其降解速率逐渐减小；尽管DMPLA在前6周的失重率略高于PDLLA和MPLA，但经12周降解，其失重率不到50%，低于PDLLA和MPLA，且随二胺含量增加，失重也减少。上述结果提示，DMPLA是一种降解产物不呈现酸性、降解速率可调
② 且降解过程不呈现体型降解特征的生物材料。
（7）采用细胞形态学观察法和细胞增殖法，以玻璃为对照，初步考查了P
Poly(DL-lactic acid) (PDLLA) with ultra-high molecular weight was prepared and a series of bulk modifications (non-surface modifications) of PDLLA were carried out with maleic anhydride(MAH), ethylenediamine and collagen type Ⅰ, aiming to develop an ideal PDLLA-based tissue engineering biomaterial with controlled degrading rate, excellent cell compatibility and biospecificty and whole physiological functions, whose degrading products are not of acidity. Their chemical structures were characterized by means of chemical analysis, FTIR (Fourier Transform Infred), 1H-NMR (Nuclear Magnetic Resonance), 13C-NMR and fluorescence labeling, their thermal properties done by DSC (Differential Scanning Calorimeter) and the mechanical properties by Instron 1011. Thereafter, the hydrophilicity, degradation and cell compatibility of PDLLA and those modified PDLLAs were investigated. The main works and conclusions are included as follows:
(1) PDLLA was prepared from DL-lactide by melt ring-opening polymerization. The effects of DL-lactide purity, polymerization time, temperature and the percent of initiator in lactide were investigated in detail, resulting in an optimum condition to synthesize PDLLA with 2200000 of viscosity-average molecular weight (Mv). The obtained results show that:
① The DL-lactide purity has significant influence on PDLLA's Mv. Ultrahigh molecular weight PDLLA with 2200000 of Mv could be obtained from lactide with purity of more than 99.8% and melting point of 126.3~126.4℃ at 160℃ for 36h.
② The stretching (compressing) strength and module, tenacity and elongation of ultrahigh PDLLA are significantly improved compared to PDLLA with 800000 of Mv, suggesting its potentially wide applications in medical areas as bone screw, surgical suture and tissue scaffolds and in general plastics as full degradable plastics.
(2) MAH modified PDLLA (MPLA) was synthesized by solution blending and subsequent free radical polymerization, attempting to introduce highly reactive anhydride into PDLLA backbone and providing chemical basis for further chemical modification.
FTIR, 13C-NMR and DSC analysis showed the successful covalent grafting of MAH into PDLLA. Furthermore, the unique Tg of 41.7℃ for MPLA and the greater Tg of 56.5℃ for PDLLA indicated in DSC proved that the purification method in this
① study was efficient enough to produce pure MPLA.
② The results of chemical titration showed that MAH grafting ratio in MPLA was 1.86% and 2.36% respectively when the percentage of fed MAH in PDLLA was 5% and 10% in weight.
(3) Diamine modified PDLLA (DMPLA) from ethylenediamine and MPLA was synthesized and its preparing technique well established. The modification of PDLLA with diamine is to eliminate or weaken acidity of degraded products from PDLLA and MPLA with the help of basic diamines and change the acid catalyzed auto-accelerating degradation, developing a new family of biomaterials with no acidic degrading products. Furthermore, DMPLA could provide reactive groups -COOH and -NH2 for further bulk modification with collagen, peptides or growth factors to obtain biospecific biomaterial with whole physiological functions.
① The chemical titration indicated the bonds in anhydride had thoroughly reacted with diamine.
② FTIR, 1H-NMR, 13C-NMR and DSC analysis exhibited the successful covalent introduction of daimine into MPLA. Furthermore, the unique Tg of 59.5℃ for DMPLA proved the efficiency of the purification method for DMPLA. The Tg of DMPLA is much greater than those of both PDLLA and MPLA. It maybe lie in the formation of inner salt between -NH2 and -COOH in DMPLA.
(4) The bulk-modification of PDLLA (CPLA) was carried out from collagen type Ⅰ and DMPLA with dicyclohexylcarbodiimide (DCC) as condensating agent, and a solution reaction technique suitable to the reaction between collagen or peptide or protein and DMPLA was well established. The purpose of bulk modification of DMPLA with collagen, peptides or proteins are to obtain a biomaterial with no acidic degrading products but exce
引文
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