输尿管支架生物降解材料丙交酯-乙交酯共聚物在体外的降解及临床应用

背景：目前不同形式的输尿管支架均有其并发症,因此,如何选择适宜的支架来治疗泌尿系统疾病是目前医学界研究的热点。 目的：探讨输尿管支架生物降解材料丙交酯/乙交酯共聚物在体外的降解规律及临床应用前景。 方法：由第一作者检索1991-01/2009-12 PubMed数据库(http://www.ncbi.nlm.nih.gov/PubMed)及万方数据库(http://www.wanfangdata.com.cn)有关输尿管支架生物降解材料丙交酯-乙交酯共聚物在体外的降解及临床应用方面的文献,英文检索词为“SR-PLGA;in-vitro degradation;degradalion rate”,中文检索词为“丙交酯-乙交酯共聚物;体外降解;降解速率”。检索文献量总计135篇,排除陈旧及重复性文章,最终纳入17篇文献进一步分析。 结果与结论：高分子降解性输尿管支架材料体内外生物降解性质的研究国外报道较少,国内则未见报道,目前该领域处于基础研究阶段。作为生物降解性高分子材料,降解性质及相容性是此种材料得以应用的首要条件,了解材料的降解及相容性对材料的临床应用具有极其重要的意义。输尿管支架生物降解材料丙交酯-乙交酯共聚物的生物相容性良好,通过调整乙交酯与丙交酯的组分比,可有效调节共聚物的降解速率。     

PGLA降解产物对材料降解性能影响的体外研究

为了探讨PGLA材料的降解产物对材料本体降解性能的影响，本研究设计了体外两种浸泡体系——磷酸缓冲液（PBS）和人工血浆，分别在替换和不替换浸泡介质两组不同条件下，分析材料的质量损耗情况，并将不替换组的各时间段降解液进行pH值的测定，以判断环境的酸碱度对材料本体降解的作用。实验降解周期分别为2、3、4、6、8、10周。结果显示：在浸泡初期，人工血浆和PBS降解液中的质量损耗两者间无显著性差异（P〉0．05）；大约从2周到6周，不替液组中材料在两种介质内的降解速度显著快于相对应的同期换液组（P〈0．01）；不替换液组材料在PBS液中的降解快于在人工血浆中的降解，而且在整个降解周期内PBS降解液的pH值基本保持稳定（pH≈7．0～7．4），而人工血浆降解液中的pH值随着降解过程的不断进行，其pH值由7．5逐渐降到5．7左右，两种降解液pH值变化之间的差异具有显著的统计学意义（P〈0．01）。由此提示：在不替换浸泡介质的条件下，降解液中持续存在的降解产物显然影响材料本体的降解速度，PGLA材料的降解产物具有加速材料质量损耗的作用；环境的酸碱度对材料的降解会产生一定的影响，pH值越低，材料的降解速度越缓慢。     

天冬氨酸-氨基丁酸共聚材料的合成、表征及体外降解

实验合成不同摩尔比的天冬氨酸、氨基丁酸共聚物(PAA)，其摩尔比分别为9：1、8：2、7；3、6：4、5；5．用核磁共振^1HNMR、^13CNMR、DSC差热分析和凝胶色谱等方法对材料作了表征，实验结果表明共聚材料结构明确并有较好的规律性。对共聚材料作了急性毒性和皮肤过敏性实验，结果显示该材料为低毒性材料，且致敏性较小。用pH7．4的磷酸盐缓冲溶液、木瓜蛋白酶和胰蛋白酶缓冲液等对材料进行了体外降解实验，结果表明该系列材料在体外有一定的降解性。     

生物可降解材料PLGA90/10的体外降解特性及生物相容性

研究生物可降解材料聚乳酸乙醇酸共聚物(PLGA 90/10)的体外降解特性,通过测量材料在体外降解过程中的重量损失并在扫描电镜下观察形态学变化,评估体外降解特性,该实验是在37℃ pH为7.4的磷酸盐缓冲液中进行的.为研究材料的细胞毒性,将小牛血管平滑肌细胞种植在PLGA膜片上,在显微镜下观察细胞生长情况,并通过MTT法测定细胞活性.研究发现结晶型的PLGA90/10显示出表面降解的特性,高分子量的PLGA90/10在开始的4个月内降解缓慢,120天时重量仅损失10%,120天后迅速降解.MTT 法检测细胞增殖指数,与对照组差异无显著意义.这为局部药物治疗工具提供了基础研究.     

