TGFβ_1抗体复合生物蛋白胶防止术后肌腱粘连的实验研究
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摘要
研究背景
鞘管区术后肌腱粘连是肌腱损伤后常见问题,是手外科尚未解决的难题之一,迄今为止,仍无有效的解决方法。肌腱粘连是指肌腱损伤修复过程中周围组织的增生和侵入,造成肌腱运动功能障碍。虽然目前治疗肌腱粘连的方法有多种,但其治疗效果并不显著。
近年来,细胞因子TGFβ逐渐受到国内外学者的关注。TGFβ是一个25 000同源二聚体,它通过促使成纤维细胞和巨噬细胞的募集、促进血管的生成、刺激胶原的产生、下调基质金属蛋白酶的活性和增加基质金属蛋白酶抑制剂的活性而发挥作用,是一个在急性炎症及伤口愈合中起重要作用的细胞因子,它的过分表达可导致过度的瘢痕增生和纤维化[1-2]。实验证实:在TGFβ的亚型中,TGFβ_1与胶原形成关系最为密切。通过利用TGFβ_1拮抗剂来抑制肌腱周围TGFβ_1的生物活性,从而抑制肌腱周围瘢痕的过度形成,已成为目前研究的热点。
本实验我们研究TGFβ_1中和抗体预防肌腱粘连的可能性及对肌腱愈合后生物力学的影响.考虑到TGFβ_1抗体在局部代谢快,作用不持久的问题,决定将TGFβ_1抗体与生物蛋白胶复合应用于局部,在局部发挥其的缓释作用,旨在找到一种效果较为理想的抗粘连药。
目的
1.研究TGF-β_1抗体复合生物蛋白胶预防鞘管区屈肌腱粘连的作用。
2.研究肌腱损伤局部应用TGFβ_1抗体复合生物蛋白胶后,对其愈合后功能有无影响。
方法
本实验将成年雄性来亨(Leghorn)鸡72只随机平均分为4组,每组18只。左足第3、4趾趾深屈肌腱横断,四股交叉缝合肌腱,鞘管未缝合。按鞘管区给药分为4组:A组TGF-β_1Ab、B组FG、C组TGF-β_1Ab+FG、D组生理盐水。仅术中注入一次药物,术后1、3、8周处死取材。
实验一形态学观察:在术后1、3、8周,每组各取6只鸡,将其第4趾制成冰冻切片,分别行大体观察和组织学观察。
实验二生物力学测定:在术后1、3、8周,每组各取6只鸡,利用特制模具对其第3趾分别行肌腱滑动距离、模拟主动屈曲度及屈曲功测定;待上述测定结束后再将标本制成末节趾骨-趾深屈肌腱复合体,行最大抗断裂载荷测定。
结果
实验一形态学观察:
1.大体观察:术后1、3、8周肌腱粘连程度分级A组与B组无统计学差异(P>0.05), C组与其余3组比较有统计学差异(P<0.05)。
2.组织学观测:术后3、8周A、B、D组胶原纤维排列紊乱,C组胶原纤维排列较其余三组整齐。
实验二生物力学测定:
1.肌腱滑动距离比值:术后3周,各组肌腱滑动距离比值分别为0.45±0.05、0.40±0.10、0.79±0.09、0.25±0.07;术后8周,各组肌腱滑动距离比值分别为0.45±0.07、0.43±0.08、0.80±0.09、0.29±0.05。术后3、8周,C组与其余三组比较差异均有统计学意义(P<0.05)。
2.模拟主动屈曲度比值:术后3周,各组模拟主动屈曲度比值分别为0.61±0.02、0.67±0.03、0.91±0.03、0.53±0.04;术后8周,模拟主动屈曲度比值分别为0.61±0.02、0.63±0.03、0.92±0.03、0.53±0.03。术后3、8周,C组与其余三组比较差异均有统计学意义(P<0.05)。
3.屈曲功:术后3周,各组屈曲功分别为18.0±0.77度/N、17.8±1.13度/N、27.6±1.73度/N、15.6±1.27度/N;屈曲功分别为18.3±0.84度/N、15.3±0.75度/N、27.9±1.24度/N、18.6±0.80度/N。术后3、8周,C组与其余三组比较差异均有统计学意义(P<0.05)。
4.最大抗断裂载荷:术后3周,各组最大抗断裂载荷分别为14.2±1.9 N、15.2±2.2N、16.0±2.2N、14.7±2.7N;术后8周,各组最大抗断裂载荷分别为51.9±3.0N,51.4±1.44N,53.3±1.3N,52.3±2.2N。术后3、8周,各组间差异均无统计学意义(P>0.05)。
结论
1. TGFβ_1抗体复合生物蛋白胶可以有效预防术后肌腱粘连;
2.肌腱损伤局部应用TGF-β_1抗体复合生物蛋白胶后,肌腱的正常愈合进程及愈后功能不受影响。
Beckground
The tendon adhesion post-operation in the sheathing canal area is a common and tough problem after tendon injury and there is no effective resolvent so far. tendon adhesion is proliferation and intrusion of periphery tissue during the process of wound healing, and induces the motor dysfunction of tendon. The therapeutic efficacy of clinical treatments of suppressing tendon adhesion is not significant.
Nowadays the transforming growth factor TGFβhas received much more schola -stic attention. TGFβis a 25 000 homodimer, and has various functions includeing promoting the aggregation of fibroblast and macrophage, enhancing the angiogenesis, stimulating the production of collagenous, down-regulating the matrix metalloprotein -ase and up-regulating the matrix metalloproteinase inhibitor. TGFβis a important cytokine in acute inflammation and wound healing and the over express -ion can induce the scar hyperplasy and fibrosis[1-2]. It is confirmed that inhibiting the biologi -cal activity of TGFβ_1 around the tendon by TGFβ_1 inhibitor become a hot spot.
In our experiments we studied the possibilities of preventing the tendon adhesion and the influence on tendon healing of TGFβ_1 antibody. Concerning about the fast region metabolism and low effectiveness of TGFβ_1, the compound of transforming growth factor-β_1 antibody and fibrin glue (TGFβ_1 Ab + FG) was investigated in order to delaying TGFβ_1 antibody release and find a therapeutic way to solve the tendon adhesion.
Purpose
1. To explore the preventing influences of the compound of transforming growth factor-β_1 antibody and fibrin glue (TGFβ_1 Ab + FG) on prevention of peritendinous adhesive formation.
2. To study the effects of applying the compound of TGFβ_1 Ab + FG in region on the function o f healed tendon .
Methods
Seventy-two Leghorn chickens were randomly divided into 4 groups (group s A , B ,C and D) , 18 chickens for each group, and the long flexor tendons of the 3rd and 4th toes in zoneⅡof 72 leghorn chickens were transversed and sutured with The 4-strand Cruciate repair technique to make defect models. In group A , TGFβ_1 antibody was applied at repair site.In group B, FG was applied at repair site. In group C, The TGF-β_1Ab and FG 0.2 ml compound was applied at repair site. In group D, normal sodium was applied at repair site. At 1, 3 and 8 weeks after operation, the chickens tendons in each group were harvested.
The first part of our study was to observe the morphological influences of the compound of TGFβ_1 Ab + FG on tendon repair. After 1, 3 and 8 weeks post operation, the tendons of 6 chickens in each group were harvested. And the 4th toes were made into frozen section for morphological and histological evaluation.
