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Research Progress in Organocatalysts Used in the Synthesis of Medical Polyurethanes and Their Biotoxicity
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摘要:
医用聚氨酯以其良好的生物相容性和优良的物理机械性能成为应用最广泛的生物医用材料之一。催化剂是医用聚氨酯合成过程必不可少的一种添加剂，其可以提高合成效率和材料性能。然而，催化剂可能会影响聚氨酯的生物相容性，对人体健康产生潜在危害。本文总结了近年来医用聚氨酯材料合成中所使用的常见有机催化剂及其生物毒性相关研究的进展。首先，将回顾医用聚氨酯材料合成中常用催化剂类型及其特点；随后，将重点关注这些催化剂可能存在的生物毒性；最后，对未来医用聚氨酯材料合成中催化剂选择提出建议。通过深入了解合成医用聚氨酯材料中催化剂的性质和生物毒性，分析当前存在的问题与面临的挑战，这将有助于更好地指导医用聚氨酯材料设计和探讨未来的发展方向，从而提高医用聚氨酯材料的生物相容性和安全性，推动其在临床应用中的进一步发展与应用。
Abstract:Medical polyurethanes have emerged as a leading choice for biomedical applications owing to their exceptional biocompatibility and good physical and mechanical properties. Catalysts play a crucial role as additives in the synthesis of medical polyurethanes, enhancing synthesis efficiency and material properties. However, the catalysts used may affect the biocompatibility of polyurethanes and pose potential harm to human health. This review encapsulates the latest findings regarding the catalysts employed in the synthesis of medical polyurethane materials and their biotoxicity. Initially, we reviewed the prevalent types of catalysts used in the synthesis of medical polyurethane materials and described their distinctive characteristics. Subsequently, our focus shifted to exploring the potential biotoxicity associated with these catalysts. Finally, we provided a forward-looking perspective and recommendations for the future trajectory of catalyst selection in the synthesis of medical polyurethane materials. By acquiring a more profound understanding of the properties and biotoxicity of catalysts used in the synthesis of medical polyurethane materials, and by uncovering existing issues and challenges, we can better guide the design of medical polyurethane materials. This, in turn, enables us to chart the course for future development and ultimately enhance the biocompatibility and safety profiles of medical polyurethane materials. Such advancements will promote the continued development and application of medical polyurethane materials in clinical settings.
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Keywords:
- Polyurethane /
- Catalyst /
- Organotin /
- Organic bismuth /
- Biotoxicity /
- Research progress
