新型载药电极对耳蜗影响的实验研究
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摘要
【目的】探索载药电极在离体环境和内耳的药代动学规律;研究该电极对人工耳蜗植入后听觉电生理的影响,评价其对内耳形态学方面的影响。
【方法】内参法建立地塞米松的高效液相色谱检测方法。离体药物释放试验采用厚薄两种载有2%地塞米松的硅胶片,以人工外淋巴为释放液,模拟人类内耳液体环境进行半年内定期取样,高效液相色谱法检测药物度。在体药代动力学试验向豚鼠耳蜗植入载有2%或10%地塞米松的硅胶电极,一周内定期取外淋巴液,同法检测样品内的药物浓度。听觉电生理学研究先对豚鼠畸变产物耳声发射刺激声频率比值f2/f1进行优化,设置检测参数;然后向鼓阶植入空白电极和载有2%地塞米松的电极,检测术后半年内听性脑干反应的阈值和畸变产物耳声发射,比较两组动物术后听力的变化。组织学研究对术后耳蜗行石蜡切片,H&E、TNF-alpha染色,光镜下评价术后一月耳蜗的形态及特异性染色的强度。
【结果】1.本文使用的地塞米松的高效液相色谱检测方法具有可靠性。离体药物释放试验证明半年内两种厚度的硅胶均能持续释放地塞米松,较厚硅胶所达到的药物浓度稍高于较薄硅胶,两者的释放特点符合零级代代动力学规律和Higuchi释放模式。2.在体药代动力学试验证明,两种不同浓度的地塞米松电极在耳蜗的达峰时间均为半小时,随后内耳的药物浓度迅速降低,术后1天至1周的时间内相对稳定。3.听力学研究显示听性脑干反应与畸变产物耳声发射的结果具有一致性;两组动物在电极植入后一周的时间内以出现全频急性和继发性听力下降;术后一周到半年载药电极组的听力有一定程度的恢复,而空白电极组的听力恢复不明显;此听力变化尤以8-16kHz为著。4.组织学观察发现电极植入一月后内耳的螺旋器形态较非手术耳差(P = 0.031),鼓阶内出现新生组织。听力较佳耳的螺旋器形态优于听力较差耳,耳蜗第2回的TNF-alpha染色略浅于后者;载药电极组的鼓阶内的新生组织TNF-alpha特异染色的细胞数较空白电极组少,第2回螺旋器及耳蜗外侧壁结构的特异性着色较后者浅。
【结论】离体和在体条件下载药硅胶电极的释药性能具有一致性,电极能够持续释放地塞米松,载药量较多的电极在稳定期的药物浓度略高于载药量较少的电极,前者的持续释药时间将长于后者。向耳蜗内植入电极对听力有损伤作用;载有地塞米松的人工耳蜗电极对能促进术后听力的恢复。电极释放的地塞米松能抑制TNF-alpha特异的炎性细胞,减轻内耳术后的炎症反应。
Aim: To study the pharmacokinetics of the drug-releasing silicone electrode in vitro and in vivo. To evaluate the effect of the drug-releasing electrode on hearing and the histological effect on the cochlea.
Methods: The assessment of dexamethasone was established by high-performance liquid chromatography with internal standard. Two sizes of silicone piece containing 2% dexamethasone were used in the in vitro study, the 1 mL-chamber and 160μL-capillary were designed as releasing container, and artificial perilymph was used as releasing medium; sampling was scheduled in the duration of half year in the study in vitro. In the pharmacokinetic study in vivo, silicone electrodes containing 2% or 10% dexamethasone was implanted into the cochlea of guinea pigs; samples were taken from cochlea apex 1 week postoperatively. All the samples were analysed by high-performance liquid chromatography. Before the hearing study the stimulus ratio f2/f1 was optimized for distortion otoacoustic emission (DPOAE). Then silicone electrodes containing 2% dexamethasone or without dexamethasone were implanted into the cochlea of guinea pigs, auditory brainstem response (ABR) and DPOAE were regularly measured half year postoperatively. The results were compared with Mann Whitney U test. In the histological study, paraffin slices were prepared with the unoperated cochlea and the cochlea 1 month post operation. H&E staining and TNF-alpha staining were carried out. For assessment 2 criterions were established - the hearing level and the type of the electrode. Morphology and staining of the cochlea were classified objectively.