The second part of our study was to detect the biomechanical influences of the compound of TGFβ_1 Ab + FG on tendon repair. After 1, 3 and 8 weeks post operation, the tendons of 6 chickens in each group were harvested. And the 3rd toes were obtained for biomechanical test including the gliding excursion,the simulated active flexion and the work of flexion. After all the tests above ,the specimens of each group were made into the compound of phalanx ungula and flexor digitorum profundus muscle to test the tendon anastomosis breaking strength.
Results
Firstly, the results of morphological observation.
1. The gross observation showed that the differences of grading of tendon adhesion were not significant among groups A , B, and D(P > 0. 05), but in group C, the differences were significant between A , B, and D after 3 and 8 weeks postoperation (P < 0. 05).
2. Histological observation showed that collagen fibers of group A, B and D were in a great disorder, but were well-formed in group C.
Secondly, the results of biomechanical tests.
1. The gliding excursion ratio of the tendons in group A , B, C and D were 0.45±0.05、0.40±0.10、0.79±0.09、0.25±0.07 respectively after 3 weeks postoperation; the same ratio of the tendons were 0.45±0.07、0.43±0.08、0.80±0.09、0.29±0.05 respectively after 8 weeks. Compared with other three groups, the group C had significant differences after 3 and 8 weeks (P < 0. 05).
2. The simulated active flexion ratio were 0.61±0.02、0.67±0.03、0.91±0.03、0.53±0.04 respectively after 3 weeks postoperation; the same ratio of the tendons were 0.61±0.02、0.63±0.03、0.92±0.03、0.53±0.03 respectively after 8 weeks. Compared with other three groups, the group C had significant differences after 3 and 8 weeks (P < 0. 05).
3. The work of flexion were18.0±0.77D/N、17.8±1.13D/N、27.6±1.73D/N、15.6±1.27 D/N respectively after 3 weeks postoperation, and were 18.3±0.84D/N、15.3±0.75 D/N、27.9±1.24 D/N、18.6±0.80D/N respectively after 8 weeks. Compared with other three groups, the group C had significant differences after 3 and 8 weeks (P < 0. 05).
4. Tendon anastomosis breaking strength were14.2±1.9N,15.2±2.2N,16.0±2.2N, 14.7±2.7N respectively after 3 weeks postoperation, and were 51.9±3.0N, 51.4±1.44 N, 53.3±1.3N, 52.3±2.2N respectively after 8 weeks. There were no significant differences among the 4 groups after 3 and 8 weeks (P > 0.05).
Conclusion
1. The compound of TGFβ_1 antibody with FG could significantly prohibit the formation of fibrous adhesions .
2. Applying the compound of TGFβ_1 antibody with FG after tendon injury did not interfere with the healing process.
鞘管区术后肌腱粘连是肌腱损伤后常见问题,是手外科尚未解决的难题之一,迄今为止,仍无有效的解决方法。肌腱粘连是指肌腱损伤修复过程中周围组织的增生和侵入,造成肌腱运动功能障碍。虽然目前治疗肌腱粘连的方法有多种,但其治疗效果并不显著。
近年来,细胞因子TGFβ逐渐受到国内外学者的关注。TGFβ是一个25 000同源二聚体,它通过促使成纤维细胞和巨噬细胞的募集、促进血管的生成、刺激胶原的产生、下调基质金属蛋白酶的活性和增加基质金属蛋白酶抑制剂的活性而发挥作用,是一个在急性炎症及伤口愈合中起重要作用的细胞因子,它的过分表达可导致过度的瘢痕增生和纤维化[1-2]。实验证实:在TGFβ的亚型中,TGFβ_1与胶原形成关系最为密切。通过利用TGFβ_1拮抗剂来抑制肌腱周围TGFβ_1的生物活性,从而抑制肌腱周围瘢痕的过度形成,已成为目前研究的热点。
本实验我们研究TGFβ_1中和抗体预防肌腱粘连的可能性及对肌腱愈合后生物力学的影响.考虑到TGFβ_1抗体在局部代谢快,作用不持久的问题,决定将TGFβ_1抗体与生物蛋白胶复合应用于局部,在局部发挥其的缓释作用,旨在找到一种效果较为理想的抗粘连药。
目的
1.研究TGF-β_1抗体复合生物蛋白胶预防鞘管区屈肌腱粘连的作用。
2.研究肌腱损伤局部应用TGFβ_1抗体复合生物蛋白胶后,对其愈合后功能有无影响。
方法
本实验将成年雄性来亨(Leghorn)鸡72只随机平均分为4组,每组18只。左足第3、4趾趾深屈肌腱横断,四股交叉缝合肌腱,鞘管未缝合。按鞘管区给药分为4组:A组TGF-β_1Ab、B组FG、C组TGF-β_1Ab+FG、D组生理盐水。仅术中注入一次药物,术后1、3、8周处死取材。
实验一形态学观察:在术后1、3、8周,每组各取6只鸡,将其第4趾制成冰冻切片,分别行大体观察和组织学观察。
实验二生物力学测定:在术后1、3、8周,每组各取6只鸡,利用特制模具对其第3趾分别行肌腱滑动距离、模拟主动屈曲度及屈曲功测定;待上述测定结束后再将标本制成末节趾骨-趾深屈肌腱复合体,行最大抗断裂载荷测定。
结果
实验一形态学观察:
1.大体观察:术后1、3、8周肌腱粘连程度分级A组与B组无统计学差异(P>0.05), C组与其余3组比较有统计学差异(P<0.05)。
2.组织学观测:术后3、8周A、B、D组胶原纤维排列紊乱,C组胶原纤维排列较其余三组整齐。
实验二生物力学测定:
1.肌腱滑动距离比值:术后3周,各组肌腱滑动距离比值分别为0.45±0.05、0.40±0.10、0.79±0.09、0.25±0.07;术后8周,各组肌腱滑动距离比值分别为0.45±0.07、0.43±0.08、0.80±0.09、0.29±0.05。术后3、8周,C组与其余三组比较差异均有统计学意义(P<0.05)。
2.模拟主动屈曲度比值:术后3周,各组模拟主动屈曲度比值分别为0.61±0.02、0.67±0.03、0.91±0.03、0.53±0.04;术后8周,模拟主动屈曲度比值分别为0.61±0.02、0.63±0.03、0.92±0.03、0.53±0.03。术后3、8周,C组与其余三组比较差异均有统计学意义(P<0.05)。
3.屈曲功:术后3周,各组屈曲功分别为18.0±0.77度/N、17.8±1.13度/N、27.6±1.73度/N、15.6±1.27度/N;屈曲功分别为18.3±0.84度/N、15.3±0.75度/N、27.9±1.24度/N、18.6±0.80度/N。术后3、8周,C组与其余三组比较差异均有统计学意义(P<0.05)。
4.最大抗断裂载荷:术后3周,各组最大抗断裂载荷分别为14.2±1.9 N、15.2±2.2N、16.0±2.2N、14.7±2.7N;术后8周,各组最大抗断裂载荷分别为51.9±3.0N,51.4±1.44N,53.3±1.3N,52.3±2.2N。术后3、8周,各组间差异均无统计学意义(P>0.05)。
结论
1. TGFβ_1抗体复合生物蛋白胶可以有效预防术后肌腱粘连;
2.肌腱损伤局部应用TGF-β_1抗体复合生物蛋白胶后,肌腱的正常愈合进程及愈后功能不受影响。
Beckground
The tendon adhesion post-operation in the sheathing canal area is a common and tough problem after tendon injury and there is no effective resolvent so far. tendon adhesion is proliferation and intrusion of periphery tissue during the process of wound healing, and induces the motor dysfunction of tendon. The therapeutic efficacy of clinical treatments of suppressing tendon adhesion is not significant.
