Repair of chronic tympanic membrane perforations with fibroblast growth factor
Repair of chronic tympanic membrane perforations with fibroblast growth factor
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DOI：
10.1016/s0194-5998(96)70008-6
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发表时间：
1996-12-01
影响因子：
3.4
通讯作者：
Jackler, RK
中科院分区：
文献类型：
--
作者：
Kato, M;Jackler, RK
许多血管生成生长因子已被证明可以加速伤口愈合。先前的工作已经证明，在动物模型中，局部应用表皮生长因子在治愈慢性鼓膜穿孔中是有效的。理论上，成纤维细胞生长因子可以通过优先刺激鼓膜中间层内的成纤维细胞而导致上级愈合的膜。为了检验这一假设，评价外源性应用的成纤维细胞生长因子对慢性穿孔鼓膜的作用。将成纤维细胞生长因子的缓冲溶液（25 μ l成纤维细胞生长因子，0.2mg/ml）施用于放置在龙猫慢性鼓膜穿孔上的Gelfoam纱布。对照耳仅用Gelfoam和缓冲溶液处理。在81%（13/16）的成纤维细胞生长因子治疗耳中观察到鼓膜穿孔完全闭合，但在对照耳中仅为41%（7/17）（p = 0.05）。愈合是逐渐发生的，平均需要4周的成纤维细胞生长因子治疗和6.5周的对照耳朵愈合。对照组相对较高的愈合率并不意味着治疗前穿孔不是慢性的，相反，重复应用明胶海绵和缓冲液的对照方案似乎具有一定的疗效。对用成纤维细胞生长因子愈合的鼓膜在闭合后立即进行的组织学分析表明鼓膜的鳞状和纤维层肥大。随着时间的推移，耳膜变薄，达到与正常鼓膜相似的比例，包括大量中间纤维层的存在。一项筛选性耳毒性研究显示，生长因子治疗后，Corti器官无结构性损伤。为了评估全身毒性的可能性，在穿孔的鼓膜上应用25 μ l I-125-成纤维细胞生长因子后48小时内的时间点分析血液和外周组织的放射性。超过78%的放射性残留在给药部位，鉴于原始剂量很小，全身吸收的小部分很小，并且根据已发表的毒性数据，极不可能诱导不良反应，基于这些有希望的栗鼠模型安全性和有效性数据，正在启动成纤维细胞生长因子修复人类慢性鼓膜穿孔的临床试验。
A number of angiogenic growth factors have been shown to accelerate wound healing. Previous work has demonstrated that topical application of epidermal growth factor is effective in healing chronic tympanic membrane perforations in an animal model, Theoretically, fibroblast growth factor may result in a superior healed membrane through preferential stimulation of the fibroblasts within the middle layer of the tympanic membrane, To test this hypothesis, the effects of exogenously applied fibroblast growth factor on the chronically perforated tympanic membrane were evaluated. A buffered solution of fibroblast growth factor (25 mu l of fibroblast growth factor, 0.2 mg/ml) was administered to a Gelfoam pledget placed over chronic tympanic membrane perforations in chinchillas. Control ears were treated with Gelfoam and the buffer solution only. Complete closure of the tympanic membrane perforation was observed in 81% (13 of 16) of the fibroblast growth factor-treated ears, but in only 41% (7 of 17) of the controls (p = 0.05). Healing took place gradually, requiring an average of 4 weeks for the fibroblast growth factor-treated and 6.5 weeks for the control ears that healed. The relatively high healing rate for the control group does not imply that the pretreatment perforations were not chronic, rather there appears to be some efficacy to the control protocol of repeated applications of Gelfoam and buffer. A histologic analysis of the fibroblast growth factor-healed eardrums immediately after closure demonstrated hypertrophy of the squamous and fibrous layers of the tympanic membrane. Over time, the eardrum thinned to reach proportions similar to those of the normal tympanic membrane, including the presence of a substantial middle fibrous layer. A screening ototoxicity study revealed no structural damage to the organ of Corti after growth factor treatment. To assess the potential for systemic toxicity, blood and peripheral tissues were analyzed for radioactivity at time points during a 48-hour period after application of 25 mu l of I-125-fibroblast growth factor to the perforated tympanic membrane. More than 78% of the radioactivity remained at the application site, Given the tiny original dosage, the small fraction absorbed systemically is minuscule and highly unlikely to induce adverse effects in light of published toxicity data, On the basis of these promising safety and efficacy data in the chinchilla model, clinical trials of fibroblast growth factor in repair of chronic tympanic membrane perforations in human beings are being initiated.