聚富马酸二羟丙酯的合成及其交联特性研究进展

聚富马酸二羟丙酯[Poly(propylene fum arate) ,PPF]是一种不饱和线性聚酯,在体内能降解生成富马酸和丙二醇,降解产物能通过正常的新陈代谢排出体外,是一种良好的骨修复材料。本文对PPF的合成方法进行了综述,介绍了PPF的交联特性、与不同交联剂所得交联产物的力学性能及其在骨科的应用情况,并对PPF在骨科的应用前景作了展望。     

天冬氨酸-氨基乙酸共聚材料的合成、表征及降解

本实验合成了不同摩尔比的天冬氨酸、氨基乙酸共聚材料（ＰＡＡ）,摩尔比分别为９：１、８：２、７：３、６;４、５：５。用核磁共振＾１ＨＮＭＲ、＾１３ＣＮＭＲ、ＤＳＣ差热分析、特性粘度等方法对材料作了表征,结果表明该共聚材料结构明确并有较好的规律性。用ｐＨ７．４的磷酸缓冲溶液、胰蛋白酶缓冲液及Ｐ４５０肝代谢酶等对材料进行了体外降解,实验结果显示,该系列材料在体外有一定的降解性。     

不同降解材料制备的分解食道支架体外降解研究

采用磷酸盐缓冲溶液(PBS)(pH =7.4)和人工胃液(pH=1.5)为降解介质,37℃下对由PLLA和PGLA丝线缝合的分解食道支架进行了体外降解实验.通过测试降解过程中支架的径向支撑力及丝线的特性粘度、熔点、结晶性及表面形貌等变化,对支架体外降解行为进行研究.结果表明,上述降解介质中由PL-LA丝线缝合的支架的径向支撑力及丝线的各性能变化不明显;由PGLA丝线缝合的支架在PBS中6周时分解,丝线的特性粘度保留率随降解时间的延长线性下降,而在人工胃液中9周时分解,特性粘度保留率随降解时间的延长呈“Z”字型变化,即初期和后期变化平缓,中期迅速下降;SEM显示在上述介质中,支架分解时PGLA丝线均以横向方式断裂.因此,PGLA丝线制备的支架可用于治疗良性食道狭窄,而PLLA丝线制备的支架分解时间大于2个月,不适于良性狭窄的治疗.     

可分解食道支架缝合线体外降解性能的研究

采用磷酸盐缓冲溶液(PBS)(pH=7.4)为降解介质,37℃下对可分解食道支架聚(L-丙交酯)(PLLA)和聚(乙交酯-丙交酯)(PGLA)缝合线进行8周的体外降解实验。通过测试降解过程中其质量损失、pH值、特性粘度、抗张强度、取向度、结晶度、熔点及表面形貌等变化情况,对其体外降解行为进行研究。结果表明PLLA缝合线各项性能无明显变化,而PGLA缝合线各项性能发生了显著变化。随着降解进行PGLA缝合线的pH值、特性粘度、抗张强度、取向度和结晶度逐渐下降,质量损失率增加,6周时抗张强度几乎为零,8周时质量损失率近70%。DSC结果表明,随着体外降解PGLA缝合线晶区熔点保持不变,晶区的熔融热焓逐渐增加,而无定形区产生新的有序区.并且含量不断增加。SEM结果表明PGLA缝合线在降解过程中,涂层首先脱落,然后线体以横向断裂方式断裂。因此,PGLA缝合线适用于良性食道狭窄的可分解食道支架,而PLLA缝合线制备的支架分解时间大于2个月,不适于良性狭窄的治疗。     