Nowadays the transforming growth factor TGFβhas received much more schola -stic attention. TGFβis a 25 000 homodimer, and has various functions includeing promoting the aggregation of fibroblast and macrophage, enhancing the angiogenesis, stimulating the production of collagenous, down-regulating the matrix metalloprotein -ase and up-regulating the matrix metalloproteinase inhibitor. TGFβis a important cytokine in acute inflammation and wound healing and the over express -ion can induce the scar hyperplasy and fibrosis[1-2]. It is confirmed that inhibiting the biologi -cal activity of TGFβ_1 around the tendon by TGFβ_1 inhibitor become a hot spot.
In our experiments we studied the possibilities of preventing the tendon adhesion and the influence on tendon healing of TGFβ_1 antibody. Concerning about the fast region metabolism and low effectiveness of TGFβ_1, the compound of transforming growth factor-β_1 antibody and fibrin glue (TGFβ_1 Ab + FG) was investigated in order to delaying TGFβ_1 antibody release and find a therapeutic way to solve the tendon adhesion.
Purpose
1. To explore the preventing influences of the compound of transforming growth factor-β_1 antibody and fibrin glue (TGFβ_1 Ab + FG) on prevention of peritendinous adhesive formation.
2. To study the effects of applying the compound of TGFβ_1 Ab + FG in region on the function o f healed tendon .
Methods
Seventy-two Leghorn chickens were randomly divided into 4 groups (group s A , B ,C and D) , 18 chickens for each group, and the long flexor tendons of the 3rd and 4th toes in zoneⅡof 72 leghorn chickens were transversed and sutured with The 4-strand Cruciate repair technique to make defect models. In group A , TGFβ_1 antibody was applied at repair site.In group B, FG was applied at repair site. In group C, The TGF-β_1Ab and FG 0.2 ml compound was applied at repair site. In group D, normal sodium was applied at repair site. At 1, 3 and 8 weeks after operation, the chickens tendons in each group were harvested.
The first part of our study was to observe the morphological influences of the compound of TGFβ_1 Ab + FG on tendon repair. After 1, 3 and 8 weeks post operation, the tendons of 6 chickens in each group were harvested. And the 4th toes were made into frozen section for morphological and histological evaluation.
The second part of our study was to detect the biomechanical influences of the compound of TGFβ_1 Ab + FG on tendon repair. After 1, 3 and 8 weeks post operation, the tendons of 6 chickens in each group were harvested. And the 3rd toes were obtained for biomechanical test including the gliding excursion,the simulated active flexion and the work of flexion. After all the tests above ,the specimens of each group were made into the compound of phalanx ungula and flexor digitorum profundus muscle to test the tendon anastomosis breaking strength.
Results
Firstly, the results of morphological observation.
1. The gross observation showed that the differences of grading of tendon adhesion were not significant among groups A , B, and D(P > 0. 05), but in group C, the differences were significant between A , B, and D after 3 and 8 weeks postoperation (P < 0. 05).
2. Histological observation showed that collagen fibers of group A, B and D were in a great disorder, but were well-formed in group C.
Secondly, the results of biomechanical tests.
1. The gliding excursion ratio of the tendons in group A , B, C and D were 0.45±0.05、0.40±0.10、0.79±0.09、0.25±0.07 respectively after 3 weeks postoperation; the same ratio of the tendons were 0.45±0.07、0.43±0.08、0.80±0.09、0.29±0.05 respectively after 8 weeks. Compared with other three groups, the group C had significant differences after 3 and 8 weeks (P < 0. 05).
2. The simulated active flexion ratio were 0.61±0.02、0.67±0.03、0.91±0.03、0.53±0.04 respectively after 3 weeks postoperation; the same ratio of the tendons were 0.61±0.02、0.63±0.03、0.92±0.03、0.53±0.03 respectively after 8 weeks. Compared with other three groups, the group C had significant differences after 3 and 8 weeks (P < 0. 05).
3. The work of flexion were18.0±0.77D/N、17.8±1.13D/N、27.6±1.73D/N、15.6±1.27 D/N respectively after 3 weeks postoperation, and were 18.3±0.84D/N、15.3±0.75 D/N、27.9±1.24 D/N、18.6±0.80D/N respectively after 8 weeks. Compared with other three groups, the group C had significant differences after 3 and 8 weeks (P < 0. 05).
4. Tendon anastomosis breaking strength were14.2±1.9N,15.2±2.2N,16.0±2.2N, 14.7±2.7N respectively after 3 weeks postoperation, and were 51.9±3.0N, 51.4±1.44 N, 53.3±1.3N, 52.3±2.2N respectively after 8 weeks. There were no significant differences among the 4 groups after 3 and 8 weeks (P > 0.05).
Conclusion
1. The compound of TGFβ_1 antibody with FG could significantly prohibit the formation of fibrous adhesions .
2. Applying the compound of TGFβ_1 antibody with FG after tendon injury did not interfere with the healing process.
引文
1. Leask A. TGF β , cardiac fibroblasts, and the fibrotic response. J Cardiovascular Research 2007,74:207-212.
2. Filyak Y, Filyak O, Stoika R. Transforming growth factor beta-1 enhances cytotoxic effect of doxorubicin in human lung adenocarcinoma cells of A549 line. J Cell Biology International 2007 ,31 :851-855.
3. Khan U, Occlestion NL, Khaw PT, Megrouther DA. Differences in proliferative rate and collagen lattice contraction between endotendon and synovial fibroblasts.J Hand surg(Am) 1998, 23: 266-273.
4. 宋永枝,王发斌,洪光祥,等. 5-氟尿嘧啶防止肌腱粘连的实验研究. 中华手外科杂志. 2004,20(4):249-251.
5. Dinsdate CJ.Mirza FM.Wiehe Glycerol alters cytoskeleton and cell adhesion while inhibiting cell proliferatlon. Cell Biol Int Rep 1992.16:591-602.
6. 潘勇卫,韦加宁,张有乐,等. 甘油合剂和透明质酸钠预防鸡鞘管区屈肌腱粘连的实验研究. 中华骨科杂志. 2000,20(4):245-248.
7. chang J, Most D, Thunder R, et al. Molecular Studies in Flexor Tendon Wound Healing: The Role of Basic Fibroblast Growth Factor Gene Expression[J]. Hand Surg 1998, 23A (6): 1052-1058.
8. Boyer MI, Goldfarb CA, Gelberman RH. Recent Progress in Flexor Tendon Healing The Modulation of Tendon Healing With Rehabilitation Variables[J]. Hand Surg 2005, 18(2): 80-85.
9. Nago M,Pham H,Longaker MT,et a1.Differential expression of transforming growth factor-beta receptors in a rabbit zone Ⅱf lexor tendonwound healing model. Plast Reconstr Surg 2001;108(5):1260～1267.
10. Klein MB, Yalamanchi N, Pham H, et al. Flexor Tendon Healing In Vitro: Effects of TGF-β on Tendon Cell Collagen Production[J]. Hand Surg 2002, 27A(4): 615-620.
