Kato M, Jackler R K
Epstein Neurotological Laboratories, Department of Otolaryngology-Head and Neck Surgery, University of California, San Francisco, USA.
Otolaryngol Head Neck Surg. 1996 Dec;115(6):538-47. doi: 10.1016/s0194-5998(96)70008-6.
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 microliters 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). Heading 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 microliters of 125I-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.
多种血管生成生长因子已被证明可加速伤口愈合。先前的研究表明，在动物模型中，局部应用表皮生长因子对慢性鼓膜穿孔的愈合有效。从理论上讲，成纤维细胞生长因子可能通过优先刺激鼓膜中层的成纤维细胞，从而使鼓膜愈合得更好。为了验证这一假设，对外源性应用成纤维细胞生长因子对慢性穿孔鼓膜的影响进行了评估。将成纤维细胞生长因子缓冲溶液（25微升成纤维细胞生长因子，0.2毫克/毫升）施用于置于栗鼠慢性鼓膜穿孔上的明胶海绵小块。对照耳仅用明胶海绵和缓冲溶液处理。在接受成纤维细胞生长因子治疗的耳中，81%（16只中的13只）的鼓膜穿孔完全闭合，而对照组中只有41%（17只中的7只）完全闭合（p = 0.05）。愈合是逐渐发生的，接受成纤维细胞生长因子治疗的耳平均需要4周愈合，而对照耳愈合则需要6.5周。对照组相对较高的愈合率并不意味着预处理的穿孔不是慢性的，而是重复应用明胶海绵和缓冲溶液的对照方案似乎有一定疗效。对成纤维细胞生长因子愈合后的鼓膜立即进行组织学分析，结果显示鼓膜的鳞状层和纤维层肥大。随着时间的推移，鼓膜变薄，达到与正常鼓膜相似的比例，包括存在相当厚的中间纤维层。一项耳毒性筛查研究表明，生长因子治疗后柯蒂氏器没有结构损伤。为了评估全身毒性的可能性，在向穿孔鼓膜应用25微升125I标记的成纤维细胞生长因子后的48小时内的不同时间点，对血液和外周组织进行放射性分析。超过78%的放射性仍留在应用部位。鉴于最初剂量极小，根据已发表的毒性数据，全身吸收的小部分剂量微不足道，极不可能引起不良反应。基于栗鼠模型中这些有前景的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。