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肝癌是导致全球范围内癌症死亡的第二大病因，全球近一半的肝癌发生在我国，发病率和病死率均较高[1]。对高危人群进行筛查有助于肝癌的早诊断、早治疗，从而降低病死率[2]。甲胎蛋白（Alpha-fetoproteins，AFP）作为最为广泛使用的肝癌血清学标志物，在约40%的患者中无升高（AFP≤20 ng/mL），这部分患者也被称为AFP阴性肝癌患者[3]。目前，对AFP阴性肝癌患者主要采用声像学和影像学进行诊断。但常规彩超检查敏感性较低，且受到设备、操作者经验技巧、受检者皮下脂肪厚度等因素影响，早期诊断价值有限；而CT或MRI用于肝癌筛查则存在检查流程繁琐、费用高昂、成本效益低等缺点，临床应用受限。因此，寻找方便易行的非AFP血清学标志物对于AFP阴性肝癌的早期诊断具有重要意义[2]。
异常凝血酶原，又称脱-γ-羧基凝血酶原（des-γ-carboxy-prothrombin，DCP），是肝脏在维生素K缺乏的情况下合成的一种无生物活性的蛋白，可出现于维生素K缺乏或肝癌患者的血清中。在正常情况下，凝血酶原前体的γ-羧基谷氨酸结构域中谷氨酸残基在维生素K的作用下完全羧化，最终产生正常的有凝血活性的凝血酶原。肝癌发生时，由于癌细胞使凝血酶原前体的合成发生异常，凝血酶原前体羧化不足，从而生成大量的异常凝血酶原[4]。近来研究发现，DCP用于肝癌筛查显示出了较高的敏感性和特异性[5]。在日本，作为与AFP相互独立的肝癌血清学标志物，其与AFP联合检测筛查肝癌手段得到认可[6]。考虑到我国肝癌发生多与乙型肝炎病毒（HBV）感染相关，发病模式与以酒精性肝癌为主的澳大利亚、西欧各国[7]，以及主要与丙型肝炎病毒（HCV）感染相关的日本、美国、新加坡等国均存在较大差异，DCP用于我国肝癌患者、特别是AFP阴性肝癌患者的诊断价值尚需进一步证实。
本研究旨在通过对照分析AFP阴性的HBV相关肝癌患者与AFP阴性的非肝癌HBV感染患者的血清DCP水平差异，以期阐明DCP对AFP阴性肝癌患者的诊断价值，并探索AFP阴性肝癌患者的血清DCP水平与肿瘤大小、TNM分期、病理类型等是否存在相关性。
1. 对象与方法
1.1 研究对象
本研究收集2016年6月−2017年12月在四川大学华西医院传染科、消化内科、肝脏外科等科室诊治的肝癌（肝癌组）、慢性乙型肝炎（肝炎组）和乙型肝炎相关肝硬化（肝硬化组）患者。以肝癌组为实验组，以肝硬化组及肝炎组为非肝癌组。所有患者乙肝表面抗原阳性且病史大于6月，AFP阴性即AFP≤20 ng/mL，均有彩超、CT或MRI等影像学资料评估病情。所有肝癌患者均经临床及病理检查确诊。本研究为回顾性研究，得到四川大学华西医院生物医学伦理委员会批准，批准号2018年（审 331）号。
1.2 诊断标准和排除标准
慢性乙型肝炎和乙型肝炎相关肝硬化的诊断标准依据《2019年慢性乙型肝炎防治指南（2019年版）》[8]。肝癌的诊断标准：①具有慢性HBV感染及肝硬化的基础；②增强CT或MRI可见肝脏占位“快进快出”的特征；③病理学符合肝细胞癌表现[9]。使用TNM分期系统确定肝癌的分期。排除标准为：非乙型肝炎其他病毒性肝炎标志物阳性者，如A、C、D、E型（甲型、丙型、丁型、戊型）肝炎；具有获得性人类免疫缺陷性疾病（如HIV）、自身免疫性疾病；具有梗阻性黄疸；肝癌经治（如射频消融术、经肝动脉化疗栓塞术等）或肝癌切除后复发的患者；肝脏转移癌；资料不全、数据缺失等患者。按以上标准，共纳入患者459例，其中肝癌组136例，非肝癌组323例（肝硬化组173例，肝炎组150例）。
1.3 检测方法
所有患者均在入院24 h之内，采集患者清晨空腹状态下静脉血，常温保存，2 h之内由专人送至四川大学华西医院实验医学科，由专业技术人员严格按照仪器操作说明书和试剂盒说明书进行操作及检测。使用电化学发光法检测AFP，检测仪器及试剂为德国罗氏公司产品；使用化学发光法检测DCP，检测试剂为日本富士瑞必欧产品。
1.4 统计学方法
使用中位数、四分位数间距、极小值和极大值描述计量资料的集中趋势和离散趋势。使用曼-惠特尼U检验进行计量数据的组间比较。使用卡方检验进行计数数据的组间比较。以病理活检结果为判定肝癌的金标准，以DCP浓度为筛选试验的研究变量绘制受试者工作特征曲线（ROC曲线）。P<0.05为差异有统计学意义。
2. 结果
2.1 肝癌组与非肝癌组患者基本临床特征比较
2.1.1 肝癌组与非肝癌组比较
见表1和图1。与非肝癌组相比，肝癌组患者男性的比例更高，年龄更大，血清DCP水平更高，差异均有统计学意义（P<0.001)。两组之间的AFP水平差异无统计学意义（P=0.084）。