Results: The assessment of dexamethasone by high-performance liquid chromatography was reliable. Stable drug concentration could be achieved in the in vitro study, the result from the chamber group and the capillary group was comparable, fitted well to the zero-order pharmacokinetics and the Higuchi model. In the pharmacokinetic study in vivo, the maximal concentration was achieved by both of the 2 types of silicone electrode (containing 2% or 10% dexamethasone) half hour postoperatively, then the concentration decreased rapidly; the drug concentration in the inner ear was relatively stable from the 1st day to the 1st week after surgery. The concentration of the 10% dexamethasone electrode group was a little higher than the 2% dexamethasone electrode group. In the functional study, the result of ABR and DPOAE measurement was consistent. All the implanted ears exhibited an immediate hearing loss just at the end of the operation and an increasing hearing loss within the 1st week post operation. From the 1st week to the half year the hearing level of the dexamethasone group recovered significantly, whereas the placebo group showed no significant recovery. This chagne of hearing took place throughout all the frequencies, whereas most apparent at 8-16 kHz. In the histological study there was new connective tissue in the scala tympani of the implanted cochlea, and the organ of Corti was destructed significantly compared with the unoperated cochlea (p=0.031). In the group with better hearing level, the morphology of the organ of Corti was better than that of the group with worse hearing level. In the DEXA group, the TNF-alpha expression in the cells of the new connective tissue as well as in the 2nd turn was less than that of the placebo group.
Conclusion: The pharmacokinetics of the in vitro and in vivo study is consistent; the silicone electrode can steadily release dexamethasone; the electrode containing more dexamethasone can achieve the concentration a little higher than the electrode containing less dexamethasone, and the releasing time of the former is longer than the latter. Cochlear implant can induce hearing loss and the drug-releasing electrode can conserve the hearing level postoperatively. The morphology of the cochlea and the TNF-alpha staining has relationship with the hearing level. Dexamethasone can potentially reduce the TNF-alpha specific cells and alleviate the inflammation after cochlear implantation.
【方法】内参法建立地塞米松的高效液相色谱检测方法。离体药物释放试验采用厚薄两种载有2%地塞米松的硅胶片,以人工外淋巴为释放液,模拟人类内耳液体环境进行半年内定期取样,高效液相色谱法检测药物度。在体药代动力学试验向豚鼠耳蜗植入载有2%或10%地塞米松的硅胶电极,一周内定期取外淋巴液,同法检测样品内的药物浓度。听觉电生理学研究先对豚鼠畸变产物耳声发射刺激声频率比值f2/f1进行优化,设置检测参数;然后向鼓阶植入空白电极和载有2%地塞米松的电极,检测术后半年内听性脑干反应的阈值和畸变产物耳声发射,比较两组动物术后听力的变化。组织学研究对术后耳蜗行石蜡切片,H&E、TNF-alpha染色,光镜下评价术后一月耳蜗的形态及特异性染色的强度。
【结果】1.本文使用的地塞米松的高效液相色谱检测方法具有可靠性。离体药物释放试验证明半年内两种厚度的硅胶均能持续释放地塞米松,较厚硅胶所达到的药物浓度稍高于较薄硅胶,两者的释放特点符合零级代代动力学规律和Higuchi释放模式。2.在体药代动力学试验证明,两种不同浓度的地塞米松电极在耳蜗的达峰时间均为半小时,随后内耳的药物浓度迅速降低,术后1天至1周的时间内相对稳定。3.听力学研究显示听性脑干反应与畸变产物耳声发射的结果具有一致性;两组动物在电极植入后一周的时间内以出现全频急性和继发性听力下降;术后一周到半年载药电极组的听力有一定程度的恢复,而空白电极组的听力恢复不明显;此听力变化尤以8-16kHz为著。4.组织学观察发现电极植入一月后内耳的螺旋器形态较非手术耳差(P = 0.031),鼓阶内出现新生组织。听力较佳耳的螺旋器形态优于听力较差耳,耳蜗第2回的TNF-alpha染色略浅于后者;载药电极组的鼓阶内的新生组织TNF-alpha特异染色的细胞数较空白电极组少,第2回螺旋器及耳蜗外侧壁结构的特异性着色较后者浅。
【结论】离体和在体条件下载药硅胶电极的释药性能具有一致性,电极能够持续释放地塞米松,载药量较多的电极在稳定期的药物浓度略高于载药量较少的电极,前者的持续释药时间将长于后者。向耳蜗内植入电极对听力有损伤作用;载有地塞米松的人工耳蜗电极对能促进术后听力的恢复。电极释放的地塞米松能抑制TNF-alpha特异的炎性细胞,减轻内耳术后的炎症反应。
Aim: To study the pharmacokinetics of the drug-releasing silicone electrode in vitro and in vivo. To evaluate the effect of the drug-releasing electrode on hearing and the histological effect on the cochlea.