11. 陈至着,王立飞. 透明质酸防止屈肌腱粘连的实验研究. 中华外科杂志. 1995,33:526-528.
12. 叶根茂,候春林. 几丁糖预防免屈肌腱粘连的试验研究. 中华手外科杂志. 1994,10:51-53.
13. 吕德威,严忠群,刘宗明. 壳聚糖预防鸡趾屈肌腱粘连的实验研究. 中华手外科杂志. 1996,12:49-51.
14. 张卫国,姜长明,曹国英,等.高分子纤维素预防肌腱粘连的实验研究. 中华手外科杂志. 1995,11:51-53.
15. Boris WJ, McGrath LB, Effectiveness of fibrin glue in the reduction of postopera -tive intrapericardial adhesions[J].J Invest Surg 1996, 9: 327-333.
16. Toosie K, Gallego K, Stabike BE, et al . fibrin glue reduces intra-abdominal adhesions to synthetic mesh in a rat ventral hernia model[J]Am Surg 2000, 66:41-45.
17. 黄启顺,王发斌,康 浩,等.聚-DL-乳酸可吸收性防粘连膜预防肌腱粘连的临床应用. 中华创伤骨科杂志. 2005,7(10):990-991.
18. Strickland JW. Flexor tendon injuries: Foundation of treatment. J Am Acad Orthop Surg 1995; 3: 44-54.
19. Lee H. Double Loop Locking suture:a technique of tendon repair for early active mobilization. Part Ⅰ: evolution of technique and experimental study. J Hand Surg 1990; 15A: 945-952.
20. Lee H. Double Loop Locking suture:a technique of tendon repair for early active mobilization. Part Ⅱ:clinical experience. J Hand Surg 1990; 15A:953-958.
21. Robertson GA, Al-Quattan MM. A biomechanical analysis of a new interlock suture technique for Flexor tendon repair. J Hand Surg 1992; 17B: 92-93.
22. Strickland JW. Flexor tendon repair: Indiana method. The Indiana Hand Center Newsletter 1993; 1: 1-12.
23. Strickland JW. Flexor tendon injuries:Ⅱ .Operative technique. J Am Acad Orthop Surg 1995; 3: 55-62.
24. Strickland JW.The Indiana method of flexor tendon repair. Atlas Hand Clin 1996; 1: 77-103.
25. Strickland JW. Flexor tendons-acute injuries.In: Green DP.Hotchkiss RN, Pederson WC, eds. Green, s operative hand surgery. 4th ed.New York: Churchill Livingstone 1999; 1851-1897.
26. Singer G,Ebramzadeh E, Jones NF, Meals R. Use of Taguchi method for biomechanical comparison of flexor tendon repair technique to allow immediate active flexion. A new method of analysis and optimization of technique to improve the quality of repair. J, Bone Joint Surg 1998; 80A:1498-1506.
27. Becker H, Davidoff M.Eliminating the gap in flexor tendon surgery. A new method of suture. Hand 1977; 9: 306-311.
28. Mclarney E, Hoffman H,Wolfe SW. Biomechanical analysis of the cruciate four-strand flexor tendon repair. J Hand Surg 1999;24A: 295-301.
29. Savage R. In vitro studies of a new method of flexor tendon repair. J Hand Surg 1985;10B: 135-141.
30. Savage R, Risitano G. Flexor tendon repair using a “six strand” method of repair and early active mobilisation. J Hand Surg 1989;14B: 396-399.
31. Lim BH, Tsai TM. The six-strand technique for flexor tendon repair. Atlas Hand Clin 1996;1: 65-76.
32. Sandow MJ, McMahon MM. Single cross-grasp six-strand repair for acute flexor tenorrhaphy: modified Savage technique. Atlas Hand Clin 1966;1: 41-64.
33. Kusano N, Yoshizu T, Maki Y. Experimental studies of two new flexor tendon suture techniques for postoperative early active flexion exercises. J Hand Surg 1999;24B: 152-156.
34. Wagner WF, Carroll C,Strickland JW, et a1. A biomechanical comparison of techniques of flexor tendon repair. J Hand Surg 1994;19A: 979-983.
35. Thurman RT, Trumbel TJ,Hanel DP, et a1. Two,four and six-strand zone Ⅱ flexor tendon repairs:an in-situ biomechanical comparison using a cadaver model. J Hand Surg 1998;23A: 261-265.
36. Silva MJ, Hollstien SB, Fayazi AH, et a1. The effects of multiple-strand suture techniques on the tensile properties of repair of the flexor digitorum profundus tendon to bone. J Bone Joint Surg 1998; 80A: 1507-1514.
37. Ejeskar A, Irstam L. Elongation in profundus tendon repair: a clinical and radiological study. Scand J Plast Reconstr Surg 1981;15: 61-68.
38. Kulick MI, Kilgore ES,Newmeyer WL. Pseudotendon formation after flexor tendon injury. J Hand Surg 1985;10A: 638-640.
39. Lin GT, An KN,Amadio PC, et a1. Biomechanical studies of running suture for flexor tendons in dogs. J Hand Surg 1988;13A: 553-558.
40. Lindsay WK, Thomson HG , Walker FG. Digital flexor tendon:an experimental study: partⅡ :the significance of a gap occurring at the line of suture. Br J Plast Surg 1960;12: 289-316.
41. Pruitt DL, Manske PR,Fink B. Cyclic stress analysis of flexor tendon repair.J Hand Surg 1991;16A: 701-707.
42. Pruitt DL, Tanaka H,Aoki M, et al. Cyclic stress testing after in vivo healing of canine flexor tendon lacerations. J Hand Surg 1996;21A: 974-977.
43. Seradge H. Elongation of the repair configuration following flexor tendon repair. J Hand Surg 1983;8: 182-185.
44. Silfverskiold KL, May EJ,Tornvall AH. Gap formation during controlled motion after flexor tendon repair in zone Ⅱ: a prospective clinical study. J Hand Surg 1992;17A: 539-546.
45. Silfverskiold KL, May EJ. Gap formation during controlled motion after flexor tendon repair in zoneⅡ : results with a new controlled motion programme. Scand J Plast Reconstr Hand Surg 1993;27: 263-268.
46. Diao E, Hariharan JS,Soejima O, et al. Effect of peripheral suture depth on strength of tendon repairs. J Hand Surg 1996;21A: 234-239.
47. Wade PJ, Muir IF , Hutcheon LL. Primary flexor tendon repairs:the mechanical limitations of the modified Kessler technique. J Hand Surg 1986;11B: 71-76.
48. Wade PJ, Wetherell RG,Amis AA. Flexor tendon repairs: significant gain in strength from the Halsted peripheral suture technique. J Hand Surg 1989;14B: 232-235.
49. Mashadi ZB, Amis AA. Strength of the suture in the epitendon and within the tendon fibres: development of stronger peripheral suture technique. J Hand Surg 1992;17B: 172-175.
50. Silva MJ, Boyer MI, Gelberman RH. Recent progress in flexor tendon healing. J Orthop Sci 2002: 7(4): 508-514.
51. Zhao C, Amadio PC, Momose T, et a1. Effect of synergistic wrist motion on adhesion formation after repair of partial flexor digitorum profundus tendonlacerations in a canine model in vivo. J Bone Joint Surg Am 2002; 84(1): 78-84.
52. Wada A, Kubota H, Miyanishi K, et a1. Effect of absorbable polydioxanone flexor tendon repair and restricted active mobilization in a canine model. J Hand Surg [Br], 2001; 26(4):301- 306.
