Application effect of a dual release system of androgen and its antagonist in the repair of full-thickness burn wounds in mice
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摘要:
目的 探讨双氢睾酮和羟基氟他胺（以下称为DH）最佳配比，构建雄激素及其拮抗剂双重释放系统，分析该系统在小鼠Ⅲ度烧伤创面修复中的应用效果。 方法 该研究为实验研究。取HaCaT细胞，按随机数字表法（分组方法下同）分为空白组（不加药物培养）、低基线组、中基线组、高基线组，对后3组细胞均分别加用3种配比的DH培养。中配比下，从低到高3个基线组中双氢睾酮质量依次为1.4、2.8、4.0 µg，羟基氟他胺质量依次为1.2、1.6、2.0 µg，以此为基准，小配比下，双氢睾酮质量减少1/2，羟基氟他胺质量增加1/2；大配比下，双氢睾酮质量增加1/2，羟基氟他胺质量减少1/2。培养2 d，采用细胞计数试剂盒8检测细胞增殖水平（样本数为4）。取16只6~8周龄雄性BALB/c小鼠，于其背部制备Ⅲ度烧伤创面后，分为空白组、小配比组、中配比组和大配比组（每组4只小鼠），伤后7 d于后3组小鼠创面局部滴加含不同配比DH的生理盐水［从小到大3个配比组中DH总量分别为127.5、165.0、202.5 µg，双氢睾酮与羟基氟他胺质量比（以下称为药物质量比）分别为8∶9、8∶3、8∶1］，之后每48小时重复给药1次，直至伤后27 d；对空白组小鼠创面于前述时间点滴加生理盐水。观察伤后0（即刻）、7、14、21、28 d创面愈合情况并计算伤后7、14、21、28 d创面愈合率（样本数为4）；伤后28 d，取创面组织，行苏木精-伊红染色后观察再上皮化情况，行Masson染色后观察胶原纤维情况并分析胶原纤维占比（样本数为3）。取20只6~8周龄雄性BALB/c小鼠，于其背部制备Ⅲ度烧伤创面后，分为普通支架组和小比例支架组、中比例支架组、大比例支架组（每组5只小鼠），伤后7 d开始对创面分别持续外敷运用静电纺丝技术制备的不含药物的聚己内酯支架和含药物质量比为1∶3、1∶1、3∶1的DH的聚己内酯支架（即雄激素及其拮抗剂双重释放系统，DH总量均约为1.7 mg）直至实验结束。同前动物实验于相同时间点行组织病理学分析（样本数为3）；伤后7、14 d，收集创面分泌物，通过16S核糖体RNA高通量测序分析菌群相对丰度（样本数为3）。 结果 培养2 d，在小配比下，低基线组、高基线组HaCaT细胞增殖水平均显著高于空白组（ P<0.05）。随着伤后时间的延长，4组小鼠创面均不断缩小。伤后14 d，大配比组小鼠创面愈合率为72.5%（61.7%，75.1%），与空白组的53.3%（49.5%，64.4%）相近（ P>0.05）；小配比组与中配比组小鼠创面愈合率分别为74.2%（71.0%，84.2%）和70.4%（65.1%，74.4%），均显著高于空白组（ Z值均为-2.31， P<0.05）。伤后21 d，小配比组小鼠创面愈合率显著高于空白组（ Z=-2.31， P<0.05）。伤后28 d，3个配比组小鼠创面完全再上皮化且表皮均较空白组厚；与空白组比较，3个配比组小鼠创面组织中胶原纤维含量均更多且排列更有序，小配比组和大配比组小鼠创面组织中胶原纤维占比均明显增大（ P<0.05）。伤后28 d，普通支架组小鼠创面部分上皮化，3个比例支架组小鼠创面基本完全上皮化，其中小比例支架组小鼠创面表皮最厚；小比例支架组小鼠创面组织中胶原纤维占比较普通支架组明显增大（ P<0.05）。伤后7 d，4组小鼠创面分泌物中相对丰度较高的菌群包括棒状杆菌属、葡萄球菌属、红球菌属菌；伤后14 d，4组小鼠创面分泌物中相对丰度较高的菌群包括寡养单胞菌属、红球菌属、葡萄球菌属菌，且3个比例支架组小鼠创面分泌物中菌群种类数都多于普通支架组。 结论 药物质量比相对较小的DH，具有促进HaCaT细胞增殖的作用；8∶9为双氢睾酮与羟基氟他胺的最佳质量比，该质量比DH可以促进小鼠Ⅲ度烧伤创面再上皮化与胶原沉积，促进创面愈合。构建的含药物质量比为1∶3的DH的雄激素及其拮抗剂双重释放系统有助于小鼠Ⅲ度烧伤创面的再上皮化和胶原沉积，且可改善创面菌群多样性。 Abstract:Objective To explore the optimal ratio of dihydrotestosterone and hydroxyflutamide (hereinafter referred to as DH), construct a dual release system of androgen and its antagonist, and analyze the application effect of this system in the repair of full-thickness burn wounds in mice. Methods This study was an experimental study. The HaCaT cells were divided into blank group (without drug culture), low baseline group, medium baseline group, and high baseline group according to the random number table (the same grouping method below), and the last three groups of cells were cultured by adding three different ratios of DH. Under a medium ratio, the mass of dihydrotestosterone in the three baseline groups from low to high was 1.4, 2.8, and 4.0 µg, respectively, and the mass of hydroxyflutamide was 1.2, 1.6, and 