Methods: The assessment of dexamethasone was established by high-performance liquid chromatography with internal standard. Two sizes of silicone piece containing 2% dexamethasone were used in the in vitro study, the 1 mL-chamber and 160μL-capillary were designed as releasing container, and artificial perilymph was used as releasing medium; sampling was scheduled in the duration of half year in the study in vitro. In the pharmacokinetic study in vivo, silicone electrodes containing 2% or 10% dexamethasone was implanted into the cochlea of guinea pigs; samples were taken from cochlea apex 1 week postoperatively. All the samples were analysed by high-performance liquid chromatography. Before the hearing study the stimulus ratio f2/f1 was optimized for distortion otoacoustic emission (DPOAE). Then silicone electrodes containing 2% dexamethasone or without dexamethasone were implanted into the cochlea of guinea pigs, auditory brainstem response (ABR) and DPOAE were regularly measured half year postoperatively. The results were compared with Mann Whitney U test. In the histological study, paraffin slices were prepared with the unoperated cochlea and the cochlea 1 month post operation. H&E staining and TNF-alpha staining were carried out. For assessment 2 criterions were established - the hearing level and the type of the electrode. Morphology and staining of the cochlea were classified objectively.
Results: The assessment of dexamethasone by high-performance liquid chromatography was reliable. Stable drug concentration could be achieved in the in vitro study, the result from the chamber group and the capillary group was comparable, fitted well to the zero-order pharmacokinetics and the Higuchi model. In the pharmacokinetic study in vivo, the maximal concentration was achieved by both of the 2 types of silicone electrode (containing 2% or 10% dexamethasone) half hour postoperatively, then the concentration decreased rapidly; the drug concentration in the inner ear was relatively stable from the 1st day to the 1st week after surgery. The concentration of the 10% dexamethasone electrode group was a little higher than the 2% dexamethasone electrode group. In the functional study, the result of ABR and DPOAE measurement was consistent. All the implanted ears exhibited an immediate hearing loss just at the end of the operation and an increasing hearing loss within the 1st week post operation. From the 1st week to the half year the hearing level of the dexamethasone group recovered significantly, whereas the placebo group showed no significant recovery. This chagne of hearing took place throughout all the frequencies, whereas most apparent at 8-16 kHz. In the histological study there was new connective tissue in the scala tympani of the implanted cochlea, and the organ of Corti was destructed significantly compared with the unoperated cochlea (p=0.031). In the group with better hearing level, the morphology of the organ of Corti was better than that of the group with worse hearing level. In the DEXA group, the TNF-alpha expression in the cells of the new connective tissue as well as in the 2nd turn was less than that of the placebo group.
Conclusion: The pharmacokinetics of the in vitro and in vivo study is consistent; the silicone electrode can steadily release dexamethasone; the electrode containing more dexamethasone can achieve the concentration a little higher than the electrode containing less dexamethasone, and the releasing time of the former is longer than the latter. Cochlear implant can induce hearing loss and the drug-releasing electrode can conserve the hearing level postoperatively. The morphology of the cochlea and the TNF-alpha staining has relationship with the hearing level. Dexamethasone can potentially reduce the TNF-alpha specific cells and alleviate the inflammation after cochlear implantation.
引文
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27. Eshraghi AA, Adil E, He J, Graves R, Balkany TJ, Van De Water TR. Local Dexamethasone Therapy Conserves in an Animal Model of Electrode Insertion Trauma Induced Hearing Loss Otol Neurotol 2007 Sep; 28(6):842-9.
28. Somdas MA, Li PM, Whiten DM, Eddington DK, Nadol JB Jr. Quantitative Evaluation of New Bone and Fibrous Tissue in the Cochlea following Cochlear Implantation in the Human Audiol Neurotol 2007; 12(5):277-84.