53. 糜箐熠,邵新中,徐建光,等.主被动活动促进屈肌腱腱鞘修复的实验研究. 中华手外科杂志. 2002,18:248-250.
54. Barrie KA, Tomak SL, Cholewieki J, et a1. Effect of suture locking and suture caliber on fatigue strength of flexor tendon repairs. J Hand Surg [Am]. 2001;26(2):340-346.
55. Choueka J, Heminger H, Mass DP. Cyclical testing of zoneⅡ flexor tendon repairs. J Hand Surg [Am]. 2000; 25(6): l127-l134.
56. Angeles JG, Heminger H, Mass DP. Comparative biomechanical performances of 4–strand core suture repairs for zoneⅡ flexor tendon lacerations. J Hand Surg [Am], 2002; 27(3): 508-517.
57. Kane CJ, Hebda PA, Mansbridge JN, Hanawalt PC. Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutan -eous wound healing. Cell Physiol 1991;1 48: 157–173.
58. LeRoy EC, Trojanowska MI, Smith EA. Cytokines and human fibrosis. Eur Cyto -kine Netw 1990;1:215–219.
59. McCartney-Francis NL, Frazier-Jessen M, Wahl SM. TGF-beta: a balancing act. Int Rev Immunol 1998;16:553–580.
60. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67:753 –791.
61. Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEBJ 2004;18:816–827.
62. Roberts AB. TGF-beta signaling from receptors to the nucleus. Microbes Infect 1999;1:1265–1273.
63. Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998;93: 11 59–1170.
64. Lyons RM, Gentry LE, Purchio AF, Moses HL. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol 1990; 110:1361–1367.
65. Zawel L, Dai JL, Buckhaults P, Zhou S, KinzlerKW,Vogelstein B, et al. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1998; 1:611–617.
66. Liu B, Dou CL, Prabhu L, Lai E. FAST-2 is a mammalian winged-helix protein which mediates transforming growth factor beta signals. Mol Cell Biol 1999;19:424 –430.
67. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, et al. Identification of Smad7, a TGF beta-inducible antagonist of TGF-beta signalling. Nature 1997; 389:631–635.
68. Ogunjimi AA, Briant DJ, Pece-Barbara N, Le Roy C, Di Guglielmo GM, Kavsak P, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell 2005;19:297–308.
69. von Gersdorff G, Susztak K, Rezvani F, Bitzer M, Liang D, Bottinger EP. Smad 3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. J Biol Chem 2000; 275: 11320–11326.
70. Chen Y, Blom IE, Sa S, Goldschmeding R, Abraham DJ, Leask A.CTGFexpre -ssion in mesangial cells: involvement of SMADs, MAP kinase, and PKC. Kidney Int 2002;62:1149–1159.
71. Leask A, Holmes A, Black CM, Abraham DJ. CTGF gene regulation: require -ments for its induction by TGFβ in fibroblasts. J Biol Chem 2003; 278: 13008–13015.
72. Stratton R, Rajkumar V, Ponticos M, Nichols B, Shiwen X, Black CM, et al. Prostacyclin derivatives prevent the fibrotic response to TGF-beta by inhibiting the Ras/MEK/ERK pathway. FASEB J 2002;16:1949–1951.
73. Thannickal VJ, Lee DY, White ES, Cui Z, Larios JM, Chacon R, et al. Myo -fibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003; 278:12384 –12389.
74. Lee AA, Dillmann WH, McCulloch AD, Villarreal FJ. Angiotensin II stimulates the autocrine production of transforming growth factor-beta1 in adult rat cardiac fibro -blasts. J Mol Cell Cardiol 1995;27:2347–2357.
75. Campbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts.J Mol Cell Cardiol 1997; 29:1947–1958.
76. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, et al. Angioten -sin II type I receptor antagonist inhibits the gene expression of TGF-1 and extracell -ular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 1995;273:509–515.
77. Kupfahl C, Pink D, Friedrich K, Zurbrugg HR, Neuss M,Warnecke C, et al. Angi otensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res 2000;46:463–475.
78. Zhou Y, Poczatek MH, Berecek KH, Murphy-Ullrich JE. Thrombospondin1 mediates angiotensin II induction of TGF-beta activation by cardiac and renal cells under both high and low glucose conditions.Biochem Biophys Res Commun 2006; 339:633–641.
79. Boer RA, Pokharel S, Flesch M, van Kampen DA, Suurmeijer AJ,Boomsma F, et al. Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR (mRen2)27. J Mol Med 2004;82:678–687.
80. Chen K, Mehta JL, LiD, Joseph L, Joseph J. Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II. Circ Res 2004;95:1167–1173.
81. Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X, et al. Dysregulation of transforming growth factor beta signaling in scleroderma:overex-pression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 2002; 46:1857–1865.
82. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, et al. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB. J 1999;13:1774–1786.
83. Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, et al. Role and interaction of connective tissue growth factor with transforming growth factor- beta in persistent fibrosis: a mouse fibrosis model. J Cell Physiol 1999;181:153–159.
84. Shah M, Foreman DM, Ferguson MW. Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci 1994;107:1137–1157.
85. Cordeiro MF, Mead A, Ali RR, Alexander RA, Murray S, Chen C, et al. Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome. Gene Ther 2003;10:59–71.
86. Hao J, Ju H, Zhao S, Junaid A, Scammell-La Fleur T, Dixon IM. Elevation of expression of Smads 2, 3, and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. J Mol Cell Cardiol 1999;3 1: 667–678.
87. Wang B, Hao J, Jones SC, Yee MS, Roth JC, Dixon IM. Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am J Physiol Heart Circ Physiol 2002;282:H1685–696.
88. Lijnen P, Petrov V, Rumilla K, Fagard R. Transforming growth factorbeta 1 promotes contraction of collagen gel by cardiac fibroblasts through their differentiation into myofibroblasts. Methods Find Exp Clin Pharmacol 2003; 25: 79 –86.
89. Seeland U, Haeuseler C, Hinrichs R, Rosenkranz S, Pfitzner T, Scharffetter -Kochanek K, et al. Myocardial fibrosis in transforming growth factor-beta(1) (TGF-beta(1)) transgenic mice is associated with inhibition of interstitial collagenase. Eur J Clin Invest 2002; 32: 295–303.
90. Waltenberger J, Lundin L, Oberg K, Wilander E, Miyazono K, Heldin CH, et al. Involvement of transforming growth factor-beta in the formation of fibrotic lesions in carcinoid heart disease. Am J Pathol 1993; 142:71–78.
91. Kulkarni AB, Karlsson S. Transforming growth factor-beta1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease. Am J Pathol 1993;143:3–9.
92. Bottinger EP, Letterio JJ, Roberts AB. Biology of TGF-beta in knockout and transgenic mouse models. Kidney Int 1997;51:1355–1360. -57-
93. Chen Y, Shi-wen X, EastwoodM, Black CM, Denton CP, Leask A, et al.ALK5 (TGFβ receptor type I) signaling contributes to the fibrotic phenotype of scleroder -ma fibroblasts. Arthritis Rheum 2006;54:1309–1316.
94. Chen Y, Shiwen X, van Beek J, Kennedy L, McLeod M, Renzoni EA,et al. Matri -x contraction by dermal fibroblasts requires TGFbeta/ALK5, heparan sulfate contain -ing proteoglycans and MEK/ERK:insights into pathological scarring in chronic fibro -tic disease. Am J Pathol 2005;167:1699–1711.