表 1 研究患者的基线特征和观察指标Table 1. Baseline characteristics of the study populationCharacteristic HCC group (n=136) Non-HCC group P Total (n=223) LC (n=173) CHB (n=150) P1 P2 Male/female (case) 125︰11 150︰73# 130︰43# 120︰30# <0.001 <0.001 Age*/yr. 53 (46-62), 25-86 44 (36-52), 16-77# 49 (42-55), 23-77# 37 (30-46), 18-77# <0.001 <0.001 AFP*/(ng/mL) 5 (3-10), 0.63-19.54 5 (3-18), 1-1 210 4 (3-8), 0.61-19.45 18 (4-138), 1.15-1 210△ 0.084 <0.001 DCP*/(mAU/mL) 159 (47-1 059), 11-75 000 22 (16-34), 3-20 298# 19 (13-27), 3-1 837# 26 (19-38), 10-20 298# <0.001 <0.001 HCC: Hepatic cellular cancer; LC: Liver cirrhosis; CHB: Chronic hepatitis; *Median (P25-P75) , Min-Max; P1：Comparison between HCC and non-HCC groups; P2: Comparison between HCC, LC and CHB groups; #P<0.05, vs. HCC group; △P<0.05, vs. HCC and LC groups ![]()
图 1 肝癌组和非肝癌组患者血清DCP水平的比较Figure 1. Comparision of DCP level in groups of HCC and non-HCC2.1.2 肝癌组、肝硬化和肝炎组比较
与肝硬化组、肝炎组比较，肝癌组患者的男性比例更高，年龄更大，血清DCP水平更高（P<0.05)。肝炎组的AFP水平高于肝硬化和肝癌组（P<0.001)。见表1和图2。
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图 2 肝癌组、肝硬化组、肝炎组患者血清DCP水平的比较Figure 2. Comparision of DCP level in groups of HCC, LC and CHB2.2 异常凝血酶原在AFP阴性的患者中诊断肝癌的ROC曲线
在AFP阴性的患者中，以血清DCP水平诊断肝癌的曲线下面积为0.858，P<0.05。以约登指数最大取其诊断的最佳切点值为61 mAU/mL，对应灵敏度为72.8%，特异度为88.2%，阳性预测值为61.1%，阴性预测值为89.7%。见图3。
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图 3 血清DCP水平在AFP阴性的患者中诊断肝癌的ROC曲线Figure 3. Diagnosis of HCC in AFP-negative HCC patients by ROC curve of DCPArrow indicates the optimal cut-off value2.3 血清DCP水平与肝癌患者临床病理特征的关系
见图4～图7。DCP在不同Child-Pugh分级以及不同分化程度肝癌中差异无统计学意义（P>0.05），DCP在肿瘤病灶直径>3 cm的患者中高于癌肿直径≤3 cm的患者（P<0.05）。不同TNM分期间DCP比较，Ⅰ期与Ⅱ期、Ⅰ期与Ⅲ期间比较，DCP水平差异有统计学意义（P<0.05），但Ⅱ期与Ⅲ间差异无统计学意义（P>0.05）。
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图 4 肝癌患者不同Child-Pugh分级的DCP水平分布Figure 4. DCP level in HCC stratified by Child-Pugh grade![]()
图 5 肝癌患者不同TNM分期的DCP水平分布Figure 5. DCP level in HCC stratified by TNM stage* P<0.05, vs. Ⅰ![]()
图 7 不同肝癌病灶直径中DCP水平分布Figure 7. DCP level in HCC stratified by tumor diameter* P<0.05，vs. >3 cm3. 讨论
肝细胞癌是预后极差的恶性肿瘤，其起病隐匿，发病早期缺乏特异性临床症状，患者明确诊断时往往已处于相对晚期阶段而错过最佳治疗时机。AFP联合腹部彩超每6个月一次的筛查方案有望提高肝癌患者早期诊断率，进而改善患者预后。但在临床实践中，约30%～40%的患者在肝癌发生发展过程中不会出现AFP水平升高，且AFP在小肝癌（直径≤3 cm）筛查中的诊断效能较差，灵敏度仅为39%～65%，因此寻求优于AFP或者与AFP联合可提高肝癌检出水平的血清学标志物，对于AFP阴性肝癌及小肝癌患者具有重要意义[10-12]。
DCP对于肝癌的诊断价值日益引起重视，既往研究表明：DCP可能是与AFP相互独立的肝癌血清学标志物，其对AFP阴性肝癌的诊断效能与AFP阳性肝癌近似，且在肝癌发生发展的各阶段均具有较好的敏感性和特异性[5, 13]。本研究发现：DCP在AFP阴性肝癌患者血清中的水平高于非肝癌组，证实了DCP对AFP阴性肝癌具有诊断价值。诊断的最佳切点值为61 mAU/mL，灵敏度为72.8%，特异度为88.2%，阳性预测值为61.1%，阴性预测值为89.7%，与既往研究得出的结果类似[14- 15]。本研究还发现：DCP在瘤体直径>3 cm的肝癌患者血清中的表达水平高于瘤体直径≤3 cm者，这在一定程度上说明其表达水平可能与肝癌进展过程相关。既往有研究提示，DCP的表达水平还与肝癌的TNM分期有关，随着肝癌恶性程度增高，DCP表达水平也随之升高[16]。由于本研究纳入的样本均为经手术治疗的肝癌患者，其TNM分期多为Ⅰ期和Ⅲ期，Ⅱ、Ⅳ期样本相对较少。虽然统计学分析显示DCP表达水平在Ⅰ期与Ⅲ期肝癌之间存在差异，但DCP水平高低与肝癌TNM分期之间的统计学相关性还需要进一步扩大样本研究证实。另外，本研究结果还提示DCP表达水平与肝脏储备功能、肿瘤分化程度可能无关。