29. Eshraghi, A.A., He, J., Mou, CH., Polak, M., Zine, A., Bonny, C., Balkany, TJ., Van De Water, TR. D-JNKI-1 treatment prevents the progression of hearing loss in a model of cochlear implantation trauma. Otol. Neurotol. 2006 Jun; 27(4):504-11.
30. Eshraghi AA, Wang J, Adil E, He J, Zine A, Bublik M, Bonny C, Puel JL, Balkany TJ, Van De Water TR. Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity Hearing Research 2007 Apr; 226(1-2):168-77.
1. Fayad J, Linthicum FR Jr, Otto SR, Galey FR, House WF. Cochlear implants: histopathologic findings related to performance in 16 human temporal bones. Ann Otol Rhinol Laryngol. 1991 Oct; 100 (10):807-11.
2. Welling DB, Hinojosa R, Gantz BJ, Lee JT. Insertional trauma of multichannel cochlear implants. Laryngoscope 1993 Sep; 103(9):995-1001.
3. Nadol JB, Shiao JYS, Burge BJ, et al. Histopathology of cochlear implants in humans. Ann Otol Rhinol Laryngol. 2001 Sep; 110(9):883-91.
4. Eshraghi AA, Yang N, Balkany TJ. Comparative study of cochlear damage with three perimodiolar electrode designs. Laryngoscope 2003 Mar; 113(3):415-9.
5. Kawano A, Seldon HL, Clark GM, Ramsden RT, Raine CH: Intracochlear factors contributing to psychophysical percepts following cochlear implantation. Acta Otolaryngol 1998 Jun; 118(3):313-26.
6. Somdas MA, Li PM, Whiten DM, Eddington DK, Nadol JB Jr. Quantitative Evaluation of New Bone and Fibrous Tissue in the Cochlea following Cochlear Implantation in the Human Audiol Neurotol 2007; 12(5):277-84.
7. Aminpour S, Tinling SP, Brodie HA: Role of tumor necrosis factor-alpha in sensorineural hearing loss after bacterial meningitis. Otol Neurotol 2005 Jul; 26(4):602-9.
8. DeSautel MD, Brodie HA: Effects of depletion of complement in the development of labyrinthitis ossificans. Laryngoscope 1999 Oct; 109(10):1674-8.
9. Nadol JB Jr, Eddington DK: Histologic evaluation of the tissue seal and biologic response around cochlear implant electrodes in the human. Otol Neurotol 2004 May; 25(3):257-62.
10. Maeda K, Yoshida K, Ichimiya I, Suzuki M. Dexamethasone inhibits tumor necrosis factor-alpha-induced cytokine secretion from spiral ligament fibrocytes. Hear Res. 2005 Apr; 202(1-2):154-60.
11. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases.N Engl J Med. 1997 Apr 10; 336(15):1066-71. Review.
12. Kiefer J, Gstoettner W, Baumgartner W, et al. Conversation of low-frequency hearing in cochlear implantation. Acta Otolaryngol (Stockh) 2003; 123:1-10.
13. Huang CQ, Tykocinski M, Stathopoulos D, Cowan R. Effects of steroids and lubricants on electrical impedance and tissue response following cochlear implantation. Cochlear Implants Int. 2007 Sep; 8(3):123-47.
14. Zou J, Pyykk? I, Sutinen P, Toppila E. Vibration induced hearing loss in guinea pig cochlea: expression of TNF-alpha and VEGF. Hear Res. 2005 Apr;202 (1-2):13-20.
15. Tornabene SV, Sato K, Pham L, Billings P, Keithley EM. Immune cell recruitment following acoustic trauma. Hear Res. 2006 Dec; 222(1-2):115-24.
16. Hirose K, Discolo CM, Keasler JR, Ransohoff R. Mononuclear phagocytes migrate into the murine cochlea after acoustic trauma. J Comp Neurol. 2005 Aug 22; 489(2):180-94.
17. Fujioka M, Kanzaki S, Okano HJ, Masuda M, Ogawa K, Okano H. Proinflammatory cytokines expression in noise-induced damaged cochlea. J Neurosci Res. 2006 Mar;83(4):575-83.
18. Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM. Tumor necrosis factor-alpha, an initiator, and etanercept, an inhibitor of cochlear inflammation. Laryngoscope. 2002 Sep; 112(9):1627-34.
1. Fayad J, Linthicum FR Jr, Otto SR, Galey FR, House WF. Cochlear implants: histopathologic findings related to performance in 16 human temporal bones. Ann Otol Rhinol Laryngol. 1991 Oct; 100 (10):807-11.
2. Welling DB, Hinojosa R, Gantz BJ, Lee JT. Insertional trauma of multichannel cochlear implants. Laryngoscope 1993 Sep; 103(9):995-1001.
3. Nadol JB, Shiao JYS, Burge BJ, et al. Histopathology of cochlear implants in humans. Ann Otol Rhinol Laryngol. 2001 Sep; 110(9):883-91.
4. Eshraghi AA, Yang N, Balkany TJ. Comparative study of cochlear damage with three perimodiolar electrode designs. Laryngoscope 2003 Mar; 113(3):415-9.
5. Barbara M, Mattioni A, Monini A, et al. Delayed loss of residual hearing in Clarion cochlear implant users. J Laryngol Otol 2003 Nov;117(11):850-3.
6. Balkany TJ, Eshraghi AA, Yang N. Modiolar proximity of three new perimodiolar cochlear implant electrodes. Acta Oto-Laryngol 2002 Jun; 122(4):363-9.
7. Eshraghi AA, Jolly C, Balkany TJ. Small fenestra cochleostomy for MED-EL Flex electrode. Cochlear Implant Internat 2004; 5:71–75.
8. Eshraghi AA, Polak M, He J, Balkany TJ, Van De Water TR. The pattern of hearing loss in a rat model of cochlear implantation trauma. Otol Neurotol 2005 May; 26(3):442-7.
9. Eshraghi AA, Van de Water TR. Cochlear Implantation Trauma and Noise-Induced Hearing Loss: Apoptosis and Therapeutic Strategies Anat Rec A Discov Mol Cell Evol Biol. 2006 Apr; 288(4):473-81.
10. Kawano A, Seldon HL, Clark GM, Ramsden RT, Raine CH: Intracochlear factors contributing to psychophysical percepts following cochlear implantation. Acta Otolaryngol 1998 Jun; 118(3):313-26.
11. Somdas MA, Li PM, Whiten DM, Eddington DK, Nadol JB Jr. Quantitative Evaluation of New Bone and Fibrous Tissue in the Cochlea following Cochlear Implantation in the Human Audiol Neurotol 2007; 12(5):277-84.
12. Aminpour S, Tinling SP, Brodie HA: Role of tumor necrosis factor-alpha in sensorineural hearing loss after bacterial meningitis. Otol Neurotol 2005 Jul; 26(4):602-9.
13. DeSautel MD, Brodie HA: Effects of depletion of complement in the development of labyrinthitis ossificans. Laryngoscope 1999 Oct; 109(10):1674-8.
14. Nadol JB Jr, Eddington DK: Histologic evaluation of the tissue seal and biologic response around cochlear implant electrodes in the human. Otol Neurotol 2004 May; 25(3):257-62.
15. Hertz CA, Torres V, Quest AFG. Beyond apoptosis: non-apoptotic cell death in physiology and disease. Biochem Cell Biol. 2005 Oct; 83(5):579-88. Review.
16. Van De Water TR, Lallemend F, Eshraghi AA, et al. Caspases, the enemy within, and their role in oxidative stress-induced apoptosis of the inner ear sensory cells. OtolNeurotol. 2004 Jul; 25(4):627-32. Review.
17. Kim R, Emi M, Tanabe K. Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 2006 May;57(5):545-53
18. Nicotera TM, Hu BH, Hendrson D. The caspase pathway in noise-induced apoptosis of the chinchilla cochlea. J Assoc Res Otolaryngol. 2003 Dec; 4(4):466-77.
19. Do K, Baker K, Praetorius M, Staecker H. A mouse model of implantation trauma. Internat Cong Ser 2004; 1273:167–170.
20. Zine A, Van De Water TR. The MAPK/JNK signaling pathway offers potential therapeutic targets for the prevention of acquired deafness. Curr Drug Targets CNS Neurol Disord 2004 Aug; 3(4):325-32.