95. Ling Hong,Li xuimei,Jha Sharda,et a1.Therapeutic role of TGF-beta Neutralizing antibody in mouse Cyclosporin A Nephrophthy:Morphologic improvement associated with functional Preservation[J]. Journal of the American Society of Nephrology,2003,14(2):377-388.
96. Andrew Y,zhang BS, Hung P, et al. Inhibition of TGF-β-Induced Collagen Production in Rabbit Flexor Tendons[J]. Hand Surg, 2004, 29A(2): 230-235.
97. liu W, Cai Z, Wang D, et al. Blocking transforming growth factor-beta receptors signaling down-regulates transforming growth factor-beta autoproduction in keloid fibroblasts. Chin J Traumatol, 2002, 5: 77-81.
98. Jaibaji M. Advances in the biology of zone Ⅱ lexor tendon healing and adhesion forming[J]. Ann Plast Surg,2000,45:83-92.
99. 李军,王金堂,韩学哲. TGF-β1抗体用于屈指肌腱术后的生物力学研究[J].中国矫形外科杂志,2004,12(16):1259-1261.
100.Hsu C, Alto P, chang J, et al. Clinical Implications of Growth Factors in Flexor Tendon Wound Healing[J]. Hand Surg, 2004, 29A(4): 551-563
101.邹剑,张长青. 可吸收膜预防鸡肌腱粘连的实验研究[J].中华创伤骨科杂志,2005,10(7):967-970.
102.黄启顺,王发斌,康浩. 聚-DL-乳酸可吸收性防粘连膜预防肌腱粘连的临床应用[J]. 中华创伤骨科杂志,2005,10(7):990-991.
103.Demirken F, Colakoglu N, Herek O, et al. The use of amniotic membrane in flexor tendon repair: an experimental model. Arch Orthop Trauma Surg, 2002,122: 396-399.
104.Tuncay I, Ozbek H, Atik B, et al. Effects of hyaluronic acid on postoperative adhesion of tendon calcaneus surgery: an experimental study in rats. J Foot Ankle Surg.2002,41:104-108.
105.吴尧平,陆裕朴,石凯军. “无人区”肌腱损伤修复的实验研究[J].中华医学杂志,1990,70(4):195-198.
2. Filyak Y, Filyak O, Stoika R. Transforming growth factor beta-1 enhances cytotoxic effect of doxorubicin in human lung adenocarcinoma cells of A549 line. J Cell Biology International 2007 ,31 :851-855.
3. Khan U, Occlestion NL, Khaw PT, Megrouther DA. Differences in proliferative rate and collagen lattice contraction between endotendon and synovial fibroblasts.J Hand surg(Am) 1998, 23: 266-273.
4. 宋永枝,王发斌,洪光祥,等. 5-氟尿嘧啶防止肌腱粘连的实验研究. 中华手外科杂志. 2004,20(4):249-251.
5. Dinsdate CJ.Mirza FM.Wiehe Glycerol alters cytoskeleton and cell adhesion while inhibiting cell proliferatlon. Cell Biol Int Rep 1992.16:591-602.
6. 潘勇卫,韦加宁,张有乐,等. 甘油合剂和透明质酸钠预防鸡鞘管区屈肌腱粘连的实验研究. 中华骨科杂志. 2000,20(4):245-248.
7. chang J, Most D, Thunder R, et al. Molecular Studies in Flexor Tendon Wound Healing: The Role of Basic Fibroblast Growth Factor Gene Expression[J]. Hand Surg 1998, 23A (6): 1052-1058.
8. Boyer MI, Goldfarb CA, Gelberman RH. Recent Progress in Flexor Tendon Healing The Modulation of Tendon Healing With Rehabilitation Variables[J]. Hand Surg 2005, 18(2): 80-85.
9. Nago M,Pham H,Longaker MT,et a1.Differential expression of transforming growth factor-beta receptors in a rabbit zone Ⅱf lexor tendonwound healing model. Plast Reconstr Surg 2001;108(5):1260～1267.
10. Klein MB, Yalamanchi N, Pham H, et al. Flexor Tendon Healing In Vitro: Effects of TGF-β on Tendon Cell Collagen Production[J]. Hand Surg 2002, 27A(4): 615-620.
11. 陈至着,王立飞. 透明质酸防止屈肌腱粘连的实验研究. 中华外科杂志. 1995,33:526-528.
12. 叶根茂,候春林. 几丁糖预防免屈肌腱粘连的试验研究. 中华手外科杂志. 1994,10:51-53.
13. 吕德威,严忠群,刘宗明. 壳聚糖预防鸡趾屈肌腱粘连的实验研究. 中华手外科杂志. 1996,12:49-51.
14. 张卫国,姜长明,曹国英,等.高分子纤维素预防肌腱粘连的实验研究. 中华手外科杂志. 1995,11:51-53.
15. Boris WJ, McGrath LB, Effectiveness of fibrin glue in the reduction of postopera -tive intrapericardial adhesions[J].J Invest Surg 1996, 9: 327-333.
16. Toosie K, Gallego K, Stabike BE, et al . fibrin glue reduces intra-abdominal adhesions to synthetic mesh in a rat ventral hernia model[J]Am Surg 2000, 66:41-45.
17. 黄启顺,王发斌,康 浩,等.聚-DL-乳酸可吸收性防粘连膜预防肌腱粘连的临床应用. 中华创伤骨科杂志. 2005,7(10):990-991.
18. Strickland JW. Flexor tendon injuries: Foundation of treatment. J Am Acad Orthop Surg 1995; 3: 44-54.
19. Lee H. Double Loop Locking suture:a technique of tendon repair for early active mobilization. Part Ⅰ: evolution of technique and experimental study. J Hand Surg 1990; 15A: 945-952.
20. Lee H. Double Loop Locking suture:a technique of tendon repair for early active mobilization. Part Ⅱ:clinical experience. J Hand Surg 1990; 15A:953-958.
21. Robertson GA, Al-Quattan MM. A biomechanical analysis of a new interlock suture technique for Flexor tendon repair. J Hand Surg 1992; 17B: 92-93.
22. Strickland JW. Flexor tendon repair: Indiana method. The Indiana Hand Center Newsletter 1993; 1: 1-12.
23. Strickland JW. Flexor tendon injuries:Ⅱ .Operative technique. J Am Acad Orthop Surg 1995; 3: 55-62.
24. Strickland JW.The Indiana method of flexor tendon repair. Atlas Hand Clin 1996; 1: 77-103.
25. Strickland JW. Flexor tendons-acute injuries.In: Green DP.Hotchkiss RN, Pederson WC, eds. Green, s operative hand surgery. 4th ed.New York: Churchill Livingstone 1999; 1851-1897.
26. Singer G,Ebramzadeh E, Jones NF, Meals R. Use of Taguchi method for biomechanical comparison of flexor tendon repair technique to allow immediate active flexion. A new method of analysis and optimization of technique to improve the quality of repair. J, Bone Joint Surg 1998; 80A:1498-1506.
27. Becker H, Davidoff M.Eliminating the gap in flexor tendon surgery. A new method of suture. Hand 1977; 9: 306-311.
28. Mclarney E, Hoffman H,Wolfe SW. Biomechanical analysis of the cruciate four-strand flexor tendon repair. J Hand Surg 1999;24A: 295-301.