聚左旋丙交酯骨折内固定物体外降解研究

通过左旋丙交酯开环聚合法制取分子量42万的聚左旋丙交酯（PLLA）用于制备可降解骨折内固定物。由PLLA原料经不同的成型工艺方法制备了三种棒状骨折棒状骨折内固定物试样。A试样：将PLLA块状原料直接切削加工成棒状物;B试样：将A试样由乙酸乙酯进行抽提;C试样：将PLLA块状原料粉碎抽提后进行熔融挤出和热拉伸。三种试样在37℃生理盐缓冲液中降解280天。考察了试样的分子量、弯曲性能、重点及缓冲液中乳酸浓度等随时间的变化规律。结果表明：不同的成型工艺,PLLA骨折内固定物的降解有很大差异,C试样的加工成型方法最为理想。因此我们认为：用PLLA材料选定合理的成型工艺方法可以制取满足临床应用要求的骨折内固定物。     

甲壳素和甲壳胺对聚乳酸体外降解的影响

考察了ＤＬ－聚乳酸（ＤＬ－ＰＬＡ）／甲素（ＣＨＩ）,ＤＬ－ＰＬＡ／甲壳胺（ＣＨＳ）两种复合物在生理盐水降解过程中生理盐水的ｐＨ值、试样的失重率和外观形态以及ＤＬ－ＰＬＡ分子量的变化,结果表明：ＣＨＩ和ＣＨＳ对ＤＬ－ＰＬＡ的降解速度有明显的抑制作用,并对抑制机理进行了探讨。     

In vitro degradation of polymeric networks of poly(propylene fumarate) and the crosslinking macromer poly(propylene fumarate)-diacrylate

Polymeric networks of poly(propylene fumarate) (PPF) crosslinked with poly(propylene fumarate)-diacrylate (PPF-DA) are currently being investigated as an injectable, biodegradable bone cement. This study examined the effect of crosslinking density, medium pH, and the incorporation of a beta-tricalcium phosphate (beta-TCP) filler on the in vitro degradation of PPF/PPF-DA. Cylindrical specimens were submerged in buffered saline at 37 degrees C and the change in weight, geometry, and compressive mechanical properties were monitored over a 52-week period. All formulations showed an initial increase in modulus and yield strength over the first 12 weeks, achieving maxima of 1307+/-101 and 51+/-3MPa, respectively, for the beta-TCP composite. PPF/PPF-DA networks with the lower crosslinking density demonstrated the greatest degradation with a 17% mass loss. Samples in the lower buffer pH 5.0 compared to physiological pH 7.4 did not show any differences in mass loss, but exhibited a faster decrease in the compressive strength over time. The beta-TCP composites maintained their mechanical properties at the level following their initial increase. These results show that the degradation of PPF/PPF-DA networks can be controlled by the crosslinking density, accelerated at a lower pH, and prolonged with the incorporation of the beta-TCP filler.     

Synthesis and properties of photocross-linked poly(propylene fumarate) scaffolds

The photocross-linking of poly(propylene fumarate) (PPF) to form porous scaffolds for bone tissue engineering applications was investigated. PPF was cross-linked using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and exposure to 30 min of long wavelength ultraviolet (UV) light. The porous photocross-linked PPF scaffolds (6.5 mm diameter cylinders) were synthesized by including a NaCl porogen (70, 80, and 90 wt% at cross-linking) prior to photocross-linking. After UV exposure, the samples were placed in water to remove the soluble porogen, revealing the porous PPF scaffold. As porogen leaching has not been used often with cross-linked polymers, and even more rarely with photoinitiated cross-linking, a study of the efficacy of this strategy and the properties of the resulting material was required. Results show that the inclusion of a porogen does not significantly alter the photoinitiation process and the resulting scaffolds are homogeneously cross-linked throughout their diameter. It was also shown that porosity can be generally controlled by porogen content and that scaffolds synthesized with at least 80 wt% porogen possess an interconnected pore structure. Compressive mechanical testing showed scaffold strength to decrease with increasing porogen content. The strongest scaffolds with interconnected pores had an elastic modulus of 2.3 ± 0.5 MPa and compressive strength at 1% yield of 0.11 ± 0.02 MPa. This work has shown that a photocross-linking/porogen leaching technique is a viable method to form porous scaffolds from photoinitiated materials.     