21. Wang J, Van De Water TR, Bonny C, et al. A peptide inhibitor of c-Jun N-Terminal Kinase (D-JNKI-1) protects against both aminoglycoside and acoustic trauma-induced auditory hair cell death and hearing loss. J Neurosci 2003 Sep 17;23(24):8596-607
22. Eshraghi, A.A., He, J., Mou, CH., Polak, M., Zine, A., Bonny, C., Balkany, TJ., Van De Water, TR. D-JNKI-1 treatment prevents the progression of hearing loss in a model of cochlear implantation trauma. Otol. Neurotol. 2006 Jun; 27(4):504-11.
23. Eshraghi AA, Wang J, Adil E, He J, Zine A, Bublik M, Bonny C, Puel JL, Balkany TJ, Van De Water TR. Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity Hearing Research 2007 Apr; 226(1-2):168-77.
24. Kiefer J, Gstoettner W, Baumgartner W, et al. Conversation of low-frequency hearing in cochlear implantation. Acta Otolaryngol (Stockh) 2003; 123:1-10.
25. Huang CQ, Tykocinski M, Stathopoulos D, Cowan R. Effects of steroids and lubricants on electrical impedance and tissue response following cochlear implantation. Cochlear Implants Int. 2007 Sep; 8(3):123-47.
26. Ye Q, Tillein J, Hartmann R, Gstoettner W, Kiefer J. Application of a corticosteroid (Triamcinolon) protects inner ear function after surgical intervention. Ear Hear. 2007 Jun; 28(3):361-9.
27. Eshraghi AA, Adil E, He J, Graves R, Balkany TJ, Van De Water TR. Local Dexamethasone Therapy Conserves in an Animal Model of Electrode Insertion TraumaInduced Hearing Loss Otol Neurotol 2007 Sep; 28(6):842-9.
28. Eshraghi AA, Nehme O, Polak M, He J, Alonso O, Dietrich WD, Balkany TJ, Van De Water TR. Cochlear temperature correlates with both temporalis muscle and rectal temperatures: application for testing the otoprotective effect of hypothermia. Acta Oto-Laryngol 2005 Sep; 125(9):922-8.
29. Henry KR. Hyperthermia exacerbates and hypothermia protects from noise-induced threshold elevation of the cochlear nerve envelope response in C57BL/J mouse. Hear Res 2003 May; 179(1-2):88-96.
30. Balkany TJ, Eshraghi AA, He J, Polak M, Mou C, Dietrich WD, Van De Water TR. Mild hypothermia protects auditory function during cochlear implant surgery. Laryngoscope 2005 Sep; 115(9):1543-7.
31. Shepherd RK, Xu J. A multichannel scala tympani electrode array incorporating a drug delivery system for chronic intracochlear infusion. Hearing Research 2002 Oct; 172 (1-2):92-8.
32. Paasche G, Gibson P, Averbeck T, Becker H, Lenarz T, St?ver T. Technical Report: Modification of a Cochlear Implant Electrode for Drug Delivery to the Inner Ear Otology & Neurotology 2003 Mar;24(2):222-7.
33. St?ver T, Paasche G, Lenarz T, Ripken T, Breitenfeld P, Lubatschowski H, Fabian T. Development of a drug delivery device: using the femtosecond laser to modify cochlear implant electrodes Cochlear Implants Int. 2007 Mar; 8(1):38-52.
34. Kiefer J, Pok M, Adunka O, Stürzebecher E, Baumgartner W, Schmidt M, Tillein J, Ye Q, Gstoettner W. Combined electric and acoustic stimulation of the auditory system: results of a clinical study. Audiol Neurootol. 2005 May-Jun; 10(3):134-44.
35. Adunka O, Unkelbach MH, Mak M, et al. Cochlear implantation via the round window membrane minimizes trauma to cochlear structures: a histologically controlled insertion study. Acta Otolaryngolol 2004 Sep; 124(7):807-12.
36. Eshraghi AA. Prevention of cochlear implant electrode damage. Curr Opin Otolaryngol Head Neck Surg. 2006 Oct; 14(5):323-8. Review.
37. Gstoettner W, Kiefer J, Baumgartner WD, Pok S, Peters S, Adunka O: Hearing preservation incochlear implantation for electric acoustic stimulation. Acta Otolaryngol2004 May; 124(4):348-52.