29. Savage R. In vitro studies of a new method of flexor tendon repair. J Hand Surg 1985;10B: 135-141.
30. Savage R, Risitano G. Flexor tendon repair using a “six strand” method of repair and early active mobilisation. J Hand Surg 1989;14B: 396-399.
31. Lim BH, Tsai TM. The six-strand technique for flexor tendon repair. Atlas Hand Clin 1996;1: 65-76.
32. Sandow MJ, McMahon MM. Single cross-grasp six-strand repair for acute flexor tenorrhaphy: modified Savage technique. Atlas Hand Clin 1966;1: 41-64.
33. Kusano N, Yoshizu T, Maki Y. Experimental studies of two new flexor tendon suture techniques for postoperative early active flexion exercises. J Hand Surg 1999;24B: 152-156.
34. Wagner WF, Carroll C,Strickland JW, et a1. A biomechanical comparison of techniques of flexor tendon repair. J Hand Surg 1994;19A: 979-983.
35. Thurman RT, Trumbel TJ,Hanel DP, et a1. Two,four and six-strand zone Ⅱ flexor tendon repairs:an in-situ biomechanical comparison using a cadaver model. J Hand Surg 1998;23A: 261-265.
36. Silva MJ, Hollstien SB, Fayazi AH, et a1. The effects of multiple-strand suture techniques on the tensile properties of repair of the flexor digitorum profundus tendon to bone. J Bone Joint Surg 1998; 80A: 1507-1514.
37. Ejeskar A, Irstam L. Elongation in profundus tendon repair: a clinical and radiological study. Scand J Plast Reconstr Surg 1981;15: 61-68.
38. Kulick MI, Kilgore ES,Newmeyer WL. Pseudotendon formation after flexor tendon injury. J Hand Surg 1985;10A: 638-640.
39. Lin GT, An KN,Amadio PC, et a1. Biomechanical studies of running suture for flexor tendons in dogs. J Hand Surg 1988;13A: 553-558.
40. Lindsay WK, Thomson HG , Walker FG. Digital flexor tendon:an experimental study: partⅡ :the significance of a gap occurring at the line of suture. Br J Plast Surg 1960;12: 289-316.
41. Pruitt DL, Manske PR,Fink B. Cyclic stress analysis of flexor tendon repair.J Hand Surg 1991;16A: 701-707.
42. Pruitt DL, Tanaka H,Aoki M, et al. Cyclic stress testing after in vivo healing of canine flexor tendon lacerations. J Hand Surg 1996;21A: 974-977.
43. Seradge H. Elongation of the repair configuration following flexor tendon repair. J Hand Surg 1983;8: 182-185.
44. Silfverskiold KL, May EJ,Tornvall AH. Gap formation during controlled motion after flexor tendon repair in zone Ⅱ: a prospective clinical study. J Hand Surg 1992;17A: 539-546.
45. Silfverskiold KL, May EJ. Gap formation during controlled motion after flexor tendon repair in zoneⅡ : results with a new controlled motion programme. Scand J Plast Reconstr Hand Surg 1993;27: 263-268.
46. Diao E, Hariharan JS,Soejima O, et al. Effect of peripheral suture depth on strength of tendon repairs. J Hand Surg 1996;21A: 234-239.
47. Wade PJ, Muir IF , Hutcheon LL. Primary flexor tendon repairs:the mechanical limitations of the modified Kessler technique. J Hand Surg 1986;11B: 71-76.
48. Wade PJ, Wetherell RG,Amis AA. Flexor tendon repairs: significant gain in strength from the Halsted peripheral suture technique. J Hand Surg 1989;14B: 232-235.
49. Mashadi ZB, Amis AA. Strength of the suture in the epitendon and within the tendon fibres: development of stronger peripheral suture technique. J Hand Surg 1992;17B: 172-175.
50. Silva MJ, Boyer MI, Gelberman RH. Recent progress in flexor tendon healing. J Orthop Sci 2002: 7(4): 508-514.
51. Zhao C, Amadio PC, Momose T, et a1. Effect of synergistic wrist motion on adhesion formation after repair of partial flexor digitorum profundus tendonlacerations in a canine model in vivo. J Bone Joint Surg Am 2002; 84(1): 78-84.
52. Wada A, Kubota H, Miyanishi K, et a1. Effect of absorbable polydioxanone flexor tendon repair and restricted active mobilization in a canine model. J Hand Surg [Br], 2001; 26(4):301- 306.
53. 糜箐熠,邵新中,徐建光,等.主被动活动促进屈肌腱腱鞘修复的实验研究. 中华手外科杂志. 2002,18:248-250.
54. Barrie KA, Tomak SL, Cholewieki J, et a1. Effect of suture locking and suture caliber on fatigue strength of flexor tendon repairs. J Hand Surg [Am]. 2001;26(2):340-346.
55. Choueka J, Heminger H, Mass DP. Cyclical testing of zoneⅡ flexor tendon repairs. J Hand Surg [Am]. 2000; 25(6): l127-l134.
56. Angeles JG, Heminger H, Mass DP. Comparative biomechanical performances of 4–strand core suture repairs for zoneⅡ flexor tendon lacerations. J Hand Surg [Am], 2002; 27(3): 508-517.
57. Kane CJ, Hebda PA, Mansbridge JN, Hanawalt PC. Direct evidence for spatial and temporal regulation of transforming growth factor beta 1 expression during cutan -eous wound healing. Cell Physiol 1991;1 48: 157–173.
58. LeRoy EC, Trojanowska MI, Smith EA. Cytokines and human fibrosis. Eur Cyto -kine Netw 1990;1:215–219.
59. McCartney-Francis NL, Frazier-Jessen M, Wahl SM. TGF-beta: a balancing act. Int Rev Immunol 1998;16:553–580.
60. Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998; 67:753 –791.
61. Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEBJ 2004;18:816–827.
62. Roberts AB. TGF-beta signaling from receptors to the nucleus. Microbes Infect 1999;1:1265–1273.
63. Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, et al. Thrombospondin-1 is a major activator of TGF-beta1 in vivo. Cell 1998;93: 11 59–1170.
64. Lyons RM, Gentry LE, Purchio AF, Moses HL. Mechanism of activation of latent recombinant transforming growth factor beta 1 by plasmin. J Cell Biol 1990; 110:1361–1367.
65. Zawel L, Dai JL, Buckhaults P, Zhou S, KinzlerKW,Vogelstein B, et al. Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1998; 1:611–617.
66. Liu B, Dou CL, Prabhu L, Lai E. FAST-2 is a mammalian winged-helix protein which mediates transforming growth factor beta signals. Mol Cell Biol 1999;19:424 –430.
67. Nakao A, Afrakhte M, Moren A, Nakayama T, Christian JL, Heuchel R, et al. Identification of Smad7, a TGF beta-inducible antagonist of TGF-beta signalling. Nature 1997; 389:631–635.
68. Ogunjimi AA, Briant DJ, Pece-Barbara N, Le Roy C, Di Guglielmo GM, Kavsak P, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell 2005;19:297–308.
69. von Gersdorff G, Susztak K, Rezvani F, Bitzer M, Liang D, Bottinger EP. Smad 3 and Smad4 mediate transcriptional activation of the human Smad7 promoter by transforming growth factor beta. J Biol Chem 2000; 275: 11320–11326.