2.0 µg, respectively. On this basis, under a small ratio, the mass of dihydrotestosterone was reduced by half and the mass of hydroxyflutamide was increased by half; under a large ratio, the mass of dihydrotestosterone was increased by half and the mass of hydroxyflutamide was reduced by half. After culture of 2 days, the cell proliferation level was detected by cell counting kit 8 ( n=4). Sixteen 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into blank group, small ratio group, medium ratio group, and large ratio group, with 4 mice in each group. On post injury day (PID) 7, normal saline containing different ratios of DH was locally dropped to the wounds of mice in the last three groups of mice (the total mass of DH in the three ratio groups from small to large was 127.5, 165.0, and 202.5 µg, respectively, and the mass ratios of dihydrotestosterone to hydroxyflutamide (hereinafter referred to as drug mass ratio) were 8∶9, 8∶3, and 8∶1, respectively), afterwards, the administration was repeated every 48 hours until PID 27; normal saline was dropped to the wound of mice in blank group at the aforementioned time points. The wound healing status on PID 0 (immediately), 7, 14, 21, and 28 was observed, and the wound healing rates on PID 7, 14, 21, and 28 were calculated ( n=4). On PID 28, the wound tissue was taken, which was stained with hematoxylin and eosin for observing re-epithelialization and with Masson for observing collagen fibers, and the proportion of collagen fibers was analyzed ( n=3). Twenty 6-8-week-old male BALB/c mice were used to establish a full-thickness burn wound on the back and divided into ordinary scaffold group, small proportion scaffold group, medium proportion scaffold group, and large proportion scaffold group (with 5 mice in each group). On PID 7, the wound was continuously dressed with a polycaprolactone scaffold without drug and a polycaprolactone scaffold containing DH with a drug mass ratio of 1∶3, 1∶1, or 3∶1 (i.e. the dual release system of androgen and its antagonist, with total mass of DH being about 1.7 mg) prepared by using electrospinning technology until the end of the experiment. Histopathological analyses of tissue ( n=3) at the same time points as those in the previous animal experiment were performed. On PID 7 and 14, the wound exudates were collected and the relative abundance of bacterial communities was analyzed using 16S ribosomal RNA high-throughput sequencing ( n=3). Results After culture of 2 days, under a small ratio, the proliferation levels of HaCaT cells in low baseline group and high baseline group were significantly higher than the level in blank group ( P<0.05). As the