38. Briggs RJ, Tykocinski M, Stidham K, Roberson JB: Cochleostomy site: implications for electrode placement and hearing preservation. Acta Otolaryngol 2005 Aug; 125(8):870-6.
2. Welling DB, Hinojosa R, Gantz BJ, Lee JT. Insertional trauma of multichannel cochlear implants. Laryngoscope 1993 Sep; 103(9):995-1001.
3. Nadol JB, Shiao JYS, Burge BJ, et al. Histopathology of cochlear implants in humans. Ann Otol Rhinol Laryngol. 2001 Sep; 110(9):883-91.
4. Eshraghi AA, Yang N, Balkany TJ. Comparative study of cochlear damage with three perimodiolar electrode designs. Laryngoscope 2003 Mar; 113(3):415-9.
5. Eshraghi AA, Van de Water TR. Cochlear Implantation Trauma and Noise-Induced Hearing Loss: Apoptosis and Therapeutic Strategies Anat Rec A Discov Mol Cell Evol Biol. 2006 Apr; 288(4):473-81.
6. Kawano A, Seldon HL, Clark GM, Ramsden RT, Raine CH: Intracochlear factors contributing to psychophysical percepts following cochlear implantation. Acta Otolaryngol 1998 Jun; 118(3):313-26.
7. Somdas MA, Li PM, Whiten DM, Eddington DK, Nadol JB Jr. Quantitative Evaluationof New Bone and Fibrous Tissue in the Cochlea following Cochlear Implantation in the Human Audiol Neurotol 2007; 12(5):277-84.
8. Kiefer J, Gstoettner W, Baumgartner W, et al. Conversation of low-frequency hearing in cochlear implantation. Acta Otolaryngol (Stockh) 2003; 123:1-10.
9. Ye Q, Tillein J, Hartmann R, Gstoettner W, Kiefer J. Application of a corticosteroid (Triamcinolon) protects inner ear function after surgical intervention. Ear Hear. 2007 Jun; 28(3):361-9.
10. Eshraghi AA, Adil E, He J, Graves R, Balkany TJ, Van De Water TR. Local Dexamethasone Therapy Conserves in an Animal Model of Electrode Insertion Trauma Induced Hearing Loss Otol Neurotol 2007 Sep; 28(6):842-9.
11. Shepherd RK, Xu J. A multichannel scala tympani electrode array incorporating a drug delivery system for chronic intracochlear infusion. Hearing Research 2002 Oct; 172 (1-2):92-8.
12. Paasche G, Gibson P, Averbeck T, Becker H, Lenarz T, St?ver T. Technical Report: Modification of a Cochlear Implant Electrode for Drug Delivery to the Inner Ear Otology & Neurotology 2003 Mar;24(2):222-7.
13. St?ver T, Paasche G, Lenarz T, Ripken T, Breitenfeld P, Lubatschowski H, Fabian T. Development of a drug delivery device: using the femtosecond laser to modify cochlear implant electrodes Cochlear Implants Int. 2007 Mar; 8(1):38-52.
14. Jackson LE, Silverstein H. Chemical perfusion of the inner ear. Otolaryngol Clin North Am 2002; 35: 639-653.
15. Hoffer ME, Allen K, Kopke RD, Weisskopf P, Gottshall K, Wester D. Transtympanic versus sustained-release administration of gentamicin: kinetics, morphology sensorineural hearing loss. Otol Neurotol 2005; 26: 890-895.
16. Selivanova OA, Gouveris H, Victor A, Amedee RG, Mann W. Intratympanic dexamethasone and hyaluronic acid in patients with low-frequency and Ménière's-associated sudden sensorineural hearing loss. Otol Neurotol 2005; 26: 890-895.
17. Sheppard WM, Wanamaker HH, Pack A, Yamamoto S, Slepecky N. Direct round window application of gentamicin with varying delivery vehicles: a comparison ofototoxicity. Otolaryngol Head Neck Surg 2004; 131: 890-896.
18. SUN Jian-jun, LIU Ya, KONG Wei-jia, JIANG Ping and JIANG Wei. In vitro permeability of round window membrane to transforming dexamethasone with delivery vehicles–a dosage estimation. Chinese Medical Journal 2007; 120 (24):2284-2289.