Synthesis and properties of photocross-linked poly(propylene fumarate) scaffolds

The photocross-linking of poly(propylene fumarate) (PPF) to form porous scaffolds for bone tissue engineering applications was investigated. PPF was cross-linked using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and exposure to 30 min of long wavelength ultraviolet (UV) light. The porous photocross-linked PPF scaffolds (6.5 mm diameter cylinders) were synthesized by including a NaCl porogen (70, 80, and 90 wt% at cross-linking) prior to photocross-linking. After UV exposure, the samples were placed in water to remove the soluble porogen, revealing the porous PPF scaffold. As porogen leaching has not been used often with cross-linked polymers, and even more rarely with photoinitiated cross-linking, a study of the efficacy of this strategy and the properties of the resulting material was required. Results show that the inclusion of a porogen does not significantly alter the photoinitiation process and the resulting scaffolds are homogeneously cross-linked throughout their diameter. It was also shown that porosity can be generally controlled by porogen content and that scaffolds synthesized with at least 80 wt% porogen possess an interconnected pore structure. Compressive mechanical testing showed scaffold strength to decrease with increasing porogen content. The strongest scaffolds with interconnected pores had an elastic modulus of 2.3+/-0.5 MPa and compressive strength at 1% yield of 0.11+/-0.02 MPa. This work has shown that a photocross-linking/porogen leaching technique is a viable method to form porous scaffolds from photoinitiated materials.     

不饱和聚磷酸酯复合聚富马酸二酯促进骨生成的作用研究*

目的通过动物实验观察小饱和聚磷酸酯（unsaturated polyphosphoester UPPE）复合聚富马酸二（1,2-丙二醇）酯[poly（propylene fumarate）PPF]修复骨缺损的效果。方法24只日本大耳白兔桡骨中段制作骨缺损动物模型,分成A、B两组,每组12只。右侧为实验组,A组填充UPPE—PPF,B组填充PPF;左侧为对照组,单纯缝合。在1、4、8、12周处死动物。通过X线检测和组织学观察评价其修复效果。结果在1、4、8、12周的X线检测均显示UPPE—PPF组的成骨效果优于PPF组和对照组,组织学检测同样表明UPPE-PPF组的成骨效果优于PPF组和对照组。结论UPPE-PPF材料促进成骨作用优于PPF材料,是一种有前景的骨缺损修每材料。     

Photocrosslinking characteristics and mechanical properties of diethyl fumarate/poly(propylene fumarate) biomaterials

The development of tissue engineered materials for the treatment of large bone defects would provide attractive alternatives to the autografts, allografts, non-degradable polymers, ceramics, and metals that are currently used in clinical settings. To this end, poly(propylene fumarate) (PPF), a viscous polyester synthesized from diethyl fumarate (DEF), has been studied for use as an engineered bone graft. We have investigated the photocrosslinking of PPF dissolved in its precursor, DEF, using the photoinitiator bis(2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO) and low levels of ultraviolet light exposure. A three factor, 2 x 2 x 4 factorial design was developed, studying the effects of PPF number average molecular weight, BAPO initiator content, and DEF content upon photocrosslinking characteristics and mechanical properties. Uncured DEF/PPF solution viscosity fell over three orders of magnitude as DEF content was increased from 0% to 75%. The exothermic photocrosslinking reaction released low levels of heat, with no more than 160J/g released from any formulation tested. As a result, the maximum photocrosslinking temperature remained below 47 degrees C for all samples. Both sol fraction and swelling degree generally increased with increasing DEF content. Compressive mechanical properties were within the range of trabecular bone, with the strongest samples possessing an elastic modulus of 195.3 +/- 17.5 MPa and a fracture strength of 68.8 +/- 9.4MPa. Finally, the results indicate that PPF crosslinking was facilitated at low DEF precursor concentrations, but hindered at higher precursor concentrations. These novel DEF/PPF solutions may be preferred over pure PPF as the basis for an engineered bone graft because they (1) exhibit reduced viscosity and thus are easily handled, (2) form polymer networks with compressive strength at fracture suitable for consideration for trabecular bone replacement, and (3) may be readily fabricated into solids with a wide range of structures.     