目前为止，DCP对于肝癌的诊断价值仍存在争议，部分研究认为其单独检测对肝癌的诊断能力优于AFP或与AFP的联合检测，但也有研究认为其单独检测不及与AFP联合检测对肝癌的筛查能力强[17-19]。研究结果不一致的原因可能在于，研究所纳入的研究对象未进行病因学的分类，多为混合性病因的肝癌患者，而DCP对肝癌的筛查能力因病因学不同而有所差别。有研究认为DCP对HBV、HCV相关的肝癌具有较好的诊断价值，而对于非酒精性脂肪肝相关的肝癌则存在诊断效能不足的情况[6, 20- 21]。且肝癌为一种异质性疾病，多因素多步骤的疾病，发病机制复杂，是否存在一种可以适用于不同发病机制的肝癌的血清学标志物尚未可知，对于不同病因及发病机制的肝癌患者采取同一种检测手段，可能会造成不理想的检测率，因此本研究避开了上述可能的误区，在乙型肝炎相关且AFP阴性的肝病人群中进行DCP诊断价值的研究，并分析DCP水平与肝功能、肿瘤分期、分化、大小等之间的关系，得出DCP对于AFP阴性的肝癌具有诊断价值的结论，并认为DCP的水平与肿瘤分期及大小之间存在相关性，可能反映了肿瘤的进展情况。
本研究纳入的病例均与HBV感染相关，反映了我国肝癌发生的病因学特点。研究结果证实了DCP对AFP阴性肝癌的诊断价值，为将DCP纳入肝癌常规筛查，作为AFP的互补检测手段提高肝癌筛查率提供了依据。但作为一项单中心回顾性病例对照研究，由于对照组均为有慢性乙型肝炎或肝硬化基础疾病的患者，而非健康人群，这对研究结果可能有一定影响。另外，研究所纳入的患者，无论良性肝病还是肝细胞癌患者，男女性别比例均存在较大差异，既往研究亦有类似现象，对于这种显著的性别差异的原因，目前尚不清楚，有待于进一步的研究。此外DCP联合AFP能否进一步提高肝癌的早期诊断率，肝癌患者血清DCP水平与预后及复发风险之间是否存在联系等问题，均需要进一步研究阐明。
总体来说，虽然更为高效的筛查手段仍有待于去发现，但就目前而言，DCP对乙肝相关性AFP阴性肝癌的诊断价值不容置疑，可以作为与AFP互补的肝癌筛查的手段应用于临床。
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表 1 常见聚氨酯催化剂以及生物毒性
Table 1 Common polyurethane catalysts and their biological toxicity
Organocatalyst type Formula Specificity Biological toxicity Triethylenediamine C6H12N2 Catalyzing the reaction of isocyanates with water Eye and skin irritant and visual impairment. Dibutyltin dilaurate C32H64O4Sn Catalyzing the reaction of isocyanates with alcohols Damage to the right parietal cortex of rats[3], inhibition of conception, and increase in abortions and fetal malformations in female rats.[4-5], causing testicular lesions in male rats and reducing sperm count and quality[6], and causing high levels of DNA damage in rat hepatocytes and lesions in liver tissue[7]。 Stannous octoate C16H30O4Sn Catalyzing the reaction of isocyanates with alcohols Inhibition of human astrocyte activity[8], causing abnormal locomotor behavior in rats[8], and inhibition of the growth of mouse fibroblasts and human endothelial cells[9]。 Bismuth C30H57BiO6 Catalyzing the reaction of isocyanates with alcohols No obvious biological toxicity[10-11] Bismuth octoate C8H16Bi2 Catalyzing the reaction of isocyanates with alcohols No obvious biological toxicity[10] 
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