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14. Eshraghi AA, Yang N, Balkany TJ. Comparative study of cochlear damage with three perimodiolar electrode designs. Laryngoscope 2003 Mar; 113(3):415-9.
15. Eshraghi AA, Van de Water TR. Cochlear Implantation Trauma and Noise-Induced Hearing Loss: Apoptosis and Therapeutic Strategies Anat Rec A Discov Mol Cell Evol Biol. 2006 Apr; 288(4):473-81.
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17.黄选兆,汪吉宝实用耳鼻咽喉科学,第1版,人民卫生出版社,2004年,756-801
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24. Eshraghi AA, Polak M, He J, Balkany TJ, Van De Water TR. The pattern of hearing loss in a rat model of cochlear implantation trauma. Otol Neurotol 2005 May; 26(3):442-7.
25. Do K, Baker K, Praetorius M, Staecker H. A mouse model of implantation trauma. Internat Cong Ser 2004; 1273:167–170.
26. Ye Q, Tillein J, Hartmann R, Gstoettner W, Kiefer J. Application of a corticosteroid (Triamcinolon) protects inner ear function after surgical intervention. Ear Hear. 2007 Jun; 28(3):361-9.
27. Eshraghi AA, Adil E, He J, Graves R, Balkany TJ, Van De Water TR. Local Dexamethasone Therapy Conserves in an Animal Model of Electrode Insertion Trauma Induced Hearing Loss Otol Neurotol 2007 Sep; 28(6):842-9.
28. Somdas MA, Li PM, Whiten DM, Eddington DK, Nadol JB Jr. Quantitative Evaluation of New Bone and Fibrous Tissue in the Cochlea following Cochlear Implantation in the Human Audiol Neurotol 2007; 12(5):277-84.
29. Eshraghi, A.A., He, J., Mou, CH., Polak, M., Zine, A., Bonny, C., Balkany, TJ., Van De Water, TR. D-JNKI-1 treatment prevents the progression of hearing loss in a model of cochlear implantation trauma. Otol. Neurotol. 2006 Jun; 27(4):504-11.
30. Eshraghi AA, Wang J, Adil E, He J, Zine A, Bublik M, Bonny C, Puel JL, Balkany TJ, Van De Water TR. Blocking c-Jun-N-terminal kinase signaling can prevent hearing loss induced by both electrode insertion trauma and neomycin ototoxicity Hearing Research 2007 Apr; 226(1-2):168-77.
1. Fayad J, Linthicum FR Jr, Otto SR, Galey FR, House WF. Cochlear implants: histopathologic findings related to performance in 16 human temporal bones. Ann Otol Rhinol Laryngol. 1991 Oct; 100 (10):807-11.
2. Welling DB, Hinojosa R, Gantz BJ, Lee JT. Insertional trauma of multichannel cochlear implants. Laryngoscope 1993 Sep; 103(9):995-1001.
3. Nadol JB, Shiao JYS, Burge BJ, et al. Histopathology of cochlear implants in humans. Ann Otol Rhinol Laryngol. 2001 Sep; 110(9):883-91.
4. Eshraghi AA, Yang N, Balkany TJ. Comparative study of cochlear damage with three perimodiolar electrode designs. Laryngoscope 2003 Mar; 113(3):415-9.
5. Kawano A, Seldon HL, Clark GM, Ramsden RT, Raine CH: Intracochlear factors contributing to psychophysical percepts following cochlear implantation. Acta Otolaryngol 1998 Jun; 118(3):313-26.
6. Somdas MA, Li PM, Whiten DM, Eddington DK, Nadol JB Jr. Quantitative Evaluation of New Bone and Fibrous Tissue in the Cochlea following Cochlear Implantation in the Human Audiol Neurotol 2007; 12(5):277-84.
7. Aminpour S, Tinling SP, Brodie HA: Role of tumor necrosis factor-alpha in sensorineural hearing loss after bacterial meningitis. Otol Neurotol 2005 Jul; 26(4):602-9.
8. DeSautel MD, Brodie HA: Effects of depletion of complement in the development of labyrinthitis ossificans. Laryngoscope 1999 Oct; 109(10):1674-8.
9. Nadol JB Jr, Eddington DK: Histologic evaluation of the tissue seal and biologic response around cochlear implant electrodes in the human. Otol Neurotol 2004 May; 25(3):257-62.
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