Development of arginine-glycine-aspartate-immobilized 3D printed poly(propylene fumarate) scaffolds for cartilage tissue engineering

Abstract

Poly(propylene fumarate) (PPF) has known to be a good candidate material for cartilage tissue regeneration because of its excellent mechanical properties during its degradation processes. Here, we describe the potential application of PPF-based materials as 3D printing bioinks to create macroporous cell scaffolds using micro-stereolithography. To improve cell-matrix interaction of seeded human chondrocytes within the PPF-based 3D scaffolds, we immobilized arginine-glycine-aspartate (RGD) peptide onto the PPF scaffolds. We also evaluated various cellular behaviors of the seeded chondrocytes using MTS assay, microscopic and histological analyses. The results indicated that PPF-based biocompatible scaffolds with immobilized RGD peptide could effectively support initial adhesion and proliferation of human chondrocytes. Such a 3D bio-printable scaffold can offer an opportunity to promote cartilage tissue regeneration.     

In vivo degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds

This study investigated the in vivo degradation of poly(propylene fumarate) (PPF)/poly(DL-lactic-co-glycolic acid) (PLGA) composite scaffolds designed for controlled release of osteogenic factors. PPF/PLGA composites were implanted into 15.0mm segmental defects in the rabbit radius, harvested after 12 and 18 weeks, and analyzed using histological techniques to assess the extent of polymer degradation as well as the tissue response within the pores of the scaffolds. Polymer degradation was limited to micro-fragmentation of the scaffold at the ends and edges of the implant at both 12 and 18 weeks. The tissue within the pores of the scaffold consisted of fibrous tissue, blood vessels and some inflammatory cells. In areas where polymer breakdown was evident, an increased inflammatory response was observed. In contrast, areas of bone ingrowth into the polymer scaffold were characterized by minimal inflammatory response and polymer degradation. Our results show that minimal degradation of porous PPF occurs within 18 weeks of implantation in a rabbit model. Further, the in vivo degradation data of porous PPF/PLGA scaffolds are comparable with earlier obtained in vitro data.     

In vitro degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds

This study investigated the in vitro degradation of porous poly(propylene fumarate) (PPF-based) composites incorporating microparticles of blends of poly(DL-lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) during a 26-week period in pH 7.4 phosphate-buffered saline at 37 degrees C. Using a fractional factorial design, four formulations of composite scaffolds were fabricated with varying PEG content of the microparticles, microparticle mass fraction of the composite material, and initial leachable porogen content of the scaffold formulations. PPF scaffolds without microparticles were fabricated with varying leachable porogen content for use as controls. The effects of including PLGA/PEG microparticles in PPF scaffolds and the influence of alterations in the composite formulation on scaffold mass, geometry, water absorption, mechanical properties and porosity were examined for cylindrical specimens with lengths of 13 mm and diameters of 6.5 mm. The composite scaffold composition affected the extent of loss of polymer mass, scaffold length, and diameter, with the greatest loss of polymer mass equal to 15+/-5% over 26 weeks. No formulation, however, exhibited any variation in compressive modulus or peak compressive strength over time. Additionally, sample porosity, as determined by both mercury porosimetry and micro-computed tomography did not change during the period of this study. These results demonstrate that microparticle carriers can be incorporated into PPF scaffolds for localized delivery of bioactive molecules without altering scaffold mechanical or structural properties up to 26 weeks in vitro.     

Synthesis and properties of elastomeric poly(propylene)

Elastomeric poly(propylene) with low percentages of isotactic pentads and high molecular weight was synthesized using unbridged “oscillating” metallocenes. The polymer sample with the highest [mmmm] content (22%) shows a small amount of crystallinity, which is highly influenced by the thermal history, and differs significantly in stress-strain and dynamic mechanical properties from all other samples. Polymers with lower isotacticity index, although lacking crystallinity in thermal analysis, differ in their viscoelastic behaviour from those of atactic poly(propylene). In dynamic mechanical analysis the γ relaxation at low temperature shows high sensitivity to low isotactic contents.