time after injury prolonged, the wounds of all four groups of mice continued to shrink. On PID 14, the wound healing rate of mice in large ratio group was 72.5% (61.7%, 75.1%), which was close to 53.3% (49.5%, 64.4%) in blank group ( P>0.05); the wound healing rates of mice in small and medium ratio groups were 74.2% (71.0%, 84.2%) and 70.4% (65.1%, 74.4%), respectively, which were significantly higher than the rate in blank group (with both Z values being -2.31, P<0.05). On PID 21, the wound healing rate of mice in small ratio group was significantly higher than that in blank group ( Z=-2.31, P<0.05). On PID 28, the wounds of mice in the three ratio groups were completely re-epithelialized and the epidermis was thicker than that in blank group; compared with that in blank group, the collagen fiber content in the wound tissue of mice in the three ratio groups was higher and arranged more orderly, and the proportions of collagen fibers in the wound tissue of mice in small and large ratio groups were significantly increased ( P<0.05). On PID 28, the wounds of mice in ordinary scaffold group were partially epithelialized, while the wounds of mice in the three proportion scaffold groups were almost completely epithelialized. Among them, the wounds of mice in small proportion scaffold group had the thickest epidermis. The proportion of collagen fibers in the wound tissue of mice in small proportion scaffold group was significantly increased compared with that in ordinary scaffold group ( P<0.05). On PID 7, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Corynebacterium, Staphylococcus, and Rhodococcus. On PID 14, the bacterial communities with high relative abundance in the wound exudation of mice in the four groups included bacteria of Stenotrophomonas, Rhodococcus, and Staphylococcus, and the number of bacterial species in the wound exudation of mice in the three proportion scaffold groups was more than that in ordinary scaffold group. Conclusions When the drug mass ratio is relatively small, DH has the effect of promoting the proliferation of HaCaT cells. The ratio of 8∶9 is the optimal mass ratio of dihydrotestosterone to hydroxyflutamide, and DH with this mass ratio can promote re-epithelialization and collagen deposition of full-thickness burn wounds in mice, and promote wound healing. The constructed dual release system of androgen and its antagonist with DH in a 1∶3 drug mass ratio contributes to the re-epithelialization and collagen deposition of the full-thickness burn wounds in mice, and can improve the diversity of wound microbiota. -
Key words:
- Burns /
- Biocompatible materials /
- Androgen antagonists /
- Nanofibers /