70. Chen Y, Blom IE, Sa S, Goldschmeding R, Abraham DJ, Leask A.CTGFexpre -ssion in mesangial cells: involvement of SMADs, MAP kinase, and PKC. Kidney Int 2002;62:1149–1159.
71. Leask A, Holmes A, Black CM, Abraham DJ. CTGF gene regulation: require -ments for its induction by TGFβ in fibroblasts. J Biol Chem 2003; 278: 13008–13015.
72. Stratton R, Rajkumar V, Ponticos M, Nichols B, Shiwen X, Black CM, et al. Prostacyclin derivatives prevent the fibrotic response to TGF-beta by inhibiting the Ras/MEK/ERK pathway. FASEB J 2002;16:1949–1951.
73. Thannickal VJ, Lee DY, White ES, Cui Z, Larios JM, Chacon R, et al. Myo -fibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. J Biol Chem 2003; 278:12384 –12389.
74. Lee AA, Dillmann WH, McCulloch AD, Villarreal FJ. Angiotensin II stimulates the autocrine production of transforming growth factor-beta1 in adult rat cardiac fibro -blasts. J Mol Cell Cardiol 1995;27:2347–2357.
75. Campbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts.J Mol Cell Cardiol 1997; 29:1947–1958.
76. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, et al. Angioten -sin II type I receptor antagonist inhibits the gene expression of TGF-1 and extracell -ular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 1995;273:509–515.
77. Kupfahl C, Pink D, Friedrich K, Zurbrugg HR, Neuss M,Warnecke C, et al. Angi otensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res 2000;46:463–475.
78. Zhou Y, Poczatek MH, Berecek KH, Murphy-Ullrich JE. Thrombospondin1 mediates angiotensin II induction of TGF-beta activation by cardiac and renal cells under both high and low glucose conditions.Biochem Biophys Res Commun 2006; 339:633–641.
79. Boer RA, Pokharel S, Flesch M, van Kampen DA, Suurmeijer AJ,Boomsma F, et al. Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR (mRen2)27. J Mol Med 2004;82:678–687.
80. Chen K, Mehta JL, LiD, Joseph L, Joseph J. Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II. Circ Res 2004;95:1167–1173.
81. Leask A, Abraham DJ, Finlay DR, Holmes A, Pennington D, Shi-Wen X, et al. Dysregulation of transforming growth factor beta signaling in scleroderma:overex-pression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 2002; 46:1857–1865.
82. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, et al. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB. J 1999;13:1774–1786.
83. Mori T, Kawara S, Shinozaki M, Hayashi N, Kakinuma T, Igarashi A, et al. Role and interaction of connective tissue growth factor with transforming growth factor- beta in persistent fibrosis: a mouse fibrosis model. J Cell Physiol 1999;181:153–159.
84. Shah M, Foreman DM, Ferguson MW. Neutralising antibody to TGF-beta 1,2 reduces cutaneous scarring in adult rodents. J Cell Sci 1994;107:1137–1157.
85. Cordeiro MF, Mead A, Ali RR, Alexander RA, Murray S, Chen C, et al. Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome. Gene Ther 2003;10:59–71.
86. Hao J, Ju H, Zhao S, Junaid A, Scammell-La Fleur T, Dixon IM. Elevation of expression of Smads 2, 3, and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. J Mol Cell Cardiol 1999;3 1: 667–678.
87. Wang B, Hao J, Jones SC, Yee MS, Roth JC, Dixon IM. Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am J Physiol Heart Circ Physiol 2002;282:H1685–696.
88. Lijnen P, Petrov V, Rumilla K, Fagard R. Transforming growth factorbeta 1 promotes contraction of collagen gel by cardiac fibroblasts through their differentiation into myofibroblasts. Methods Find Exp Clin Pharmacol 2003; 25: 79 –86.
89. Seeland U, Haeuseler C, Hinrichs R, Rosenkranz S, Pfitzner T, Scharffetter -Kochanek K, et al. Myocardial fibrosis in transforming growth factor-beta(1) (TGF-beta(1)) transgenic mice is associated with inhibition of interstitial collagenase. Eur J Clin Invest 2002; 32: 295–303.
90. Waltenberger J, Lundin L, Oberg K, Wilander E, Miyazono K, Heldin CH, et al. Involvement of transforming growth factor-beta in the formation of fibrotic lesions in carcinoid heart disease. Am J Pathol 1993; 142:71–78.
91. Kulkarni AB, Karlsson S. Transforming growth factor-beta1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease. Am J Pathol 1993;143:3–9.
92. Bottinger EP, Letterio JJ, Roberts AB. Biology of TGF-beta in knockout and transgenic mouse models. Kidney Int 1997;51:1355–1360. -57-
93. Chen Y, Shi-wen X, EastwoodM, Black CM, Denton CP, Leask A, et al.ALK5 (TGFβ receptor type I) signaling contributes to the fibrotic phenotype of scleroder -ma fibroblasts. Arthritis Rheum 2006;54:1309–1316.
94. Chen Y, Shiwen X, van Beek J, Kennedy L, McLeod M, Renzoni EA,et al. Matri -x contraction by dermal fibroblasts requires TGFbeta/ALK5, heparan sulfate contain -ing proteoglycans and MEK/ERK:insights into pathological scarring in chronic fibro -tic disease. Am J Pathol 2005;167:1699–1711.
95. Ling Hong,Li xuimei,Jha Sharda,et a1.Therapeutic role of TGF-beta Neutralizing antibody in mouse Cyclosporin A Nephrophthy:Morphologic improvement associated with functional Preservation[J]. Journal of the American Society of Nephrology,2003,14(2):377-388.
96. Andrew Y,zhang BS, Hung P, et al. Inhibition of TGF-β-Induced Collagen Production in Rabbit Flexor Tendons[J]. Hand Surg, 2004, 29A(2): 230-235.
97. liu W, Cai Z, Wang D, et al. Blocking transforming growth factor-beta receptors signaling down-regulates transforming growth factor-beta autoproduction in keloid fibroblasts. Chin J Traumatol, 2002, 5: 77-81.
98. Jaibaji M. Advances in the biology of zone Ⅱ lexor tendon healing and adhesion forming[J]. Ann Plast Surg,2000,45:83-92.
99. 李军,王金堂,韩学哲. TGF-β1抗体用于屈指肌腱术后的生物力学研究[J].中国矫形外科杂志,2004,12(16):1259-1261.
100.Hsu C, Alto P, chang J, et al. Clinical Implications of Growth Factors in Flexor Tendon Wound Healing[J]. Hand Surg, 2004, 29A(4): 551-563
101.邹剑,张长青. 可吸收膜预防鸡肌腱粘连的实验研究[J].中华创伤骨科杂志,2005,10(7):967-970.
102.黄启顺,王发斌,康浩. 聚-DL-乳酸可吸收性防粘连膜预防肌腱粘连的临床应用[J]. 中华创伤骨科杂志,2005,10(7):990-991.
103.Demirken F, Colakoglu N, Herek O, et al. The use of amniotic membrane in flexor tendon repair: an experimental model. Arch Orthop Trauma Surg, 2002,122: 396-399.
104.Tuncay I, Ozbek H, Atik B, et al. Effects of hyaluronic acid on postoperative adhesion of tendon calcaneus surgery: an experimental study in rats. J Foot Ankle Surg.2002,41:104-108.
105.吴尧平,陆裕朴,石凯军. “无人区”肌腱损伤修复的实验研究[J].中华医学杂志,1990,70(4):195-198.