- Electrospinning /
- Androgen /
- Wound repair /
- Wound microbiota
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参考文献
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1 4组Ⅲ度烧伤小鼠伤后各时间点创面愈合情况。1A、1B、1C.分别为空白组伤后0（即刻）、14、28 d的创面，愈合速度缓慢；1D、1E、1F.分别为小配比组伤后0、14、28 d的创面，图1D创面情况与图1A相近，图1E、1F创面面积分别明显小于图1B和1C；1G、1H、1I.分别为中配比组伤后0、14、28 d的创面，图1G创面情况与图1A相近，图1H创面面积明显小于图1B；1J、1K、1L.分别为大配比组伤后0、14、28 d的创面，情况分别与图1A、1B、1C相近
注：对空白组创面滴加生理盐水；对其余3组创面均分别滴加含相应配比双氢睾酮与羟基氟他胺的生理盐水，双氢睾酮和羟基氟他胺总量分别为127.5、165.0、202.5 µg，双氢睾酮与羟基氟他胺质量比分别为8∶9、8∶3、8∶1
2 采用静电纺丝技术制备的4种聚己内酯支架的表面结构 扫描电子显微镜×50 000。2A、2B、2C、2D.分别为不含药物的聚己内酯支架和含双氢睾酮与羟基氟他胺质量比为1∶3、1∶1、3∶1的混合药物的聚己内酯支架，其表面均多孔，纤维清晰、纵横交错，图2C中纤维有融合成片的趋势，图2B、2C、2D均未见药物颗粒
3 4组Ⅲ度烧伤小鼠伤后各时间点创面愈合情况。3A、3B、3C.分别为普通支架组伤后0（即刻）、14、28 d的创面，愈合速度缓慢；3D、3E、3F.分别为小比例支架组伤后0、14、28 d的创面，图3D创面情况与图3A相近，图3E、3F创面面积分别小于图3B和3C；3G、3H、3I.分别为中比例支架组伤后0、14、28 d的创面，图3G创面情况与图3A相近，图3H创面面积较图3B小；3J、3K、3L.分别为大比例支架组伤后0、14、28 d的创面，情况分别与图3A、3B、3C相近
注：对普通支架组和小比例支架组、中比例支架组、大比例支架组创面分别外敷不含药物的聚己内酯支架和含双氢睾酮与羟基氟他胺质量比为1∶3、1∶1、3∶1的混合药物的聚己内酯支架（2种药物总量均约为1.7 mg）
4 4组Ⅲ度烧伤小鼠伤后各时间点创面分泌物中菌群情况。4A.伤后7 d；4B.伤后14 d
注：对普通支架组和小比例支架组、中比例支架组、大比例支架组创面分别外敷不含药物的聚己内酯支架和含双氢睾酮与羟基氟他胺质量比为1∶3、1∶1、3∶1的混合药物的聚己内酯支架（2种药物总量均约为1.7 mg）；左侧1、2、3、4分别指示普通支架组、中比例支架组、小比例支架组、大比例支架组；其他指相对丰度未达到0.05%的细菌
表1 4组HaCaT细胞经不同配比的DH培养2 d后增殖水平比较（
表1. Comparison of proliferation levels of HaCaT cells in four groups after being cultured with DH in different ratios for 2 days
组别 样本数 小配比 中配比 大配比 低基线组 4 1.27±0.09 0.83±0.04 1.17±0.10 中基线组 4 1.22±0.03 0.82±0.06 1.14±0.20 高基线组 4 1.26±0.09 0.90±0.04 1.19±0.18 P 1值 0.031 0.417 0.388 P 2值 0.119 0.339 0.644 P 3值 0.043 0.914 0.277 P 4值 >0.999 >0.999 >0.999 P 5值 >0.999 0.995 >0.999 P 6值 >0.999 0.987 >0.999 注：对空白组细胞行常规培养，不加药物；其余3组细胞均分别加用3种配比的DH（双氢睾酮和羟基氟他胺）培养，中配比下，从低到高3个基线组中双氢睾酮质量依次为1.4、2.8、4.0 µg，羟基氟他胺质量依次为1.2、1.6、2.0 µg，以此为基准，小配比下双氢睾酮质量减少1/2，羟基氟他胺质量增加1/2；大配比下，双氢睾酮质量增加1/2，羟基氟他胺质量减少1/2；空白组细胞增殖水平为1；基线因素主效应， F=0.74， P=0.484；配比因素主效应， F=45.56， P<0.001；二者交互作用， F=0.20， P=0.974； P 1值、 P 2值、 P 3值分别为低基线组、中基线组、高基线组与空白组比较所得， P 4值、 P 5值分别为中基线组、高基线组与低基线组比较所得， P 6值为中基线组与高基线组比较所得 
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表2 4组Ⅲ度烧伤小鼠伤后各时间点创面愈合率比较[%， M( min， max)]
表2. Comparison of wound healing rates at various time points after injury in four groups of mice with full-thickness burns
组别 创面数（个） 7 d 14 d 21 d 28 d 空白组 4 14.6（0.8，17.6） 53.3（49.5，64.4） 87.4（84.0，91.9） 100（98.7，100） 小配比组 4 21.4（5.6，40.0） 74.2（71.0，84.2） a 94.1（94.5，100） a 100（100，100） 中配比组 4 14.2（9.0，18.3） 70.4（65.1，74.4） a 94.1（90.7，97.9） 100（100，100） 大配比组 4 13.6（1.0，31.2） 72.5（61.7，75.1） 93.1（89.7，97.3） 100（100，100） H值 1.13 9.60 9.33 3.00 P值 0.801 0.007 0.010 0.392 注：对空白组创面滴加生理盐水；对其余3组创面均分别滴加含相应配比双氢睾酮与羟基氟他胺的生理盐水，从小到大3个配比组中双氢睾酮和羟基氟他胺总量分别为127.5、165.0、202.5 µg，双氢睾酮与羟基氟他胺质量比分别为8∶9、8∶3、8∶1；与空白组比较， a P<0.05
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表3 3种含不同配比DH的聚己内酯支架在磷酸盐缓冲液中浸泡1~21 d释放双氢睾酮的量[μg， M( min， max)]
表3. The amount of dihydrotestosterone released by three types of polycaprolactone scaffolds with different ratios of DH after being soaked in phosphate buffer solution for 1-21 days
配比 1 d 3 d 5 d 7 d 9 d 11 d 13 d 15 d 17 d 19 d 21 d 1∶3 27.7（25.5，30.0） 30.5（30.0，30.8） 28.4（28.1，38.8） 26.0（17.0，28.4） 22.1（21.2，26.5） 23.1（13.8，26.0） 32.4（25.0，34.3） 17.7（17.1，18.3） 22.7（20.9，25.2） 19.0（18.8，20.0） 15.3（11.7，15.5） 1∶1 26.7（24.8，29.6） 31.6（30.1，33.7） 30.0（29.6，45.4） 27.7（25.5，32.9） 22.5（20.1，27.8） 22.0（20.8，23.1） 30.9（30.3，34.1） 17.8（17.2，20.1） 22.0（19.9，24.1） 21.5（13.9，24.3） 16.1（15.8，17.3） 3∶1 37.1（33.1，54.0） 33.6（31.4，36.5） 31.2（26.4，50.2） 33.2（24.0，39.4） 33.1（30.8，33.7） 33.4（27.3，45.6） 38.2（30.7，38.7） 33.1（30.4，35.9） 24.7（21.8，30.5） 21.9（20.1，22.4） 18.7（18.6，63.3） 注：样本数均为3；DH指双氢睾酮和羟基氟他胺，总量为10 mg；配比为双氢睾酮与羟基氟他胺的质量比
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表4 3种含不同配比DH的聚己内酯支架在磷酸盐缓冲液中浸泡1~21 d释放羟基氟他胺的量[μg， M( min， max)]
表4. The amount of hydroxyflutamide released by three types of polycaprolactone scaffolds with different ratios of DH after being soaked in phosphate buffer solution for 1-21 days
配比 1 d 3 d 5 d 7 d 9 d 11 d 13 d 15 d 17 d 19 d 21 d 1∶3 23.1（22.7，23.7） 22.2（22.0，22.8） 21.9（13.4，22.0） 21.3（20.8，21.7） 29.2（28.7，29.3） 17.8（17.4，18.3） 21.6（20.3，21.7） 19.9（18.4，21.3） 16.5（16.3，16.9） 13.1（12.5，13.6） 13.4（11.8，13.6） 1∶1 22.7（14.8，23.1） 20.8（19.9，22.1） 21.4（20.0，21.6） 20.7（20.4，20.8） 25.2（25.2，26.1） 16.6（16.3，17.9） 12.4（12.0，13.1） 15.2（14.3，16.0） 11.3（11.1，12.8） 11.4（9.3，12.2） 9.8（8.1，10.1） 3∶1 22.7（21.6，22.9） 17.9（15.5，18.6） 16.0（15.7，16.4） 11.9（11.1，15.1） 20.1（19.8，22.4） 7.9（7.1，8.5） 11.4（11.3，12.0） 9.2（7.1，10.2） 6.4（4.4，7.1） 4.3（2.8，7.2） 4.2（3.4，5.5） 注：样本数均为3；DH指双氢睾酮和羟基氟他胺，总量为10 mg；配比为双氢睾酮与羟基氟他胺的质量比
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表5 4组Ⅲ度烧伤小鼠伤后各时间点创面愈合率比较[%， M( min， max)]
表5. Comparison of wound healing rates at various time points after injury in four groups of mice with full-thickness burns
组别 创面数（个） 7 d 14 d 21 d 28 d 普通支架组 5 7.4（-4.0，22.4） 47.3（37.6，61.1） 80.1（60.1，85.6） 93.6（79.2，95.2） 小比例支架组 5 12.5（2.4，25.3） 61.0（42.8，76.8） 90.2（80.7，93.9） 96.0（92.1，100） 中比例支架组 5 18.4（3.3，30.7） 56.7（55.6，73.8） 84.8（76.0，94.8） 97.6（90.1，100） 大比例支架组 5 18.6（15.1，28.1） 56.5（44.5，65.6） 88.0（78.1，93.4） 100（93.3，100） H值 4.70 2.91 4.63 6.54 P值 0.195 0.406 0.201 0.088 注：对普通支架组和小比例支架组、中比例支架组、大比例支架组创面分别外敷不含药物的聚己内酯支架和含双氢睾酮与羟基氟他胺质量比为1∶3、1∶1、3∶1的混合药物的聚己内酯支架（2种药物总量均约为1.7 mg）
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